EPIDEMIOLOGY—AGINGCATEGORY glucose metabolism (AGM) for women postpartum with previous gestational health care priorities. We conducted an epidemiologic analysis using the diabetes mellitus (GDM). A 75 g OGTT underwent at 6-8 weeks after delivery National Health and Nutrition Examination Survey (NHANES) to assess in 179 GDM patients. The clinical and obstetric characteristics, serum lipid trends in glycemic, blood pressure (BP), and cholesterol controls. ADA level (TCH, TG, LDL-C, HDL-C), insulin level, GA, IGF-1, IGF-BP3, HOMA-B, recommended treatment goals for older adults were used to evaluate the and HOMA-IR were compared between the two groups. We found that: (1) metabolic control. This analysis included 1604 adults aged ≥ 65 who reported 45.8% (82/179) of GDM patients remained abnormal glucose level. The rates a diabetes diagnosis at age 30 and older. The mean (SE) age was 73 (0.2) of DM, IGT, IFG and IGR were 20.1% (36/179), 17.3% (31/179), 3.3% (6/179) years; 55% female; 72% white, 13% black, and 5% Mexican Americans. The and 5% (9/179) respectively. (2) Compared to the women who reverted to mean diabetes duration was 12.4 (0.2) years, and mean BMI was 30.7 (0.23) normal, women with AGM showed shorter pregnant period (38.04±1.18 kg/m2. A1c, BP, and LDL-C had improved overall from 1999 to 2010. The mean weeks vs. 38.42±1.11 weeks, P=0.003), signifi cantly higher fasting insulin A1c was 7.3% (0.10), 6.7% (0.07), and 7.0% (0.06) in 1999-2002, 2003-2006, (FINS) level (58.59±38.22 pmol/L vs. 46.46±28.32 pmol/L, P=0.021), higher and 2007-2010, respectively (p for trend, 0.029). The mean SBP was 144 (1.6), 2h postprandial insulin (2hINS) concentration (375.63±325.83 pmol/L vs. 142 (2.0), and 137 (1.3) mmHg in the respective 3 periods; the mean LDL-C 223.93±169.17 pmol/L, P=0), higher GA level (13.53±2.45% vs. 11.85±0.99%, was 110 (5.5), 101 (2.7), and 92 (0.7) mg/dL in the 3 periods (both p for trends P=0), lower HOMA-B (71.29±50.73 vs. 89.27±55.86, P=0.03), higher HOMA- <0.0001). Still, in 2007-2010 about 40% did not meet the recommended goals IR (2.41±1.81 vs. 1.51±0.96, P=0) as well as more DM family history (43.9% for BP or LDL-C, and more than 60% did not meet the LDL-C goals in persons vs. 27.8%, P=0.025). (3) Compared to the prediabetic patients after GDM with CVD history (Table). Improving diabetes care remains a public health (IFG, IGT and IGR), diabetic patients had higher BMI (P=0.042), higher priority in older adults. maximum pre-pregnancy weight (P=0.012), higher maximum pre-pregnancy U.S. Older Adults with Diabetes Achieved Metabolic Targets According to BMI (P=0.011), higher GA level (P=0.001) and higher HOMA-IR (P=0.002). (4) 2014 ADA Recommendations. Multiple stepwise regression analysis revealed that fasting blood glucose, 1999-2002 2003-2006 2007-2010 P for trend FINS and 1hPG were the independent risk factors for the development of insulin resistance after delivery. This study has identifi ed a high prevalence of HbA1c 60(3) 79(2) 74(2) <0.0001 AGM after GDM. Insulin resistance is the major contributor. The medication HbA1c 73 (5) 88 (2) 88 (2) 0.21 of relieving insulin resistance may be useful for the GDM patients with BP 40(3) 45(3) 58(2) <0.0001 sustained higher FBG, FINS and 1hPG after delivery. LDL 40 (9) 53 (5) 63 (7) <0.0001 Supported By: Chinese Society of Endocrinology LDL 25 (3) 28 (3) 34 (6) <0.0001 1316-P Supported By: Sun Yat-sen University-Johns Hopkins University Collaboration; Screening for Gestational Diabetes—Oral Glucose Challenge Test NIDDK vs. Fasting Plasma Glucose OLALEYE SANU, GREGORY KALU, London, United Kingdom, Brighton, United & 1318-P Kingdom Hyperglycemia Is Associated with Persistently Lower Grip Strength This study aimed to compare detection rate for Gestational Diabetes in Older Persons without History of Diabetes: The Rancho Bernardo (GDM) in women using two stage screening - 1hour 50gram Oral Glucose Study Genetics

Challenge Test ( 1-h 50g OGCT) irrespective of last meal , and subsequent RITA R. KALYANI, SHENGCHUN KONG, BIN NAN, DONNA KRITZ-SLIVERSTEIN, POSTERS 75 gram - 2hour Oral Glucose Tolerance Test (2 -h 75g OGTT) for those with GAIL A. LAUGHLIN, LUIGI FERRUCCI, CATHERINE KIM, ELIZABETH L. BARRETT- Epidemiology/ positive 1-h OGCT ; with one stage screening using Fasting Plasma Glucose CONNOR, Baltimore, MD, Ann Arbor, MI, San Diego, CA (FPG). Persons with diabetes have accelerated muscle loss. Yet, the relationship The analysis was carried out at Brighton and Sussex University Hospital of hyperglycemia per se to decreased grip strength, a clinical marker of poor (BSUH), United Kingdom with approximately 5900 deliveries per year, over mobility, has not been previously described. Participants were 1020 women a 12 month period. Women with positive 1-h 50g OGCT result of ≥140 mg/ and 636 men (mean age 71.3) without self-reported history of diabetes who dl (7.8 mmol/l) were offered the 2-h 75g OGTT. A diagnosis of Gestational had fasting plasma glucose (FPG) and 2-hr glucose (2HG) levels after a 75- Diabetes (GDM) was established using the American Diabetes Association gram OGTT at visit 7 (1992-1996). Grip strength, defi ned as the maximum (ADA) guidelines - FPG of ≥ 92mg/dl (5.1mmol/l) and/or 2-h post 75g OGTT of 3 trials in the non-dominant hand, was assessed at baseline and at an of ≥ 153mg/dl (8.5mmol/l). Women with no risk factors for GDM were average of 3.0±1.6 follow-up visits over a median 7 years. When categorized excluded. by sex-specifi c glucose quartiles, persistently lower grip strength was A total of 4536/5990 (77%) women, with risk factors for GDM, underwent observed in highest versus lowest glucose quartiles over time, with more 1-h 50g OGCT; of which 554/4536 (12%) were screened positive (≥140 mg/ dramatic differences in 2HG vs. FPG relationships for both sexes (Figure 1). dl (7.8mmol/l). Of the 554 women, 119/554 (21%) were diagnosed with GDM In men, after adjusting for age, education, height, weight, and neuropathy in post 2 -h 75g OGTT. Eighty-fi ve-85/119 (71%) women had FPG of ≥ 92mg/dl mixed effects regression models, each standard deviation (SD) higher FPG (5.1mmol/l). (SD=16.7 mg/dl) and 2HG (SD=49.8 mg/dl) was associated with lower grip Another 221 women, with risk factors for GDM, but negative 1-h 50g strength over time (-0.50 kg, p=0.04; and -0.85 kg, p=0.003; respectively). OGCT < 140mg/dl (7.7mmol/l and below) consented for 2 -h 75g OGTT. A In women, each SD higher 2HG (SD=45.4 mg/dl) was associated with total of 26/212 (12%) women were diagnosed with GDM, of which 22/26 lower grip strength (-0.36 kg, p=0.01) over time with no differences by FPG. (84%) had FPG of ≥ 92mg/dl (5.1mmol/l). Hyperglycemia is associated with persistently lower grip strength over time These data suggest that screening for GDM using a one stage screening and may be related to greater disability in the elderly. with FPG cut-off of ≥ 92mg/dl (5.1mmol/l), appears to be a good alternative to the two stage screening with 1-h OGCT, and subsequent 2 -h 75g OGTT.

EPIDEMIOLOGY—AGING

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& 1317-P Trends in Metabolic Control in U.S. Older Adults with Diabetes, 1999-2010 DAIZHI YANG, JIANPING WENG, NINA SHAH, HSIN-CHIEH YEH, Baltimore, MD, Guangzhou, China The care of older adults with diabetes is complicated by clinical heterogeneity. With continued increase in diabetes prevalence, a better understanding of metabolic control in this population is critical for setting

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73% White, 14% Black, 2% Other race, 11% Unknown race, mean age 72). Cox & 1319-P analysis was used to test the relationship of updated mean A1c (average A1c Chronic Comorbidities and Glycemic Control in Older Adults with over follow-up) w/ time to fi rst fracture since baseline and logistic regression Diabetes for most recent A1c w/ fracture. We used the number of BMI measurements CHRISTINE LEE, GREGORY NICHOLS, Portland, OR as a surrogate for frequency of discrete visits. During followup (mean 3 yrs), Many older adults have chronic comorbidities (CC), thus we examined there were 969 events. Modeled continuously and controlled for age, sex and how CC are associated with glycemic control in older adults with diabetes race, updated mean A1c showed a cubic (J-shaped) relationship w/ fracture risk mellitus (DM). (p=0.005). When analyzed by category, compared to an updated mean A1c of This cross-sectional study included 11009 adults ages 65+ with DM in the 7-<8%, HRs (95% CIs) were: A1c <6.5% HR= 0.93 (0.79-1.10); 6.5-<7% HR=0.74 Kaiser Permanente Northwest Diabetes Registry 1997-2010. Thirteen CC (Table) (0.61-0.90); 8-<9% HR=1.45 (1.19-1.76); ≥9% HR=1.56 (1.21-2.01). Multivariable were found +90 days of the index date (diagnosis date for new DM or 65th HRs for sex were (1.71, 1.49-1.95, F vs. M), and race were: Blacks HR=0.74 (0.61- birthday for existing DM). Glycated hemoglobin (A1C) levels closest to the index 0.88), Other HR=1.30 (0.82-2.05), Unknown HR=0.40 (0.26-0.61) compared to date (+6 months) were categorized as A1C<6%, A1C 6-9% and A1C≥9%, given Whites. Unknown race had the least number of BMI measures. Controlling for higher mortality risks for older adults with A1C<6% and ≥9%. Multivariable linear number of BMI measures (HR=0.97, 0.96-0.97) eliminated the risk in the A1c ≥9% and logistic regression models were used to examine associations between the category (HR=1.22, 0.95-1.57), but had no effect on remaining A1c categories, number of CC and A1C, and associations for each CC and A1C<6% and A1C≥9% sex, or race. Most recent A1c was not associated w/ fracture. Average A1c of using A1C 6-9% as the referent group, respectively. 6.5 -< 7% appears the safest range for protection against fracture in geriatric Mean age was 74.2 ± 6.9 years, DM duration was 8.9 ± 6.2 years, and patients, w/ increased risk both below and above this range; risk associated w/ number of CC was 3.75 ± 1.8. Each additional CC was associated with a A1c ≥9% may be an artifact of not visiting the provider. 0.03% lower A1C (p<0.001). Compared to patients with A1C 6-9%, those with Supported By: Vanderbilt University; NCATS/NIH (UL1TR00445) depression or chronic kidney disease had a signifi cantly higher likelihood of A1C<6%, and those with depression or chronic obstructive pulmonary & 1321-P disease had a signifi cantly higher likelihood of A1C 9% (Table). ≥ Physical Function Decline in the Diabetes Prevention Program Out- There was an inverse association between overall number of CC and come Study A1C in older adults with DM, but the relationship between specifi c CC and HERMES FLOREZ, YONG MA, JOSE A. LUCHSINGER, ANDREA M. KRISKA, A1C differed. Glycemic management for older adults with DM may need to SHERITA HILL GOLDEN, GEORGE A. BRAY, JILL CRANDALL, ELIZABETH M. account for specifi c CC. VENDITTI, HELEN HAZUDA, Miami, FL, Rockville, MD, New York, NY, Pittsburgh, PA, Table. Likelihood of A1C<6% and A1C≥9% Associated With Chronic Comor- Baltimore, MD, Baton Rouge, LA, Bronx, NY, San Antonio, TX bidities (ORs are Adjusted for Age, Race, Gender, Body Mass Index, Number of Diabetes is associated with increased risk of disability. There are Comorbidities, Number of Diabetes Drug Classes, and Duration of Diabetes). knowledge gaps regarding the ability of diabetes interventions to slow Comorbidity Prevalence A1C<6% A1C≥9% decline in physical function (PF) in older adults. In the Diabetes Prevention (%) OR (95% CI) OR (95% CI) Program (DPP) and the follow-up DPP Outcomes Study (DPPOS), intensive Hypertension 86.0 0.86 0.81 lifestyle (ILS) and metformin (MET) interventions in reduced the development (0.67, 1.11) (0.63, 1.04) of diabetes over at least 10 years, compared to placebo (PLA); however, their Genetics

POSTERS Dyslipidemia 75.0 0.66 1.06 impact on PF is unknown. We evaluated PF in years 8 and 10 of the DPPOS Epidemiology/ (0.54, 0.80) (0.86, 1.31) in 2325 participants, mean age 63±10 years, all of whom were offered group Ischemic heart disease 31.8 0.83 1.07 lifestyle intervention with long-term support, with participants originally (0.68, 1.02) (0.87, 1.31) randomized to metformin continuing the drug. Measures included the Short Physical Performance Battery (SPPB) (range 0-12, 0=worst) and grip Chronic kidney disease 37.6 1.34 1.10 (1.11, 1.61) (0.90, 1.34) frailty (Cardiovascular Health Study criteria for reduced grip strength). Over this 2-year observational period, the percent with grip frailty increased Arthritis 29.9 1.11 0.70 (p<0.0001) in ILS (from 42% to 53%), MET (from 43% to 51%), and PLA (from (0.92, 1.33) (0.57, 0.87) 42% to 51%) participants but no difference was found across treatment Cancer 23.3 0.96 0.71 groups (p=0.9). No differences in the SPPB change were observed across (0.80, 1.16) (0.57, 0.90) groups (from 9.3 to 9.2 for ILS, 9.2 to 9.1 for MET, 9.3 to 9.1 for PLA) (p=0.5 Depression 23.2 1.38 1.39 between and p=0.055 within groups). SPPB decreased only in those 60 years (1.13, 1.68) (1.13, 1.71) and older (from 7.8 to 7.5, p=0.0002), while grip strength decreased (p<0.01) Atrial fi brillation 17.9 1.15 1.07 in all age groups (range from 1.4 to 2.2 Kg-force). After adjusting for age and (0.93, 1.43) (0.83, 1.37) time in study, HbA1c was inversely associated with SPPB (p=0.01) but not Osteoporosis 13.3 0.95 1.01 with grip frailty. Diabetes status (55% of participants) was not associated (0.75, 1.21) (0.75, 1.36) with PF (p>0.05). These results suggest that PF declined modestly over 2 Asthma 13.2 0.87 0.88 years with no major differences across DPPOS treatment groups, possibly (0.68, 1.11) (0.67, 1.15) related to the lifestyle intervention offered to all participants. Given the relatively young age of this cohort, longer follow-up and examination of Chronic obstructive pulmonary disease 12.9 0.78 1.41 (0.61, 1.00) (1.09, 1.83) mechanisms of PF decline and disability are warranted to preserve function in those with or at high risk for diabetes. Stroke 8.5 0.82 1.17 Supported By: NIH/NIDDK (0.61, 1.10) (0.86, 1.60) Dementia 3.0 1.12 0.90 (0.71, 1.74) (0.49, 1.67) & 1322-P Genome-Wide Association Study Identifi ed Novel Loci for Non-HDL Supported By: U.S. Dept. of Veterans Affairs Cholesterol PING AN, IVA MILJKOVIC, BHARAT THYAGARAJAN, JOSEPH H. LEE, INGRID & 1320-P B. BORECKI, KAARE CHRISTENSEN, JOHN H. ECKFELDT, RICHARD MAYEUX, Glycemic Control and Fracture Risk in Geriatric Patients with Diabetes THOMAS T. PERLS, ANNE B. NEWMAN, MICHAEL A. PROVINCE, St. Louis, MO, BAQIYYAH N. CONWAY, DUSTIN LONG, MICHAEL E. MAY, Morgantown, WV, Pittsburgh, PA, Minneapolis, MN, New York, NY, Odense, Denmark, Boston, MA Nashville, TN Objective: NHDL represents a spectrum of atherogenic lipid fractions Elderly patients with diabetes are at increased risk of fractures. Although with possibly a distinct genomic signature. It is an independent and superior long exposure to hyperglycemia may increase fracture risk via adverse effects predictor of CVD risk as compared to LDL alone. Role of lipidomics in on bone metabolism, tight glycemic control may increase risk via trauma aging diseases and human longevity has been widely acknowledged. We subsequent to hypoglycemia. Using Vanderbilt University’s deidentifi ed performed GWAS to identify genetic loci associated with NHDL. electronic health record (Synthetic Derivative), we tested the hypothesis that Research Design and Methods: We carried out GWAS in 2583 participants both tight and poor glycemic control increase fracture risk in geriatric patients of European descent who fasted overnight and did not use anti-dyslipidemia (≥65 yrs) w/ diabetes. Baseline was defi ned as fi rst HbA1c (A1c) after the latter medications in the Long Life Family Study (LLFS). Our replication cohort of age 65 or ICD 9 code for diabetes, providing 12,693 patients (51% female, included 2470 participants of European descent from the Family Heart Study

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A344 EPIDEMIOLOGY—AGINGCATEGORY

(FamHS). A linear mixed model with the kinship matrix was used adjusting adjusting for key covariates. Primary outcomes included diabetes, obesity, for age, sex, BMI, centers and PCs. Genome-wide threshold of p < 5e-8 was hypertension, and hyperlipidemia. Secondary outcomes included HbA1c, used to select signifi cant variants in the LLFS for replication in the FamHS. BMI, blood pressure and lipids. A lower prevalence of diabetes was Results: A cluster of fi ve loci on 19q13 have been identifi ed to have genome- observed in highest (6.3%) versus lowest (14.4%) neighborhood quartiles wide signifi cance - BCAM (rs118147862, minor allele frequency MAF=0.04, but was not signifi cantly different across quartiles (p= 0.24 for trend). r2=1.4%, p=2.5e-8), PVRL2 (rs41290120, MAF=0.05, r2=1.7%, p=1.2e-9), Higher neighborhood quartile associated with a lower prevalence of obesity TOMM40 (rs1160983, MAF=0.04, r2=1.8%, p=4.8e-10), APOE (rs7412, MAF=0.09, (highest vs. lowest quartile = 13.5% vs. 36.5%; p<0.001 for trend across r2=3.8%, p=2.3e-19) and APOC1 (rs390082, MAF=0.11, r2=2.6%, p=1.9e-13). quartiles). Highest versus lowest neighborhood quartile was associated Four of the fi ve loci were replicated (BCAM, p=2.3e-7; PVRL2, p=3.2e-7; APOE, with lower HbA1c (-0.31%, p=0.02) in unadjusted models. Women in the p=3.5e-8; APOC1, p=4.9e-4). These loci were found to be associated with TC highest versus lowest neighborhood quartile had lower BMI (-2.01 kg/m2, and LDL but not with TG, glycemic and blood pressure measures. NHDL raising p=0.001) and higher HDL-cholesterol (+6.09 mg/dL, p=0.01) after accounting allele frequencies of APOE and APOC1 variants were found signifi cantly less for age, race, infl ammation, and smoking. No associations of neighborhood frequent in offspring compared to their spouses in the LLFS. score with hypertension or non-HDL lipid components were found. Worse Conclusions: For the fi rst time, fi ve genetic loci (BCAM, PVRL2, TOMM40, neighborhood characteristics are associated with hyperglycemia, adiposity, APOE, APOC1) were found to be genome-wide signifi cant for NHDL in the and low HDL. Future studies should investigate if improving neighborhood healthy aging cohort. All except TOMM40 were replicated in an independent characteristics is associated with better metabolic status in older adults. population. APOE was confi rmed before to infl uence TC, LDL and HDL. The fi ndings highlight their importance in lipid metabolism and associated 1325-P healthy aging process. Challenges of Diabetes Care and Insulin Delivery in Nursing Home Facilities SUSAN E. SPRATT, MELANIE E. MABREY, HEIDI WHITE, BERNADETTE PAVLIS, & 1323-P KRISTEN HYLAND, CARLY KELLEY, JACK TWERSKY, Durham, NC The Relationship between Olfactory Dysfunction and Cognitive In order to improve diabetes (DM) care in nursing facilities, focus groups and Impairment in Elderly Patients with Type 2 Diabetes Mellitus chart reviews were performed to determine characteristics and challenges to HARUNA SANKE, TOMOYA MITA, YOSHIFUMI TAMURA, KANAE ISHIDA, DM care. 198 charts were retrospectively reviewed on all patients with DM at KOJI KOMIYA, KANAKO HARA, AYAKO YOKOTA, NORIKO INAGAKI, KEIKO (Durham VAMC- DuVAMC and Croasdaile Village Retirement Center - CVRC). YAMASHIRO, HIDENORI YOSHII, TOMIO ONUMA, HIROTAKA WATADA, Tokyo, Residents with DM are more prevalent, younger, more likely to be on insulin, Japan and more likely to be male at DuVAMC than at CVRC. Dementia, stroke, heart Patients with type 2 diabetes mellitus (T2DM), especially elderly people, disease and vision loss are common in both populations. have higher risk for dementia. To prevent the onset of cognitive impairment, A total of 7 nursing and provider focus groups were conducted to assess it is important to identify markers for early cognitive decline in patients current practices and barriers to DM care. Participants identifi ed key areas with T2DM. Recent studies have shown that decrease in olfactory function impacting DM care: presence of dementia, risk of hypoglycemia, dignity and could be used as a predictor for cognitive dysfunction in general population. privacy concerns, nutritional content concerns, and matching insulin dose to On the other hand, olfactory function was shown to be impaired in patients carbohydrate intake and timing of both monitoring and insulin delivery. Genetics with T2DM compared to healthy subjects, suggesting the possible presence DM care must account for serious co-morbidities (dementia, vision loss, POSTERS of unique pathogenesis of olfactory dysfunction related to cognitive stroke) and patient preferences infl uencing the intensity and course of Epidemiology/ dysfunction in patients with T2DM. However, it remains unclear whether treatment. Coordinating insulin delivery to nutritional intake is complicated olfactory dysfunction is related to cognitive dysfunction in patients with by both maintaining patient privacy (prevents glucose monitoring and insulin T2DM like general population. administration in community areas) and erratic eating habits, particularly in To investigate the relationship between olfactory function and cognitive those with dementia. The concern for hypoglycemia and its complications function in elderly patients with T2DM, we performed olfaction test (Open is profound among medical professionals in nursing homes and infl uences Essence) and cognitive test (Mini-mental State Examination (MMSE)) in medical treatment plans and practices. 214 elderly outpatients with T2DM. The study subjects were composed by DM Patients in Nursing Facilities. 110 male and 104 female. Their mean age, DM duration, and mean HbA1c level was 72.5 ± 5 years, 14.0 ± 8.7 years, and 7.2 ± 0.9%, respectively. We ..Patients w/ DM DuVAMC CVRC Male Number (%) Number (%) analyzed the correlations between MMSE scores and clinical variables with 120 (43%) 69 (18%) olfaction test scores by simple regression. We identifi ed age, DM duration, 110 (92%) 21 (30%) schooling history, urine albumin excretion, GOT, and olfaction test as factors Age 50-59 20 (17%) 0 signifi cantly correlated with cognitive function (P<0.01). Furthermore, Age 60-69 48 (40%) 4 (6%) multiple regression analysis accounted for above factors revealed that Age 70-79 25 (21%) 17 (25%) olfactory function, in addition to schooling history, was the independent Age 80-89 15 (13%) 44 (64%) factor that had the strongest correlation with cognitive function in these 2 Type 2 DM 98 (82%) 66 (96%) subjects (R = 0.40, P<0.01). Dementia 85 (71%) 61 (88%) In conclusion, our data demonstrated that olfactory function may be a Retinopathy 44 (37%) 7 (10%) useful marker for cognitive decline in elderly patients with T2DM similar to Blindness 17 (14%) 8 (12%) general population. Active Infection 56 (47%) 9 (13%) Amputation 37 (31%) 0 & 1324-P Nephropathy 66 (55%) 10 (14%) The Association of Neighborhood Characteristics with Diabetes, CAD 58 (48%) 34 (49%) Obesity, and Other Metabolic Conditions in Older Women Stroke 54 (45%) 28 (41%) MARK D. CORRIERE, WENLIANG YAO, QIAN-LI XUE, ANNE CAPPOLA, LINDA P. PVD/PAD 65 (54%) 3 (4%) FRIED, ROLAND THORPE, SARAH SZANTON, RITA R. KALYANI, Baltimore, MD, Enteral feeds 14 (12%) 4 (6%) Philadelphia, PA, New York, NY Corticosteroids 18 (15%) 4 (6%) Previous studies exploring the relationship of neighborhood characteristics Laboratory Avg (range) Avg (range) with metabolic conditions have focused on middle aged adults but none A1c 7% (4.5-11.8) 6.7% (5-9.4) have investigated associations in older adults. We explored the relationship Creatinine 2.6 (0.5-14.7) 1 (0.4-8.7) of neighborhood characteristics with diabetes, obesity, and other metabolic Hct 34.7 (24-63) 34.5 (11.6-45.3) conditions in 384 community dwelling women aged 70-79 years enrolled Glucose POC min 133(62-247) 111 (56-166) at baseline in the Women’s Health and Aging Study II. Neighborhood Z Glucose POC max 218 (104-377) 220 (74-508) scores were calculated from census derived neighborhood data on income, Glucose average 168 (85-311) 143 (69-293) housing, education, and occupation. Participants were categorized by quar- Meds- 1 oral 11 (9%) 14 (20%) tile of neighborhood Z score with higher quartile representing relative Meds- Multi orals 12 (10%) 7 (10%) neighborhood advantage. Logistic regression models were created to Basal/Bolus Insulin 27 (23%) 14 (20%) BID Insulin 22 (18%) 0 assess the association of neighborhood quartiles to metabolic outcomes, Supported By: Sanofi

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A345 EPIDEMIOLOGY—CARDIOVASCULARCATEGORY DISEASE

1326-P Association of Diabetes and Periodontitis with the Incidence of & 1328-P Frailty in Mexican Elderly Dose-Response Relationship between Sulfonylurea Use and Acute SOCORRO AIDA BORGES-YAÑEZ, ROBERTO C. CASTREJÓN-PÉREZ, Distrito Coronary Syndrome in Patients with Type 2 Diabetes Federal, Mexico AHMED ABDELMONEIM, DEAN T. EURICH, AMBIKAIPAKAN SENTHILSELVAN, Diabetes has shown to predict frailty. Periodontitis is frequent in non- WEIYU QIU, SCOT H. SIMPSON, Edmonton, AB, Canada controlled diabetics and in persons with non-healthy lifestyle behaviors. To Previous literature showed a cardiovascular risk difference among identify if the presence of diabetes and severe periodontitis are associated sulfonylureas in patients with type 2 diabetes. The aim of this study with incidence of frailty in home-dwelling Mexican elders controlling by was to assess whether there is a dose-response relationship between sex, age, schooling, myocardial infarction, stroke, hypertension, hyper- gliclazide and glyburide use and risk of acute coronary syndrome (ACS). cholesterolemia, hypertriglyceridemia, osteoporosis, arthritis, number Using administrative health records (Alberta, Canada; 2004-2010), we of medications, xerostomia, number of teeth, cognitive impairment, self- conducted a retrospective cohort analysis on patients using gliclazide or perception of oral health and self-rate of general health. Household survey glyburide. Exposure level was categorized into high and low doses based in a representative sample of the elders’ ≥70 years living in one district on the patients’ average daily dose in reference to the WHO’s defi ned of Mexico City. Sample size was 1294, 1124 were interviewed, 838 were daily dose and updated every 6 months (i.e., time varied). The primary clinically evaluated, 594 non-frail were followed for 3 years, 252 completed outcome was time to an ACS related hospital admission or death, and the follow up. Dependent variable: Frailty (having ≥3 of fi ve components compared between higher vs. lower dose and glyburide vs. gliclazide using [weakness, slowness, fatigue, low physical activity and weight loss]). Cox proportional hazards models; while adjusting for key confounders and Independent variables: severe periodontitis (≥2 teeth with ≥5mm time-varying propensity scores. We identifi ed 12,812 gliclazide and 12,409 attachment loss), self-report of diabetes, myocardial infarction, stroke, glyburide users: average age 73.0 (SD 7.3) years; 14,129 (56.0%) were males; hypertension, hypercholesterolemia, hypertriglyceridemia, osteoporosis, and mean duration of follow up was 2.5 (SD 2.1) years. Among gliclazide arthritis (yes/no), self-rate of oral health and general health, cognitive users, higher dose was associated with lower ACS event rate compared to impairment (MMSE), xerostomia, dental condition (edentulous/partially lower dose (17.0 vs. 21.2 per 1000 person-years, respectively; adjusted HR dentate/completely dentate). Univariate analysis and a logistic regression (aHR) 0.83, 95% CI 0.71 - 0.97). In contrast, the ACS event rate was similar model (LRM) were performed. Mean age was 77 years, 51% were women. between higher and lower doses of glyburide (21.2 vs. 22.5 per 1000 person- Prevalence of diabetes = 18.6%, and severe periodontitis = 17%, incidence years, respectively; aHR 0.98; 95% CI 0.84 - 1.13). Restricting the analysis of frailty=14.7%.Signifi cant variables in the univariate analysis were to the higher dose category, glyburide use was associated with signifi cantly included in the LRM. Diabetes (OR=2.7 95%CI .99-7.6), severe periodontitis higher risk of ACS events compared to gliclazide (aHR 1.27; 95% CI 1.08 - (OR=3.4 95%CI 1.1-10.8), each additional year of age (OR=1.2; 95%CI1.1-1.3) 1.50); however, no statistically signifi cant association between glyburide and each additional medicament used (OR=1.4; 95%CI 1.1-1.8) increases the and gliclazide was observed among those with lower doses subgroup (aHR risk for developing frailty. clinicians should consider diabetes and severe 1.08; 95% CI 0.93 - 1.25). Our study suggests a dose-related difference in periodontitis as health conditions associated with the incidence of frailty. risk of adverse cardiovascular events associated with gliclazide use but not Supported By: CONACYT (SV-670324-08) glyburide. However, this fi nding needs to be confi rmed in a clinical trial.

Genetics POSTERS & 1329-P Epidemiology/ EPIDEMIOLOGY—CARDIOVASCULAR DISEASE Association of Individual and Composite Risk Factor Control in Diabetes with Future Cardiovascular Disease Event Risk NATHAN D. WONG, ROHINI J. PATEL, CHRISTOPHER PATAO, ALAIN BERTONI, Guided Audio Tour: Diabetes and Cardiovascular Disease (Posters: 1327-P ADOLFO CORREA, AARON R. FOLSOM, SUMESH KACHROO, SHAISTA MALIK, to 1334-P), see page 13. JAYANTI MUKHERJEE, ELIZABETH SELVIN, Irvine, CA, Winston-Salem, NC, Jackson, MS, Minneapolis, MN, Princeton, NJ, Baltimore, MD & 1327-P Composite goal attainment of cardiovascular disease (CVD) risk factors Prediction of Coronary Artery Stenosis in Type 2 Diabetes Patients in persons with diabetes mellitus (DM) remains poor. We examined the Using Multidetector Computed Tomography association of control of low density lipoprotein-cholesterol (LDL-C), AKIRA YOSHIDA, KOICHIRO USUKU, JUN HIROSE, TATEKI SEGATA, KAZUE glycated hemoglobin (HbA1c), and blood pressure individually and together FURUTA, KEIZO KAJIWARA, KUNIO HIESHIMA, SEIGO SUGIYAMA, TOMIO with future coronary heart disease (CHD) and CVD events in a multiethnic JINNOUCHI, HIDEAKI JINNOUCHI, Kumamoto, Japan sample of subjects with DM. We pooled 2341 subjects with diagnosed DM Asymptomatic cardiac ischemia (ACI) is an important problem in patients (without prior CVD) in the prospective Atherosclerosis Risk in Communities, (pts) with Type2 diabetes (T2DM). In order to estimate degree of reduced Jackson Heart, and Multiethnic Study of Atherosclerosis followed for coronary lumen diameter by risk factors, in this study we have evaluated 11.2 +/- 7.0 years for the development of initial CHD and CVD events. coronary stenosis using 64-slice multi-detector Computed Tomography We examined the relation of control of HbA1c (<7%), blood pressure (BP) angiography (MDCTA) and propose the prediction model for coronary (<130/80 mmHg), and LDL-C (<100 mg/dl) individually and in combination stenosis. with the risk of future CHD and CVD events using Cox proportional hazards MDCTA were done in all pts regardless of symptom nor sign. Pts were regression, adjusted for age, gender, race, and other risk factors. Overall also underwent measurements for anthropometric values, biochemical 38.1%, 43.2%, 30.4%, and 6.3% of subjects were in control for HbA1c, BP, examination, blood pressure, carotid intima media thickness (IMT) and LDL-C, and all three factors at baseline, respectively; 410 (17.5%) and 728 ankle-brachial pressure index (ABI). T2DM pts were divided into derivation (31.1%) subjects suffered CHD and CVD events, respectively. The table and validation cohorts. The derivation cohort consisted of 413 pts with mean shows individual and composite control of DM risk factors in relation to age 67.6±9.3 years and HbA1c 7.5±1.3 and 40.8% females. Patients with future CHD and CVD event risk. DM subjects at individual and composite at least one stenotic lesion with 50% or more obstruction of the coronary goal levels of key measures HbA1c, BP, and LDL-C are at signifi cantly lower artery were considered to have signifi cant coronary artery stenosis. risks for future CHD and CVD events. Multiple logistic regression analyses showed that duration, hypertension, ABI, HDL, max-IMT and eGFR were signifi cantly associated with coronary stenosis. ROC curve analysis revealed that the AUC signifi cantly increased after addition of ABI, max-IMT and eGFR to conventional coronary risk factors from 0.64 to 0.73(p <0.01). We then confi rmed our new formula in the validation cohort of 326 pts with mean age 65.3±10.5 years and HbA1c 7.5±1.2 and 32.2% females. The positive predictive values and negative predictive values in this validation cohort were 55% and 70%, respectively. In conclusion, the addition of noninvasive tests of ABI, max-IMT and eGFR to conventional risk factors improves the prediction ability of coronary artery stenosis in T2DM. Supported By: University of California, Irvine

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& 1330-P & 1332-P Longitudinal Profi les of Blood Pressure, Lipids and HbA1c, and Regression from Prediabetes to Normal Glucose Regulation Is Their Association with Vascular and Mortality Risks in Patients Associated with Reduction in Cardiovascular Risk: Results from with T2DM Under Cardioprotective Medications the Diabetes Prevention Program Outcomes Study SANJOY PAUL, KERE KLEINE, AZEEM MAJEED, KAMLESH KHUNTI, Brisbane, LEIGH PERREAULT, ELLA TEMPROSA, KIEREN J. MATHER, EDWARD S. HORTON, Australia, London, United Kingdom, Leicester, United Kingdom ABBAS E. KITABCHI, MARY LARKIN, MARIA G. MONTEZ, DEBRA THAYER, Studies evaluating the longitudinal vascular and glycemic risks profi les TREVOR J. ORCHARD, RICHARD F. HAMMAN, RONALD B. GOLDBERG, Aurora, simultaneously in pts with T2DM, in conjunction with macrovascular events CO, Rockville, MD, Indianapolis, IN, Boston, MA, Memphis, TN, San Antonio, TX, (CVE) and mortality risks (ACM) are rare. This retrospective cohort study Hyattsville, MD, Pittsburgh, PA, Miami, FL evaluates the time-varying profi les of blood pressure (BP), lipids and HbA1c Our objective was to quantify and compare cardiovascular (CVD) risk (A1c) and their association with CVE and ACM in pts receiving antidiabetes, during the Diabetes Prevention Program Outcomes Study (DPPOS) among antihypertensive and lipid lowering drugs (CPM). those who returned to normal glucose regulation (NGR) at least once during A cohort of 17941 pt was extracted from UK General Practice Research DPP compared to those who remained with pre-diabetes or those who Database with complete data on demographics at diagnosis of T2DM and developed diabetes during DPP. Framingham (2008) score (as a measure of 6-monthly data on BMI, BP, A1c and lipids during 2 y immediately before global CVD risk) and individual CVD risk factors were calculated annually CVE or ACM or censoring, prescription dates for all medications within 1y of for DPPOS year 1-10 for subjects with NGR, pre-diabetes or diabetes diagnosis, and a min 3 y follow-up before any event. status defi ned during DPP. Generalized linear mixed models were used to Pts were 62 y old, 53% male, 22% had previous CVD, 13% current smokers, quantify the impact of previous (DPP) glycemic status on measures of CVD 67% obese and 59% had A1c > 7.5% at diagnosis. During median 7 y follow- risk. Included in this analysis are 2775 participants randomized during DPP up 16% were on insulin and 7% developed renal disease. Median time on with follow-up during DPPOS: N=914 to intensive lifestyle (ILS), N=926 to antidiabetes drugs / CPM was 6/6 y. In the cohort 4.7% had experienced a metformin (MET), and N=935 to placebo (PLB). The Framingham scores by CVE and 6.4% died. During 2 y immediately before event, pts with SBP ≥ 140 glycemic exposure did not differ among the treatment groups; therefore, mmHg, LDL ≥ 2.6 mmol/L and A1c > 7.5% consistently were 48%, 26% and pooled estimates were stratifi ed by glycemic status and adjusted for 32% respectively. Pts experiencing CVE/ACM had signifi cantly higher levels differences in baseline risk factors. During 10 years of follow-up, the mean of SBP, LDL, triglyceride (TRIG) and A1c. The adjusted risk of CVE/ACM were Framingham scores were highest in the pre-diabetes group (16.2 vs. 15.2 signifi cantly higher by 21 / 46%, 18 / 55%, 27 / 43% and 8 / 12% for SBP ≥ in NGR and 14.3 in diabetes, all pairwise comparisons p<0.001), however 140 mmHg, LDL 2.6 mmol/L, A1c > 7.5% and higher level of TRIG consistently ≥ the score did decline in the pre-diabetes group over time. The lower score during 2y, respectively (p<0.01). Higher HDL was associated with 26 / 11% in diabetes vs. other groups, a declining score in the pre-diabetes group reduced risks of CVE / ACM. Pts without CVD before diagnosis of T2DM had and favorable changes in each individual risk factor were partly explained similar risk estimates. The CVE / ACM risks were lower by 20 / 47% for pts by higher medication use for lipids and blood pressure. We conclude that maintaining recommended levels of BP, lipids and A1c during 2 y before event. Pts with T2DM had signifi cantly elevated levels of BP, LDL, TRIG and A1c pre-diabetes represents a high-risk state for CVD. Restoration of NGR during 2 y immediately before CVE or death, even after 6 y of antidiabetic, and/or medical treatment of CVD risk factors can signifi cantly reduce risk antihypertensive and lipid lowering therapy. in people with pre-diabetes. Supported By: NIH/NIDDK Genetics

Supported By: Therapeutic Innovations (Australia) POSTERS Epidemiology/ & 1331-P & 1333-P Lipoprotein Heterogeneity May Help to Detect Individuals with Insulin Ethnicity and Risk of Acute Myocardial Infarction in 121,289 Resistance: The Insulin Resistance Atherosclerosis Study (IRAS) Patients with Type 2 Diabetes CARLOS LORENZO, ANTHONY J. HANLEY, MARIAN J. REWERS, STEVEN M. SOFFIA GUDBJÖRNSDOTTIR, ARAZ RAWSHANI, ANNIKA ROSENGREN, ANN- HAFFNER, San Antonio, TX, Toronto, ON, Canada, Aurora, CO MARIE SVENSSON, Gothenburg, Sweden It is not known whether lipoprotein heterogeneity provides additional Little is known about ethnicity and the risk of coronary heart disease information to the ability of triglyceride and HDL cholesterol levels to detect (CHD) and acute myocardial infarction (AMI) in diabetes. We examined insulin resistance (IR). We examined this issue in 882 non-diabetic participants the relationship between ethnicity and CHD death or hospitalization for in the IRAS who were not on lipid-lowering medications. Insulin sensitivity AMI in patients with type 2 diabetes. Patients included in the Swedish index (SI) and lipoprotein heterogeneity were measured by the frequently National Diabetes Register (2002-2006) were followed until a diagnosis of sampled intravenous glucose to lerance test and proton nuclear magnetic AMI or CHD death, death (other causes) or December 31 2011, through the resonance spectroscopy (NMR), respectively. IR was defi ned as the lowest SI nationwide Inpatient Registry and National Death Registry. All individuals quartile. The area under the receiver operating characteristic curve (AUC) for (15.5% foreign-born) had access to low-cost health care. NMR lipoproteins was greater than that for HDL cholesterol and triglyceride Incidence rates for AMI/CHD death were estimated by Poisson regression. levels (0.790 vs. 0.743, p <0.001) (Table). A reduced NMR lipoprotein set Relative risk was estimated by Cox regression adjusted for nine risk factors yielded similar results (AUC 0.784, p = 0.004). We generated clinically relevant of AMI. a priori categories using as cut points IR prevalence in lean (10%) and obese In 121289 patients with type 2 diabetes, 12861 (10.6 %) had an event individuals (50%). The reduced set improved the ability of HDL cholesterol and (mean follow-up 6.1 years). Incidence rates (fi gure) varied strikingly by triglyceride levels for classifying individuals according to the risk of having ethnicity. Non-Western groups, particularly Sub-Saharan Africa and Latin IR (net reclassifi cation improvement [NRI] of 0.229, p <0.001; integrated America displayed particularly high fi gures. Adjusted hazard ratios for AMI/ discrimination improvement [IDI] of 0.072, p <0.001). In summary, lipoprotein CHD death by ethnicity was: High-income Europe, North America, 1.10 heterogeneity may help to detect individuals with IR. NMR lipoproteins permit (0.97-1.25); Low-income Europe, 1.19 (1.03-1.37); Latin America & Caribbean, the correct reclassifi cation of additional 23% of individuals. 1.30 (0.90-1.88); Middle East & North Africa, 1.37 (1.16-1.62); Sub-Saharan Predictive Discrimination and Discriminatory Value of Lipoproteins for Detecting IR. Africa, 1.15 (0.79-1.55) and South & East Asia 1.10 (0.77-1.48), compared AUC NRI IDI with Nordic countries. Conclusion: Ethnic disparities in risk of AMI/CHD death could be explained Age, sex, race/ethnicity, and clinic 0.662, —— p <0.001 by modifi able risk factors. + log triglycerides and HDL cholesterol 0.743, Referent Referent Referent + NMR lipoproteins 0.790, —— p <0.001 + reduced NMR lipoprotein set * 0.784, —— p =0.004 + log triglycerides, HDL cholesterol, 0.798, 0.229, 0.072, and reduced NMR lipoprotein set * p<0.001 p<0.001 p<0.001 * Reduced NMR lipoprotein set includes LDL, HDL, and medium VLDL parti- cles plus LDL, HDL, and VLDL sizes. Supported By: HL-47887, M01RR431

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A347 EPIDEMIOLOGY—CARDIOVASCULARCATEGORY DISEASE

photocoagulation, were free of CAD, and had known pregnancy status at baseline (mean T1D duration=18.5, age=26.9). Computer assisted grading was used to measure central retinal arteriolar (CRAE) and venular (CRVE) equivalent. Data to 22 years of follow-up were used ascertain CAD incidence (fi rst instance of CAD death, myocardial infarction, revascularization or stenosis ≥50%, ischemic ECG or angina). Low CRAE was defi ned as <25th percentile (165.1 µm). Mean CRAE was 172.4 µm (sd 19.9) in women with prior pregnancy (n=111) and 178.9 (sd 19.7) in those without (n=154) (age-adjusted p=0.98). There were 72 (27.1%) total incident CAD events (48 events in those with prior pregnancy, 24 in those without). Smaller CRAE was signifi cantly predictive of CAD incidence in women with prior pregnancy (per sd HR=1.86, p=0.003) but not in those without prior pregnancy (HR=1.10, p=0.72), after adjustment for potential confounders (age, HbA1c, retinopathy severity, and CAD risk factors). There was a signifi cant additive interaction between prior pregnancy and low CRAE, such that women with both were at greater risk of CAD (p=0.01). CRVE was not associated with CAD regardless of pregnancy status. The relationship between CRAE and CAD in women is modifi ed by prior pregnancy status in the EDC study, suggesting that smaller CRAE in women & 1334-P with a history of pregnancy may be related to maternal vascular adaptation to pregnancy. The Importance of Heart Failure on the Outcomes and Health Care Costs of Medicare Patients with Type 2 Diabetes Supported By: NIH/NIDDK (R01DK034818) KRISTEN A. HYLAND, MELISSA GREINER, LAURA QUALLS, ASHLEY A. DUNHAM, ADRIAN HERNANDEZ, MARIE L. MIRANDA, ROBERT CALIFF, LESLEY CURTIS, 1336-P Durham, NC, Ann Arbor, MI Diabetes Status Modifi es the Association between Carotid Intima- Diabetes is common among heart failure patients, but the combination Media Thickness and Incident Heart Failure: The Atherosclerosis of both on contemporary outcomes and healthcare costs is unknown. Using Risk In Communities (ARIC) Study 5% Medicare fee-for-service claims from January 1 through December 31, VALERY S. EFFOE, ERIC E. MCCLENDON, CARLOS J. RODRIGUEZ, LYNNE E. 2011 for benefi ciaries aged 65 years or older with prevalent diabetes, we WAGENKNECHT, GREGORY W. EVANS, PATRICIA P. CHANG, ALAIN G. BERTONI, compared outcomes and healthcare costs in patients with and without Winston-Salem, NC, Chapel Hill, NC prevalent heart failure (HF). Increasing carotid intima-media thickness (CIMT) is associated with Compared to those without HF, the patients with diabetes and HF had a incident heart failure (HF). We investigated whether CIMT can be used to 50% higher rate of any emergency room visit, twice the rate of all-cause predict HF among those with diabetes mellitus (DM), a condition associated Genetics

POSTERS admissions, and 3 times the rate of cardiovascular-related admissions. with a higher risk of HF. We characterized a cohort of 13,590 ARIC Epidemiology/ Lower extremity amputations and dialysis occurred more frequently and participants free of baseline HF into normal fasting glucose (NFG), impaired 1-year mortality was 3 times higher in the diabetes with HF group than fasting glucose (IFG, glucose 100-125mg/dl), and DM (glucose >125mg/ without HF. dl, self-report, or use of diabetes drugs). CIMT was assessed by B-mode Average Medicare payments were twice as high in the diabetes with HF ultrasound. Incident HF was defi ned using ICD-9 428 and ICD-10 I-50 codes group compared to those without HF. from hospitalizations and death certifi cates. The CIMT-HF association As coded in claims, concomitant heart failure with diabetes is associated was analyzed using Cox proportional hazards, adjusting for demographics, with increased healthcare utilization, Medicare payments, and worse CVD risk factors and interim CHD. Over 20.6 years of follow-up, 15% outcomes. More effective strategies of treating patients with diabetes and of participants (age 54±6 years, 55% women, 10.5% DM) developed HF. HF are needed to improve outcomes and healthcare costs. The absolute HF risk was highest for those with DM, than those with NFG and IFG (Figure). The adjusted CIMT-HF association signifi cantly varied by diabetes status with a higher HF risk for those with NFG and IFG than those with DM [hazard ratio per standard deviation increase in CIMT (95%CI): 1.25 (1.19, 1.32), 1.19 (1.11, 1.27), and 1.14 (1.05, 1.23), respectively]. In conclusion, CIMT may be a less reliable predictor of incident HF among adults with DM due to a high absolute risk of HF in this population.

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1335-P Is the Relationship between Retinal Vessel Diameter and Coronary Artery Disease (CAD) Incidence in Women Modifi ed by History of Pregnancy in Type 1 Diabetes (T1D)? RACHEL G. MILLER, RONALD KLEIN, TREVOR J. ORCHARD, Pittsburgh, PA, Madison, WI As previously reported in the Pittsburgh Epidemiology of Diabetes Supported By: NHLBI Complications (EDC) study of T1D smaller retinal arteriolar diameter at baseline is associated with an increased risk of CAD in women but not men. Our current objective was thus to determine whether the relationship between retinal arteriolar diameter and CAD differs by history of pregnancy in women from the EDC study. Of the 658 total participants examined at baseline (1986-1988) 325 are women. Of those, 265 had retinal photographs, no history of laser

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A348 EPIDEMIOLOGY—CARDIOVASCULARCATEGORY DISEASE

1337-P 1339-P Circulating Resistin Levels and Mortality Risk Results of the Albiglutide HARMONY Program Prospective Major ANDREA FONTANA, SARA SPADARO, ANTONELLA MARUCCI, LUCIA SALVE- Adverse Cardiovascular Event (MI, Stroke, Cardiovascular Death, MINI, MASSIMILIANO COPETTI, LUCIA FRITTITTA, SIMONETTA BACCI, FABIO and Unstable Angina) Meta-analysis PELLEGRINI, VINCENZO TRISCHITTA, CLAUDIA MENZAGHI, San Giovanni PHILIP D. AMBERY, JILL DONALDSON, JUNE YE, JOHN J.V. MCMURRAY, Rotondo, Italy, Catania, Italy, Santa Maria Imbaro, Italy Uxbridge, United Kingdom, Research Triangle Park, NC, Glasgow, United Kingdom Studies concerning the association between circulating resistin levels and In keeping with guidance issued by the FDA in 2008 requiring mortality yielded mixed results with only some studies reporting signifi cant demonstration of the cardiovascular (CV) safety of new glucose-lowering associations, while many others showing negative results. We sought to agents for type 2 diabetes, GSK conducted a meta-analysis of CV events address this issue by: i) investigating it in the Gargano Heart Study (GHS) for albiglutide. prospective design (n=359 diabetic patients; 81 and 58 incident cases of Possible CV events were collected prospectively across 1 Phase II and all-cause and cardiovascular (CV) mortality, respectively); ii) meta-analyzing 8 Phase III albiglutide studies for blinded adjudication by an independent in a dose-risk fashion our present GHS and all studies from MEDLINE and Clinical Endpoint Committee. Subjects were randomized to albiglutide or EMBASE) reporting adjusted hazard ratios (HR) of circulating resistin for placebo or active comparators (sitagliptin, insulin lispro, insulin glargine, all-cause or CV mortality. pioglitazone, liraglutide and glimepiride). 5 of the phase III studies were up In GHS, the adjusted HRs per 10 ng/ml resistin increment were: 1.45 (95% to 3 years in duration. There were 5107 subjects in the safety population CI: 1.10-1.91) and 1.52 (95% CI: 1.09-2.12) for all-cause and CV mortalities, of whom 2524 were exposed to albiglutide (4870 person-yrs) and 2583 to respectively. comparators (5213 person yrs). The dose-risk meta-analyses included 7 studies (n=3,699, 997 events) for The primary endpoint was the fi rst occurrence of MACE+ (MACE + all-cause mortality and 6 studies (n=4,187, 412 events), for CV mortality. unstable angina) for albiglutide versus all comparators. MACE (CV death, Pooled HRs per 10 ng/ml resistin increment were 1.33 (95% CI: 1.03- 1.72, non-fatal myocardial infarction or non-fatal stroke) was a pre-defi ned p=0.028, Q-test p for heterogeneity<0.001) and 1.16 (95% CI: 0.95-1.43, secondary endpoint. Results are shown in the table. p=0.147, Q-test p for heterogeneity=0.039) for all-cause and CV mortality, Although the upper bound of the 95% CI for MACE+ events in this respectively. prospective adjudicated meta-analysis was below 1.8, because it is above Due to the presence of between-studies heterogeneity, meta-regression 1.3, a cardiovascular endpoint study is required for albiglutide. No difference analyses were performed. was seen in heart failure events or all-cause mortality for albiglutide versus For all-cause mortality, study mean age (HR=1.08, 95%CI=1.01-1.14, comparators in this meta-analysis. p=0.017) explained 68.8% of heterogeneity resulting in a pooled HR per 10 ng/ml resistin increment equal to 1.33 (95% CI: 1.12-1.57, p=0.001). Comparison MACE+/ Hazard 95% CI NI P Value for NI P Value for For CV mortality, study mean BMI (HR=1.07, 95%CI=1.02-1.11, p=0.004) MACE Ratio (3 Year) 1.8 Margin 1.3 Margin (3 Year) (3 Year) explained the whole heterogeneity resulting in a pooled HR per 10 ng/ml resistin increment equal to 1.11 (95% CI: 1.02-1.22, p=0.016). Albiglutide vs. All Comparators MACE+ (116 events) 1.00 0.68, 1.49 0.002 0.10 Our results provide strong evidence for an association between higher MACE (105 events) 0.99 0.65, 1.49 NA NA circulating resistin levels and increased mortality risk. Albiglutide vs. Placebo MACE+ (41 events) 0.72 0.38, 1.37 NA NA Genetics

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MACE (37 events) 0.69 0.35, 1.35 NA NA Epidemiology/ 1338-P Albiglutide vs. Active Comparators MACE+ (93 events) 1.15 0.74, 1.78 NA NA Angiopoietin-like Protein 4 Signifi cantly Predicts Future Cardio- MACE (83 events) 1.13 0.71, 1.80 NA NA vascular Events in Coronary Patients Supported By: GlaxoSmithKline AXEL MUENDLEIN, ANDREAS LEIHERER, ELENA KINZ, PHILIPP REIN, ALEX- ANDER VONBANK, CORNELIA MALIN, HEINZ DREXEL, CHRISTOPH H. SAELY, 1340-P Feldkirch, Austria The Relationship of Adiposity and Mortality among People with Angiopoietin-like protein 4 (Angptl4) has been associated with many Diabetes in the U.S. General Population cardiometabolic disorders including dyslipidemia and diabetes. However, ANDY MENKE, SARAH STARK CASAGRANDE, CATHERINE C. COWIE, Silver the infl uence of Angptl4 on the cardiovascular risk still remains unclear. Spring, MD, Bethesda, MD We therefore examined the association of plasma Angptl4 levels with Several studies have found a U-shaped association between body mass cardiovascular risk markers as well as with the risk of future cardiovascular index (BMI) and mortality in the general population. In similar studies among events in a cohort of 490 patients undergoing coronary angiography. people with diabetes, the shape of the association is inconsistent. We Further, we prospectively investigated the infl uence of the tagging single investigated the relationship of BMI and waist circumference with mortality nucleotide polymorphisms (SNPs) rs4076317, rs2278236, rs1044250, among diabetic participants of the Third National Health and Nutrition and rs11672433 of the ANGPTL4 gene on the cardiovascular risk in 1007 Examination Survey Mortality Study (N=1370). In 1988-1994, height and coronary patients. Plasma Angptl4 concentration correlated positively with weight were measured to calculate BMI, and participants were followed age (r=0.190, p<0.001), fasting glucose (r=0.125, p=0.006), insulin (r=0.100, through 2006 for mortality. Compared to people with a BMI <25 kg/m2, the p=0.032), CRP (r=0.103, p=0.023), and central fat mass (r=0.153, p=0.002) multivariable adjusted hazard ratios (95% confi dence interval) of mortality and correlated negatively with HDL cholesterol (r=-0.119, p=0.008). Plasma were 0.88 (0.58-1.33) for 25-29.9 kg/m2, 0.80 (0.48-1.32) for 30-34.9 kg/m2, Angptl4 concentration was signifi cantly increased in patients with type 2 and 0.86 (0.52-1.42) for ≥35 kg/m2. When we modeled BMI as a restricted diabetes compared to non-diabetic subjects (26.5±21.4 ng/ml vs. 22.3±19.1 quadratic spline, the relationship with mortality was consistent with a ng/ml; p=0.037). Prospectively, plasma Angptl4 was signifi cantly associated U-shaped association but there were no signifi cant differences (Figure 1). with the risk of future cardiovascular events (HR=1.26 [1.08-1.44], p=0.002). In similar analyses, waist circumference was not signifi cantly associated After adjustment for age, sex, and type 2 diabetes plasma Angptl4 still with mortality. In a nationally representative group of people with diabetes, predicts cardiovascular risk (HR=1.19 [1.03-1.39], p=0.021). No association measures of adiposity were not associated with risk of mortality. between included ANGPTL4 SNPs and plasma Angptl4 could be observed Figure 1. Multivariable adjusted relative hazard of mortality associated (all p-values >0.05). However, rs4076317, rs2278236, and rs1044250 with BMI. Gray shading represents 95% confi dence interval; background signifi cantly infl uenced risk of future cardiovascular events (adjusted histogram of BMI is displayed on the right axis. HR=0.68 [0.53-0.87], p=0.003; HR=0.73 [0.59-0.95] p=0.004; and HR=1.33 [1.06-1.67] p=0.013, respectively) suggesting ANGPTL4 SNPs modulates cardiovascular risk beyond plasma Angptl4 levels. We conclude that plasma Angptl4 levels as well as ANGPTL4 variants are signifi cantly predictive of cardiovascular events among patients undergoing coronary angiography. Supported By: OeNB Jubilaeumsfonds

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A349 EPIDEMIOLOGY—CARDIOVASCULARCATEGORY DISEASE

1342-P Both Fasting and 2-hour Post Load Glycemic Progression Predicts Subsequent Cardiovascular Events in Persons with Impaired Glucose Tolerance: Long-term Follow-up of the Da Qing Diabetes Prevention Study XIAOXIA SHEN, YALI AN, PING ZHANG, JINPING WANG, EDWARD W. GREGG, BO ZHANG, HUI LI, QIUHONG GONG, YANYAN CHEN, XIAOYAN XING, MICHAEL ENGELGAU, YINGHUA HU, PETER H. BENNETT, GUANGWEI LI, Beijing, China, Atlanta, GA, Daqing, China, Phoenix, AZ We sought to determine if glycemic progression in persons with IGT after initiation of a lifestyle intervention trial predicted cardiovascular events, and if so, to determine if fasting plasma glucose (FPG) or 2-hour post-load plasma glucose levels (2hPG) had a differential effect in predicting such events. In 1986, 576 adults aged 25 years and older with IGT in Da Qing China were randomly assigned by clinic to control or diet, exercise, and diet plus exercise intervention groups for a 6-year period. Subsequently participants received medical care in their local clinics. In 2009, we tracked participants to ascertain cardiovascular (CVD) events and other outcomes. Among the 542 subjects who completed the 6-year trial, 182 fi rst non- fatal or fatal (CVD) events (myocardial infarction or stroke) occurred during the subsequent 17-year follow-up. Epidemiological analysis found that after controlling for age, sex, body-mass index, blood pressure and smoking at the baseline, each 1 mmol/l increase in FPG and 2hPG levels at the end of the 6-year trialwas associated with 8% (HR=1.08; 95%CI 1.05-1.12) and Supported By: NIDDK (GS10F0381L) 5% (HR=1.05; 95%CI 1.02-1.09) increase in having a fi rst CVD event. In contrast, there were no signifi cant associations between the glucose levels 1341-P measured at the time of randomization and fi rst CVD events (FPG: HR=1.19, First Cardio-Renal Events in Patients with Type 2 Diabetes and 95%CI 0.98-1.45; 2hPG: HR=1.06, 95% CI 0.90-1.25). Classifying participants Subsequent Risk of Death: An Analysis of Aliskiren Trial in Type 2 by diabetes(FPG>= 126mg/dl or 2hPG>=200mg/dl) at 6-years,controlling for Diabetes Using Cardio-Renal Endpoints (ALTITUDE) the same covariates, showed that those who had developed diabeteshad PARDEEP S. JHUND, JOHN J.V. MCMURRAY, PATRICK BRUNEL, NISHI CHATUR- a higher incidence of subsequent CVD events than those who had not VEDI, AKSHAY S. DESAI, PETER V. FINN, STEVEN M. HAFFNER, SCOTT D. (HR=1.45, 95%CI1.07-1.95). SOLOMON, LARRY A. WEINRAUCH, MARC A. PFEFFER, Boston, MA, Glasgow, We conclude that both fasting and post-load glucose levels at the end Genetics

POSTERS United Kingdom, Basel, Switzerland, London, United Kingdom, San Antonio, TX of the 6-year trial predicted the development of fi rst CVD eventsin adult Epidemiology/ Aims: We compared the burden of different cardiovascular (CV) and renal Chinese with IGT and that faster glycemic progression predicted a higher events and subsequent risk of death in patients with type 2 diabetes (T2DM) risk of subsequent CVD events. and evidence of chronic kidney disease, or CV disease or both in ALTITUDE. Methods: 8,561 patients were followed for a median of 30 months and 1343-P we assessed the relative frequency of the fi rst type of non-fatal CV event Change in Intra-abdominal Fat Predicts Risk of Hypertension in of myocardial infarction (MI), stroke, hospitalization for heart failure (HF) Japanese Americans or renal event (dialysis, transplantation, creatinine >6.0mg/dL) during the CATHERINE A. SULLIVAN, STEVEN E. KAHN, WILFRED Y. FUJIMOTO, TOMOSHIGE trial. The subsequent risk of death following each initial event, as a time HAYASHI, MARGUERITE J. MCNEELY, DONNA L. LEONETTI, EDWARD J. BOYKO, varying covariate, was compared to those that did not experience an event Seattle, WA, Osaka, Japan adjusting for covariates in a Cox model. In Japanese Americans, intra-abdominal fat area (IAF) at baseline Results: In the 1036 with an event, the commonest fi rst event was HF is positively associated with both the prevalence and incidence of 349 (4.1%), then MI, 256 (3.0%), stroke, 244 (2.9%), and the renal event 184 hypertension (HTN). In other population groups it has been shown that (2.1%). Overall, there were 734 deaths in 8561 patients, most (463, 63% of certain fat areas, specifi cally thigh, may be protective against HTN. To deaths) were not preceded by an initial cardio-renal event. In those who had determine whether a change in fat distribution predicts the development of a non-fatal event, regardless of the type the adjusted risk of death was over HTN, we prospectively followed 286 subjects from the Japanese American 5 fold higher (Figure). Aliskiren had no effect on these outcomes. Community Diabetes Study for 10 years who at baseline did not have HTN Conclusion: Although most deaths were not preceded by a non-fatal (defi ned by blood pressure ≥ 140/90 mmHg) and were not taking blood cardio-renal event, the most common fi rst event in the trial was HF and all pressure or glucose lowering medications. Mid-thigh subcutaneous fat area subsequent events were associated with a multi-fold higher risk of death. (THISU), abdominal subcutaneous fat area (ABDSU) and IAF, measured at the level of the umbilicus, were directly measured by CT scan at baseline and at 5 years. Logistic regression was used to estimate the odds of incident HTN over 10 years in relation to baseline and 5 year change in CT-measured fat areas while adjusting for covariates. Population characteristics were 50.3% male, age 49.5 ± 11.6 y and BMI 23.7 ± 3.1 kg/m2 (mean±SD). The 10-year incidence of HTN was 28.6%. Relative odds (OR) of developing HTN for a 1-SD 5 year increase in IAF was 1.73 (95% CI 1.27-2.36), after adjusting for age, sex, BMI, baseline IAF, alcohol use, current smoking status and weekly exercise energy expenditure. This relationship remained signifi cant when adjusted for baseline fasting insulin and 2-h glucose levels (OR 1.74, 95% CI 1.27-2.37). When further adjusted for either change in THISU or ABDSU, change in IAF remained signifi cantly associated with incident HTN: OR 1.70 (95% CI 1.24-2.32) and 1.73 (95% CI 1.24-2.42), respectively. There were no signifi cant associations between baseline or change in THISU or ABDSU and incident HTN, including after adjustment for both baseline and change in IAF. In conclusion, in this cohort of Japanese Americans, the risk of developing HTN appears to be related to the accumulation of IAF rather than the accrual of subcutaneous fat in either the thigh or abdominal areas. Supported By: NIH (P30DK017047)

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A350 EPIDEMIOLOGY—CARDIOVASCULARCATEGORY DISEASE

1344-P calculated the change in the c-statistic after the addition of each marker, as well as the continuous net reclassifi cation index (NRI) and relative WITHDRAWN integrated discrimination index (rIDI). The addition of hs-cTnT signifi cantly improved the c-statistic, more so than the addition of NT-proBNP (Table). However, the absolute improvements in the c-statistic, overall NRI and rIDI were not large. The clinical utility of incorporating these markers into risk prediction equations for cardiovascular events in persons with diabetes is unclear.

1345-P GlycA Complements C-Reactive Protein as a Measure of Infl amma- tion: The Insulin Resistance Atherosclerosis Study CARLOS LORENZO, ANTHONY J. HANLEY, ANDREAS FESTA, STEVEN M. HAFFNER, San Antonio, TX, Toronto, ON, Canada, Vienna, Austria Measured by proton nuclear magnetic resonance spectroscopy, N-acetyl- glucosamine/galactosamine (GlycA) and sialic acid (GlycB) moieties of glycosylated serum proteins refl ect glycosylated acute phase proteins Supported By: NIDDK (R01DK089174); NHLBI (HHSN268201100005C-12C, released from the liver. Although both are increased with insulin resistance, T32HL007024) it is not known whether GlycA and GlycB have utility similar or complementary to existing infl ammatory markers. Thus, we aimed to examine the relation 1347-P of GlycA, GlycB, and C-reactive protein (CRP) to direct measures of insulin Weight Change and Change in N-Terminal pro-Brain Natriuretic sensitivity (insulin sensitivity index [S ]) and acute insulin response (AIR) in Peptide (NT-proBNP)

I Genetics

980 non-diabetic participants in the IRAS. SI and AIR were measured by the MARIANA LAZO, CHIADI NDUMELE, JOSEF CORESH, DHANAJAY VAIDYA, POSTERS frequently sampled intravenous glucose tolerance test. Log-transformed CHRISTIE M. BALLANTYNE, ELIZABETH SELVIN, Baltimore, MD, Houston, TX Epidemiology/ CRP, SI, and AIR were used in all analysis to meet the assumptions of the Higher levels of N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) tests. The correlation of GlycA and GlycB with log-transformed CRP was have been associated with reduced risk of diabetes independent of other risk strong (r = 0.60 and 0.48, respectively). There were gender differences factors. Furthermore, animal studies have shown that mice overexpressing in GlycA and GlycB (increased levels in women, p <0.01), but not racial/ BNP do not gain weight after a high-fat diet and have increased lipolysis. ethnic differences (p >0.2 and >0.12 for all GlycA and GlycB comparisons, To examine the prospective association between NT-proBNP changes respectively) after the adjustment for age, glucose tolerance, and smoking. and weight in humans, we conducted a prospective analysis of 9202 ARIC However, minority populations (p <0.03) and women had increased CRP Study participants (60% women, 78% white, mean age 56 years) without concentrations (p <0.001). In a linear regression model with both GlycA and cardiovascular disease or heart failure. NT-proBNP and weight were CRP as independent variables, GlycA (β × 1 SD, - 0.05 ± 0.02, p <0.01) and measured at 2 visits, 6 years apart. Mean overall weight change was +4.3 CRP (β - 0.07 ± 0.02, p <0.001) were independently associated with SI after pounds (SD, 12.7), a +2.6%(SD, 7.3%) increase from baseline. Median overall accounting for the effect of demographics, glucose tolerance, BMI, and change in NT-proBNP was 11.2 pg/mL , (percentile 25 and 75: -8.8 to +45.7), smoking. In a separate model, GlycB was not independently associated with a +28% (percentile 25 and 75:-20.2 to +112.0) increase from baseline. Higher SI (β - 0.03 ± 0.02, p >0.05), but CRP was (β - 0.07 ± 0.02, p <0.001). GlycA, baseline levels of NT-proBNP were independently associated with reduced GlycB, and CRP were not associated with AIR after covariate adjustment risk of developing obesity (p for trend<0.001), and there was an independent including SI (p >0.05 for all three variables). In summary, there is racial/ethnic and inverse association between change in NT-proBNP and weight change variation for CRP, but not for GlycA and GlycB. GlycA may be complementary (Figure). While higher levels of NT-proBNP have been associated with to CRP for evaluating the relationship between infl ammation and insulin increased risk of cardiovascular outcomes in the general population; resistance. inverse associations are observed between NT-proBNP levels and the risk Supported By: HL-47887, M01RR431 of diabetes and obesity, and suggest the existence of a cross-talk between adipose tissue and the heart. 1346-P High-Sensitivity Cardiac Troponin T and NT-proBNP in Cardio- vascu lar Risk Prediction in Persons with Diabetes CHRISTINA M. PARRINELLO, JOHN W. MCEVOY, MARK WOODWARD, AARON R. FOLSOM, CHRISTIE M. BALLANTYNE, JOSEF CORESH, ELIZABETH SELVIN, Baltimore, MD, Minneapolis, MN, Houston, TX While persons with diabetes are considered at high risk for cardiovascular disease (CVD), traditional CVD risk prediction equations are known to be problematic in the setting of diabetes. We sought to determine whether adding high sensitivity cardiac troponin T (hs-cTnT) and/or N-terminal probrain natriuretic peptide (NT-proBNP) improved CVD risk prediction in persons with diabetes. We included 904 ARIC participants with diagnosed diabetes and no history of CVD at baseline (visit 2; 1990-92). We calculated predicted 10-year risks using the following equations: 2013 ACC/AHA Pooled Cohort Equations for ASCVD, Framingham Hard CHD, UKPDS and ARIC CHD. Cox proportional hazards regression models were used to assess the association between each risk score and respective outcome over 10 years of follow-up, with and without the addition of hs-cTnT and NT-proBNP. We Supported By: NIH/NIDDK (R01DK089174); Roche Diagnostics

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A351 EPIDEMIOLOGY—CARDIOVASCULARCATEGORY DISEASE

1348-P 1350-P The Pooled Cohort Equations for Non-Hispanic Whites Overesti- Smoking Potentiates the Diabetes-related Increase of Skin Auto- mates the Risk in Hispanics with Diabetes fl uorescence KENNY SHUM, TUAN DINH, PENGFEI ZHENG, San Francisco, CA BRUCE H.R. WOLFFENBUTTEL, HELEN L. LUTGERS, REINDERT GRAAFF, KAREN The Pooled Cohort Equations for 10-year atherosclerotic cardiovascular ENY, SANDRA N. SLAGTER, JANA V. VAN VLIET-OSTAPTCHOUK, MELANIE M. disease (ASCVD) risk are used to determine statin treatment dosage for VAN DER KLAUW, ANDREW D. PATERSON, Groningen, Netherlands, Toronto, ON, diabetics. Due to limited availability of follow up data for Hispanics, the Canada equations were built with only non-Hispanic cohorts. To estimate risk in Skin autofl uorescence (SAF) can be measured non-invasively with an AGE Hispanics, the full work group report provided a grade E (expert opinion) Reader, and is a strong predictor of cardiovascular events and diabetes- recommendation of using the sex-specifi c Pooled Cohort Equations for non- related complications. Earlier studies have shown that people who smoke Hispanic Whites. Our goal is to determine the difference in risk of ASCVD have higher SAF than non-smokers. We assessed the effects of smoking between Hispanics and non-Hispanic Whites after controlling for the risk on SAF in people with and without type 2 diabetes (T2DM) in the LifeLines factors in the Pooled Cohort Equations. We fi t a Cox proportional hazard Cohort study, a random population-based sample of inhabitants of three model to the ALLHAT data (median duration of 4.6 years) to estimate the Northern provinces of the Netherlands. For this cross-sectional analysis, we hazard ratio between Hispanics and non-Hispanic Whites. The risk factors included subjects 18-80 years of age, who had both genetic data available and at baseline are controlled via an offset term in the log hazard function. SAF measurement (AGE Reader, DiagnOptics Technologies BV, Netherlands; The analysis includes 1621 Hispanics and 2747 non-Hispanic Whites with software version 2.3) collected between January 2008 and March 2011. We diabetes diagnosis but no history of ASCVD. By the end of the study, 122 and excluded subjects who were known to have type 1 diabetes, leaving 9039 359 ASCVD events were observed in the Hispanic subgroup and non-Hispanic individuals (of whom n=318, 3.5% with T2DM) for analysis. Mean±SD age white subgroup, respectively. After controlling for the risk factors, the hazard was 49±11 yrs for the non-diabetic participants and 59±11 yrs for the T2DM ratio for ASCVD between Hispanic and non-Hispanic white is statistically group, while mean SAF was 2.04±0.44 arbitrary units (AU) vs. 2.45±0.59 AU, signifi cant HR=0.77 (95% CI: 0.63 - 0.95). Using data from NHANES 2007- respectively. Age-corrected SAF Z-score (mean±SE) was -0.04±0.01 in non- 2012, we estimate 8.4% of Hispanics aged 40-75 with diabetes in the U.S. smoking and 0.48±0.02 in smoking non-diabetic subjects (p<0.001). Age- would receive a different treatment recommendation (switching from high- corrected SAF Z-score in the T2DM subjects was 0.36±0.08 in non-smoking intensity to moderate-intensity statin) if the hazard ratio of 0.77 is applied to (p<0.001 vs. nonT2DM), and 1.27±0.17 in smoking subjects (p<0.001 vs. non- the sex-specifi c Pooled Cohort Equations for non-Hispanic Whites to predict smoking T2DM). Linear regression showed signifi cant interaction between the risk for Hispanics. Analysis of the ALLHAT data indicates the use of the smoking and T2DM in their effect on SAF (p<0.001). These differences could equations for non-Hispanic Whites would over-predict the risk of ASCVD for not be explained by sex, amount of cigarettes smoked daily, differences Hispanics with diabetes. Adjustment to the prediction score is needed to in kidney function, glycemic control, or genetic polymorphisms of the determine the appropriate treatment in the Hispanic population. N-acetyltransferase gene. We conclude that SAF is more severely elevated in diabetic compared to non-diabetic individuals who smoke. This supports 1349-P the concept that cardiovascular risk increase associated with smoking is Metabolic Predictors of Ischemic Heart Disease and Cerebro- stronger in diabetes. vascular Attack in Late Elderly Diabetic Individuals: Lessons from 9 Genetics

POSTERS Years Observation of 4014 Diabetic Patients 1351-P Epidemiology/ TOSHIO HAYASHI, KOUTARO YOKOTE, MINORU TAKEMOTO, MITSUHIKO NODA, Visceral and Subcutaneous Adipose Depots and Change in HIROSHI NOTO, ATSUSHI ARAKI, HIROHITO SONE, KOICHIRO INA, HIDEKI Cardiometabolic Risk Factors: The Framingham Heart Study NOMURA, JAPAN CDM GROUP, Nagoya, Japan, Chiba, Japan, Tokyo, Japan, Mito, TOBIN M. ABRAHAM, ALISON PEDLEY, JOSEPH M. MASSARO, UDO HOFFMANN, Japan CAROLINE S. FOX, Boston, MA, Framingham, MA LDL-cholesterol(LDL-C) and glucose levels are risk factors for ischemic Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) are heart disease(IHD) in middle-aged diabetic individuals; however, the risk distinct fat depots. We evaluated whether VAT or SAT predict metabolic risk among elderly, especially late elderly, and legend effect of the risk are not factor changes beyond body mass index (BMI). well known. The aim of this study is to identify factors predicting IHD and Participants were drawn from the Framingham Heart Study Multi-detector cerebrovascular attack(CVA) in elderly and to investigate their differences Computed Tomography Study (n=1730, 44.6% women, mean age 44.1 years by age. We performed a prospective cohort study(Japan Cholesterol [men] and 46.0 years [women]), who attended a follow-up visit a mean of and Diabetes Mellitus Study) with 9 years of follow-up. A total of 4,014 6.2 years later. VAT and SAT volume (in cm3) were assessed at baseline. patients with type 2 diabetes and without previous IHD or CVA(1,936 Outcomes included changes in systolic and diastolic blood pressure (SBP women; 67.4±9.5 years, <65 y.o., n=1,261; 65 to 74 y. o., n=1,731 and ≥75 y.o., and DBP), fasting lipids and glucose. Sex-specifi c linear regression models n=1,016) were recruited on a consecutive outpatient basis from 40 hospitals predicting change in each outcome from baseline to follow-up were throughout Japan. Lipids, glucose, and other factors related to IHD or CVA constructed. The models were adjusted for age, physical activity, alcohol risk, such as blood pressure (BP), were investigated using the multivariate intake, smoking status, menopausal status (women only), use of hormone Cox hazard model etc. Two hundred eighteen cases of IHD and 138 CVAs replacement therapy (women only) and baseline level of each risk factor. A occurred over 8.8 years. Systolic BP on registration was correlated with second model additionally adjusted for BMI. IHD in all patients(hazard ratio:HR:1.014, P<0.01). Fasting plasma glucose, Among women, per 500 cm3 increment in baseline VAT, we observed HDL-C and age were correlated with CVA in all subjects (P<0.05) and HDL-C a 2.81 mg/dL increase in fasting glucose (95% CI 1.78-3.84), a 1.86 mg/dL was correlated with CVA in all three generations (<65, 65-74 and >=75 y. decrease in HDL-cholesterol (95% CI 0.74-2.98) and a 0.07 mg/dl increase o.). Fasting plasma glucose and glycated hemoglobin(HbA1C) was correlated in log triglycerides (95% CI 0.03-0.10) (p<0.01 in all cases), after BMI with CVA in patients of 65 to 74 y. o. Age was correlated in patients >=75 adjustment. Results were similar among men. y. o. Kaplan-Meier estimator curves showed same tendency, however, Similarly, increments in baseline SAT volume among women were laboratory data on registration (legend effect) and those just before IHD or associated with worsening of several metabolic parameters. For example, CVA affects differently. Conclusively, IHD and CVA in late elderly diabetic each 500cm3 increment in baseline SAT volume was associated with a 1.22 patients were predicted by LDL-C or HDL-C. LDL-C, HDL-C, fasting blood mm Hg increase in SBP (95% CI 0.51-1.92), a 0.93 mm Hg increase in DBP glucose, HbA1C and SBP may have the effect for IHD or CVA as legend (95% CI 0.46-1.40), and a 0.03 mg/dL increase in log triglycerides (95% CI effect, age dependently. These age-dependent differences are important 0.00-0.05) (p<0.02 in all cases) after BMI adjustment. These associations for developing individualized strategies to prevent atherosclerotic disease. were not observed among men. Trial Registration: UMIN00000516. In conclusion, increases in VAT volumes are associated with worsening Supported By: Ministry of Health, Labour and Welfare metabolic risk factors at follow-up, even after BMI adjustment. Among women only, SAT volumes are associated with incident metabolic risk factors after BMI adjustment.

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A352 EPIDEMIOLOGY—CLINICAL—DIAGNOSISCATEGORY AND SCREENING

1352-P Reliability of Different Defi nitions of T2DM, using A1C ≥6.5% as the Gold Adverse Plasma Fatty Acid Composition in Persons with Type 2 Standard. Diabetes Who Use Statins May Contribute to Residual Cardio- vascular Risk Potential Defi nition % Identifi ed Sensitivity Specifi city PPV NPV Accuracy as DM DAWN C. SCHWENKE, JOHN P. FOREYT, EDGAR R. MILLER, REBECCA S. REEVES, MARA Z. VITOLINS, BIOMARKERS OF OXIDATIVE STRESS SUBGROUP OF LOOK (1) FBG levels ≥126 mg/dL 36% 83% 73% 37% 96% 74% AHEAD RESEARCH GROUP, Phoenix, AZ, Houston, TX, Baltimore, MD, Winston- (2) FBG levels >140 23% 72% 86% 50% 94% 84% Salem, NC (3) RBG >140 34% 74% 74% 35% 94% 74% Statins reduce cardiovascular disease (CVD) risk yet residual CVD risk may (4) RBG >180 14% 54% 93% 60% 91% 87% remain high. Statins may alter plasma fatty acid (FA) composition in ways that could promote CVD [increased saturated (SFA), cis-monounsaturated (5) RBG ≥200 11% 47% 96% 70% 91% 88% (MUFA) or trans-fatty acids (TFA) and reduced polyunsaturated (PUFA) fatty (6) FBG ≥126 + RBG ≥200 9% 44% 98% 83% 90% 90% acid]. We compared plasma SFA, MUFA, PUFA and 18-carbon TFA between (7) FBG >140 + RBG ≥200 8% 42% 99% 87% 90% 90% Look AHEAD participants at two sites (Baltimore, n = 120; Houston, n=185) * who used (52%) and did not use statins. Look AHEAD was a multi-center Prevalence of diabetes per A1c screening = 16% controlled trial of intensive lifestyle intervention for weight loss versus control in 5145 overweight/obese adults (aged 45-76) with type 2 diabetes. 1354-P Percentage women (56 %) and minorities (19 % black, 8 % Hispanic) in this Association between FTO rs9939609 Polymorphism with BMI and substudy were similar to Look AHEAD. At baseline (2002-2004), clinical Physical Activity on Metabolic Syndrome in Whites and African measures were obtained by standard protocols, nutrients were estimated Americans With and Without Diabetes from the Look AHEAD food frequency questionnaire, physical activity was DALE S. HARDY, SUSAN RACETTE, MIKE FOLEY, HONGYAN XU, LYN STEFFEN, assessed by accelerometry, and concentrations of SFA, MUFA, PUFA, and Augusta, GA, St. Louis, MO, Minneapolis, MN TFA were measured in plasma collected fasting. Associations between The fat mass and obesity-associated (FTO) rs9939609 single nucleotide statin use and plasma FA concentrations were estimated with multivariable polymorphism, body mass index (BMI), and physical activity are associated models. In cross-sectional analyses adjusting for demographics, body mass with metabolic syndrome (MetS) in cross-sectional studies. We examined index, sampling time, season, plasma insulin, and total plasma FA, statin the interaction of BMI or physical activity on the relation between FTO use was associated with higher plasma concentrations of SFA [+1.8% (95% rs9939609 and MetS in whites and African Africans with or without diabetes CI 0.2 , 3.4 p<0.03)] and MUFA [+6.1% (3.4, 8.8 p<0.0001), no difference in over 11 y. Data were analyzed for 38,882 white and 11,764 African American TFA (p=0.675) and lower PUFA [-4.3 (-6.3, -2.4 p<0.0001)] concentrations. adults aged 45-75 y enrolled in the Atherosclerosis Risk in Communities Associations between statin use and FA concentrations were unaltered by study for 4 exams from 1987-98. Data was obtained from the Database of further adjusting for nutrients (total calories, dietary fat, SFA, oleic acid, Genotypes and Phenotypes. MetS was defi ned according to ATP III criteria. PUFA, and TFA) and physical activity. In conclusion, statin use in persons with A physical activity score was created as work+sports+leisure-time activities type 2 diabetes was associated with adverse plasma fatty acid composition. from the Baecke questionnaire. During 11 y of follow-up there were 14,658 Further work will be needed to determine if increasing the ratio of dietary and 5,042 MetS cases for whites and African Americans, respectively. PUFA to other fatty acids may further reduce CVD risk in statin users. Genetics In generalized estimating equation logistic models FTO rs9939609 was POSTERS Supported By: NIH (7R01HL70300) signifi cantly associated with MetS in whites and African Americans after Epidemiology/ adjusting for covariates and timescale. BMI interacted with FTO rs9939609 1353-P in whites (p= 0.0363), but not African Americans. Among overweight or Diagnosing Diabetes Mellitus during Hospitalization for Myocardial obese physically inactive whites without diabetes, AA high-risk carriers Infarction had 14% (odds ratio=0.14; 95% CI: 0.03, 0.26) higher risk for MetS than TT SUZANNE V. ARNOLD, KASIA J. LIPSKA, SILVIO E. INZUCCHI, YAN LI, DARREN low-risk carriers. Among normal weight inactive African Americans without K. MCGUIRE, ABHINAV GOYAL, MARCUS LIND, JOHN A. SPERTUS, MIKHAIL diabetes, the risk for AT carriers was 72% higher (0.72; 0.28, 1.16) than TT KOSIBOROD, Kansas City, MO, New Haven, CT, Dallas, TX, Atlanta, GA, Gothenburg, carriers. Overweight or obese physically active African American AT carriers Sweden with diabetes had 59% (-0.41;-0.71, -0.11) lower risk of MetS than TT carriers. New diabetes (DM) is common and important to recognize in patients These fi ndings suggest that FTO rs9939609 is associated with increased risk with myocardial infarction (MI), but diagnosis in the acute setting is for MetS over time. Higher levels of physical activity may lower the risk challenging due to the variability of blood glucose (BG) levels. We explored for MetS in FTO rs9939609 high-risk carriers among overweight or obese the use of random BG on arrival (RBG) and fasting BG (FBG)--values routinely whites without diabetes and in African Americans regardless of weight or collected during clinical care--to determine an optimal (most sensitive and diabetes status. least costly) DM screening method, prior to confi rmatory A1C testing. We examined 1574 MI patients at 24 U.S. hospitals who were diet-controlled or non-DM and had A1C tested at a core lab; of whom 16% had A1C ≥6.5%. All EPIDEMIOLOGY—CLINICAL—DIAGNOSIS AND patients had an RBG and ≥2 FBGs during hospitalization. A single FBG ≥126 SCREENING mg/dL (Def #1) or a RBG >140 mg/dL (Def #3) had high sensitivity and NPV (Table). Combining these into a screening program (if admission RBG >140, check A1C; else, if FBG ≥126 on a subsequent day, check A1C) would require Guided Audio Tour: Diabetes—Diagnosis and Screening (Posters: 1355-P A1C testing in only 50% of patients yet still identify 89% of DM patients. to 1362-P), see page 15. Alternatively, using an RBG threshold for screening of >180 would result in screening 40% of the MI patients and identify 86% of DM. In summary, we & 1355-P have established 2 potential selective screening methods for DM that could Only the Parameters on Insulin Resistance, but Not Insulin Secretion, identify the vast majority of incident DM by only screening 40-50% of all Have Changed in Korean Population During Last Decade MI patients. Using these methods to diagnose DM without global screening HAE KYUNG YANG, JIN-HEE LEE, HYUK SANG KWON, SEUNG-HWAN LEE, JAE with A1C may effi ciently identify MI patients with a new diagnosis of DM so HYOUNG CHO, KWAN HOON JO, KYUNG-JIN YOON, BORAMI KANG, YEO-REE that treatment of this common comorbidity could be promptly initiated. YANG, BONG-YUN CHA, KUN HO YOON, Seoul, Republic of Korea The aim of this study is to compare the patterns of in insulin secretion and resistance between subjects from 1990’s and 2000’s in Korean population. Subjects who underwent 75g-oral glucose tolerance test in 1990’s (1997- 1999) and in 2000’s (2007-2011) were enrolled at Seoul St. Mary’s Hospital, Korea. They were categorized into 3 groups according to glucose tolerance status (normal glucose tolerance, prediabetes and diabetes). Indices on insulin secretion and resistance were obtained. Total of 578 subjects from 1990’s (mean age of 48.5) and 504 subjects from 2000’s (mean age of 50.2) were enrolled with no signifi cant differences in baseline clinical characteristics. Compared to subjects from 1990’s, those

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A353 EPIDEMIOLOGY—CLINICAL—DIAGNOSISCATEGORY AND SCREENING

from 2000’s showed increased insulin resistance with signifi cantly lower categories using as cut points the prevalence of insulin resistance in normal level of Matsuda index and QUICKI and higher level of HOMA-IR, both in weight (9.4%), overweight (25.5%), and obese individuals (67.4%). Matsuda nondiabetic and diabetic population. However early-phase insulin secretion, index improved the ability of HOMA-IR for classifying individuals according measured by insulinogenic index showed no signifi cant differences between to the risk of having insulin resistance (NRI, 0.134 (p = 0.039); IDI, 0.041 [p two decades, regardless of glucose tolerance status. Distinct hyperbolic <0.001]). The use of a modifi ed Matsuda index using OGTT sampling times relationship was confi rmed between insulin sensitivity index (Matsuda at 0, 30, 60, and 120 min yielded similar results (NRI, 0.143 [p = 0.032]; IDI, index) and insulin secretion index (total AUC (I/G)) for each glucose tolerance 0.044 [p <0.001]), but not the use of a modifi ed Matsuda index using OGTT groups. The mean product of Matsuda index and total AUC (I/G) as well as sampling times at 0, 30, and 120 min (NRI, 0.082 [p = 0.127]; IDI, 0.031 [p = oral disposition index was lower in normal glucose tolerance subjects from 0.002]). In summary, Matsuda index has additional value for detecting insulin 2000’s compared to those from 1990’s. resistance beyond the ability of HOMA-IR. Matsuda index reclassifi es a net After rapid economic growth and changes in lifestyle patterns, insulin of 13% of individuals more appropriately. resistance have worsened throughout the glucose tolerance status, but Supported By: Academy of Finland (124243) insulin secretory function remained unchanged, which result in more susceptible to the development of type 2 diabetes mellitus in nondiabetic & 1358-P subjects. HLA Typing and C-Peptide Measurement to Target MODY Genetic Testing in Antibody-Negative Diabetes & 1356-P SHIDEH MAJIDI, ALEXANDRA R. FOUTS, TAYLOR ARMSTRONG, RACHEL M. Changes in HbA1c Values and Diabetes Risk Score Categories: Are SIPPL, KEVIN COLCLOUGH, ZHENYUAN WANG, DEV SAT BATISH, MALGORZATA European Prediction Models Overly Complicated? JAREMKO, SIAN ELLARD, ANDREW T. HATTERSLEY, GEORGEANNA J. KLINGEN- BENJAMIN J. GRAY, RICHARD M. BRACKEN, DANIEL TURNER, KERRY MORGAN, SMITH, ANDREA K. STECK, Aurora, CO, Exeter, United Kingdom, Worcester, MA STEPHEN D. MELLALIEU, MICHAEL THOMAS, SALLY P. WILLIAMS, MEURIG Mature Onset Diabetes of the Young (MODY) is an antibody negative (Ab-), WILLIAMS, SAM RICE, JEFFREY W. STEPHENS, ON BEHALF OF THE PROSIECT autosomal dominant form of diabetes. With the increasing prevalence of SIR GÂR GROUP, Swansea, United Kingdom, Llanelli, United Kingdom, Carmarthen, type 2 diabetes and the expense of MODY testing, markers able to identify United Kingdom who needs further genetic testing would be useful. We investigated HbA1c values are now recognised diagnostic criteria for Type 2 diabetes. whether HLA genotypes and/or random C-peptide levels could be helpful However, validated risk-assessment tools do not account for this variable markers for MODY in Ab- diabetes. Subjects (N=82) with diabetes onset < in their diabetes risk algorithms and accompanying risk categories. This age 25, measurable C-peptide (>0.1 ng/mL), and negative for all diabetes study examined whether changes in HbA1c values are refl ected in the autoantibodies (GADA, IA-2, ZnTA and IAA) were enrolled at the Barbara risk scores and categories of four validated risk-assessment tools (3 with Davis Center (BDC), excluding 21 with secondary diabetes or refusal to European origins and 1 from the USA). Retrospective analysis of 642 participate. Genetic testing for MODY 1-5 was performed through Athena individuals with no prior diagnosis of cardiovascular disease or diabetes Diagnostics, and all variants of unknown signifi cance were further analyzed who participated in a workplace-based diabetes risk-assessment initiative by Dr. Ellard at Exeter, UK. Fifteen patients had a positive or very likely was performed. Predicted risk of Type 2 diabetes was calculated using the pathogenic mutation for MODY. HLA genotypes were categorized as validated QDiabetes (3 risk categories), Leicester Risk Assessment (LRA) (4 susceptible (having at least one HLA DR3 and/or one HLA DR4-DQB1*0302), Genetics

POSTERS risk categories), FINDRISC (5 risk categories) and ADA Diabetes Risk Test (2 protective (HLA DR2-DQB1*0602) and other. A group of type 1 diabetes (T1D) Epidemiology/ risk categories). Non-parametric analysis was used to examine differences antibody positive subjects (n=467) seen at the BDC was used for comparison. between HbA1c values and risk categories within the risk-assessment tools The frequency of susceptible HLA genotypes was 27% in MODY subjects and any associations were investigated by Spearman’s correlation. There compared to 63% in the Ab- participants without MODY (p=0.02) and 84% were signifi cant positive correlations (P<0.01) between HbA1c values and in T1D subjects (MODY vs. T1D, p<0.001). The frequency of protective predicted risk scores in all four risk assessment tools; QDiabetes (r=0.364), HLA genotype was 20% in MODY subjects versus 10% in the remaining LRA (r=0.317), FINDRISC (r=0.202) and the ADA Diabetes Risk Test (r=0.342). Ab- subjects (p=0.38) and 2% in T1D (MODY vs. T1D, p=0.01). C-peptide HbA1c values increased with risk prediction categories and at ‘high risk’ levels were higher in MODY (mean=1.94 + 1.51) versus Ab- participants categories median HbA1c values were 40 mmol.mol-1 (5.8%), 41 mmol.mol-1 without MODY (mean=1.02 + 1.07; p=0.01) and T1D subjects (mean=0.05 + (5.9%), 39 mmol.mol-1 (5.7%) and 39 mmol.mol-1 (5.7%) in QDiabetes, LRA, 0.16; p<0.001). In this cohort, lack of a susceptible HLA genotype gave FINDRISC and the ADA Diabetes Risk Test, respectively. In summary, we a sensitivity for MODY of 73% with a specifi city of 63%, while a cut-off observed a positive association between HbA1c scores and predicted risk value of C-peptide >0.5ng/mL gave a sensitivity for MODY of 90% with a of diabetes in all prediction models. Similar median values in the higher risk specifi city of 43%. In subjects with Ab- diabetes, lack of susceptible HLA categories were also observed between the different risk prediction models. genotypes and preservation of C-peptide may be useful markers to identify Therefore, it could be argued that when predicting risk of Type 2 diabetes, a those who need genetic testing for MODY. risk score comprising of simply only 2 risk categories is as effective as risk prediction models with 3 or more risk prediction categories. & 1359-P Supported By: European Social Fund Pathophysiological Phenotypes of Clinically Diagnosed Type 2 Diabetes & 1357-P JACOB V. STIDSEN, REIMAR W. THOMSEN, JENS S. NIELSEN, JØRGEN RUNGBY, Fasting and OGTT-derived Measures of Insulin Resistance as SINNA P. ULRICHSEN, KLARA BERENSCI, SØREN FRIBORG, IVAN BRANDSLUND, Compared with the Hyperinsulinemic Clamp ANETA A. NIELSEN, JENS S. CHRISTIANSEN, HENRIK SØRENSEN, ALLAN STEVEN M. HAFFNER, CARLOS LORENZO, MARKKU LAAKSO, San Antonio, TX, A. VAAG, THOMAS B. OLESEN, MICHAEL H. OLSEN, JAN ERIK HENRIKSEN, Kuopio, Finland HENNING BECK-NIELSEN, Odense, Denmark, Aarhus, Denmark, Vejle, Denmark, It is not known whether Matsuda index, a measure of insulin sensitivity Copenhagen, Denmark derived from oral glucose tolerance test (OGTT), improves the ability of Type 2 diabetes (T2D) can be considered a syndrome with several different homeostasis model assessment of insulin resistance (HOMA-IR) to detect pathophysiological mechanisms leading to hyperglycemia. We investigated individuals who are insulin resistant. To examine this issue, we conducted the prevalence of different pathophysiological phenotypes among newly a cross-sectional analysis of the EUGENE2 Kuopio cohort (272 non-diabetic diagnosed T2D patients in Denmark. Finnish offspring of type 2 diabetic individuals aged 24 - 50 years). Using In a Danish national cohort study we investigated 1048 incident T2D data from the last 60 min of the euglycemic hyperinsulinemic camp, insulin patients diagnosed based on clinical judgement by general practitioners and resistance was defi ned as the lowest whole-body glucose uptake (steady outpatient clinics. Specifi c phenotypes were classifi ed into the following fi ve state glucose disposal per kg lean body mass divided by steady state insulin hierarchical groups: Rare subtypes of diabetes, latent autoimmune diabetes concentrations) quartile. Matsuda index derived from OGTT sampling times (LADA) (GAD antibody titer >= 20 IE/ml and not T1D), secondary diabetes at 0, 30, 60, 90, and 120 min had a borderline greater predictive discrimination (recent history of pancreatitis, pancreatectomy or pancreas amylase > 65U/l, than HOMA-IR (areas under the receiver operating characteristic curve of and GAD negative), steroid-associated diabetes and WHO defi ned T2D. The 0.890 and 0.869, respectively [p = 0.099]). The difference in the discriminative homeostatic assessment model (HOMA2) model was used to assess insulin value between Matsuda index and HOMA-IR was determined by measures of sensitivity (HOMA2S) and beta cell function (HOMA2B). By this model reclassifi cation, the net reclassifi cation improvement (NRI) and the integrated genuine T2D was further phenotyped into three groups: insulinopenic T2D discrimination improvement (IDI). We generated clinically relevant a priori (low HOMA2B and high HOMA2S), classical T2D (Low HOMA2B and low

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A354 EPIDEMIOLOGY—CLINICAL—DIAGNOSISCATEGORY AND SCREENING

HOMA2S) and hyperinsulinemic T2D (high HOMA2B and low HOMA2S). Cut- Europe (n=3128), Mediterranean Basin (n=511), low-income Europe, Russia off values were defi ned by the median of HOMA2S and HOMA2B in a healthy & Central Asia (n=3870), North America & Oceania (n=178), Middle East & Danish population. North Africa (n=5031), Sub-Saharan Africa (n=1127), South Asia (n=610), East Mean age of our newly diagnosed T2D patients was 61 years (range 21- Asia (n=802), Latin America & The Caribbean (n=860). 95 years) and 57% were men. 0.6% had rare subtypes of diabetes, 3.0% We examined phenotype, risk factors and socioeconomic variables at suffered from LADA, 3.9% from secondary diabetes, 5.8% from steroid- disease onset. associated diabetes and 86.7% had WHO defi ned T2D. Among the latter There were striking age and sex differences at disease onset; the proportion patients 11.7% of the cohort had insulinopenic T2D, 51 % had classical T2D of males varied between 37% (East Asia) and 71% (Mediterranean Basin); and 24.0 % had hyperinsulinemic T2D. Classical T2D subjects were obese age varied between 46.8 years (South Asia) and 63.5 years (high-income (BMI 30.5) and 18.4 % had known cardiovascular disease (CVD), whereas Europe). Body mass index varied between 30.7 kg/m2 (Nordic countries) Insulinopenic T2D subjects were fairly lean (BMI 26.9) and 13 % had CVD and 27.0 kg/m2 (East Asia); HbA1c varied between 50.0 mmol/mol (North (p=0.12 vs. classical T2D). Hyperinsulinemic subjects were severely obese America & Oceania) and 59.9 mmol/mol (Sub-Saharan Africa); smoking (BMI 33.5) and 25.1 % had CVD (p<0.05 vs. classical T2D). varied between 15% (Sweden) and 25% (low-income Europe, Russia & We conclude that T2D is a heterogeneous disease, which can be divided Central Asia); use of evidence based medications was lower in non-Western into specifi c pathophysiological phenotypes of great clinical implication. groups; albuminuria was more frequent in non-Western populations, as was Supported By: Danish Agency for Science, Technology and Innovation the cumulative number of risk factors. Level of education was considerably higher in non-Western populations while annual income was much lower. & 1360-P Conclusion: Non-Western groups develop diabetes early in life. Their risk Does Diabetes Incidence Differ by the Measure of Glycemic Status factor profi le at baseline demands attention. among African American Adults? Jackson Heart Study SHARON H. SAYDAH, KAI M. BULLARD, EDWARD W. GREGG, ADOLFO CORREA, & 1362-P GIUSEPPINA IMPERATORE, Washington, DC, Atlanta, GA, Jackson, MS Insulin Resistance and Beta Cell Dysfunction in Subtypes of An estimated 4.9 million African American adults in the United States Prediabetes and Type 2 Diabetes: The ADDITION-PRO Study have diabetes (DM). It is unknown whether the incidence of DM among KRISTINE FÆRCH, NANNA B. JOHANSEN, DANIEL R. WITTE, TORSTEN LAU- the African American population in the United States differs by the type RITZEN, ANNELLI SANDBÆK, MARIT E. JØRGENSEN, DORTE VISTISEN, Gentofte, of glycemia measure. Therefore, this analysis compares the incidence of Denmark, Strassen, Luxembourg, Aarhus, Denmark DM among African Americans by glycemia measure, A1c vs. FPG. We used It is unclear which defects are captured when using HbA1c for diagnosis. Jackson Heart Study data (Jackson, Mississippi) from visit 1 (2000-2004) We examined whether insulin resistance and beta cell dysfunction differed and visit 2 (2005-2008) that included measurements of A1c and FPG levels in individuals with pre-diabetes or type 2 diabetes defi ned by ADA criteria along with self-report of DM medication use. There were 2,192 participants for glucose or HbA1c. We studied 1,727 participants from the Danish without DM in visit 1, who had both FPG and A1c values for the two visits ADDITION-PRO study. 1089 had pre-diabetes and 192 had screen-detected (mean duration of follow-up: 5 years). DM incidence at visit 2 was defi ned as diabetes by OGTT and 886 had pre-diabetes and 60 had diabetes by HbA1c. self-report of medication use for DM or established glycemic criteria (i.e., A1c We estimated insulin sensitivity (ISI0-120) and absolute insulin response ≥ 6.5% or FPG ≥ 126 mg/dL). We used proportional hazard regression models (BIGTT-AIR0-30-120). After adjustment for age, sex and BMI, individuals with Genetics

to estimate the relative hazard (RH) of incident DM among participants isolated impaired glucose tolerance (i-IGT) had lower insulin sensitivity POSTERS with pre-DM in visit 1, defi ned as A1c 5.7-6.5% and/or FPG 100-126 mg/dL, than those with isolated impaired fasting glycaemia (i-IFG), and the same Epidemiology/ compared to participants with normal glycemia, adjusting for age, sex, and pattern was seen for those with diabetes diagnosed by 2-hour glucose only change in waist circumference. At visit 1, prevalence of pre-DM by FPG was (2h-DM) versus fasting glucose only (F-DM; Fig. 1A, P<0.05). Absolute insulin 11% & by A1c was 38.5%. The table presents RH for incident DM up to 5 response was lower in i-IFG and IFG+IGT than in normal glucose tolerance years after visit 1 by pre-DM by FPG or A1c levels. Among individuals at risk (NGT). Individuals with pre-diabetic and diabetic HbA1c levels had reduced for diabetes, A1c levels identifi es more people than FPG and corresponds to insulin sensitivity and insulin response (Fig. 1B; P<0.05). People with HbA1c- a higher subsequent risk of diabetes. defi ned diabetes had the same reductions in insulin sensitivity and beta cell Relative Hazard (95% CI) for Incident Diabetes Adjusting for Age, Sex, and function as the most severe cases of diabetes captured by the OGTT. Pre- Waist Circumference. diabetes by HbA1c refl ects an average of the different trajectories towards diabetes visible with the OGTT-defi ned pre-diabetic groups. Defi nition of Diabetes Self report of Self report of Self report of Self report of Self report of diabetes medication diabetes medication diabetes medication diabetes medication diabetes medication use use or FPG ≥ 126 use or FPG use or A1c ≥ 6.5% use or A1c ≥ 6.5% or A1c ≥ 6.5% mg/dl or A1c ≥ 6.5% ≥ 126 mg/dl and FPG < 126 mg/dl and FPG ≥ 126 mg/dl incident diabetes 237 134 221 180 120 cases (n) Pre-diabetes defi nition FPG 100 to 3.1 (2.3, 4.1) 4.6 (3.2, 6.6) 3.0 (2.3, 4.1) 2.7 (2.0, 3.8) 4.6 (3.1, 6.8) < 126 mg/dl A1c 5.7 to < 6.5% 6.7 (4.7, 9.6) 4.0 (2.6, 6.1) 7.9 (5.3, 11.6) 8.0 (5.2, 12.3) 4.7 (2.9, 7.5)

& 1361-P The Relation between Ethnicity/Race and Characteristics at 1363-P Disease Onset: An Observational Study of 131,935 Cases of Type 2 Predicting Glycaemic Changes in the Non-Diabetic General Popu- Diabetes lation—A DIRECT Study SOFFIA GUDBJÖRNSDOTTIR, ARAZ RAWSHANI, ANNIKA ROSENGREN, ANN- SIMONE P. RAUH, MARTIJN W. HEYMANS, MARJAN ALSSEMA, GIEL NIJPELS, MARIE SVENSSON, Gothenburg, Sweden COEN D. STEHOUWER, BARBARA THORAND, WOLFGANG RATHMANN, Sweden is an ethnically heterogeneous nation where 14% are foreign- CHRISTA MEISINGER, ANNETTE PETERS, TONIA LUDWIG, CHARLOTTE GLÜMER, born, with roughly two thirds born outside the EU. Immigration from DORTE VISTISEN, OLUF PEDERSEN, HENNA CEDERBERG, JOHANNA KUUSISTO, countries outside the EU is accelerating. All inhabitants enjoy access to EWAN R. PEARSON, PAUL W. FRANKS, FEMKE RUTTERS, JACQUELINE M. health care at a low cost. DEKKER, Amsterdam, Netherlands, Maastricht, Netherlands, Neuherberg, Germany, Ethnic differences in characteristics at onset of type 2 diabetes has not Düsseldorf, Germany, Hovedstaden, Denmark, Gentofte, Denmark, Copenhagen, been well studied in a large representative sample. We used the Swedish Denmark, Kuopio, Finland, Dundee, United Kingdom, Malmö, Sweden National Diabetes Register (2002-2011) to include 131935 recently diagnosed Recently, glycated haemoglobin (HbA1c) levels have been introduced as cases of type 2 diabetes (17.3% immigrants). The ethnic groups were: a diagnostic criterion for type 2 diabetes. Our study evaluates whether in Sweden (reference, n=109058), Nordic countries (n=6760), high-income addition to baseline HbA1c levels, non-invasive measures can be used to

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A355 EPIDEMIOLOGY—CLINICAL—DIAGNOSISCATEGORY AND SCREENING

predict changes in HbA1c levels during 6 years follow-up. 10(8%) Afro-Caribbean and 5(4%) other, p=0.20, with serum creatinine 98(86 Data from 2,887 initially non-diabetic subjects (based on ADA 2011 criteria) to 112) umol/L, p=0.001. from 3 population-based cohorts (Hoorn Study, Inter99, KORA S4) were used In LP (solid symbol) HbA1c measured by Tosoh G8 IE HPLC (%/mmol/mol) to develop sex-specifi c linear regression models predicting change in HbA1c was 5.9(5.1 to 7.3)/41(32 to 56) and RPG (mmol/L) 8.4(7.0 to 11.2) compared levels during follow-up. By using change in HbA1c levels, lab differences to OP 7.7(6.9 to 8.6)/61(52 to 70), p<0.001, and 7.3(5.2 to 11.5), p=0.17. Overall were avoided. To minimize overfi tting of the model, we performed internal HbA1c was depressed relative to glucose in LP compared to OP, in terms of validation using bootstrapping techniques. Calibration was assessed the intercept by 1.6%/17 mmol/mol, p<0.001. Shorter red blood cell half-life with calibration graphs. Discriminative performance was assessed with may be caused by changes to membrane lipids in some LP resulting in fragile, classifi cation tables, dichotomizing HbA1c levels (≥ 5.7% vs. < 5.7%). more labile cells. Fructosamine is a possible alternative unless excluded by At baseline, mean HbA1c level was 5.6% (38 mmol/mol). During a mean high icteric index or urinary albumin creatinine ratio. follow-up of 6 years (SD: 0.7 years), median change in HbA1c levels was +0.02% (0.24 mmol/mol). HbA1c levels increased in 51% of the subjects, 2.3% of the subjects developed HbA1c levels ≥6.5% (48 mmol/mol). After backward selection, next to baseline HbA1c levels, for men: age, waist circumference, smoking, and parental history of diabetes were retained in the prediction model (explained variance (R2): 33%); and for women: BMI and waist circumference (R2: 23%). Calibration plots showed good agreement between predicted and observed HbA1c levels at follow-up. With respect to discrimination, our model classifi ed 75% of the subjects correctly as having high/low HbA1c levels. In the non-diabetic population, non-invasive predictors can be used next to baseline HbA1c levels to predict change in HbA1c levels during 6 years follow-up. This model can be used in clinical practice to determine which patients are at high risk of glycemic deterioration. High-risk patients can then be monitored more regularly than low-risk patients and targeted preventive interventions can be initiated. Supported By: Innovative Medicines Initiative

1364-P 1366-P HbA1c, Fasting Blood Glucose, and OGTT in the Diagnosis of WITHDRAWN Diabetes Mellitus in Ho Chi Minh City, Vietnam TRAN Q. KHANH, HA T. DUC, HO D. PHUONG, Ho Chi Minh, Vietnam, Can Tho, Vietnam Objectives: (1) To estimate the prevalence of diabetes mellitus in Genetics

POSTERS participants in Nguyen Tri Phuong Hospital (HoChiMinh City) by using the Epidemiology/ fasting blood glucose, HbA1c, and OGTT and (2) To choose the best test or combination test for diagnosing diabetes mellitus. Research design and method: cross sectional study including subjects over 18 years old and never been diagnosed as diabetes mellitus before. The diagnosis criteria was based on the diagnosis criteria suggested by the ADA 2009 and approved by the IDF and WHO in 2011: (1) fasting blood glucose ≥ 7 mmol/L, (2) 75g glucose OGTT ≥ 11 mmol/L, (3) HbA1c ≥ 6.5%. The HbA1c value was analyzed by high pressure liquid chromatography method. Results: There were 1010 healthy subjects participated to the study. Among them, 721 (71,4%) were women and 298 (28.6%) were men. The average age of the study population was 51.1 years old. The average weight was 58.9 kg and the average body mass index was 23.9. The prevalence of diabetes mellitus was 5.8% (using fasting blood glucose alone), 12% (using OGTT alone), 8.7% (using HbA1c alone), and 4.1% (using all the three criteria) respectively. The prevalence of diabetes mellitus when using fasting blood glucose in combination with HbA1c level was 4.5%. In comparison with diabetic group achieving HbA1c value ≥ 6,5%, the diabetic group with HbA1c value < 6,5% had a tendency to be older (63 vs. 53years old, p=0,058) and have a smaller waist circumference (81 vs. 86 cm, p=0,067). Conclusion: The estimated prevalence of diabetes mellitus using the fasting blood glucose criteria was approximately the estimated prevalence of diabetes mellitus using the most strictly “gold standard” (FBG, 1365-P OGTT, and HbA1c) criteria. The prevalence of diabetes mellitus will double if HbA1c Depressed Relative to Random Plasma Glucose in Patients using HbA1c criteria alone and will triple if using OGTT criteria alone. Fasting with Cirrhosis of the Liver blood glucose in combination with HbA1c was considered the best test to SANDRA VRACAR, DEBAMITA BHATTACHARJEE, PETER W. MANNING, RACHEL diagnose diabetes mellitus in our population. A. ROUND, PETER G. NIGHTINGALE, IRENE M. STRATTON, RICHARD PARKER, Supported By: Bayer HealthCare; Novo Nordisk SA; Merck Serono SANDIP GHOSH, SUSAN E. MANLEY, Birmingham, United Kingdom, Cheltenham, United Kingdom 1367-P Attention is focussed on the extent to which conditions compromise HbA1c Seasonal Variation of Hemoglobin A1c Is Dependent on Measure- now it is used for diagnosis. Patients, 240 from different areas of the UK ment Method: A Comparison between HPLC and Immunoassay were assessed for liver transplant at a university hospital in a multi-ethnic SHUICHI OTABE, NORIAKI TOHGI, MASARU ISHIMATSU, HISATO HIRANO, city. HbA1c and random plasma glucose (RPG) were measured in 29 out of 50 HISATO HIRANO, KEIKO MORITA, TSUYOSHI OHKI, YUKI KUMASHIRO, MIKIKO patients with cirrhosis and diabetes (LP), and compared to 125 outpatients HARADA, JUNKO KAMEO, HONAMI NAKAO, MIKA MIGITA, HITOMI NAKAYAMA, with diabetes (OP). YUJI TAJIRI, KENTARO YAMADA, Kurume, Japan LP were 55(49 to 62) years old, median (IQ range), 21(72%) male, 27(93%) Both HPLC and immunoassay have become widely used for the white Caucasian, 2(7%) South Asian, with serum creatinine 77(63 to 110) measurement of A1c. However, A1c values obtained by the two methods are umol/L. The MELD score (Model for End-stage Liver Disease: normality 6, not always identical. To investigate the issue, we measured A1c in diabetic up to 40 gravely ill) was 12(9 to 17). OP were 60(50 to 71) years old, p= 0.13 v patients by immunoassay well as by the commonly used HPLC method for 1 LP, 86(69%) male, p= 0.82, 94 (75%) white Caucasian, 16(13%) South Asian, year, and compared the results of the two methods.

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The subjects were 14 patients with type 2 diabetes in Japan (63 ± 1369-P 8 years of age). A1c values were measured every month for 1 year by an Metabolite Traits and Genetic Risk Provide Complementary HPLC method using an automatic glycohemoglobin analyzer (ADAMS A1c Information for the Prediction of Future Type 2 Diabetes HA-8160, Arkray, Kyoto) and an immunoassay (Determiner L, Kyowa Medex, GEOFFREY A. WALFORD, BIANCA PORNEALA, MARCO DAURIZ, JASON VASSY, Tokyo) simultaneously, and the differences between the values of the two SUSAN CHENG, EUGENE P. RHEE, THOMAS J. WANG, JAMES B. MEIGS, ROBERT methods were compared. Body weights were measured at the time of blood E. GERSZTEN, JOSE C. FLOREZ, Boston, MA, Nashville, TN collection. Predicting the development of type 2 diabetes (T2D) is a fi rst step in A1c values measured by the HPLC method in winter (December, January, providing effective preventive interventions. A genetic risk score (GRS) and February), spring (March, April, and May), and autumn (September, comprised of single nucleotide polymorphisms (SNPs) and metabolite October, and November) were signifi cantly higher (p < 0.0001) than those biomarkers have each been shown, separately, to predict incident type 2 measured by immunoassay (0.3 ± 0.2%, 0.3 ± 0.2%, 0.3 ± 0.3%, respectively). diabetes (T2D). We tested whether genetic and metabolomic information is The difference was largest in January (0.5 ± 0.2%, p < 0.0001). On the complementary in predicting incident T2D. Risk of T2D was modeled with a other hand, A1c values measured by the HPLC method tended to be lower 62 SNP-GRS, levels of 9 serum metabolites, and validated predictive clinical compared with those measured by immunoassay (−0.1 ± 0.3%, p < 0.08) in factors among 1622 participants of the Framingham Heart Study who did summer (June, July, and August). In July A1c values were signifi cantly lower not have diabetes at baseline. Age- and sex-adjusted logistic regression by the HPLC method than by the immunoassay method (Δ−0.2 ± 0.3%, p < models were used to test the association of these sources of information, 0.001), irrespective of body weight changes. separately and jointly, with incident T2D. Accuracy of models was assessed It has been assumed that environmental factors (decreased physical by area under the curve (AUC). During 13.5 years of follow-up, there were activity and overeating in winter, and increased activity and overall 206 new diabetes cases. The AUC was greater for models containing the metabolism in summer) play an essential role in the seasonal variation of GRS and metabolite measurements together than for models containing the A1c values. However, the variation may depend on assay method. Although GRS alone or metabolites with or without validated clinical predictors of it is not known which method accurately showed real A1c levels throughout T2D (P<0.05 for all, Figure). Our fi ndings suggest that metabolite and genetic the year, the seasonal variation in the difference between HPLC values and traits provide complementary information for the prediction of future T2D. immunoassay values should be considered when evaluating changes in A1c levels in diabetic patients.

1368-P Racial Differences in Hyperglycemia: A Comparison of Traditional and Alternative Glycemic Markers with Retinopathy CHRISTINA M. PARRINELLO, A. RICHEY SHARRETT, RONALD KLEIN, RICHARD BERGENSTAL, JOSEF CORESH, ELIZABETH SELVIN, Baltimore, MD, Madison, WI, Minneapolis, MN Clinical implications of racial differences in hyperglycemia, particularly HbA1c, are hotly debated. Previous studies suggest similar associations of Genetics

fasting glucose and HbA1c with retinopathy in black and white adults but have POSTERS not compared associations of nontraditional markers of hyperglycemia with Epidemiology/ retinopathy by race. We compared absolute values and relative associations of fasting plasma glucose, HbA1c, fructosamine and glycated albumin with retinopathy in white and black adults and tested for interaction by race. Supported By: NIH (N01HC25195, R01DKHL081572) We included 7,266 white and 1,707 black participants from the ARIC Study with no history of diabetes. Retinopathy was defi ned as ≥20 on the Early 1370-P Treatment of Diabetic Retinopathy Study scale. Prevalence of retinopathy Prevalence and Incidence of Chronic Kidney Disease in U.S. Adult was 3.7% in blacks (n=63) and 1.6% in whites (n=119). Median levels of Type 2 Diabetics glycemic markers were higher in blacks compared to whites. At similar GORDON H. SUN, KELLY F. BELL, IFTEKAR KALSEKAR, AYANNA ANENE, TANYA levels of fasting glucose, blacks had higher levels of HbA1c, fructosamine G.K. BENTLEY, Beverly Hills, CA, Princeton, NJ and glycated albumin than whites. Associations with retinopathy were Diabetes mellitus (DM) is the most common cause of chronic kidney similar between whites and blacks and interactions were not statistically disease (CKD) in the U.S. Patients with diabetic CKD have worse medical signifi cant (Table). Results were similar before and after adjustment for risk outcomes, higher mortality rates, and higher healthcare costs than do factors. Our fi ndings suggest that blacks have higher levels of glycemia than diabetics without CKD. We used peer-reviewed literature to estimate the whites, that retinopathy prevalence is higher in blacks, and that all glycemic prevalence and incidence of diabetic CKD among U.S. adults with type 2 markers were similarly predictive in blacks compared to whites. DM (T2DM). We searched PubMed using MeSH keywords and free text phrases for diabetic nephropathy, CKD, end-stage renal disease (ESRD), T2DM, prevalence, and incidence, limited to English-language reviews and original research from 2004 to 2013. Ten articles described CKD prevalence or incidence from 1988 to 2008 among U.S. adult T2DM populations (Table). CKD prevalence did not vary with race/ethnicity. The incidence of stage 5 CKD (ESRD) was 108.2-236 per million T2DM adults. The incidence of stages 1-4 among this population was not identifi ed. Diabetic CKD is highly prevalent among T2DM patients, with mild CKD being the most common. Due to the potentially serious health and economic implications of the disease, physicians, payers, and other stakeholders should be cognizant of this information in their efforts to improve clinical practice, reduce disease burden, and facilitate effective policymaking. Given the aging U.S. population, future studies examining CKD prevalence in Medicare patients are warranted.

Supported By: NIDDK (R01DK089174); NHLBI (HHSN268201100005C-12C, T32HL007024)

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1372-P Table. Diabetic CKD Prevalence Among All U.S. Adults and Veterans, by Age and Stage. Metabolomic Characterization of Impaired Fasting Glucose (IFG) and Impaired Glucose Tolerance (IGT) All T2DM Patients Veterans JEFF E. COBB, ANDREA ECKHART, KLAUS-PETER ADAM, KIRK PAPPAN, MARGA- with T2DM RET SINNOTT, BERNADETTE CARR, Durham, NC, Dublin, Ireland AGE Both IFG and IGT are considered prediabetes though they have differing ≥20 years 34.5%-42.3% 48% pathophysiology. The metabolomic profi le of IFG and IGT remains uncertain. 20 to <65 years 24.6%-28.0% — In order to characterize IFG and IGT, a targeted metabolomic study was ≥65 years 49.5%-51.2% — carried out in a subgroup of an Irish cohort, DMVhi, as part of the DEXLIFE CKD STAGE project. Using the isotope dilution technique, fasting levels of 23 metabolites Mild (Stages 1-2) 19.7%-24.8% 18% previously linked to dysglycemia and type 2 diabetes were measured Moderate (Stage 3) 14.1%-19.4% 26% Stage 3A 10.0%-11.9% 18% quantitatively in 672 non-diabetic subjects (normal=487, isolated IFG=106, Stage 3B 3.7%-4.1% 8% isolated IGT=31, IFG+IGT=48; % female: 56, 43, 65, 44 respectively). Most of Severe (Stage 4-5) 2.3%-2.7% 4% the metabolites showed signifi cant differences by sex (e.g., valine was 15% CKD, Chronic Kidney Disease; T2DM, Type 2 Diabetes Mellitus. lower in women; p<0.0001). All three branched-chain amino acids, their 2-oxo acid catabolites, and tyrosine were found to be associated with isolated IFG but not isolated IGT 1371-P in women. In contrast, alpha-hydroxybutyric acid (AHB) was associated with When Hemoglobin A1c Fails: Serum Glycated Albumin to Guide Oral IGT in both males and females. Linoleoylglycerophosphocholine (LGPC) was Glucose Tolerance Tests in the Diagnosis of Diabetes Mellitus more strongly associated with isolated IGT in men while oleic acid, serine WEN-YA MA, WAN-CHEN WU, JUNG-NAN WEI, MAO-SHIN LIN, SHYANG-RONG and glycine were in women. Subjects with combined IFG/IGT tended to have SHIH, CYUE-HUEI HUA, YING-JHU LIAO, LEE-MING CHUANG, HUNG-YUAN LI, metabolomic profi les consistent with a combination of both states. Taipei, Taiwan, Tainan, Taiwan, Yunlin, Taiwan In summary, isolated IFG, isolated IGT and combined IFG/IGT have Hemoglobin A1c (HbA1c) is sometimes used to guide oral glucose tolerance different metabolomic profi les albeit with some differences by sex. These test (OGTT) to diagnose diabetes. However, measurement of HbA1c is not fi ndings may be useful in characterizing these prediabetic states. accurate in some situations. In this study, we investigated the use of serum glycated albumin (GA) for this purpose. A total of 1559 subjects were included Fasting Metabolite Levels by Glycemic Status (Fold Difference from Normal) in this community-based study. Diabetes was diagnosed by the results of p: *<.05; ^<.005. OGTT. Serum GA correlated closely to plasma GA (r=0.999, p<0.001) and Metabolite Female Male Female Male Female Male was not affected if the samples were collected in fasting, postprandial, or isolated IFG isolated IFG isolated IGT isolated IGT IFG+IGT IFG+IGT after glucose challenge (p=0.8). There was quadratic relationships between Valine 1.11^ 1.04 0.98 1.04 1.08* 1.06* serum GA, plasma glucose, and HbA1c. The performance of serum GA to 2-Oxovaline 1.11^ 1.05* 1.00 1.05 1.07* 1.07 diagnose DM was good (sensitivity 74%, specifi city 85%, area under the Tyrosine 1.10^ 1.05* 1.02 1.05 1.06 1.14* ROC curve= 0.86). In Figure, using current criteria of fasting plasma glucose AHB 1.12* 1.05* 1.34^ 1.23^ 1.28^ 1.28^ Genetics (FPG) <5.56 mmol/L to exclude and ≥7 mmol/L to diagnose diabetes, the POSTERS

Epidemiology/ sensitivity, specifi city and people need to receive OGTT (OGTT%) were LGPC 0.90* 0.95 0.89 0.74^ 0.74^ 0.80^ 78.8%, 100% and 14.4%, respectively. Using serum GA <14% to exclude Oleic Acid 1.12 1.10 1.27^ 1.09 1.30^ 1.21* and ≥17% to diagnose diabetes, the sensitivity, specifi city and OGTT% were Glycine 0.98 0.94 0.87* 0.97 0.90* 0.97 83.3%, 98.2% and 35%, respectively. Using FPG <5.56 mmol/L and serum GA <15% to exclude, and FPG ≥5.56 mmol/L and serum GA ≥17% to diagnose Supported By: Dexlife (279228) diabetes, the sensitivity, specifi city and OGTT% were 85.6%, 98.2% and 22.5%, respectively. In conclusion, serum GA can guide OGTT to diagnose 1373-P diabetes. Glycemic Progression among Asian Indians in the United States: Longitudinal Results from the MASALA Study ALKA M. KANAYA, SUSAN EWING, ERIC VITTINGHOFF, San Francisco, CA Asian Indians have high prevalence of type 2 diabetes, but rates and factors associated with glycemic progression from normal to pre-diabetes to diabetes in this ethnic group are unk now n. We examined glycemic progression in a community-based sample of Asian Indians from the San Francisco Bay Area. In 2006-2007, 149 participants without known cardiovascular disease between 45-84 years underwent oral glucose tolerance testing (OGTT). Approximately 2.5 years later (2009-2010), 130 individuals repeated an OGTT; another 2.0 years later (2011-2013), 114 participants repeated an OGTT. The table shows incident rates (per 1000 person-years (PY), with 95% confi dence intervals) over 4.5±0.4 years for glycemic progression from normal to isolated impaired glucose tolerance (IGT, 2-hr glucose 140-199 mg/ dl), to impaired fasting glucose (IFG, 100-125 mg/dl), to diabetes (2-hr glucose ≥200 mg/dl, fasting glucose ≥126 mg/dl or diabetes medication use). There were 8 cases of incident DM over 410 PY (19.5 per 1,000 PY, 8.4 - 38.4). The overall average rate for any glycemic progression was 54 per 1,000 PY. There was a trend for faster progression from IFG to DM and from IGT to IFG than from normal glucose tolerance to IGT (p=0.09). Higher BMI was signifi cantly associated with any glycemic progression. Longitudinal follow-up of a larger South Asian cohort is underway to make stable comparisons with other U.S. ethnic groups. Glycemic Progression from Baseline to Third Examination (per 1,000 PY). Baseline Category: Incidence Rate Incidence Rate Incidence Rate to IGT to IFG to DM Normal, 37% 18 (5, 47) 14 (3, 40) 5 (0, 26) IGT, 25% — 51 (21, 105) 22 (5, 64) IFG, 10% — — 70 (19, 180) DM, 28% — — — Supported By: NTUH (102-M2262) Supported By: K23HL080026, 5R01HL093009

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1374-P 5.1 mmol/L, there was sensitivity of 41.6%, specifi city of 77.2% and false- Prevalence of Type 2 Diabetes among High-Risk Adults in Shanghai positive rate of 22.8%. The agreement between the fi rst visit FPG and the from 2002 to 2012 results of the OGTT was poor (kappa = 0.179, p = 0.049). YINAN ZHANG, CONGRONG WANG, XUHONG HOU, HUIJUAN LU, YIXIE SHEN, Conclusion: There was no complete correspondence between the fi rst RUIHUA CHEN, PINGYAN FANG, HONG YU, MING LI, FENG ZHANG, HAIBING prenatal visit FPG and the results of 75-g OGTT performed in the third CHEN, HAOYONG YU, JIAN ZHOU, FANG LIU, YUQIAN BAO, WEIPING JIA, trimester in diagnosing GDM. High false-positive rate makes fi rst visit FPG Shanghai, China (cut-off value ≥ 5.1 mmol/L) an insuffi cient test for gestational diabetes The aim of this study was to evaluate the trend and prevalence of diagnosis. prediabetes and diabetes among high-risk adults in Shanghai from 2002 to 2012. From 2002 to 2012, 10043 subjects with known risk factors for diabetes 1376-P participated in the diabetes-screening project at the Shanghai Sixth People’s Incidence and Risk Factors of Diabetes among Chinese Subjects Hospital of Shanghai Jiao Tong University. All participants were asked to Aged Over 55 Years: A Community-based Study complete a nurse-administered standard questionnaire concerning age, sex, SHUO LIN, LI HU, XIAOFENG LI, YANMING CHEN, BILIAN ZHU, SHENGQING HE, smoking status, and personal and family histories of diabetes, cardiovascular XIXIANG TANG, PANWEI MU, LONGYI ZENG, Guangzhou, China disease, stroke, hypertension and other diseases. The participants’ Body This study aims to explore the incidence and risk factors of diabetes Mass Index (BMI) scores, blood pressures and blood glucose levels at 0, among subjects over 55 years old in Shipai community (a typical village in 30, 60, 120 and 180 min were measured in response to a 75 g oral glucose Guangzhou, China). Three surveys conducted in this community were used tolerance test. The overall prevalence of diabetes increased from 27.93% to to explore the incidence and risk factors of diabetes in this population. 34.78% between 2002 and 2012 in high-risk subjects. The study also showed Non-diabetic subjects (n=547) in survey 2002 were used as baseline that the prevalence increased much faster in male compared to female population. The glucose status of these population were determined in subjects. Specifi cally, an increased rate was seen in middle-aged men, with 2007 and 2010. Incidence of diabetes were defi ned as fasting plasma no change observed in middle-aged females over the eleven-year period.This glucose (FPG)≥7.0mmol/l or 2h-PG during OGTT or diagnosed with diabetes study showed that sex, age, parental diabetic history, and being overweight by doctors. Diagnosis of impaired fasting glucose (IFG) were made by 1999 were associated with an increased risk for diabetes in high-risk people. WHO criteria. A total of 406 non-diabetic subjects (74.2%) had follow-up Therefore, as prediabetes and diabetes are highly prevalent in people with data. Of them, 40 subjects (78.4%) were identifi ed as IFG at baseline, and multiple diabetes risk factors in Shanghai, screening programs targeting 366 subjects(73.8%)were with normal FPG (<6.1mmol/l). Fifty four subjects these individuals may be benefi cial. were diagnosed as diabetes during follow-up. The cumulative incidence of diabetes were 13.3% (15.1% in male and 12.8% in female, P>0.05), while the incidence rate of diabetes were 17.96/1000 person years(20.69/1000 person years in male and 17.24/1000 person years in female, P>0.05). Among 366 subjects with normal FPG, the cumulative incidence and incidence rate of diabetes were 7.9% and 10.58/1000 person years. By multivariate logistic regression, after adjusted by age, sex, systolic pressure and triglycerides, body mass index(BMI), waist circumference and FPG were independent risk Genetics

factors of diabetes. The area under ROC curve is 0.817(95%CI 0.776-0.854) POSTERS for FPG in predicting incidence of diabetes among all subjects (n=406). An Epidemiology/ FPG cut point of ≥5.58mmol/l yielded the highest combination of sensitivity (75.9%) and specifi city (83.8%) for predicting diabetes. These results suggested the incidence of diabetes in subjects over 55 years old was high; FPG, waist circumference and BMI were independent risk factors of diabetes in this population. FPG ≥5.6mmol/l may be a good predicting index of incidence of diabetes in this population.

1377-P Supported By: 2011ZX09307-001-02, 12DZ2295004, 81170760 High Frequency of Chronic Kidney Disease and Lifestyle Problems in Japanese Prediabetes 1375-P KOJI KASHIMA, MICHIKO KAWASAKI, HIROYUKI SHIMIZU, MASANOBU YAMADA, Evaluation of Correspondence between Fasting Plasma Glucose Kiryu, Japan, Ohtawara, Japan, Maebashi, Japan in the First Prenatal Visit and the Oral Glucose Tolerance Test in Objective: To assess the lifestyle problems and metabolic complications Gestational Diabetes Diagnosis among people in pre-diabetes who would be potential candidate for POLINA V. POPOVA, ALEXANDRA V. DRONOVA, ELSA R. SADIKOVA, MARY P. diabetes prevention. Methods: In a total of 386 subjects who visited for PARKKINEN, MARIA V. BOLSHAKOVA, ELENA N. GRINEVA, Saint Petersburg, annual health check, frequency of exercise and eating habit were checked Russian Federation by questionnaire, and metabolic complication rates were checked. Each Introduction: Since adoption of new diagnostic criteria for Gestational item was compared between subjects with normal glucose tolerance (NGT), Diabetes Mellitus (GDM), the prevalence of this condition among pregnancies impaired glucose tolerance (IGT), overt diabetes mellitus (DM) and non-IGT has increased substantially, so that pregnancies previously classifi ed as whose 0-h or 2-h plasma glucose level are within normal glucose tolerance normoglycemic now would be labeled as hyperglycemic ones. The aim of this (NGT) defi nition by IDF but 1-h plasma glucose level is more than 180mg/dl study was to evaluate the correspondence between fasting plasma glucose after 75g oral glucose load. Results: 1) The prevalence of non-IGT, IGT, and (FPG) in the fi rst prenatal visit and the results of the oral glucose tolerance DM were 8%, 20%, and 11 % respectively. 2) Dyslipidemia complication rate: test (OGTT) in GDM diagnosis. 49.4%, 61.2%, 56.4%, and 77.3 respectively. Dyslipidemia untreated: 53.4%, Design: The medical records of 477 pregnant women who had undergone 42.1%, 53.5%, and 50.0% respectively. 3) Hypertension complication rate: 2-h 75-g OGTT during 2011-2012 were retrospectively reviewed. Patients 24.1%, 25.8%, 41.0%, and 70.5 respectively. Hypertension untreated: 10.7%, with pre-GDM were excluded. Data for FPG at the fi rst prenatal visit and 75-g 37.5%, 17.2% and 14.3% respectively. 4) Chronic Kidney Disease (CKD) OGTT performed between 24 and 28 weeks of gestation were analyzed. complication rate: 7.7% in NGT, 6.5% in non-IGT, highest rate (16.7%) in IGT Results: GDM was revealed by OGTT in 113 women (23.7%). However, and 9.1% in DM. 5) Obesity: 12.9%, 9.7%, 23.1%, and 36.4% respectively. 6) when the fi rst visit FPG for each patient was retrospectively considered, No exercise: 21.9%, 29%, 14.1%, 20.5% respectively. 7) IGT group had the there were a further 83 patients who should have been diagnosed as GDM highest rate in no breakfast habit (11.5%), and few vegetables habit (26.9%). cases (glycaemia ≥ 5.1 mmol/L), although their OGTT was normal. When 8) Non-IGT had most high rate (54.8%) in quickly eating habit. 9) Soft drinking the value of FPG was considered not diagnostic, but only predictive there taking habit: 60.9% in NGT, 54.8% in non-IGT, 60.3% in IGT and 52.3% in were 347 negative patients and 130 patients with an FPG greater or equal DM. Conclusions: Although identifying pre-diabetes and informing them to 5.1 mmol/L. Our data suggest that diagnosis of GDM would have been about their increased risk for DM are the fi rst steps to prevent diabetes, performed in up to 27.3% of the cases by fi rst visit FPG. However, 63.8 % early lifestyle modifi cations are needed to increase physical activity and to of these cases diagnosed by FPG presented 75g-OGTT results that didn’t make a healthy eating habit. In addition, IGT state with untreated metabolic meet threshold values for GDM diagnosis. Given the FPG cut-off value ≥ abnormalities that may induce the CKD is also to be informed and cared of.

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1378-P 1380-P Predictive Value of Combined Single Nucleotide Polymorphisms for Diabetes Risk Related to Carrying 1 Risk Allele of a Diabetes- Diabetes Mellitus—A Meta-analysis Susceptible Gene Is Comparable to That Related to 1 Unit of Increased SATORU KODAMA, CHIKA HORIKAWA, SATOSHI MATSUNAGA, KAZUYA Body Mass Index: A Meta-analysis FUJIHARA, YORIKO HEIANZA, AYUMI HIROSE, TAKAHO YAMADA, AKIKO CHIKA HORIKAWA, SATORU KODAMA, SATOSHI MATSUNAGA, SAKIKO YOSHI- SUZUKI, OSAMU HANYU, HIROHITO SONE, Niigata, Japan, Mito, Japan ZAWA, YORIKO HEIANZA, YOKO YACHI, NOBUMASA OHARA, AKIKO SUZUKI, Increasing numbers of single nucleotide polymorphisms (SNPs) associated OSAMU HANYU, HIROHITO SONE, Niigata, Japan, Mito, Japan, Yamana shi , Japan with diabetes mellitus (DM) have been identifi ed in genome-wide association A meta-analysis by Vasquez et al. indicated that a 1 kg/m2 increment studies. This meta-analysis aims to quantitatively assess the predictive value in body mass index (BMI) was associated with an approximately 16% of combining multiple SNPs. Electronic literature search was systematically increased risk of diabetes mellitus (DM). This meta-analysis aims to quantify conducted for cross-sectional or cohort studies that assessed DM risk in the magnitude of DM risk in relation to carrying increased risk alleles of relation to the cumulative number of risk alleles where at least 2 SNPs were DM-associated genes. A comprehensive electronic literature search was used and 0, 1, and 2 points were assigned for each genotype. We included conducted for cross-sectional or cohort studies that investigated the DM 44 studies that allowed reproduction of a 2 x 2 contingency table using the risk associated with the cumulative number of risk alleles where at least 2 cut-off value of the number of risk alleles that could maximize the Youden genes with a common diabetes-associated variation were used and 0, 1, and index (sensitivity [Se] + specifi city [Sp]). Pooled estimate (95% confi dence 2 points were assigned for each genotype. We analyzed 32 eligible studies interval) using a hierarchical summary receiver operating curve (HSROC) that presented the odds ratio (OR) with adjustment at least for age and model was 0.57 (0.51-0.63) for Se, 0.57 (0.51-0.62) for Sp, 1.32 (1.27-1.39) gender. The OR for 1 increment in the number of risk alleles was estimated for positive likelihood ratio (LR), and 0.75 (0.71-0.79) for negative LR (Figure). in each study and pooled with a random-effects model. The pooled OR These values were not infl uenced by study design (cross-sectional or cohort), (95% confi dence interval) was 1.13 (1.09-1.17) for cohort studies and 1.16 study population (Western or non-Western), or number of SNPs in each (1.13-1.19) for cross-sectional studies (Figure). These fi ndings indicated that study (<10 or ≥10). When limiting analysis to cross-sectional studies, mean the magnitude of DM risk associated with 1 risk allele was comparable age, gender proportion, or mean body mass index did not signifi cantly affect to that associated with a 1-unit increase in BMI although the two major study results. This meta-analysis confi rmed that depending exclusively on assumptions, i.e., linearity between the number of risk alleles and DM risk DM-susceptible genes minimally helped us to predict DM risk. and equality in the contribution to DM risk among any DM susceptible gene, Figure legend: Pooled point estimates with 95% confi dence region of might be noted as important study limitations. sensitivity/specifi city and the HSROC for predictive value of diabetes risk using combined common genetic variants associated with diabetes risk. Each data point is indicated by an open circle. Size of each circle is proportional to study sample size. Pooled point estimates are plotted in a fi lled square.

1379-P Magnitude of Risk of Diabetes Mellitus in Relation to Carrying Risk Alleles of Diabetes-Susceptible Genes Was Not Infl uenced by Genetics

POSTERS Covariates: A Meta-analysis Epidemiology/ HAJIME ISHIGURO, SATORU KODAMA, CHIKA HORIKAWA, KAZUO FURUKAWA, HIROMI SUZUKI, KAZUYA FUJIWARA, YORIKO HEIANZA, AKIKO SUZUKI, OSAMU HANYU, HIROHITO SONE, Niigata, Japan, Mito, Japan The risk of diabetes mellitus (DM) in relation to carrying an increased number of risk alleles is believed to be partly explained by the interaction between these genes and classical DM risk factors such as obesity. This meta-analysis aims to compare the magnitude of DM risk between the crude odds ratio (OR) and the adjusted OR. A comprehensive electronic literature search was conducted for epidemiological studies that investigated DM risk associated with a cumulative number of risk alleles where at least 2 genes with common diabetes-associated variations were used and 0, 1, and 1381-P 2 points were assigned for each genotype. Novel Metabolite Models that Distinguish Impaired Glucose Tolerance Focusing on 15 case-control studies that made it possible to estimate both (IGT) from Normal Glucose Tolerance (NGT) ORs for one increment in the number of risk alleles that were crude and JEFF E. COBB, ANDREA ECKHART, KLAUS-PETER ADAM, REGIS PERICHON, adjusted at least for body mass index (BMI), the pooled OR (95% confi dence JACOB WULFF, MATTHEW MITCHELL, ROBERT ELVERSON, KAY LAWTON, interval [CI]) using a random-effects model was 1.20 (1.16-1.25) for the ROBERT WOLFERT, ERIC BUTTON, ZHEN LI, MARGARET SINNOTT, BERNADETTE crude OR and 1.21 (1.16-1.27) for the adjusted OR (Figure). When limiting CARR, ELE FERRANNINI, Durham, NC, Dublin, Ireland, Pisa, Italy the analysis to 5 studies that presented the risk measure adjusted for any Metabolomic profi ling studies have identifi ed a number of metabolites confounders other than age, gender, and BMI, the pooled OR (95% CI) was where fasting levels are associated with dysglycemia and type 2 diabetes. 1.22 (1.10-1.35) for the crude OR and 1.24 (1.12-1.37) for the adjusted OR. The aim of this study was to identify metabolites and metabolite-based These results suggested that DM risk in relation to carrying risk alleles of models that distinguish IGT from NGT in non-diabetic subjects. any diabetes-associated genes was independent of well-known confounders Using the stable isotope dilution technique, quantitative assays were associated with DM. developed for a set of 23 candidate biomarker metabolites previously linked to dysglycemia. This set included: α-hydroxybutyric acid (AHB), linoleoylglycerophosphocholine (LGPC), oleic acid, α-ketoglutaric acid, 2-aminoadipic acid, glycine, aromatic amino acids, and the 3 branched-chain amino acids and several of their catabolites. These metabolites were measured in fasting plasma samples taken just prior to an OGTT from 1,679 non-diabetic subjects: 979 from the RISC Study 3 year follow up (11.5% have IGT) and 679 subjects from the DMVhi cohort in the DEXLIFE project (11.8% have IGT). Random forest decision tree analysis using subject metabolite, anthropometric, and metabolic characteristic data were generated to rank variables for their ability to distinguish IGT from NGT. The top 4 were found to be AHB, fasting glucose, LGPC, and oleic acid in RISC and fasting glucose, age, LGPC, and AHB in DMVhi. Multivariate models for estimating risk of IGT were evaluated using AUCs calculated from the corresponding ROC curves. AUCs generally did not increase in models having more than 7 variables. A number of 7 variable, metabolite only models were developed that had

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AUCs >0.80. For example, in RISC, a model consisting of AHB, glucose, LGPC, 1384-P oleic acid, glycine, creatine, and 2-oxoisoleucine had an AUC of 0.825. In Examining the Thresholds for Diagnosing Gestational Diabetes contrast, a model consisting of age, sex, BMI, glucose, insulin and HDL had Mellitus (GDM): How Many Adverse Outcomes Will Be Missed? a signifi cantly lower (p=0.0001) AUC of 0.731. MARY HELEN BLACK, DAVID A. SACKS, XIA LI, JEAN M. LAWRENCE, Pasadena, CA In conclusion, AHB and LGPC have been identifi ed as metabolite markers IADPSG guidelines defi ne GDM as ≥1 elevated glucose value on a 2-hr 75g of IGT and metabolite-based models may be useful for identifying IGT in OGTT (fasting >92, 1-hr >180 or 2-hr >153 mg/dl). These criteria are based on non-diabetic subjects. values corresponding to a 1.75 adjusted odds ratio (aOR) for selected adverse Supported By: Dexlife (279228) outcomes among HAPO study participants. Values corresponding to aOR=2.0 (fasting >95, 1-hr >191 or 2-hr >162 mg/dl) were considered but not chosen 1382-P due to concern over failure to identify a substantial proportion of women and The Effect of Ethnicity on Indices of Insulin Sensitivity and Beta- infants with these outcomes. We examined differences in the rates of 10 Cell Function among New Mexicans with Prediabetes adverse outcomes (e.g. LGA, pre-eclampsia, preterm birth) among women MARK R. BURGE, CRAIG WONG, JENNY CAMMACHO, Albuquerque, NM screened for GDM with a 2-hr OGTT, who delivered a live, singleton infant at Introduction: Reduced insulin sensitivity and insulin secretion are key in Kaiser Permanente Bellfl ower hospital in 2006-2010. Of 10,459 women, 624 (6%) the pathogenesis of type 2 diabetes (T2D), and Hispanic ethnicity is a known were treated for GDM (if ≥2 values: fasting >100, 1-hr >195, 2-hr >160 mg/dl) risk factor for it. We hypothesized that differences in insulin sensitivity and and excluded from analysis. The remaining women were divided into 3 mutually secretion would exist between Hispanic and Non-Hispanic White (NHW) exclusive groups: women with normoglycemia, women with glucose values subjects with prediabetes from New Mexico as measured by the Quantitative meeting IADPSG criteria but lower than those corresponding to aOR=2.0 (low- Insulin Sensitivity Check (QUICKI) and Oral Disposition (ODI) indices. level GDM) and women with values corresponding to aOR=2.0 (high-level GDM). Methods: 218 adults with at least one risk factor for T2D were screened to Of 9,835 untreated women, 771 (7.8%) had low-level GDM and 1,121 (11.4%) had determine their diabetes status. Criteria included age greater than 18 years high-level GDM. Overall, 60% of women were overweight or obese and 49% plus at least one of the following: history of T2D in a fi rst degree relative, had excess weight gain (WG). Across all outcomes studied, 59-81% occurred history of gestational diabetes, Hispanic ethnicity, non-Caucasian race, among women with normoglycemia, 7-10% among women with low-level GDM or obesity. Plasma glucose, insulin, and A1c were determined by a central and 13-34% among women with high-level GDM. Rates of most outcomes for laboratory. Prediabetes status was assigned using A1c between 5.7-6.4%, women with low-level GDM did not signifi cantly differ than those for women inclusive. with normoglycemia. Adjustment for maternal age, race/ethnicity, parity, BMI Results: There were a total of 98 prediabetes subjects. Of these, 41 were and WG further diminished any small differences observed between groups. In of Hispanic ethnicity and 39 were NHW. Descriptive characteristics and conclusion, the vast majority of adverse outcomes occur in women with normal summary results are shown in the Table. We used the Mann-Whitney test to glucose levels in pregnancy, while relatively few occur in those with low-level compare results for each category (* = p < 0.05). GDM. Therapies targeting modifi able factors such as weight gain may be more Conclusions: Hispanics with prediabetes from New Mexico exhibit effective in limiting adverse outcomes for all women. signifi cantly greater insulin resistance as determined by QUICKI than do NHW. There is no difference between ethnicities in insulin secretory ability 1385-P as determined by ODI. Nonfasting Plasma Glucose Concentration and Prediction of Future Genetics

2 -1 Risk of Diabetes Mellitus: The Sado Cohort Study POSTERS Ethnicity n A1c (%) Age (years) Gender (M,F) BMI (kg/m ) ODI (mM ) QUICKI Epidemiology/ NAOHITO TANABE, MASAHIKO YAMAMOTO, TAKESHI MOMOTSU, KEISUKE SUZUKI, KAZUHIRO SANPEI, TOMOMI TSUJI, HIROHITO SONE, Niigata, Japan, Hispanic 41 5.9±0.2 46±12 9,32 33±7 5.0±12.3 0.31±0.03 Sado, Japan NHW 39 5.9±0.2 55±9* 16,23 30±6 3.6±9.9 0.33±0.03* Post-challenge plasma glucose concentration (PG) during an oral glucose Supported By: CDC (1H75DP002861) tolerance test and fasting PG (FPG) are associated with the future risk of diabetes mellitus (DM). However, the role of non-fasting PG (NFPG) in the prediction of future diabetes risk has not been fully elucidated. In our cohort study, 5,045 1383-P DM-free men and women aged 40-89 years were monitored for the onset of A1C Combined with Fasting Glucose Is Superior to A1C Alone in the DM through annual health check-ups until 2012. During the 31,904 person-years Detection of Glucose Tolerance Status in Africans of follow-up, 596 instances of incident DM were identifi ed. Baseline PG was ANNE E. SUMNER, CAROLINE K. THORESON, MICHELLE Y. O’CONNOR, MADIA assessed in the specifi c quartiles of the fasting-interval category (0 to <1 h, 1 to RICKS, MARSHALL K. TULLOCH-REID, STEPHANIE T. CHUNG, JAY N. LOZIER, <2 h, 2 to <3 h, 3 to <10 h, or ≥10 h), and the association with the risk of incident DAVID B. SACKS, Bethesda, MD, Kingston, Jamaica DM was evaluated using a sex- and age-adjusted Cox hazards model. In the Cox Africans have the highest worldwide prevalence of undiagnosed pre- model, fasting-interval categories 0 to <1 h and 1 to <2 h were integrated owing diabetes and diabetes. Yet, the most effective screening tests to detect to a small number of subjects in the 0 to <1 h category. PG at the ≥10-h fasting- glucose tolerance status in Africans is unknown. Therefore, with OGTT as interval category was considered as the FPG, and that in any other category was the diagnostic standard, we determined in 211 self-identifi ed healthy African considered as the NFPG. When the lowest quartile of FPG was considered as the immigrants the ability of A1C, A1C combined with fasting glucose and potential reference, the risk of DM showed dose-dependent elevation that increased in the alternatives such as glycated albumin (GA) and fructosamine to detect either PG quartile of each fasting-interval category, and the hazard ratios were similar pre-diabetes or diabetes. With diabetics and pre-diabetics combined into between the fasting-interval categories. Therefore, NFPG has the potential to a single group, the diagnostic sensitivity and specifi city of A1C≥5.7% were predict the future risk of DM similar to FPG. determined relative to fasting glucose≥100 mg/dl and 2h glucose≥140 mg/ dL. Area under the receiver operator characteristic (AUC-ROC) curve was calculated for the prediction of 2h glucose≥140 mg/dL by fasting glucose, GA and fructosamine. If the AUC-ROC curve was ≥0.70 the optimal threshold for the prediction of 2h glucose was assessed by Youden index. The prevalence of previously unknown glucose intolerance was 36% (64 pre-diabetics, 12 diabetics). As a single test, the sensitivity of A1C≥5.7% was only 52% with a specifi city of 77%. When A1C≥5.7% was combined with fasting glucose ≥100 mg/dL, sensitivity increased to 66% and specifi city remained at 77%. AUC- ROC curve for prediction of 2h glucose by fasting glucose, GA and fructosamine was 0.76, 0.59 and 0.50, resp. By Youden index the optimal fasting glucose for prediction of 2h glucose≥140 mg/dl was ≥93 mg/dL. Lowering the threshold for fasting glucose from 100 mg/dL to 93 mg/dL increased the combined sensitivity of A1C and fasting glucose to 79% with a specifi city of 67%. Overall, the lower threshold for fasting glucose of 93 mg/dL enhanced the ability to predict 2h glucose≥140 mg/dL and increased the detection of pre-diabetes and diabetes in Africans. Yet, independent of the fasting glucose threshold, the diagnostic sensitivity of A1C as a single test was only 52% but combining A1C with fasting Supported By: Japan Arteriosclerosis Prevention Fund glucose was markedly superior.

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1386-P 1388-P A Global View of Undiagnosed Diabetes and Its Correlates: Doctors, Improvement of Inpatient Diabetes Care via Diabetes Discovery Dollars, and Deaths Program JESSICA BEAGLEY, LEONOR GUARIGUATA, CLARA WEIL, AYESHA MOTALA, NYUK VUN PANG, JEFFREY D. ZAJAC, GRAEME HART, ELIZABETH OWEN- Brussels, Belgium, Durban, South Africa JONES, JANE ROSS, VICTORIA STEVENSON, ELIF I. EKINCI, Melbourne, Australia Type 2 diabetes may remain undetected for many years, leading to severe The aim of this study is to assess the prevalence of undiagnosed diabetes complications and increased healthcare costs. We compared estimates for at Austin Health, a metropolitan tertiary hospital in Australia, and to improve undiagnosed diabetes mellitus (UDM) to other variables relating to health the care of diabetes in hospitalised patients after the introduction of routine system strength, economics, and mortality. HbA1c measurement. A total of 219 countries and territories were divided into 15 IDF data As part of routine clinical care, HbA1c was automatically ordered using a regions based on geographical location and World Bank income classifi cation computerised information system in all inpatients over the age of 54 who (e.g. high income countries in North America and the Caribbean). Estimates were admitted to Austin Health. HbA1c was not measured if it had already of UDM prevalence were generated for each data region, and compared been done within 90 days of admission. A daily automated HbA1c report to physician density, health expenditure, and the percentage of diabetes- was obtained by the diabetes registrar for all inpatients who had an HbA1c attributable deaths occurring in individuals aged under 60. measured. This report included all HbA1c results which were generated Globally, 45.8%, (174.8 million) of all diabetes cases in adults are from the automated orders and also from orders placed by other treating estimated to be undiagnosed, ranging from 24.1% to 75.1% across the 15 physicians. Patients whose HbA1c was greater than 8.5% were reviewed IDF data regions. An estimated 83.8% of all cases of UDM are in low- and by the diabetes registrar to optimise their diabetes management. In order to middle-income countries. UDM proportion has a moderately strong inverse calculate the prevalence of diabetes in our centre, patients were categorised correlation with physician density (r = - 0.63) and a moderate positive as having known, undiagnosed or no diabetes. correlation with under-60 diabetes mortality (r = 0.52). With regard to From 17th July to 17th November 2013, 10668 HbA1c results were identifi ed diabetes-attributable health expenditures, inverse correlation with UDM and of these, 3836 or 36% of all inpatients were found to have diabetes with proportion was observed within all income groups, with moderately strong a HbA1c greater or equal to 6.5%. A more detailed analysis was conducted correlation across high-income countries (r = - 0.77), strong correlation to assess the number of patients with newly diagnosed diabetes for the across middle-income countries (r = - 0.92), and moderate correlation across months of August and September 2013. Results showed that within those 2 low-income countries (r = - 0.45). months, 26% of all inpatients with diabetes were newly diagnosed. There is a high proportion of UDM across the globe, especially in Diabetes is common in hospitalised patients. 36% of all inpatients in our developing countries. A high physician density is indicative of strong health centre were identifi ed to have diabetes and of these 26% of them were systems, and is associated with reduced rates of UDM. Lack of diagnosis undiagnosed. HbA1c is a useful test that can be automated using existing of diabetes is associated with increased mortality in younger age groups. clinical blood samples. Not only can routine HbA1c measurement identify Higher diabetes-related expenditures may signify greater availability of new hospitalised patients with undiagnosed diabetes, it can assist in clinical resources for diabetes, which may lead to a lower proportion of UDM. The care of patients with diabetes. Further prospective studies are warranted to absence of strong correlations in all but one of the comparisons made is determine if identifi cation and improvement of inpatient diabetes care lead refl ective of the multifactorial nature of UDM and its correlates. to reduction of the length of stay or inpatient morbidity and mortality. Genetics Supported By: Eli Lilly and Company; Merck & Co., Inc.; Novo Nordisk A/S; Pfi zer, POSTERS Epidemiology/ Inc.; Sanofi 1389-P Prevalence and Factors Associated with Prediabetes and Diabetes 1387-P in Three Megacities in South Asia Novel Clinical Anthropometric Method in Relation to Adiposity- MOHAN DEEPA, MUNDU BAHALEN GRACE, RAJENDRA PRADEEPA, SHIVA- related Cardiovascular Risk Factors SHANKAR ROOPA, KHAN M. HASSAN, ZAFAR FATMI, MUHAMMAD M. KADIR, JUNG HWAN PARK, SANGMO HONG, CHANG BEOM LEE, YONG SOO PARK, NAEEM IMRAN, AJAY S. VAMADEVAN, RANJIT M. ANJANA, MOHAMMED K. DONG SUN KIM, YOU HERN AHN, KEVIN WILSON, WOONG HWAN CHOI, Seoul, ALI, DORAIRAJ PRABHAKARAN, TANDON NIKHIL, VISWANATHAN MOHAN, Republic of Korea, Bedford, MA K.M. VENKAT NARAYAN, Chennai, India, New Delhi, India, Karachi, Pakistan, Atlanta, High levels of visceral adipose tissue (VAT) are associated with GA cardiovascular risk. Instead of measuring VAT directly, various anthro- We estimated the prevalence of diabetes and prediabetes in three South pometries like waist circumference (WC), body mass index (BMI), and total Asian megacities (Delhi, Chennai, Karachi) using data from the Centre for fat mass are used to assess cardiovascular risk and WC is most reliable cArdiometabolic Risk Reduction in South-Asia surveillance study, 2011. Using method as yet. However, cut-off values of WC are different according to a multi-stage cluster random sample representative of each city, 16288 the sex, race and country. Computed tomography (CT) is currently used to subjects aged ≥20 years (Chennai: 6906, Delhi: 5365 and Karachi: 4017) were measure VAT. But, there are problems associated with amounts of radiation recruited. Fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) and cost. Dual-energy x-ray absorptiometry (DXA)-derived VAT measurement was estimated in 13720 subjects [Response rates 86.3%, 79.1%, and 87.5%, is easier, safer and cheaper than CT. We analyzed Korean National Health respectively, in Chennai, Delhi, Karachi]. Prediabetes was defi ned as FPG and Nutrition Examination Survey 2010 data. We measured DXA-derived VAT 100-125 mg/dl or HbA1c 5.7-6.4%, while diabetes was defi ned by self-report, with Hologic’s APEX software (Version 5.5). Metabolic syndrome followed drug treatment for diabetes, FPG ≥126 mg/dl or HbA1c ≥6.5%. For each city, the AHA/NHLBI criteria. Receiver Operating Characteristic (ROC) curves we estimated prevalence (and 95% confi dence intervals [CI]), proportion were used to assess clinical utility. This study included 4480 subjects, aged with undiagnosed diabetes, and assessed factors associated with diabetes equal to or greater than 20 years (1938 men; 2542 women). VAT (r = 0.833, and prediabetes using polytomous regression models. Between 45-75% of p < 0.01) had higher correlation with WC than BMI (r = 0.825, p < 0.01) and the population had either diabetes or prediabetes: (Chennai 60.9% [95%CI: total fat mass (r = 0.597, P < 0.01). The prevalence of metabolic syndrome 57.3-64.5%]; diabetes-22.3% [19.5-25.1%], prediabetes-38.6% [34.9-42.3%]; was 29.9%. Based on the area under the ROC curve (AUC), accuracy of VAT Delhi 75.8% [70.2-81.4%]; diabetes-26.9% [23.6-30.3%], prediabetes-48.9% to diagnose metabolic syndrome (AUC = 0.847; p < 0.01; 95% CI, 0.83-0.859) [42.4-55.4%]; Karachi 44.9% [41.9-47.9%]; diabetes-19.2% [17.2-21.1%], was higher than WC (AUC = 0.832; p < 0.01; 95% CI, 0.819-0.844), BMI (AUC = prediabetes-25.8% [22.6-28.9%]). Proportions of undiagnosed diabetes were 0.786; p < 0.01; 95% CI, 0.772-0.801), and total fat mass (AUC = 0.721, p 44.8%, 69.5%, and 63.0% in Chennai, Delhi, and Karachi respectively. In < 0.01; 95% CI, 0.705-0.737). We compared diagnostic accuracy of AHA/ polytomous logistic regression, age, family history of diabetes, generalized NHLBI criteria components except WC using ROC curves according to VAT, obesity (body mass index ≥25 kg/m2), abdominal obesity (waist ≥90 for WC, BMI, and total fat mass. Except component of reduced HDL cholesterol, male, ≥80 cm for female) and high triglyceride levels were associated diagnostic accuracies of VAT were higher than other anthropometric methods. with diabetes in all three cities, while age and generalized obesity were In diagnosis of reduced HDL cholesterol, total fat mass had higher accuracy associated with prediabetes. Based on self-report, fasting glucose, and than other anthropometric methods. These results demonstrate that DXA- HbA1c measurements, 6 in 10 urban adult residents in three large South derived VAT is a more useful clinical marker to evaluate cardiovascular risk. Asian cities have either prediabetes or diabetes. These data call for urgent action to prevent diabetes in South Asia. Supported By: NHLBI; NIH

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1390-P Table 1. Examining the Gender-specifi c Effect of Adding Hemoglobin A1c to Existing Risk Prediction Models: The Jackson Heart Study Characteristics MODY-negative MODY-positive P-value MARY E. LACY, GREGORY WELLENIUS, CHARLES B. EATON, ERIC LOUCKS, (n=67) (n=15) ADOLFO CORREA, ANNIE GJELSVIK, WEN-CHIH WU, Providence, RI, Pawtucket, Female Gender 48% 80% 0.0425 RI, Jackson, MS Ethnicity: 64%/25%/10% 60%/40%/0% 0.3981 In 2010, the ADA updated the diagnostic criteria for diabetes to include Non-Hispanic White/Hispanic/Other hemoglobin A1c (A1c). However, the appropriateness of these criteria First-degree relative with diabetes 34% 93% <0.0001 in African Americans (AAs) is unclear as A1c may not refl ect glycemic control as accurately in AAs as in whites. Moreover, existing diabetes risk Age at diagnosis, years 10.7 +/- 5.2 13.5 +/- 5.0 0.0547 prediction models were developed in populations composed primarily of HbA1c at onset, % 10.4 +/- 2.4 7.6 +/- 2.5 0.0003 whites. We examined the performance of 3 diabetes risk prediction models Diabetic Ketoacidosis at onset 24% 0% 0.0346 in the Jackson Heart Study (JHS), a prospective cohort of 5,301 AA adults Pharmacologic treatment at study visit: 82%/8%/11% 33%/40%/27% <0.0001 and explored the impact of incorporating A1c into these models focusing Insulin/oral agent only/none on gender-specifi c effects. Models were evaluated based on their ability to accurately predict 5-year diabetes risk among 3,185 JHS participants free of diabetes at baseline and who returned for the 5 year follow-up 1392-P visit. Incident diabetes was identifi ed at 5-year follow-up based on current Cancer Risk and Diabetes: Comparing the Risk Before and After antidiabetic medications, fasting glucose ≥126 mg/dl, or A1c ≥6.5%. Over 5 Diabetes Diagnosis years of follow-up, 9.8% developed diabetes. Each model suffered a drop ILIANA C. LEGA, HADAS FISCHER, PETER AUSTIN, PETER C. AUSTIN, ANDREW in prediction when applied to JHS using ADA 2010 criteria (Table 1). The WILTON, JEFFREY A. JOHNSON, LORRAINE L. LIPSCOMBE, Toronto, ON, Canada, performance of all 3 models improved signifi cantly with the addition A1c Edmonton, AB, Canada with greater improvement among females than males. Despite evidence that Cancer risk is increased in people with type 2 diabetes, possibly due A1c may not refl ect glycemic control as well in AAs, adding A1c to existing to hyperinsulinemia. Recent studies indicate that cancer risk is highest models signifi cantly improved the predictive power of all 3 models among right after diabetes diagnosis, raising concerns that this fi nding is due to AA participants in JHS. surveillance bias. However, if hyperinsulinemia is responsible for this association, then risk would also be higher both early after diabetes and beforehand when insulin levels are highest. To explore this hypothesis, we compared the relative risk of cancer during the time periods before and after diabetes diagnosis. We used population-based data from Ontario, Canada from 1997 to 2009 to identify incident diabetic cohorts that were age- and sex- matched 1:1 to patients without diabetes. Using time-varying cox regression models we compared the risk of any invasive cancer between patients with and without Genetics

diabetes in three separate time windows: 1) 10 years prior to, 2) 3 months POSTERS after, and 3) more than 3 months after diabetes diagnosis. Epidemiology/ Cancer risk before diabetes was assessed in 186,441 diabetes patients and matched controls, and after diabetes in 51,463 diabetes patients and matched controls. Among diabetes patients, cancer risk was signifi cantly 1391-P increased before (HR 1.23, p=0.015) and 3 months after diabetes diagnosis Characteristics of Maturity Onset Diabetes of the Young in a Large (HR 1.69, p < 0.001). The association was attenuated beyond 3 months after Diabetes Center diabetes diagnosis. (HR 1.04, p=0.13). CHRISTINA M. CHAMBERS, ALEXANDRA R. FOUTS, RACHEL M. SIPPL, KEVIN We found an increased cancer risk in diabetes patients before and shortly COLCLOUGH, ZHENYUAN X. WANG, SAT DEV BATISH, MALGORZATA JAREMKO, after diabetes diagnosis that did not persist after the peri-diagnostic period. SIAN ELLARD, ANDREW T. HATTERSLEY, GEORGEANNA J. KLINGENSMITH, Our fi ndings support a role for hyperinsulinemia in the relationship between ANDREA K. STECK, Aurora, CO, Exeter, United Kingdom, Worcester, MA diabetes and cancer, over surveillance bias. While further research is Maturity Onset Diabetes of the Young (MODY) is a monogenic form of needed, these results support enhanced cancer screening in patients with diabetes caused by a single autosomal dominant mutation, often not diagnoses of pre-diabetes or diabetes. requiring insulin. The aim of this study was to estimate the frequency and Supported By: Ontario Institute for Cancer Research clinical characteristics of MODY at the Barbara Davis Center. A total of 82 subjects with diabetes onset before age 25, a random C peptide >/= 0.1 ng/ 1393-P mL, and negative for all diabetes autoantibodies (GADA, IA-2, ZnT8 and IAA) Prediction of Undiagnosed or Future Diabetes Based on Non- were enrolled, excluding 21 subjects with secondary diabetes or refusal laboratory or Laboratory Risk Scores to participate. Monogenetic testing for MODY 1-5 was performed through CHANG HO AHN, JI WON YOON, MIN KYEONG KIM, EUN ROH, KYONG YEON Athena Diagnostics, and all variants of unknown signifi cance were further JUNG, EU JEONG KU, DONG HWA LEE, SOO HEON KWAK, BO KYUNG KOO, HYE analyzed at Exeter, UK. A total of 15 subjects (17% when excluding one SEUNG JUNG, MIN KYONG MOON, SOO LIM, KYOUNG SOO PARK, HAK CHUL sibling) were found to have a mutation in HNF4a (n=2), GCK (n=7), or HNF1a JANG, YOUNG MIN CHO, Seoul, Republic of Korea, Seongnam, Republic of Korea (n=6). Of these 15 mutations, 8 were known to be pathogenic and 7 were Early detection of undiagnosed diabetes and prediction of future diabetes novel mutations, predicted to be pathogenic. Only 1 of the 15 subjects had are crucial for preventing or delaying the detrimental complications been given the appropriate MODY diagnosis prior to testing. Characteristics of diabetes. For this purpose, various risk scoring systems have been of MODY-positive compared to MODY-negative subjects are shown in Table developed. We evaluated the validity of various risk assessment scores 1. MODY-positive subjects had lower HbA1c and no diabetic ketoacidosis at composed of non-laboratory parameters for screening of undiagnosed onset; however, these characteristics are not specifi c for MODY. In summary, diabetes or predicting future diabetes. The data of 28,218 subjects who in this population, we found a high frequency of MODY mutations with the visited Seoul National University Healthcare System Gangnam Center for majority of subjects clinically misdiagnosed. Clinicians should have a high health check-up program were reviewed for cross-sectional validation of index of suspicion for MODY in antibody negative diabetes. undiagnosed diabetes and the data of 3,278 subjects with median 8 years of follow-up were reviewed for longitudinal validation of future diabetes. Total 17 previously published risk scoring systems were evaluated. Also, we developed our own scoring system using laboratory parameters and compared the performance to predict future diabetes with the non- laboratory scores. For the screening of undiagnosed diabetes, all risk scoring system revealed comparable AUCs of ROC curves. Among them, the recently developed Non-Laboratory Korean Diabetes Scoring System (NLKDSS) exhibited a sensitivity of 81%, a specifi city of 58%, and an AUC

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A363 EPIDEMIOLOGY—CLINICAL—DIAGNOSISCATEGORY AND SCREENING

of ROC curve of 0.754. For the prediction of incident diabetes, the NLKDSS that the specifi city of an A1c cutoff of 6.5% (47 mmol/mol) for an FPG of 126 demonstrated a sensitivity of 74%, a specifi city of 54%, and an AUC of ROC mg/dL was 98.0%, the current diagnostic criteria of an A1c of ≥6.5% (47 curve of 0.696. Relative to the NLKDSS, the risk prediction score composed mmol/mol) may be acceptable in the Korean adult population. of laboratory parameters (fasting plasma glucose (mg/dl) * 0.7 + HbA1c (%) * 29) which was derived from our current data, demonstrated a signifi cantly 1396-P higher AUC of the ROC curve (0.838 vs. 0.696, p value < 0.001). Addition of Gender Specifi c Alterations of Mitochondrial Function in Healthy the NLKDSS to the risk prediction score composed of laboratory parameters First-Degree Relatives of Type 2 Diabetic Patients did not improve the prediction power. In conclusion, the NLKDSS is useful for BOTOND LITERÁTI-NAGY, BARBARA BUDAY, MÁRTA VITAI, ENDRE KISS, detecting undiagnosed diabetes but inferior to the laboratory risk score for ZSUZSANNA LITERATI-NAGY, KÁLMÁN TORY, LÁSZLÓ KORÁNYI, ATTILA predicting future diabetes. KOLONICS, Balatonfüred, Hungary, Budapest, Hungary Mitochondrial dysfunction in skeletal muscle plays a vital role in the 1394-P pathogenesis of type 2 diabetes: FFA may not be oxidized properly by mito- Association between Maternal Retinal Microvasculature and chondria resulting in lipid accumulation and insulin resistance in the skeletal Gestational Diabetes Mellitus during Pregnancy muscle. Type 2 diabetics and their insulin resistant children have fewer LING-JUN LI, CAROL CHEUNG, YAP-SENG CHONG, SEANG-MEI SAW, TIEN-YIN mitochondria in their muscle than those with normal insulin sensitivity, WONG, Singapore, Singapore which is the cause or consequence of insulin resistance. However, high fat Evidence has shown that pathological changes in retinal microvasculature diet-fed, insulin resistant rats have more mitochondria and enhanced lipid are seen in adult with type 2 diabetes and adolescents with type 1 diabetes, oxidation in their muscle. including wider retinal venular caliber, more tortuous retinal vessels and We compared age and BMI matched healthy, diabetic risk subjects (GD = larger retinal vascular branching angle. Such changes of microvasculature fi rst-degree type 2 diabetic relative) with ones without diabetic risk (GND). might be chronically imposed by diabetes, however, whether the changes Healthy, normal insulin sensitive females (n = 11) and males (n = 12) can occur in a transient phase of hyperglycemia such as gestational diabetes without and with type 2 diabetic relatives (females: n = 6; males: n = 4) were mellitus (GDM) is still unknown. We aimed to study the association between investigated to reveal the differences of metabolic characteristics, number maternal retinal microvasculature and GDM during pregnancy. Pregnant and function of mitochondria at this early even not prediabetic stage. Insulin women aged 18-46 years were recruited during their early pregnancy from sensitivity was measured by hyperinsulinemic euglycemic glucose clamp the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) study. (HEGC). The mitochondrial function in peripheral blood mononuclear (PMNC) Blood pressure, anthropometric measurements, fasting plasma glucose cells was performed by FACS analysis. Mitochondrial NO production, level, 2-hr plasma glucose level and retinal photography were measured membrane potential (dΨm) and mass were determined either by DAF, JC-1 at the 26 weeks gestation following a standardized protocol. GDM were and MitoTracker dyes respectively. diagnosed using OGTT data according to WHO guideline. Quantitative retinal Females in the GD group had lower mitochondrial mass (GD: 63.5 ± 22 vs. vascular parameters were assessed by a semi-automated computer program GND: 103 ± 34, p=0.021) and membrane potential (GD: 23.7 ± 20 vs. GND: (Singapore I Vessel Assessment [SIVA], version 3.0). Among the 824 pregnant 66.9 ± 46, p=0.049) than in the GND group. Males in GD groups had lower women who included in this study, 117 (14.2%) were diagnosed as GDM at 26 NO production (GD: 257 ± 218 vs. GND: 1018 ± 830, p=0.023) as compared to weeks gestation. In age- and ethnicity-adjusted logistic regression model, those without diabetic risk and the FFA level was not suppressed by glucose Genetics

POSTERS changes in retinal vascular caliber, retinal vascular branching angle and during IvGTT. Epidemiology/ retinal vascular fractal dimension had borderline association with risk of These results suggest that the genetic risk of development of insulin GDM. After further adjusting for household income, hypertension history, resistance is preceded by the abnormalities of mitochondrial number and systolic blood pressure and pre-pregnancy BMI, each unit increase in retinal function with gender differences. arteriolar tortuosity was associated with 1.02 times (95% Confi dence Interval: 1.00, 1.04) of the risk in getting GDM during the second trimester. 1397-P Our fi nding suggests a possible impact of GDM on the microcirculation Metabolic and Adipose Tissue Predictors of Impaired Glucose during pregnancy, which may be a pathophysiologic pathway for evidence Tolerance and Type 2 Diabetes—A Prospective Cohort Study on the development of future metabolic diseases in women. JOSEFIN A.M. HENNINGER, ANN HAMMARSTEDT, BJORN ELIASSON, Gothen- Supported By: NMRC burg, Sweden We characterized in detail (adipose tissue biopsy, OGTT, IVGTT, 1395-P euglycemic clamp), healthy fi rst-degree relatives (FDR) of individuals with Optimal A1C Cutoff Value for Fasting Plasma Glucose of 126 mg/dL type 2 diabetes (T2D), to examine predictive factors for future development in the Korean Adult Population: The 2011 Korea National Health and of impaired glucose tolerance (IGT) or T2D. Nutrition Examination Survey 147 non-diabetic FDR (mean age 40.3±6.7 yrs, 57% women) underwent JUNGHYUN NOH, JUNG MIN KIM, JONG CHUL WON, YUN JEONG LEE, KYUNG an extended OGTT every 3 years to assess any deterioration in glucose SOO KO, BYOUNG DOO RHEE, DONG-JUN KIM, Koyang, Republic of Korea, Seoul, tolerance status. If so, a new adipose tissue biopsy, IVGTT and clamp were Republic of Korea performed. Differences between groups were assessed by logistic fi t for The use of glycosylated hemoglobin (A1c) to diagnose diabetes is continuous variables and by contingency analysis for categorical variables. recommended by the American Diabetes Association as an A1c ≥ 6.5% Multiple logistic regression analysis was applied to adjust for confounding to diagnose diabetes and A1c between 5.7 and 6.4% for identifying variables. prediabetes. These cutoff values for A1c are derived based on several cross- At follow-up (mean 5.6±2.5 yrs) 20 had IGT and 4 had T2D. At baseline sectional studies that included an Egyptian population, Pima Indians and these 24 subjects had higher % body fat, fasting p-glucose and OGTT AUC, NHANES population. We aimed to estimate the cutoff value of A1c for a HbA1c, s-triglycerides and LDL-cholesterol. At follow-up they had greater fasting plasma glucose (FPG) of 126 mg/dL in the Korean adult population increase in body weight, OGTT AUC and reduced insulin sensitivity (M) and using the 2011 Korea National Health and Nutrition Examination Survey IVGTT acute insulin response (AIR). (KNHANES V-2). A total of 5421 participants in the KNHANES V-2 (2288 At baseline, lower s-adiponectin and higher adipose tissue cell size males, 3133 females) without a history of diabetes and aged >19 years were correlated to IVGTT AIR and IVGTT late insulin response (p-values <0,05). included in the analysis. The point-wise area under the receiver operating Crude predictors of deteriorating glucose tolerance were heredity for characteristic curve was used to estimate the optimal A1c cutoff value for hypertension, higher OGTT AUC, lower adipocyte IRS-1 protein, s-IL-6 and an FPG of 126 mg/dL. An A1c threshold of 6.1% (43 mmol/mol) proved to be s-adiponectin (p-values <0.05). A multiple nominal logistic regression model the optimal limit for an FPG of 126 mg/dL, with 82.2% sensitivity and 90.5% revealed that % body fat, waist circumference, AIR, M, Disposition index, specifi city (area under the curve, 0.941; P < 0.001). An A1c of 6.5% (47 mmol/ and s-HDL independently (p-values <0.05) predicted development of IGT/ mol), which is currently the diagnostic cutoff, produced a sensitivity of 67.7% T2DM. and specifi city of 98.0% for an FPG of 126 mg/dL. The A1c cutoff increased In sum, genetically predisposed individuals for T2D exhibit unfavorable with age (6.1% [43 mmol/mol] at 18-39 years, 6.3% [45 mmol/mol] at 40-64 anthropometrics as well as reduced insulin sensitivity, beta-cell dysfunction and >65 years). An A1c cutoff of 5.7% (39 mmol/mol) produced the highest and dyslipidemia prior to developing IGT/T2D. Individuals with deteriorating sum of sensitivity (71.2%) and specifi city (70.4%) for an FPG of 100 mg/dL. glucose tolerance showed increasing insulin resistance as well as markers The optimal A1c value for an FPG of 126 mg/dL was 6.1% (43 mmol/mol) in a of beta cell and adipose tissue dysfunction, emphasizing the multifactorial national representative sample of the Korean adult population. Considering pathophysiology in the development of IGT and T2D.

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1398-P 1400-P Predictors of Beta-Cell Function in Chinese Adolescents and Adults Clinical and Biochemical Markers of Nonprogression to Type 2 RONALD C. MA, CLAUDIA H. TAM, ANDREA O. LUK, RISA OZAKI, ALICE P. KONG, Diabetes Mellitus from a “Prediabetes” Stage WING YEE SO, JULIANA C. CHAN, Hong Kong, China ZAHRA N. SOHANI, SONIA S. ANAND, HERTZEL C. GERSTEIN, Hamilton, ON, Impaired beta cell function is an important pathophysiology defect in the Canada pathogenesis of type 2 diabetes, though factors that determine beta cell Type 2 Diabetes Mellitus (T2DM) is a metabolic disorder resulting from function is not well understood. We evaluated beta-cell function in 2 cohorts the interplay between insulin secretion and action, likely moderated by a recruited from the community, including 235 healthy adolescents (mean combination of genetic and environmental factors. Prior to its onset, patients age 15.1 ± 1.8, 44.9 % male) and 635 adults (mean age 43.0 ± 8.5 , 46.7% are classifi ed as having impaired fasting glucose (IFG) and/or impaired male). All subjects were evaluated at a fasting state and beta-cell function glucose tolerance (IGT). Interestingly, between 35-55% of individuals with was evaluated using oral glucose tolerance test with measurements of IFG/IGT do not progress to T2DM during follow-up periods approaching glucose and insulin at 0,15, 30, 60 and 120minutes, with calculation of AUC 12 years. Whereas it may simply be that not enough time has elapsed to glucose, AUC insulin, insulinogenic index, and oral disposition index (ODI). allow progression to T2DM, it is also plausible that systematic differences Oral disposition was signifi cantly reduced in adolescents and adults with exist between patients whose blood glucose levels continue to increase prediabetes or type 2 diabetes. Oral disposition index (adjusted for insulin from IFG/IGT (i.e. progressors) and those who maintain IFG/IGT or regress resistance) in normal, IFG/IGT or T2D adolescents were 18.5 (95% C.I.: 16.75- to normoglycemia (i.e. non-progressors). We aimed to derive and validate 20.43), 12 (9.72-14.81), 2.09 (0.07-62.72), and ODI in normal, IFG/IGT or T2D a risk model of commonly measured clinical and biochemical measures to adults were 10.4 (9.51-11.3), 5.12 (4.23-6.2) and 1.57 (1.14-2.17), respectively. identify individuals who do not progress to T2DM from IFG/IGT and fi nd Beta-cell function as calculated by ODI was negatively correlated with BMI, novel biomarkers of non-progression. Individuals with ‘non-critical’ IFG/IGT, waist circumference, WHR, Ln TG, LDL, and maternal history of diabetes defi ned as fasting glucose <6.5 mmol/L and 2 hour glucose <10.1 mmol/L in adolescents. Beta-cell function was negatively correlated with gender, (i.e. levels ≥1 standard deviation from the T2DM thresholds), followed for age, BMI, waist circumference, WHR, SBP, DBP, LnTG, HDL, LDL, LnACR and up to 5 years in the DREAM trial were included in this analysis (n=3,389). maternal history of diabetes in adults. Birthweight was not correlated to Forward multivariable logistic regression was used to identify those who beta-cell function in either cohort. On multivariate linear regression, WHR do not progress from IFG/IGT. Internal validation was performed using split- was identifi ed as an independent predictor of reduced beta cell function sample methods and model fi t was assessed with the Hosmer-Lemeshow in adolescents, whilst WHR, DBP, maternal history of diabetes were test. Individuals who did not smoke, were physically active, had elevated independent predictors of reduced beta-cell function in adults. In conclusion, apolipoprotein A1 levels, and lower ALT, 2 hour and fasting glucose levels central obesity and maternal history of diabetes are important determinants were protected from progression to T2DM. Results were consistent across of beta-cell function. clinically relevant subgroups. Using multiple clinical and biochemical Supported By: Hong Kong Research Grants Council (4055/01M, 4465/06M, measures from the DREAM trial, we have developed a simple model to 4717/13); HKFRDD identify individuals less likely to progress to T2DM from a pre-diabetes stage. 1399-P High Risk of Diabetes Mellitus (DM) in Ethiopian Jewish Immigrants 1401-P Genetics to Israel: The Effect of Lifestyle Changes May Differ by Age at Incident Diabetes Mellitus in Heavy Smokers POSTERS Occurrence GREGORY L. KINNEY, EMMA BAKER, OANA L. KLEIN, JENNIFER BLACK- Epidemiology/ ANAT JAFFE, SHMUEL GIVEON, ARNONA ZIV, LIAT WULFFHART, BERNICE SHINN, EMILY WAN, BARRY MAKE, ELIZABETH REGAN, RUSSELL BOWLER, OBERMAN, LAURENCE FREEDMAN, OFRA KALTER-LEIBOVICI, Hadera, Israel, SHARON LUTZ, EDWIN SILVERMAN, JAMES CRAPO, JOHN E. HOKANSON, THE Sharon Shomron District, Israel, Tel Aviv, Israel COPDGENE INVESTIGATORS, Aurora, CO, London, United Kingdom, San Francisco, The prevalence of DM in Ethiopian Jewish Immigrants [EJI] was <0.4% on CA, Boston, MA, Denver, CO arrival in Israel and has been increasing ever since. Diabetes mellitus (DM) and its complications are a large and increasing We aimed to compare DM risk among EJI and non-Ethiopian Jews [NEJ] burden for healthcare worldwide. Pulmonary effects of altered glucose living in the same geographical area in Israel; and assess whether differences homeostasis and infl ammation resulting from insulin resistance may be in DM risk between the two ethnic groups are explained by differences in evident prior to diagnosis of DM. Several studies have shown that adults baseline levels of the metabolic syndrome [MetS] components. with DM have reduced lung function, exercise tolerance and pulmonary- Data on baseline levels of the MetS components and DM incidence associated quality of life compared to those without DM. Hyperglycemia between 2008 and 2011 were retrieved for 7,722 EJI and 14,683 age- and causes an increase in glucose concentration in airway surface liquid, which sex-matched NEJ. may result in pulmonary-associated serious adverse events (PSAE) requiring Sex-adjusted hazard ratios [HRs] for DM were calculated in selected age- hospitalization or ER visit by promoting bacterial growth and impairing groups, and further adjusted for the MetS components. the lung innate immune system, for example through reduced Surfactant The 4y DM risk was 3.6%, 15.2%, 14.8% for EJI and 2.1%, 11.8%, 17% for Protein-D. Smoking is also an independent predictor of type 2 (T2) DM. We NEJ, in the < 50y, 50-60y, ≥60y age-groups, respectively. Compared to NEJ, investigated non-traditional pulmonary-related risk factors for incident EJI had signifi cantly greater DM risk in the <50y and 50-60y age groups. T2DM in a cohort of heavy smokers (COPDGene). DM risk in people >60y did not differ by ethnicity, implying a possible birth During 22,924 person years of follow-up, 392 of 7080 participants with no cohort effect (see table). Adjustments for MetS components except BMI did T2DM at baseline reported incident (I) T2DM. Risk of IT2DM was assessed not materially change the HR estimates, while BMI adjustment increased using Cox Proportional Hazards models using baseline and longitudinal them, implying that differences in BMI or MetS components do not explain variables. Baseline variables of known risk for IT2DM included current the difference in risks between the two communities. smoking (HR=2.2, 95% confi dence intervals (C.I.) 1.8-2.8, p <0.0001), BMI (5 The effect of lifestyle changes associated with immigration on DM risk unit change; HR=1.5, 95% C.I. 1.4-1.6), high blood pressure (HR=1.5, 95% C.I. may differ by age at change occurrence. 1.2-1.8, p=0.0004) and high cholesterol (HR=1.3, 95% C.I. 1.1-1.6, p=0.01). In DM Risk in EJI vs. NEJ in 3 Age-Groups. addition to the baseline model of known risk factors, PSAE (HR=1.5, 95% C.I. 1.2-2.0, p=0.0009), reduced 6 Minute Walk Distance (-100 feet; HR=0.94, 95% Age <50y Age 50-60y Age ≥60y C.I. 0.91-0.97, p <0.0001) and preserved ratio/impaired spirometry (PRISm) n [EJI / NEJ] 6,029/11,244 725/1,533 968/1,906 abnormality (PRISm vs. unimpaired; HR=1.7, 95% C.I. 1.3-2.2, p=0.0003) were Model Hazard ratio (95% CI) Reference group: selected into the model. COPD was not signifi cantly associated with incident NEJ diabetes (HR=0.95, 95% C.I. 0.7-1.2, p=0.7). Pre or undiagnosed T2DM can Sex-adjusted only 1.81 (1.50, 2.17) 1.36 (1.07, 1.73) 0.89 (0.73, 1.08) be detected in heavy smokers by observing aspects of their pulmonary health, specifi cally a propensity for PSAE, PRISm abnormality and reduction Plus Triglycerides 1.95 (1.62, 2.35) 1.34 (1.05, 1.70) 0.87 (0.72, 1.07) in exercise capacity. Plus Body Mass Index 2.31 (1.91, 2.79) 1.55 (1.22, 1.98) 1.02 (0.83, 1.24) Supported By: 1U01HL089897-06A Plus HDL Cholesterol 1.84 (1.53, 2.22) 1.30 (1.03, 1.66) 0.87 (0.71, 1.06) Plus Systolic Blood Pressure 1.72 (1.43, 2.07) 1.34 (1.05, 1.70) 0.90 (0.73, 1.09)

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1402-P Baseline Characteristics of the Patients. Infl uence of Serum Osteocalcin and Liver Fat Content on Glucose Metabolism in Middle-aged and Elderly Chinese Population Age (mean±SD) 58.8±34 (Years) MING-FENG XIA, HUAN-DONG LIN, HONG-MEI YAN, HUA BIAN, XIN-XIA CHANG, Female 43 % XIN GAO, Shanghai, China Male 57 % The interaction among adipose tissue, the liver and the bone has been African American 47.7 % disclosed. Dysregulation of this network promotes the development of Hispanic 25.5 % diabetes. We investigated the relationship of serum osteocalcin (OCN) White 16.3 % secreted by osteoblasts, liver fat content (LFC) and glucose metabolism in Other 10.5 % a middle-aged and elderly Chinese community population. A cross-sectional Steroid use 27 % study was performed on 3782 eligible subjects from Shanghai Changfeng Baseline HgbA1c (mean±SD) 5.33±0.32 (%) Community. LFC was measured via a newly-established ultrasound quantitative method. ANOVA and multivariate linear regression analysis Highest BG during admission (mean±SD) 233.8±48.17 (mg/dl) were used to determine the independent and joint association of OCN and Length of stay (mean±SD) 9.46±9.38 (Days) LFC with glucose metabolism. Decreased serum OCN was associated with Duration of follow - up (mean±SD ) 3.5±1.9(years) higher fasting and postprandial blood glucose, LFC and insulin resistance The incidence of subsequent DM was 8.1% .The incidence of subsequent level. There was a synergistic increase seen in serum fasting and postprandial Pre-DM was 13.9%. We can conclude from the study that there is a low risk glucose, insulin and HOMA-IR in individuals with both increased LFC and of subsequent development of DM in patients with HRH on general wards in decreased serum OCN (Figure 1). Multivariate regression analysis showed a mean 3.5 year follow-up. that both OCN and LFC were independently associated with FBG (std β=- 0.122,P<0.001 and stdβ=0.110, P<0.001), PBG (stdβ=-0.074, P<0.001 and stdβ=0.147, P<0.001) and HOMA-IR (stdβ=-0.053, P<0.001 and stdβ=0.169, 1404-P P<0.001). Our results suggest that both liver and bone contribute to the development of diabetes and serum OCN and LFC may have a synergistic WITHDRAWN effect on human glucose metabolism. Genetics POSTERS Epidemiology/

Supported By: National Key Basic Research Program of China (2012CB524906, 2011CB504004)

1403-P Incidence of Subsequent Diabetes Mellitus in Non-Diabetic Patients with Hospital-related Hyperglycemia When Admitted to General Wards JYOTHSNA PALLA, YANNIS GUERRA, Chicago, IL The consequence of hospital-related hyperglycemia (HRH) in non-diabetic patients is not well studied. Do these patients have higher risk of developing subsequent Diabetes Mellitus(DM) or Pre-DM ? Few studies in non- diabetic patients with HRH when admitted to intensive care units(ICU) showed that the 5 year risk for development of DM was 40%. No such studies have been 1405-P done in patients admitted to general wards. High Prevalence of Carbohydrate Intolerance and Impaired Insulin This is a retrospective chart review of a cohort of 86 patients with HRH Response to Oral Glucose Load in Ecuadorian Andean Population defi ned as a random blood glucose (BG) on point of care testing or serum level MIGUEL PASQUEL, MARINA MORENO, LUIS ARIAS, LUIS NARVAEZ, GUILLERMO more than 180 mg/dl ), admitted to general wards over a 7 year duration. The E. UMPIERREZ, FRANCISCO J. PASQUEL, Quito, Ecuador, Atlanta, GA absence of DM or pre-DM was confi rmed with a Hemoglobin A1c (HgbA1c) The prevalence of carbohydrate (CHO) intolerance in Ecuadorian Andean level of ≤ to 5.7 %, absence of DM documented in the charts and absence population has not been examined. Accordingly, we studied 293 subjects of use anti- diabetic medication. A follow up duration of at least 12 months with a 75 gram oral glucose tolerance test (OGTT) with measurement of and onwards after the admission was surveyed for development of DM. glucose and insulin at 0, 30, 60, and 120 minutes. Subjects had a mean age Primary outcome was the incidence of subsequent DM. Development of DM 45±16 years, female 65%; positive family history of diabetes 69%, BMI 29±5 was confi rmed either with a HgbA1c level of ≥ 6.5 % or documentation of kg/m2; HbA1c 5.8±0.7. Following ADA criteria, 43% had CHO intolerance-- a diagnoses of DM in clinical notes and/or evidence of use of anti-diabetic impaired fasting glucose (IFG) 23%, impaired glucose tolerance (IGT) 5%, medication, in the follow-up period. combined IFG/IGT 9%, and newly diagnosed T2D in 6%. Normal glucose tolerance (NGT) was present in 57%. Baseline insulin levels were similar across groups, except for subjects with IFG/IGT vs. NGT (Table). At 30 min NGT and IFG subjects had ~ three-fold higher insulin levels compared to T2D

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(both p<0.05), IGT subjects having the highest insulin levels at 60 and 120 and 165 (85.5%) were categorized as high risk in DiabetesUK, of which min compared to DM and IFG. only 43 (53.1%) and 84 (43.5%) were at risk in Qdiabetes and only 5 (6.2%) In summary, the results of this pilot study in an Ecuadorian Andean and 49(25.4%) were at risk in FINDRISC. Only 49 (17.9%) were classifi ed population indicate a high frequency of carbohydrate intolerance and simultaneously as high risk by all three scores, of which 5 (6.2%)were males insulin resistance. These results suggest the need for large screening and and 44(26.6%) were females. FINDRISC classifi ed 5 participants as high risk, intervention studies for diabetes prevention in Andean populations. whom were not classifi ed as high risk by QDiabetes and all were females. The prevalence of subjects at high risk of diabetes considerably differs by NGT IFG IGT IFG/IGT T2D the risk score used. Hence a risk score should be validated for the population BG 0 min ** 89±6 108±6 92±7 111±7 138±29 that is intended to use. BG Delta 0-30 min 38±28* 65±39† 50±27^ 70±19 87±29†*^ BG 120 min*** 90±20 103±20 162±17 157±13 249±48 1408-P Insulin 0 min 13±8* 16±11 19±8 23±23* 18±11 Incidence of Metabolic Syndrome According to Changes of GGT Value in Korean Genomic Rural Cohort † † Insulin Delta 0-30 min 93±66* 87+59 81±50 71±35 35±16 * MI YOUNG LEE, SONG VOQUE AHN, JANG YOUNG KIM, EUN HEE CHOI, SOO MIN Insulin 120 min 51±52*† 64±56^# 126±53*^ 127±75†# 84±51 NAM, JANG YEL SHIN, JUNG SOO LIM, CHOON HEE CHUNG, Wonju, Republic of BG in mg/dL, Insulin in uU/mL. Korea, Daejeon, Republic of Korea Analysis of variance: P < 0.001 across groups for all time points. The positive association between serum γ-glutamyltransferase (GGT) levels and the incidence of metabolic syndrome was well established. Also, Multiple pairwise comparisons (Tukey): P < 0.05 (*, †, ^, #). **All comparisons P < 0.05 except for NGT vs. IGT and IFG vs. IFG/IGT. recent study reported the existence of relationship between longitudinal ***All P < 0.05 except for IGT vs. IFG/IGT. changes in GGT levels and the risk of metabolic syndrome. In our study, we examined the association of longitudinal changes in GGT level with the incidence of metabolic syndrome according to baseline GGT value. In the 1406-P Korean Genomic Rural Cohort, 2,303 subjects were divided into the lower Risk of Diabetes in Patients Treated with HMG-CoA Reductase baseline GGT group (baseline GGT level below the 27 IU/L in men and 13 Inhibitors IU/L in women) and the higher baseline GGT group. The longitudinal changes HYE JIN WANG, YONGIN CHO, EUN YEONG CHOE, JI WON SEO, YONGHO LEE, were categorized increased, stable, and decreased group by the tertiles of YU JUNG YUN, GYURI KIM, SEHEE PARK, JAEHYUN BAE, CHUL WOO AHN, delta GGT levels. The relative risk of metabolic syndrome was not increased BONG SOO CHA, HYUN CHUL LEE, EUN SEOK KANG, Seoul, Republic of Korea by the delta GGT levels in the lower baseline GGT group. But, the incidence 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase Inhibitors of metabolic syndrome was signifi cantly increased in the third tertile of (statins) are used to control blood cholesterol levels and reduce cardiovascular delta GGT levels in the higher baseline GGT group (adjusted relative risk disease. It has been repeatedly reported that statins may cause new-onset [RR], 2.81; 95 % confi dence interval [CI], 1.29-6.11 in men, adjusted RR, 3.51; diabetes mellitus. However, there is controversy whether the risk of diabetes 95 % CI, 1.02-12.06 in women). Among the relative risk for the existence of differs among statins. We investigated the risk of development of new-onset abnormal metabolic syndrome component, the relative risks of high waist diabetes in subjects treated with different statins. Our study enrolled 1,172 circumference (adjusted RR, 1.81; 95 % CI, 1.08-3.02 in men, adjusted RR, patients without DM who were receiving statin treatment for cholesterol Genetics

1.95; 95 % CI, 1.21-3.17 in women) and high triglyceridemia (adjusted RR, POSTERS control. We evaluated the incidence of new-onset diabetes according to 1.95; 95 % CI, 1.21-3.17 in men, adjusted RR, 2.02; 95 % CI, 1.31-3.11 in Epidemiology/ the type of statin. The mean duration of follow-up was 56.4 ± 7.9 months. women) were statistically signifi cant in the third tertile of delta GGT in the The incidence of diabetes was signifi cantly higher in the pitavastatin group higher baseline GGT group. The changes of GGT level may be a risk factor (11.64%) compared to that in the other statin groups [atorvastatin (4.76%), for metabolic syndrome especially in the patients with the higher baseline rosuvastatin (6.02%), simvastatin (4.08%), and pravastatin (3.64%); p=0.003]. GGT levels. The risk of diabetes was the highest in the pitavastatin group compared with that in the atorvastatin group [hazard ratio (HR) =2.43, p=0.005]. Other statins showed no signifi cant risk differences compared to that for atorvastatin. 1409-P An older age was associated with the development of diabetes (HR=1.03, High Serum Uric Acid Level Is More Predictive of Risk of Future p=0.030). Other factors including gender, body-mass index, duration of statin Type 2 Diabetes in Nonobese Than in Overweight/Obese People: use, and total cholesterol level at baseline showed no association with the The Niigata Wellness Study development of diabetes. Among the fi ve statins, pitavastatin showed the SATOSHI MATSUNAGA, YORIKO HEIANZA, TATSURO SUZUKI, MASARU strongest effect on the development of new-onset diabetes. KITAZAWA, SHINICHI MINAGAWA, TAKAHO YAMADA, AKIKO SUZUKI, OSAMU Supported By: Yonsei University HANYU, KIMINORI KATO, KOJI SATO, HIROHITO SONE, Niigata, Japan Although a high serum uric acid (SUA) value is known as a risk factor for the development of type 2 diabetes, whether obesity would affect the 1407-P relationship between SUA and the long-term risk of diabetes has not been Use of Different Risk Scores in Predicting Risk of Developing Type 2 clarifi ed. To investigate this issue, we followed a total of 12,494 Japanese Diabetes: A Sri Lankan Population Study men (mean (SD) age was 47.0 (7.8) y and body mass index (BMI) was 23.1 NAYANANJANI KARUNASENA, UDITHA BULUGAHAPITIYA, PUBUDU CHULASIRI, (2.8) kg/m2) for over 10 years who were without diabetes at the baseline SHALIKA ARIYAWANSA, Colombo, Sri Lanka examination. Participants were categorized into 4 groups by SUA values Lifestyle intervention in population at risk of diabetes can reduce the (A: <5.0, B: 5.0-5.9, C: 6.0-6.9, D: ≥7.0 mg/dl). The analysis was stratifi ed incidence of diabetes. Aim of this study was to determine the Sri Lankan according to the presence or absence of an overweight or obese state population at risk of developing Type 2 diabetes and compare several risk (BMI ≥25 kg/m2). Type 2 diabetes was indicated by self-reported history scores among Sri Lankan population. of previously diagnosed diabetes, fasting glucose ≥126 mg/dl, or HbA1c A descriptive cross sectional study conducted within fi ve health divisions ≥6.5%. During the 10-year follow-up period 1112 individuals developed in Colombo district in Sri Lanka. Among 374 adults screened , 25% (n=95) had diabetes. In the non-obese group, groups C and D with SUA ≥6 mg/dl had diabetes and 1.3% (n=5) were newly diagnosed. Overall 73.3% (n=274) were a signifi cantly increased hazard ratio (HR) for the development of diabetes free of diabetes and included in the study. The risk of developing diabetes (HR 1.33 (95% CI, 1.05-1.69) or HR 1.38 (95% CI, 1.07-1.78, respectively) was calculated using three risk scores in each participant. The scores were compared with group A after adjustment for age, smoking status, drinking DiabetesUK (D), QDiabetes (Q) and FINDRISC (F). habits, estimated glomerular fi ltration rate, hypertension, and low levels of Among the studied population 29.6% (n=81) were males and 70.4% high-density lipoprotein cholesterol (<40 mg/dl). However, an association of (n=193) were females. Prevalence of participants at high risk of diabetes an elevated risk of diabetes with high SUA concentrations was not observed among total population was 89.4% (95% CI 85.8-93.1) (D), 46.4% (40.5- among individuals with overweight/obesity. The HRs compared to group A 52.2)(Q) and 19.7% (15.3-24.8)(F) according to three scores. It was 98.8% were HR 0.85 (95% CI, 0.61-1.18) in group B, HR 1.10 (95% CI, 0.82-1.50) in (95.8-100) (D), 53.1% (42.9-64.9)(Q) and 6.2%(1.3-12.4)(F) among males and group C, and HR 1.11 (95% CI, 0.81-1.50) in group D among the overweight 85.5% (80.0-90.5) (D), 43.5% (36.24-51.0)(Q) and 19.7%(19.5-31.5)(F) among or obese individuals. These data suggest that SUA concentrations were females. According to DiabetesUK and QDiabetes, males and according to a better marker for predicting the development of future diabetes in non- FINDRISC, females were at a higher risk. Of 245 (89.4%), who were at high obese individuals rather than in overweight/obese individuals. risk in Diabetes UK, only 127 (46.4%) were also at risk in QDiabetes and only 54 (19.7%) in FINDRISC. Among males and females respectively, 80 (98.8%)

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1410-P 0.671-0.697, r<0.001) while AUCs of apoB/apoA1 was 0.676 (95% CI 0.664- Comparison of Screening for Gestational Diabetes Mellitus in 0.690, r<0.001). Based on multivariable Cox proportional Hazard model with Fasting and Nonfasting (Random) OGTT adjustment for traditional risk factors, non-HDL-C/HDL-C and apoB/apoA1 VISWANATHAN MOHAN, GUNASEKARAN KALAIYARASI, BALAJI BHAVA- were independent risk factor for future MetS, respectively. However, when DHARINI, MANNI MOHANRAJ MAHALAKSHMI, KUMAR MAHESWARI, RANJIT adding the non-HDL-C/HDL-C to apoB/apoA-I in risk models, non-HDL-C/ MOHAN ANJANA, MOHAN DEEPA, RAM UMA, BELMA MALANDA, ANNE HDL-C remained having signifi cant predictive values for MetS while apoB/ BELTON, ARIVUDAINAMBI KAYAL, Chennai, India, Brussels, Belgium apoA-I did not. The Diabetes in Pregnancy Study Group of India (DIPSI) guidelines Conclusion: Our fi ndings indicate that the non-HDL-C/HDL-C ratio is a recommends that the oral glucose tolerance test (OGTT) to diagnose better marker than the apoB/apoA1 ratio for predicting development of gestational diabetes mellitus (GDM) can be done in a non fasting state. The MetS. aim of this study was to compare the 2 hour venous plasma glucose (2H-VPG) values of OGTT done in the fasting state and in the non fasting state for 1413-P diagnosis of GDM. A total of 1040 pregnant women (≥18 years) attending Detecting Cases of Undiagnosed Diabetes and Prediabetes: Com- antenatal clinics in urban and rural Tamil Nadu underwent a 75 g OGTT both paring the Effectiveness of ADA and USPSTF Guidelines vs. a in fasting and non fasting state two days apart. VPG were measured using Random Glucose-based Screening Strategy an auto analyser. Diagnosis of GDM was based on 2H-VPG ≥140 mg/dL. MICHAEL E. BOWEN, LEI XUAN, ETHAN A. HALM, Dallas, TX Eighty four women (8.1%) were diagnosed to have GDM using the fasting Neither ADA nor USPSTF diabetes (DM) screening guidelines include OGTT. Their mean body mass index (BMI) was 23.7± 4.8 kg/m2 and 27.3% random blood glucose (RBG) as criteria. We examined the performance of of women had family history of diabetes mellitus. Only 46 (4.4%) women ADA or USPSTF guidelines compared to RBG alone and in combination with were diagnosed to have GDM using non fasting criteria. Their mean BMI was guidelines to detect undiagnosed DM and dysglycemia (DM+preDM). 24.8± 5.4 kg/m2 and 30.4% of women had family history of diabetes mellitus. Non-pregnant, non-fasting adults without DM in NHANES (2007-2012) Out of the 84 GDM women identifi ed by fasting OGTT, only 24 (28.6%) were with RBG and A1C values were included (N=7483). ADA and USPSTF picked up by the non fasting OGTT. Of the 46 women diagnosed by non guidelines were based on survey and exam data. We examined the fasting OGTT, 24 (52.2%) were picked up by the fasting OGTT. The sensitivity performance of ADA, USPSTF, RBG≥100mg/dL (RBG100), ADA+RBG100, and of the non fasting OGTT was 28.6% while the specifi city was 97.7%, positive USPSTF+RBG100 strategies to detect cases of undiagnosed DM (A1C≥6.5%) predictive value, 52.2% and negative predictive value, 94%.The non fasting and dysglycemia (A1C≥5.7%). OGTT would miss a signifi cant number of women with GDM. The number screened varied by strategy (ADA 5639, USPSTF 2144, RBG100 Supported By: IDF; Abbott Laboratories 1968). As a single test, RBG100 (AROC=0.79) performed better than ADA (0.62) and USPSTF (0.63) to detect undiagnosed DM. For DM, adding RBG100 1411-P to USPSTF guidelines achieved clinically similar sensitivity (92% vs. 99%) Prevalence of Gestational Diabetes Mellitus (GDM) in Asian Indians but much better specifi city (61% vs. 31%) than ADA. Compared with USPSTF Using the World Health Organization Criteria and the International alone, adding RBG100 to USPSTF guidelines improved AROC from 0.63 to Association of Diabetes and Pregnancy Study Groups Criteria 0.76 (p<0.001) for DM and from 0.61 to 0.66 for dysglycemia (p<0.001). No VISWANATHAN MOHAN, KUMAR MAHESWARI, BALAJI BHAVADHARINI, difference was seen adding RBG100 to ADA guidelines. Genetics

POSTERS MANNI MOHANRAJ MAHALAKSHMI, GUNASEKARAN KALAIYARASI, RANJIT RBG100 alone detects cases of undiagnosed DM better than current Epidemiology/ MOHAN ANJANA, MOHAN DEEPA, RAM UMA, BELMA MALANDA, BELTON guidelines. Including RBG100 in USPSTF guidelines could improve detection ANNE, ARIVUDAINAMBI KAYAL, Chennai, India, Brussels, Belgium of DM and dysglycemia. The aim of the study is to compare the prevalence rates of gestational diabetes mellitus (GDM) using the World Health Organization (WHO) and the International Association of Diabetes and Pregnancy Study Groups Criteria (IADPSG) in Asian Indians. A total of 1040 pregnant women (≥18 years) attending antenatal clinics in urban and rural Tamil Nadu, India, underwent oral glucose tolerance testing with a 75 g of glucose load and the fasting, 1 hour, 2 hour venous samples were collected. According to the WHO criteria, 2hr VPG ≥140 mg/dl (7.8 mmol/L) was classifi ed as GDM. According to IADPSG criteria, any one of the following was used for diagnosis of GDM (fasting ≥92 mg/dl (5.1 mmol/L), 1 hour ≥180mg/dl (10.0 mmol/L) or 2 hour ≥153 mg/dl (8.5 mmol/L). According to the WHO criteria, 84 (8.1%) subjects were identifi ed as GDM while by the IADPSG criteria, 131 (12.6%) subjects were identifi ed as GDM. Out of the 84 identifi ed by WHO, 53 (63.1%) cases were picked up by the IADPSG. Of the 131 cases picked up by IADPSG, 53 (40.5%) cases were identifi ed by the WHO criteria. Use of the IADPSG criteria results in almost 50% higher prevalence rates of GDM in Asian Indians. Moreover, the IADPSG and WHO criteria identify different individuals as having GDM. Supported By: IDF; Abbott Laboratories

1412-P Supported By: NIH/NCATS (KL2TR001103) Non HDL-Cholesterol/HDL-Cholesterol Is a Better Predictor of Future Development of Metabolic Syndrome Than Apolipoprotein 1414-P B/Apolipoprotein A1 Oral Glucose Tolerance: The Unrealized Burden of Prediabetes and JI CHEOL BAE, SANG-MAN JIN, JAE HYEON KIM, KYU YEON HUR, MYUNG-SHIK Diabetes in Mexican Americans LEE, MOON KYU LEE, Seoul, Republic of Korea JENNIFER E. BELOW, NANCY J. COX, GRAEME I. BELL, SUSAN REDLINE, CRAIG Background: The apolipoprotein B (ApoB)/apolipoprotein A-I (ApoA1) ratio L. HANIS, Houston, TX, Chicago, IL, Boston, MA has been reported to be associated with metabolic syndrome (MetS). Non- Although less sensitive, the fasting plasma glucose (FPG) test is the most HDL-C provides a measure of all apolipoprotein B-containing lipoproteins. common test used for diagnosing diabetes because it is quicker and cheaper We examined whether the ratio of non-HDL-C to HDL-C is an equal or a than the oral glucose tolerance test (OGTT). better predictor than the apoB/apoA1 ratio for future development of MetS. To assess the undiagnosed burden of untoward glucose levels in Mexican Methods: A retrospective analysis was conducted among subjects who Americans we utilized a representative sample that was selected from participated in comprehensive health check-ups consecutively at least 4 a systematic survey of the population centers in Starr County, TX from times for 7 years (2006-2012). A total of 8,432 (5389 men, 3043 women) 2002-2006. Blocks were randomly selected, and from each household an subjects without MetS at baseline were analyzed. individual aged 20-77 years (mean age 36.9) with no prior diagnosis of T2D Results: During the mean follow-up period of 49.8 months, 2,111(25.0%) of was selected for and consented to a physical evaluation including an oral the 8,432 subjects developed MetS. Based on ROC analysis, AUCs of non- glucose tolerance test with a 75 g glucose load. HDL-C/HDL-C for predicting future development of MetS was 0.684 (95% CI

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From 1,345 individuals (407 male), we identifi ed 29 newly diagnosed cases these would have been 16 and 14% respectively. If mortality had declined as based on FPG (≥126 mg/dl), and 77 new prediabetes cases (100-125 mg/dl). observed and incidence remained stable at the 1995 level, the fi gures would Among those with normal glycemic levels based on a fasting sample, we have been 14% and 13% form men and women respectively. identifi ed an additional 62 T2D cases (≥200 mg/dl), and 444 new prediabetes The increase in diabetes prevalence as measured by percentage of the (140-199 mg/dl) cases by OGTT. Twice as many T2D cases, and nearly 6 times population can be attributed to both increase in incidence and to a decrease as many prediabetes cases, were missed in individuals with normal fasting in mortality. So broadly speaking, failure of prevention and success of glucose than are diagnosed by this criterion. treatment both contribute to the increase in prevalence of diabetes in In 2013, we re-performed OGTT on 601 people who were not diagnosed Denmark. with T2D previously. We identifi ed 45 newly diagnosed cases based on FPG, and 204 new prediabetes cases; by OGTT, an additional 3 T2D and 71 1417-P prediabetes cases. As expected age, sex, and BMI are signifi cant predictors NMR-based Diabetes Risk Index Is Capable of Identifying Normal of T2D incidence based on Cox proportional hazard models. 101 incident Weight Subjects with High Likelihood of Progressing to Type 2 cases of T2D were identifi ed corresponding to an incidence rate of 2.0% Diabetes per year, more than 6 times the average estimate for the state of Texas. MARGERY A. CONNELLY, IRINA SHALAUROVA, JAMES D. OTVOS, Raleigh, NC Incidence of prediabetes over the same time period is 3.3% per year. OGTT A body mass index (BMI) >30 is often an indicator of high risk for may also be a better predictor of incidence of T2D. Cases of prediabetes developing Type 2 diabetes (T2D). However, it is well known that individuals defi ned solely by FPG have an incidence of T2D of 0.4% per year but 1.3% with widely varying BMIs become diabetic. To identify highest-risk patients by OGTT. These numbers point to a much larger population of undiagnosed who would benefi t most from intervention, we developed a Diabetes cases of T2D and prediabetes than typically considered and auger poorly for Risk Index (DRI) score (1-10) that uses information derived from a nuclear current prevention efforts. magnetic resonance (NMR) spectrum of plasma: 1) lipoprotein subclass/size parameters, 2) branched-chain amino acid valine and 3) infl ammatory signal 1415-P that arises largely from glycosylated acute phase proteins. Baseline samples Short- and Long-term Diabetes Risk Assessed by Markers Derived from MESA subjects with glucose levels 90-110 mg/dL were used to develop from a Nuclear Magnetic Resonance Spectrum of Fasting Plasma the DRI score. Within this glucose range, there is often ambiguity as to JAMES D. OTVOS, IRINA SHALAUROVA, Raleigh, NC whether a patient will progress to T2D. To determine whether the DRI score Many patients with moderate glucose elevations (90-110 mg/dL) develop was capable of identifying normal BMI individuals with a high likelihood of diabetes (DM) within 5 years, some in a short timeframe (<2 yr) and others becoming diabetic, we compared the percentage of subjects progressing to later. Both types are likely to have insulin resistance in common, but short- T2D across quartiles of the DRI score in 3 BMI categories (Table) in a subset term converters are likely to also have beta-cell impairment. Several of MESA subjects (glucose <110 mg/dL; 9.5 yr avg. follow-up). Regardless parameters derived from a nuclear magnetic resonance (NMR) spectrum of the BMI category, as the DRI score increased there was an increasing of fasting plasma have potential to differentially assess short- and longer- likelihood of becoming diabetic. In addition, the DRI score added signifi cantly term DM risk. This possibility was investigated using NMR data collected to a logistic regression model (adjusted for age, gender, race, glucose) in all at baseline from 2038 nondiabetic subjects in the MESA study with glucose subjects, including those whose BMI was normal (ρ<0.0001). levels 90-110 mg/dL. New converters to DM were identifi ed at visit 2 (n=77;

LS Means for Conversion Rate Adjusted for Age, Gender, Race, and Glucose Genetics mean 1.6 yr) , visit 3 (n=56; 3.2 yr), visit 4 (n=77; 4.8 yr), and visit 5 (n=109; 9.5 (Number of Subjects). POSTERS yr). Valine and lipoprotein subclass/size parameters previously associated Epidemiology/ DRI Score BMI with insulin resistance were identifi ed as independent predictors of DM in converters at visits 3 or 4. These variables were used to create a long-term (n=4752) <25 25-30 ≥30 risk score (LTRNMR). Two unique variables independent of LTRNMR, GlycA (a <2.5 5.2 (672) 5.8 (377) 5.9 (130) novel NMR infl ammation marker) and medium HDL, contributed to short- 2.5-5.0 4.7 (431) 7.6 (535) 11.8 (242) term risk (DM at visit 2) but not later DM conversion (Figure). STR , a NMR 5.0-7.5 8.1 (271) 8.5 (520) 12.0 (394) multimarker of short-term risk, may be useful in identifying patients with likely impairment of beta-cell function who would benefi t from prompt >7.5 13.7 (139) 11.9 (462) 19.0 (579) intervention. 1418-P GCK-related Hyperglycemia: Frequently Misdiagnosed and Inappro- priately Treated in the U.S. DAVID CARMODY, CHARLES D. BELL, SHIVANI BERRY, JAZZMYNE T. DICKENS, JESSICA L. HWANG, SIRI ATMA W. GREELEY, LOUIS H. PHILIPSON, ROCHELLE N. NAYLOR, Chicago, IL Heterozygous mutations in GCK have an estimated prevalence of 1 in 1000 individuals and lead to a stable fasting plasma glucose concentration ≥100 and <126 mg/dl. GCK-related hyperglycemia (or MODY2) does not need glucose-lowering therapy, except in some instances during pregnancy. Through the web-based U.S. Monogenic Diabetes Registry (http:// monogenicdiabetes.uchicago.edu/registry/) we assessed demographics, time to diagnosis and longitudinal treatment patterns of individuals with GCK-related hyperglycemia (Table). 85% received genetic testing 1416-P on a research basis due to barriers to clinical genetic testing. 76% were How Much of the Diabetes Prevalence Is due to Decreasing referred to the Registry by physicians, and 79% of referring physicians Mortality and How Much to Increasing Incidence? were endocrinologists. Zip-code data analysis shows that the majority of BENDIX CARSTENSEN, Gentofte, Denmark participants have education levels and household incomes exceeding the The aim was to describe the diabetes prevalence in Denmark as it is now, U.S. national average. Nearly half were on medical therapy prior to genetic and show how much can be attributed to decreasing mortality and how diagnosis. much to increasing incidence. Our data suggest that GCK-related hyperglycemia is frequently mis- The National Diabetes Register (NDR) was established in 2006, and covers diag nosed and inappropriately treated as diabetes, unnecessarily driving the entire Danish population from 1995 up to the end of 2010. We modeled up health care costs. An over-representation of individuals from higher incidence and mortality rates by sex, age and calendar time. By replacing the socioeconomic status and under subspecialty care in the Registry under- actual trends in incidence and mortality rates by rates constant over time we scores the importance of efforts to educate all physicians and patients could simulate what the diabetes prevalence in 2010 would have been if no about monogenic forms of diabetes and increase access to genetic testing changes had occurred. to inform appropriate clinical care in an equitable fashion. The highest age-specifi c prevalence in 2010 is in the late 70’s, about 19% for men and 16% for women; in 1995 these were 12 and 11%. If mortality had remained as high as in 1995 and incidence rates developed as observed,

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incidence has declined and plateaued at about 2.6% starting in 2007. n 149 Prediabetes, based on diagnosis codes and laboratory tests, has increased Female 81 (54.4%) dramatically over the 12 years with prevalence of 18.4% (1 million) in 2012. Ethnicity — Much, but not all, of this increase is attributable to increased A1C testing Non-Hispanic White 74.5% and use of new prediabetes codes. Other impaired glucose (random glucose African American 3.4% >= 140 mg/dl) contributes an additional 3.8% in 2012 so that over half of Hispanic 4.0% the population (51.6%) has hyperglycemia, with or without diagnosed Asian American 3.4% diabetes. Age and proportion with complications at diabetes onset have Other 1.4% declined over time, as has the time from fi rst measure of hyperglycemia to Undeclared 13.3% disease assignment (diagnosis). This tragic picture of the diabetes epidemic Age at DM diagnosis 18.32 yrs (0.01-60.82 yrs) in Veterans provides data useful for planning treatment and prevention Time to genetic diagnosis 4.65 yrs (0.01-18.89 yrs) efforts. HbA1c at diagnosis 6.48 ± 0.42% Pharmacotherapy (>3 months) — None/ Not reported 52.3% 1 agent 38.3% >1 agent 9.4% Drugs used — Insulin 42.2% Metformin 42.2% Sulfonylurea 11.3% Others 14% (exceeds 100% due to multi-therapy) Supported By: ADA (1-11-CT-41); DK020595, DK094866

1419-P The Utility of E-Med Scan and Foot Mate Print Technologies in Diabetic Neuropathy Ascertainment, Dar es Salaam, Tanzania ZULFIQARALI G. ABBAS, JANET LUTALE, DIAMANTO M. PAPASAVVAS, LENNOX K. ARCHIBALD, Dar es Salaam, United Republic of Tanzania, Nicosia, Cyprus, Gainesville, FL In Africa, diabetic foot ulceration is often associated with peripheral neuropathy (PN) and is associated with substantial morbidity and mortality. EPIDEMIOLOGY—DIABETES COMPLICATIONS

Genetics Thus, new affordable technologies for PN screening have the potential

POSTERS to improve patient outcomes across Africa. We carried out this study to Epidemiology/ (i) evaluate two technologies--the foot E-med scan system (EMS) and the Guided Audio Tour: It’s Complicated! The Epidemiology of Diabetes simple Foot Mate print (FMP)--in plantar pressure measurement; and (ii) Complications (Posters: 1421-P to 1428-P), see page 13. correlate these measurements with PN ascertained clinically. During Jan 2011 - Nov 2013 (study period), all patients attending a diabetes centre in Dar es Salaam were evaluated clinically. Pressure at various sites on each & 1421-P foot was measured with EMS and FMP with an ink pad (dark areas refl ected Safety of Glucose-Lowering Medications: The Diabetes Adverse high pressures.) PN was ascertained by thermal sensation, biothesiometry, Event Monitor (DIABMON) Project: Cancer and with monofi lament. Of 1407 patients enrolled during the study period, PETER BOYLE, MATHIEU BONIOL, ALICE KOECHLIN, MARIA BOTA, CHRIS 801 (60 %) were male; 747 (53%) had PN by clinical assessment. Median age ROBERTSON, JAY SKYLER, GEREMIA B. BOLLI, JULIO ROSENSTOCK, PHILIPPE =52 (range: 11-90) yrs; median body mass index (BMI)=29 (range: 14-59) kg/ AUTIER, Lyon, France, Glasgow, United Kingdom, Miami, FL, Perugia, Italy, Dallas, TX m2). Patients with PN were signifi cantly more likely than those without to be Effi cacy of glucose-lowering medications is demonstrated in clinical trials older (54 vs. 50 years, p <0.01) or to have a longer diabetes duration (6 vs. but effectiveness in practice depends on a number of factors including the 4 years, p <0.001). On correlation with the presence of PN, EMS revealed safety profi le. A systematic evaluation of the published literature has been signifi cantly high plantar pressures at the big toe (p <0.0001), 3rd, 4th, and undertaken to evaluate the effect of such medications on serious adverse 5th toes (p <0.0001), central hind foot (p <0.05), and mid hind foot (p=0.005). events notably cancer. In contrast, the FMP was sensitive in detecting signifi cantly high plantar No signifi cant difference was found in the incidence of malignancies among pressure only at the 2nd (p <0.05) and 3rd (p=0.008) toes. In conclusion, rosiglitazone treated patients (SRR=0.91, 95% CI (0.71, 1.16)). In prospective pressure measurements were largely predictive of PN. While EMS was studies, there appears to be an increased risk of bladder cancer among more sensitive than FMP in detecting high plantar pressures with underlying users of pioglitazone when compared to other medications (SRR=1.24, 95% PN confi rmed by thermal sensation, biothesiometer and monofi lament test CI (1.05, 1.46)) although the two studies with the best methodology showed across various anatomic areas of the foot, FMP was sensitive in predicting no increased risk. Compared to users of other insulins, there is no increased problems in the toes rather than the hind foot. Thus, both technologies have risk of cancer among glargine users in all forms combined (SRR=0.92, 95% a major role to play in the management of diabetic foot complications in CI (0.85, 0.99)) nor in breast cancer (SRR=1.11, 95% CI (0.98, 1.21)), colorectal Africa. cancer (SRR=0.85, 95% CI (0.76, 0.95)), prostate cancer (SRR=1.12, 95% CI (0.92, 1.35)), lung cancer (SRR=1.04, 95% CI (0.91, 1.10) nor pancreas cancer (SRR=0.98, 95% CI (0.94, 1.14)). Pancreas cancer has been postulated to be 1420-P increased among users of incretin therapies although supportive human Update on the Epidemiology of Diabetes among U.S. Veteran Patients data are not available: more rigorous study is essential. There is no reduction DONALD R. MILLER, MADHURI PALNATI, VARSHA VIMALANANDA, CINDY in risk of breast cancer associated with metformin use (SRR=0.96, 95% CI L. CHRISTIANSEN, BENJAMIN G. FINCKE, QING SHAO, MANGALA RAJAN, (0.85, 1.08)) even for the longest duration of use (SRR=0.94, 95% CI (0.81, LEONARD POGACH, Boston, MA, Bedford, MA, Newark, NJ, East Orange, NJ 1.09)). The scourge of diabetes is well documented. Over a decade ago, we Cancer is a chronic disease which can take many years to develop into developed methods to study diabetes in the national population of Veteran a clinical entity from the initial cellular damage. The follow-up time of the patients served by the Dept. of Veterans Affairs (VA), with formation of the studies of glucose-lowering medications is brief by comparison. However, Diabetes Epidemiology Cohorts. We have updated methods and data and the overall situation regarding an increased risk of cancer with use of provide new estimates of rates and trends. Diabetes assignment is based glucose-lowering medications appears reassuring although there are a few on diagnosis codes from medical encounters (inpatient and outpatient in specifi c issues which still require clarifi cation. VA and Medicare) and prescription records, with confi rmation by laboratory An on-going project of meta-analyses and their continuous update is core tests. Diabetes prevalence increased from 19.2% in 2000 to 25.0% in 2006 to the DIABMON project. remaining at about that level through 2012 (1.4 million patients). Diabetes

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goal was to predict PPHA among people with type 2 diabetes (T2D) using & 1422-P administrative claims. Skin Collagen-linked Fluorophore LW-1 Predicts Micro- and Sub- We used the Truven MarketScan® Commercial Claims and Encounters clinical Macrovascular Complication Progression in Type 1 Diabetes Database, which incorporates de-identifi ed private insurance claims DAVID R. SELL, WANJIE SUN, JOHN M. LACHIN, PATRICIA A. CLEARY, SAUL for inpatient, outpatient and pharmacy services. T2D was defi ned using GENUTH, VINCENT M. MONNIER, DCCT/EDIC RESEARCH GROUP, Cleveland, OH, diagnosis and antihyperglycemic drug codes. PPHA was defi ned using the Rockville, MD, Washington, DC AHRQ’s Preventive Quality Indicators 1 (Diabetes Short-term Complications) Skin collagen Long Wave autofl uorescence (LW) is widely used as a and 14 (Uncontrolled Diabetes). An index date was randomly selected from surrogate marker for accumulation of advanced glycation end-product patient healthcare encounters, and covariates within 1 year before were (AGE). We determined the relationship between LW-1, a novel fl uorescent used to predict risk of PPHA within 1 year after the index date. We randomly skin collagen marker of partially known structure, with glycemia, other split data into equal training, testing and validation sets. Regularized logistic collagen AGEs and the severity of complications in 216 participants regression models were fi t using a cyclic coordinate descending method. from the Diabetes Control and Complications Trial (DCCT) study who had Area under the Receiver Operating Characteristics curve (AUC) was the skin biopsies performed as part of a substudy in 1992, one of which was primary measure of model performance. recently processed for analysis of novel AGEs. LW-1 was measured by HPLC- There were 2,563 PPHA among 555,785 T2D patients. The training, fl uorescence and correlated with the AGEs and clinical endpoints described testing, and validation sets included between 814 and 886 PPHA among the below. LW-1 levels increased with age and diabetes duration(P<0.0001) approximately 185,000 patients with T2D in each set. From 10,698 candidate and when corrected for these parameters were signifi cantly decreased predictors, 368 covariates were automatically chosen in the fi nal model, with intensive vs, conventional diabetes therapy in both primary and which included strong predictors for PPHA such as prior hospitalizations, secondary DCCT cohorts (P3 microaneurysms ever in DCCT) (P=0.0004) and Diabetes Complications Severity Index, number of comorbidities and albumin excretion rate (AER closest to biopsy > 40 mg/24 hr) (P= 0.0038) medications, as well as healthcare procedures. AUC in the testing and which remained signifi cant after adjustment for DCCT HbA1c. In EDIC, LW-1 validation set were 0.74 and 0.72, respectively, at or above AUC reported for correlated with retinopathy progression at EDIC Year 13-16, intima media other models of PPHA in the literature. The model calibration was excellent thickness(IMT) at Yr 6 (n=147, P=0.014) and left ventricular mass (EDIC Yr when comparing predicted probabilities of PPHA with observed data in the 14-16) adjusted for EDIC A1c (P=0.004). LW-1 correlated highly (P<0.0001) validation set. with collagen modifi cations in the order glucosepane >pentosidine >pepsin These results suggest that predictive modeling using routine electronic insolubility >collagen fl uorescence >MG-H1, and weaker with fructose-lysine healthcare data may potentially be a useful tool for T2D preventive care and (P = 0.0021), and explained almost 10% of the variability in DCCT HbA1c. case management. In conclusion, LW-1 is a novel robust marker which predicts progression of retinopathy and nephropathy and future progression of IMT and LVM & 1425-P increase independently of the effects of HbA1c. Incidence of End-Stage Renal Disease Continues to Decline in the Supported By: DK-79432; JDRF (17-2010-318); NEI (EY-07099); NIH/NIDDK/NEI U.S. Diabetic Population NILKA R. BURROWS, ISRAEL HORA, DESMOND E. WILLIAMS, LINDA S. GEISS, & 1423-P Atlanta, GA Genetics

Visit-to-Visit Systolic Blood Pressure (SBP) Variability and the We examined trends in end-stage renal disease (ESRD) incidence POSTERS Incidence of Microvascular Complications among a Nonelderly attributed to diabetes in the diabetic (DM) population and compared with Epidemiology/ Diabetic Population trends in ESRD due to causes other than diabetes in the nondiabetic (NonDM) MIN-WOONG SOHN, ELLY BUDIMAN-MAK, ELBERT HUANG, ELISSA H. OH, population. The U.S. Renal Data System was used to identify adults aged JENNY HUO, NOAM EPSTEIN, Hines, IL, Chicago, IL ≥18 years who began ESRD therapy from 1980 to 2011 with and without Objective: To examine the relationship between visit-to-visit SBP diabetes listed as the primary cause. Incidence per 100,000 was calculated variability and incidence of diabetic microvascular complications. using U.S. population estimates from the National Health Interview Survey Methods: Individuals <60 years who were treated for diabetes in 2003 in as denominator and age-adjusted to the 2000 U.S. population. Joinpoint the U.S. Department of Veterans Affairs healthcare system were followed for regression was used to assess trends and the annual percentage change fi ve years for any new diagnosis of diabetic retinopathy (ICD-9 250.5x, 369.xx, (APC). The age-adjusted rate in the DM population increased from 1980 to 366.41, 366.44, 362.01, 362.02), nephropathy (250.4x, 583.81), and neuropathy 1994 and then declined (APC= -3.2%, p<0.001). In the NonDM population, (250.6x, 354.xx, 337.1, 357.2). SBP variability (SBPV) were computed based on the rate increased from 1980 to 2002 and then leveled off (Figure with all measures taken on ≥3 days each year and the incidence of each complication different scales). In the DM population, rates declined beginning in 1990 for was modeled as a function of SBPV quartile in the previous year, adjusting for those aged 18–44 (APC= -3.3%), and in the late 1990s for those aged 45–64 demographic and clinical factors and mean SBP. (APC= -3.8%), 65–74 (APC= -4.1%), and ≥75 (APC= -2.8%) (all p<0.001). In the Results: The study cohort included 198,950 patients who had diabetes NonDM population, after an initial increase, rates leveled off around 2000 and BP measured on ≥3 days in 2003. On average, 2.8%, 0.9%, and 3.5% of in all groups except those aged 45-64, in whom rates increased signifi cantly diabetic patients experienced an incident diabetic retinopathy, nephropathy, throughout the period. ESRD incidence rates declined in the DM population and neuropathy, respectively, in each year of follow-up. Increased SBPV only. Better management of diabetes and other ESRD risk factors or better was associated with increased incidence of each complication and of any detection and management of kidney disease may explain the decline. complication (P for trend < 0.001 for all associations). This relationship persisted in all models examined, including one that controlled for mean SBP. Patients with the highest variability (Quartile 4) had 18% (OR = 1.18; 95% CI, 1.13 - 1.23; P < 0.001), 210% (OR = 2.10; 95% CI, 1.95 - 2.25; P < 0.001), 32% (OR = 1.32; 95% CI, 1.27 - 1.37; P < 0.001), 21% (OR = 1.21; 95% CI, 1.17 - 1.25; P < 0.001) higher incidence of retinopathy, nephropathy, neuropathy, and any complication, respectively, compared to the patients with the lowest variability (Quartile 1), after adjusting for mean SBP and demographic and clinical factors. Conclusions: Increased SBP variability was signifi cantly associated with increased incidence of microvascular diabetic complications. This is the fi rst study observing a graded association between increasing SBPV and risk of neuropathy and retinopathy.

& 1424-P Predictive Modeling of Potentially Preventable Hospital Admissions for Diabetes in Electronic Health Care Databases YITING WANG, PATRICK B. RYAN, MARTIJN SCHUEMIE, PAUL E. STANG, Titusville, NJ Potentially preventable hospital admissions (PPHA) may be avoided if at-risk patients can be identifi ed and effective interventions delivered. Our

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& 1426-P & 1428-P Sulfonylurea Use and Risk of Coronary Heart Disease among Risk for Alzheimer’s Disease in Type 2 Diabetic Patients Treated Patients with Type 2 Diabetes: A Prospective Cohort Study among with Metformin Women HUI WEN HSIAO, YI SUN YANG, YING LI LU, EDY KORNELIUS, JENG YUAN CHIOU, YANPING LI, YANG HU, SWAPNIL RAJPATHAK, FRANK B. HU, Boston, MA, Whiteh - CHIEN NING HUANG, Taichung, Taiwan ouse Station, NJ We aim to investigate whether using metformin in type 2 diabetes (T2D) Sulfonylureas (SU) may increase the risk of coronary heart disease (CHD) increase the risk of developing Alzheimer’s disease (AD). This is a case- by inhibiting ischemic preconditioning in the myocardium. Existing evidence control study from a Longitudinal Cohort of Diabetes Patients retrieved for the association of SU use and CHD among patients with diabetes is from databank of national health insurance in Taiwan. We obtained 65620 limited and inconsistent. Our study aimed to prospectively evaluate this patients with T2D treated with oral hypoglycemic agents (OHA) during association over a long term follow-up within a well-established cohort of 1999-2011. Risk-set sampling was used to defi ne patients suffering from U.S. women: the Nurses’ Health Study (NHS). We followed 5,798 women AD. Propensity score was performed for case pairing control. We used (mean age:68.3 years) with diabetes (mean duration:11years) who were free conditional logistic regression to analyze the risk of developing AD. A of CVD at baseline. Use of SU and other medications was self-reported at total of 462 patients diagnosed with AD, and 1848 patients in the control baseline and during follow-up. Cox proportional hazard regression models group. There were 85.1% and 79.7% treated with metformin in AD and were used to estimate the relative risk (RR) and 95% confi dence intervals control group, respectively. When adjusted for macro-, and microvascular (CI) for the association of SU use and incident CHD risk while accounting for complications, hypertension, hyperlipidemia, OHA other than metformin and several potential confounders (age, diabetes duration, BMI, lifestyle factors, insulin), there was no statistically signifi cant association between metformin family history of cardiovascular diseases, chronic conditions, regular use of use and the development of AD (OR 1.35). However, in patients who were medications, diabetic complications and plasma levels of hbA1c, HDL, TG and currently treated and who were given metformin cumulatively for more than creatinine). During the follow-up period of up to 10 years, we documented 4 years had a signifi cantly higher risk of developing AD (OR 2.79 and 1.79, 259 cases of incident CHD (fatal and non-fatal events). Compared to never respectively). In general, metformin did not signifi cantly increase the risk of users of SU, patients with diabetes who reported current use of SU were AD, however, for those who were currently treated and those who long-term at an elevated risk of incident CHD (RR:1.53;95% CI:1.06-2.21). In addition, used metformin had a higher risk of developing AD. The relevant mechanism increasing duration of SU use was signifi cantly associated with CHD risk need to be clarifi ed and are worthy of further investigation. (P-trend=0.01): the RR for CHD was 1.46 (0.99-2.17), 1.26 (0.78-2.03), 1.58 Table. Risk of Alzheimer’s Disease in Type 2 Diabetes Treatment with Met- (0.91-2.75) and 2.38 (1.27-4.45) for diabetic patients who had used SU therapy formin. for 1-5, 6-10, 11-15 and >15 years, respectively, as compared with never users. Crude OR 95%CI Adjusted OR 95%CI Furthermore, compared to metformin monotherapy, the multivariable RR for CHD was 2.58 (95%CI:1.14-5.86, P=0.02) for those on combination therapy of Metformin use - Nonuse Reference Reference metformin and SU. In conclusion, our fi ndings suggest that that current and Any use of metformin 1.46** 1.10-1.94 1.35 0.99-1.84 longer-term use of SU among patients with diabetes is associated with a Past use (discontinued metformin >30 days 1.11 0.82-1.50 1.08 0.79-1.50 signifi cantly increased risk of developing CHD. before AD) Genetics

POSTERS Recent use (discontinued metformin 1.46 0.97-2.20 1.22 0.78-1.90

Epidemiology/ & 1427-P Current use (continued to use metformin 3.20** 2.28-4.50 2.79** 1.94-4.03 The Impact of Ethnicity on Risk of Complications in Patients with when AD was diagnosed) Type 2 Diabetes—Findings from Multiethnic Asian Population Cumulative use of metformin < 2 years 1.38* 1.03-1.86 1.33 0.97-1.82 SUBRAMANIAM TAVINTHARAN, SU CHI LIM, LEE YING YEOH, XIAOWEI NG, WERN E.E. TANG, BIING MING SIMON LEE, CHEE FANG SUM, Singapore, Cumulative use of metformin ə 4 years 2.01** 1.40-2.89 1.79** 1.19-2.69 Singapore Complications in Type 2 diabetes (T2D) vary across different ethnic groups; contributed by genetic, cultural and environmental factors. In this 1429-P cross-sectional observation study, adults with type 2 diabetes (n=1818) were Real-World Evidence of Sub-optimal Treatment of Diabetic Peri- recruited from August 2011 in the ongoing SMART2D study. Urine, venous pheral Neuropathic Pain in U.S. blood, were collected after a 10-hour overnight fast. Anthropometry, foot- MEI YANG, CHUNLIN QIAN, Parsippany, NJ screen, retinal photography, microcirculatory endothelial dysfunction and Purpose: Diabetic peripheral neuropathic pain (DPNP) is a common measurements of vascular stiffness (PWV and AI) were performed. complica tion of diabetes mellitus. Current standard of care often does not Chinese made up 51%, Malays 23% and Indians 23%. Mean age was provide adequate pain relief and has dose-limiting side effects. This study 57.7 (10.6) years, diabetes duration 11.5 (9.0) years, with 50% males. Self- aims to understand the treatment patterns associated with commonly used reported history of coronary artery disease (CAD) was present in 12.1%, medications for DPNP. highest in Indians 19.6% (95%CI 14.4-26.0%), compared to 10% in Chinese Methods: Patients with diabetes (ICD-9-CM: 250.xx), and ≥1 diabetic and Malays, p<0.005. Compared to Chinese, peripheral artery disease (PAD) neuropathy diagnosis (250.6x or 357.2) during 2006- 2011 were selected and borderline low ABI was more common in Indians and Malays, p<0.005. from the MarketScan Commercial and Medicare Supplemental databases. Compared to non-Malays, Malays had a higher risk of nephropathy [OR 1.7 Other inclusion criteria included age ≥18 years at the date of the fi rst diabetic (95% CI 1.4 to 2.l)], and neuropathy [OR 2.0 (95% CI 1.4 to 2.9)], p<0.0001. neuropathy diagnosis (index date), continuous enrollment for ≥12 months No signifi cant ethnic difference was noted for retinopathy. While Malays before and after, and ≥1 prescription for any of the following drugs no later had signifi cantly higher weight and LDL-C, Indians, had higher visceral fat than 60 days after the index date (and none pre-index): anticonvulsants and augmentation index when compared to Chinese and Malays, and lower (pregabalin, gabapentin), antidepressants (amitriptyline, nortriptyline, HDL-C when compared to Chinese. desipramine, venlafaxine, valproate, duloxetine), opioids (morphine, tramadol, In conclusion, there exist signifi cant ethnic differences in risks of compli- oxycodone), and topical agents (capsaicin cream, lidocaine 5% patch). Adher- ca tions in our T2D patients. Indians have higher risk of macrovascular ence was defi ned as percent of days covered (PDC) and categorized into low complications: PAD and CAD, while Malays are at higher risk of microvascular (<.5), medium (.5-.8), and high (≥.8).Discontinuation (fi rst coverage gap of ≥90 complications: nephropathy and neuropathy, despite a signifi cantly shorter days) rates were calculated using Kaplan-Meier curve. duration of diabetes than Chinese. Further studies to explain the mechanisms Results: A total of 10,912 patients met the inclusion criteria, 52% male and for varying risk may provide options for risk reduction. mean age 61 years old. Gabapentin was most often fi rst dispensed (43.8%), Abbreviations and defi nitions: followed by pregabalin (22.7%), tramadol (9.5%), amitriptyline (6.8%) and duloxetine (5.4%). These rates for the rest of the medications were <5%. PWV-pulse wave velocity. Low adherence was frequent among pregabalin (69%), gabapentin (68%) and AI-Augmentation index. duloxetine (51%) patients. The 1-year discontinuation rates for duloxetine, ABI-Ankle brachial Index. gabapentin, and pregabalin were 63%, 75%, and 78%, respectively. Nephropathy-Estimated GFR <60 micromole/l or ACR>30mcg/mg. Conclusions: This study found that anticonvulsants were the most often PAD-ABI 0.9. ≤ used treatments for patients with DPNP despite their low adherence and Borderline ABI-0.91 to 0.99. high discontinuation rates. Supported By: NMRC

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1430-P The Impact of Language Barriers on Acute and Chronic Complications of Diabetes KAREN OKRAINEC, GILLIAN BOOTH, CHAIM BELL, Toronto, ON, Canada Language barriers have been associated with decreased access to care and increased mortality in some immigrant populations. We examined the impact of language barriers on the risk of acute and chronic complications of diabetes using linked administrative health and immigration databases from Ontario, Canada. Adults (≥ 20 yrs) with diabetes who immigrated between 1985 and 2002 were included in our cohort and categorized as having or not having a language barrier based on their self-reported assessment of language ability at the time of their offi cial immigration application. We examined the impact of a language barrier on the risk of acute or chronic complication and all-cause mortality from March 31st, 2005 until February 29th, 2012. A total of 87,707 immigrants with diabetes were included in our cohort with 38% of immigrants having a language barrier. Immigrants with language barriers were older at landing (mean age 49±15 vs. 42±13 yrs, P<.001) and at time of diabetes diagnosis (mean age 55±14 vs. 48±13 yrs, P<.001), more likely to be female (59% vs. 43%, P<.001), to have immigrated for family reunifi cation (66% vs. 38%, P<.001), had less education (secondary or less 82% vs. 53%, P<.001) and higher use of health care (mean visits 9±12 vs. 8±11, P<.001). There was a higher unadjusted rate of complications among immigrants with language barriers (acute complications HR=1.12, 1432-P 95%CI=1.06-1.17; cardiac complications or all-cause mortality HR=1.37, Caffeine Intake Contributes to Skin Intrinsic Fluorescence (SIF) in 95%CI=1.33-1.42) however these differences were largely eliminated Subjects with Type 1 Diabetes (T1DM) after adjusting for baseline characteristics (acute complications HR=0.99, KAREN M. ENY, TREVOR J. ORCHARD, RACHEL G. MILLER, JOHN D. MAYNARD, 95%CI=0.93-1.05; cardiovascular complications or all-cause mortality DENIS M. GRANT, PATRICIA A. CLEARY, BARBARA H. BRAFFETT, ANDREW D. HR=0.95, 95%CI=0.91-0.99). Signifi cant predictors included being unmarried, PATERSON, DCCT/EDIC RESEARCH GROUP, Toronto, ON, Canada, Pittsburgh, PA, settling in a rural neighbourhood and having less education. There is an Albuquerque, NM, Rockville, MD equal if not slightly lower risk of diabetic complications among immigrants SIF is a non-invasive biomarker, which partially refl ects advanced glycation with language barriers; however the impact of language may vary based on end-products and has been positively associated with coronary artery disease level of family support, education and social isolation. (CAD). A genetic variant (rs1495741) in NAT2, which tags acetylation status, was Supported By: CIHR recently identifi ed as a major locus for SIF. Since NAT2 metabolizes caffeine and variants in complete linkage disequilibrium with rs1495741 have also Genetics

1431-P been associated with plasma and urine metabolites of caffeine, we examined POSTERS Characterization of Sitagliptin Use in Patients with Type 2 Diabetes whether caffeine intake is associated with SIF and how they jointly relate Epidemiology/ and Chronic Renal Disease with SIF. SIF was measured in 1181participants with T1DM (age 35-67 years) KIMBERLY G. BRODOVICZ, YONG CHEN, ZHIWEN LIU, MARY E. RITCHEY, JANE in the Epidemiology of Diabetes Interventions and Complications (EDIC) study. LIAO, SAMUEL S. ENGEL, Whitehouse Station, NJ Two measures of SIF were used; SIF1, using a 375nm excitation light emitting Chronic renal disease (CRD) is common in patients with type 2 diabetes diode (LED) and SIF14, using a 459nm LED. Food frequency questionnaires were (T2DM); 20-30% of patients have moderate-severe renal impairment, used to calculate mean caffeine intake. Higher caffeine intake was signifi cantly complicating T2DM treatment choices. As CRD patients are particularly associated with higher SIF1 (p=2x10-32) and SIF14 (p=7x10-31). In unadjusted susceptible to safety/tolerability issues related to many other classes of analyses, caffeine explained 11% of the variance in SIF1 and SIF14, and explained oral antihyperglycemic agents (OAHA), DPP-4 inhibitors such as sitagliptin 4-5% after accounting for covariates including age, smoking and repeated may be preferentially used in CRD patients. To further assess this, the measures of hemoglobin A1c. When analyzed together, caffeine intake and characteristics of sitagliptin users with CRD were analyzed. NAT2 both remained highly signifi cantly associated with SIF1 and SIF14. Mean Patients with T2DM and CRD were identifi ed from MarketScan between caffeinated coffee intake was also positively associated with SIF1 (p=9x10- 2006-2012. Patients starting sitagliptin or OAHA as mono, dual, or triple 12) and SIF14 (p=4x10-12), but no association was observed for decaffeinated therapy were compared. Demographic and clinical characteristics within 5 coffee intake. In order to determine whether the caffeine association with SIF years before therapy start were assessed. was reproducible, we examined a second cohort of participants with T1D from Compared to patients starting OAHAs, CRD patients starting sitagliptin the Pittsburgh Epidemiology of Complications study. Using similar methods for as mono or dual therapy were older, had more physician visits, were more measuring SIF and caffeine intake, caffeine was positively associated with likely to have a history of heart failure or arrhythmia, and were more likely SIF1 (p<0.0001) and SIF14 (p<0.0001). These fi ndings demonstrate that caffeine to use loop diuretics or beta-blockers (table). In triple therapy patients, contributes to SIF. Accounting for caffeine intake may improve risk prediction the differences between groups were not as pronounced but the overall models for SIF and CAD in individuals with diabetes. proportion of comorbidities in these patients was higher. Similar to prior Supported By: NIDDK observations in a general T2DM population, CRD patients prescribed sitagliptin tend to be older and have more comorbidities than patients 1433-P prescribed other classes of OAHA. Active Cocaine Use Does Not Increase Likelihood of Hyperglycemic Crisis among Inpatients with Hyperglycemia in an Urban Hospital DEVIN STEENKAMP, DENIS RYBIN, JANICE WEINBERG, SARA ALEXANIAN, MARIE MCDONNELL, Boston, MA Hyperglycemic crisis (HC); including diabetic ketoacidosis (DKA,) hyper - osmolar hyperglycemic state (HHS,) and the overlap syndrome of hyper- osmolar ketoacidosis (HK) are common endocrine emergencies. Cocaine has the potential to exacerbate hyperglycemia and directly increases counter-regulatory hormones involved in the pathophysiology of HC. Previous research has suggested that cocaine may contribute as an independent risk factor for DKA. We performed a retrospective case-control analysis to compare a group of individuals with HC to a group of non-crisis hyperglycemic (glucose >250mg/ dl on admission) individuals with respect to cocaine exposure. Cocaine use was defi ned as positive urinary cocaine metabolites on admission. Our primary aim was establishing whether cocaine is an independent risk factor for hyperglycemic crisis.

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We used multivariable logistic regression to adjust for the following 2006 to March 2011. To determine precise outcomes, we simultaneously potential confounders: age, gender, race, language, education, BMI and A1c. used a national representative database: claims data from the Health We retrospectively identifi ed 950 hyperglycemic inpatients between July Insurance Review & Assessment Service of Korea. 2004 and December 2010 with available admission data for hyperglycemic During a mean follow-up period of 3.4±0.9 years, 118 subjects experienced crisis determination and urine cocaine metabolites. 133 patients met criteria hypoglycemia-related events. In the subjects, the incidence of dementia was for hyperglycemic crisis [77 DKA (8.1%), 67 HHS (7.1%) and 15 HK (1.6%)] HC 7.50 cases per 1,000 person-years (PY), and the incidence of other cognitive group was younger (44.9 vs. 47.7 years, p=0.008), was different ethnically dysfunction was 0.61 cases per 1,000 PY. The incidence of dementia was (p=0.035) and had higher A1c (11.7% vs. 10.3%, p<0.001) Cocaine use was signifi cantly higher in the subjects who experienced hypoglycemic events not signifi cantly different (p=0.901) among the groups i.e. 16.9% non-crisis (p=0.0139), while the incidence of other cognitive dysfunction was not hyperglycemic group vs. 14.3% HC group (16.9% DKA, 16.4% HHS and 6.7% (p=0.1106). Hypoglycemic event was signifi cantly associated with dementia HK.) The multivariable analysis showed no signifi cant association between (HR 2.689, 95%CI 1.080-6.694, p=0.0335) after multiple adjustments. We cocaine use and HC (adjusted OR 0.74, 95%CI 0.27-2.08, p=0.572). also observed a signifi cant linear trend of increased dementia risk with Our results suggest that among patients admitted with hyperglycemia, increasing number of hypoglycemic events (p=0.0286). cocaine is not independently associated with the development of HC and In conclusion, hypoglycemia is signifi cantly associated with the risk of that cocaine does not lead to increased severity of HC. dementia in Korean patients with T2DM whose age is ≥60 years old. Supported By: Korea Healthcare Technology R&D Project (HI10C2020) 1434-P Incidence of Diabetes and Diabetes Complications among Migrants 1436-P in Denmark Estimated from 6.5 Million Individuals 10-Year Trends in Care and Outcomes of Medicare Patients with MARIT E. JØRGENSEN, ZAZA KAMPER-JØRGENSEN, BENDIX CARSTENSEN, Type 2 Diabetes MARIE L. NØRREDAM, IB C. BYGBJERG, GREGERS S. ANDERSEN, Gentofte, Den- KRISTEN A. HYLAND, MELISSA GREINER, LAURA QUALLS, ASHLEY A. DUNHAM, mark, Copenhagen, Denmark ADRIAN HERNANDEZ, MARIE L. MIRANDA, ROBERT CALIFF, LESLEY CURTIS, Background: Studies of diabetes among migrants have generally shown Durham, NC, Ann Arbor, MI higher prevalence compared to the countries of origin, but incidence studies The prevalence of diabetes in the United States is growing, and guidelines of complications are lacking. The aim of the study was to examine incidence give recommendations for care of diabetes patients. Contemporary trends in rates of diabetes and diabetes complications among ethnic minorities in care and outcomes have not been described among Medicare benefi ciaries. Denmark compared to the Danish background population. We evaluated trends in diabetes health care and outcomes using a 5% Methods: Information was obtained from linkage of the National Diabetes sample of Medicare fee-for-service claims from January 1, 2001 through Register, the Cause of Death Database and the National Patient Register December 31, 2011 for benefi ciaries aged 65 years or older with prevalent with information from the Central Personal Register on country of origin. diabetes as defi ned by the Medicare Chronic Condition Warehouse. Age- and sex-specifi c incidence rates, mortality rates and standardised From 2002 to 2011, diabetes prevalence in the Medicare fee for service mortality ratios relative to the non-diabetic part of the population were population increased from 20.0 to 27.8%. Average age of Medicare patients calculated by Poisson regression and Cox regression analysis, based on with diabetes increased slightly from 76.3 to 76.7 and age was similar in the follow up of the entire Danish population. overall Medicare population. Over the time period, the proportion of men Genetics

POSTERS Results: Compared with Danes, the incidence of diabetes was about 2.5 increased (42.3 to 45.1) and proportion of whites decreased (83.1 to 82.3). From Epidemiology/ times higher among migrants from Africa, Asia and Middle East, whereas 2002 to 2011, the coded prevalence of many comorbid conditions increased. the incidence among migrants from Europe and America was some 20% Screening practices in diabetics improved from 2002 to 2011, with rising lower. The highest incidence of microvascular complications was observed rates of foot exams, renal screening, A1c labs, and lipid profi le labs. The among migrants from Africa, Asia and Middle East (fi gure). Higher incidence coded prevalence of nephropathy and neuropathy increased, while 1-year rates of coronary heart disease were observed among migrants from the mortality declined. Although inpatient admissions declined from 2002 to Middle East and Asia (fi gure). 2011, emergency room visits increased. Conclusion: The burden of diabetes and its complications is greater among Despite marked improvement in screening practices among Medicare several ethnic minorities compared to Danes. patients with diabetes, diabetic outcomes as coded in claims data have not improved consistently.

1435-P Hypoglycemia Is Signifi cantly Associated with Cognitive Dys- function in Elderly Patients with Type 2 Diabetes Mellitus: An Analysis Based on the Korea National Diabetes Program Cohort SANG YOUL RHEE, SUK CHON, SOO MIN HONG, SO YOUNG PARK, SANG OUK CHIN, JOO YOUNG KIM, IE BYUNG PARK, KYU JEUNG AHN, IN JU KIM, SUNG- HOON KIM, HYOUNG WOO LEE, KYUNG SOO KO, DOO MAN KIM, SEI HYUN BAIK, YONGSOO PARK, MOON SUK NAM, KWAN WOO LEE, JEONG-TAEK WOO, YOUNG SEOL KIM, Seoul, Republic of Korea, Suwon, Republic of Korea, Incheon, Republic of Korea, Busan, Republic of Korea, Daegu, Republic of Korea There is some evidence that hypoglycemia is associated with cognitive dysfunction such as dementia in patients with type 2 diabetes mellitus (T2DM). However, this is controversial. We evaluated the associations among hypoglycemia, dementia, and other cognitive dysfunction in T2DM patients based on the Korea National Diabetes Program (KNDP), which is the largest multi-center, prospective cohort in Korea. We used the data for subjects ≥60 years with no history Supported By: U.S. Dept. of Health and Human Services (1C1CMS331018); Bristol- of hypoglycemia or cognitive dysfunction (n=1,957) in the cohort from June Myers Squibb Foundation

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1437-P areas and 50% use both VA and Medicare systems (dual use) for outpatient Prevalence of Vestibular Pathology in People with Type 2 Diabetes care; such dual use may result in fragmented and poorly coordinated care. The LINDA J. D’SILVA, JAMES LIN, CARLA H. SABUS, KEVIN SYKES, HINRICH purpose of this study was to assess whether rural residence and dual system STAECKER, PATRICIA M. KLUDING, Kansas City, KS use are associated with wound outcomes. This retrospective cohort study was Diabetes has the potential to cause microvascular damage to the vestibular conducted in the VA’s Northwest Health Network and included 320 Veterans system. As the inner ear does not have the capacity for energy storage, it is (160 rural and 160 urban) who had incident chronic LL wounds between sensitive to fl uctuations in blood glucose levels. The purpose of this retrospective October 1, 2006 and September 30, 2007. All wounds were identifi ed through chart review was to identify the prevalence of specifi c vestibular disorders in VA medical record visit notes and followed for 1 year. Medicare administrative patients with and without type 2 diabetes (T2D) with complaints of vertigo. fi les were searched to identify dual care. We used Cox proportional hazards Retrospective data from the electronic medical records of patients seen models to calculate hazard rates for wound healing, treating amputation and at an academic medical center was collected from 10/1/2006- 12/31/2012. death as competing risks, and adjusted for confounders. 21% of rural Veterans Data extracted include include type of vertiginous disorder, age, sex, smoking and 19% of urban Veterans received wound care through VA and Medicare history and presence of comorbidities like T2D and hypertension. Descriptive (dual use) and 57% and 61%, respectively, had diabetes. Chronic wound statistics were used to summarize the patient demographics. Chi square healing did not differ by rural residence, and in fact, there was a suggestion tests were used to compare differences in population proportions (α=0.05). of better wound healing among rural compared to urban patients (age- and Logistic linear regression models were used to determine the variables that chronic condition-adjusted HR=1.26, 95%CI: 0.98-1.63, p=0.075). Dual use are most predictive of benign paroxysmal positional vertigo (BPPV). compared to exclusive VA wound care was associated with a 50% lower Of the 4033 patients with vertiginous symptoms, 3322 were non-diabetic hazard of healing (HR=0.51, 95%CI: 0.35-0.74). Dual system wound care, but and 711 patients had diabetes. Greater prevalence of BPPV (p<0.001) and not rural residence, was associated with poorer chronic wound outcomes. This labyrinthitis (p<0.001) were seen in people with T2D. Unspecifi ed peripheral association was not explained by variation in the quality of VA wound care; vertigo (p= 0.014), other disorders of labyrinth (p= 0.0005) and Meniere’s Medicare quality and coordination should be investigated along with other disease (p= 0.0002) were more frequent in people without T2D. Of the features of dual use that might impede healing. predictive variables examined in the regression model, hypertension was Supported By: U.S. Dept. of Veterans Affairs (IBA 09-061) most predictive of BPPV (p<0.001). However, diabetes showed a strong relationship with hypertension (p<0.001). 1440-P These results indicate a higher prevalence of two vestibular conditions, Additive Effects of Blood Glucose Lowering Drugs, Statins, and BPPV and labyrinthitis, in people with T2D. BPPV is a condition that is Renin Angiotensin System Blockers on All-Site Cancer Risk successfully treated when appropriately identifi ed. Knowing that T2D ALICE KONG, RONALD C. MA, ANDREA LUK, JULIANA C.N. CHAN, Sha Tin, China, increases the prevalence of BPPV will help clinicians develop their evaluation Hong Kong, China and treatment plans to assess dizziness promptly as BPPV is an easily Hyperglycemia is associated with increased risk of all-site cancer which treatable condition. Future studies looking at the impact of T2D and BPPV on may be mediated through activation of the renin-angiotensin system (RAS) the clinical presentation of these patients are necessary. and 3-hydroxy-3-methyl-glutaryl-CoA-reductase (HMGCR) pathways. Supported By: T32HD057850 We examined the joint associations of optimal glycemic control (A1c<7%) and use of RAS and HMGCR inhibitors on incident cancer in a prospective Genetics

1438-P cohort of Chinese type 2 diabetic patients without history of cancer and POSTERS Incretin Therapies and Risk of Pancreatitis prior exposure to these drugs. After a median (interquartile range) follow- Epidemiology/ PETER BOYLE, JULIO ROSENSTOCK, MARIA BOTA, Lyon, France, Dallas, TX up period of 4.9 (2.81-6.98) years, 271 of 6103 patients developed all-site Concerns have been raised about an association between incretin-related cancer. At baseline, patients with incident cancer were older, had longer therapies for type 2 diabetes and the risk of pancreatitis. To shed light on this disease duration, higher alcohol and tobacco use, higher systolic blood association, meta-analyses were undertaken between use of incretin-based pressure and albuminuria but lower triglyceride levels and estimated therapies, use of GLP-1 RAs and use of DDP-4 inhibitors and risk of pancreatitis. glomerular fi ltration rate (p<0.05). During follow-up, patients who developed Combined use of incretin-based therapies carries a Summary Relative Risk cancer were less likely to be started on statins (22.5%versus38.6%,p<0.001), (SRR)=1.08 (95% CI (0.87, 1.34)) for pancreatitis compared to use of other anti- fi brates (5.9%versus10.2%,p=0.02), metformin (63.8%versus74.5%,p<0.001) diabetic medications. The use of GLP-1 RAs (SRR=1.09 (0.79, 1.52)) and DPP-4 and thiazolidinedione (TZD) (0.7%versus6.8%,p<0.001) than those who inhibitors (SRR=1.15 (0.85, 1.54)) do not appear to have an increased risk of remained cancer-free. After adjusting for covariables, new treatment with pancreatitis. When short-term randomized trials are excluded, combined use metformin [hazard ratio(95% confi dence intervals): 0.39(0.25-0.61),p<0.001), of incretin-based therapies have an increased risk for pancreatitis compared to TZD [0.18(0.04-0.72),p=0.015], sulphonylurea [0.44(0.27-0.73),p=0.014], using other anti-diabetic medications (SRR=1.26, (1.01, 1.57)). However, specifi c insulin [0.58(0.38-0.89),p=0.01], statins [0.47(0.31-0.70),p<0.001] and RAS use of GLP-1 RAs (SRR=1.27 (0.95, 1.71)) nor DPP-4 inhibitors (SRR=1.26 (0.71, inhibitors [0.55(0.39-0.78),p<0.001) were associated with reduced cancer 2.24) do not appear to signifi cantly increase the risk of pancreatitis although risk. Patients with all 3 risk factors of A1c≥7%, non-use of RAS inhibitors unexplained variability in individual fi ndings is substantial. and statins had 4-fold adjusted higher risk of cancer than those without Despite point estimates in excess of 1.0, the wide CIs (due to relatively low any [incidence per 1000-person-years for 0 versus 1 versus 2 versus 3 risk events) do not appear to indicate an increased pancreatitis risk with specifi c factors: 3.40(0.07-6.72); 6.34(4.19-8.50); 8.40(6.60-10.20), 13.08(9.82-16.34) incretin therapies when compared to other anti-diabetic agents. Important respectively, p<0.001]. Hyperglycemia may promote cancer growth which limitations of these meta-analyses include incomplete data sources, selective can be attenuated by optimal glycemic control and inhibition of the RAS and populations, short follow-up, inconsistent criteria for diagnosing pancreatitis HMGCR pathways. and, consequently, a large degree of unexplained variability between individual Supported By: HKFRDD; Chinese University of Hong Kong study fi ndings which limit drawing defi nitive conclusions. This systematic review and meta-analysis suggests that there may be a 1441-P real signal in pancreatitis risk with incretin-based therapies but the increased Vitamin D Status and Diabetic Retinopathy in a Biracial Cohort risk is small. Carefully designed large prospective, population-based registry AMY E. MILLEN, MICHELLE W. SAHLI, MICHAEL J. LAMONTE, JING NIE, PAMELA L. studies with appropriate follow-up and key clinical information are urgently LUTSEY, BARBARA E. KLEIN, JULIE A. MARES, KRISTEN J. MEYERS, CHRISTOPHER needed to answer these critical safety questions. A. ANDREWS, RONALD KLEIN, Buffalo, NY, Minneapolis, MN, Madison, WI, Ann Arbor, MI 1439-P Vitamin D status has been hypothesized to protect against development Rural Residence, Dual System Use, and Chronic Wound Outcomes of diabetic retinopathy (DR) via its anti-infl ammatory and anti-angiogenic ERIN D. BOULDIN, ALYSON J. LITTMAN, KENNETH M. RICE, GAYLE E. REIBER, properties. Additionally, in vitro and in vivo studies suggest vitamin D infl uences Seattle, WA blood pressure and blood glucose control, two strong risk factors for DR. People with diabetes have an increased risk of chronic lower limb (LL) We investigated the association between vitamin D status and prevalent wounds and a more complicated healing process. Wounds become chronic DR among 1,355 participants (917 Whites, 438 Blacks), with diabetes at visit when they fail to progress through the expected phases of healing, contributing 3 (1993-95), in the Atherosclerosis Risk in Communities Study, a population- to disability, decreased quality of life, and amputation. The VA health care based biracial cohort. system serves a large population of adults, among whom the burden of chronic Vitamin D status was assessed with serum 25-hydroxyvitamin D (25(OH) conditions and the risk for LL wounds is high. 41% of Veterans live in rural D) concentrations from visit 2 (1989-92). DR was assessed at visit 3 with

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nonmydriatic retinal photographs of one randomly chosen eye. Logistic The GRS was signifi cantly associated with BMI in all 3 cohorts (increase regression was used to estimate odds ratios (ORs) and 95% confi dence of 1.62 kg/m2 per average risk allele, P< 0.001). BMI was not signifi cantly intervals (CIs) for DR by clinically defi ned categories of 25(OH)D in nmol/L associated with DKD in any of the 3 cohorts (combined odds ratio [OR] for an (defi cient <30, inadequate 30-<50, and two categories with adequate status increase of 1 kg/m2 in BMI, 1.00, 95% CI 1.00 – 1.01, P=0.19). However, each 50-<75 and ≥75). P for linear trend was estimated using continuous 25(OH) 1 kg/m2 in BMI due to GRS was signifi cantly associated with increased risk D concentrations. ORs were adjusted for race and duration of diabetes. We of DKD in all 3 cohorts (OR 1.05, 95% CI 1.02 – 1.08, P=0.001). further adjusted for HbA1C and hypertension to examine if vitamin D status We also investigated the impact of BMI on DKD subtypes. Higher BMI infl uenced DR via its effects on either glycemic control or blood pressure. was associated with risk of macroalbuminuria by both observational The prevalence of DR was 21%, and 7% of participants were vitamin epidemiology (OR 1.02, 95% CI 1.01 – 1.02, P<0.001) and GRS (OR 1.05, 95% D defi cient. ORs (95% CIs) for DR, with adjustment for race and duration CI 1.02 – 1.08, P=0.001). In contrast, for end-stage renal disease (ESRD), of diabetes, were 0.82 (0.47-1.43), 0.69 (0.40-1.21), and 0.42 (0.21-0.83), p there was a lower risk for each 1 kg/m2 increase in BMI from observational for trend=0.003, for participants with 25(OH)D concentrations of 30-<50, epidemiology (OR 0.99, 95% CI 0.98 – 0.99, P<0.001), and a trend toward an 50-<75, and ≥75 nmol/L, respectively, versus those defi cient (<30). Further increased risk of ESRD in 2 of 3 cohorts with higher BMI by GRS (OR 1.02, adjustment for hypertension minimally infl uenced results (OR [95% CI] for 95% CI 1.00 – 1.04, P=0.069). ≥75 versus <30 nmol/L =0.41 [0.21-0.82], p for trend=0.002), but adjustment In conclusion, genetic factors associated with increased BMI raise the for HbA1C attenuated the OR (0.50 [0.24-1.03], p for trend=0.04). Results did risk of DKD even in the context of T1D, suggesting a causal link between not vary signifi cantly by race. obesity and DKD. As obesity prevalence rises in people with T1D, this fi nding An adequate vitamin D status of ≥75 nmol/L was associated with reduced predicts an increase in DKD in this population unless intervened upon. odds of DR, perhaps through its infl uence on blood glucose control. Supported By: T32DK007260-35 Supported By: NIH (R01AG041776) 1444-P 1442-P Plasma Homocysteine and Carotid Intima-Media Thickness in Type Type 1 Diabetes Complications Are Associated with Risk of Falls, 1 Diabetes Fall Injuries, and Fractures in Middle-aged Adults ARPITA BASU, ALICIA J. JENKINS, JULIE A. STONER, SUZANNE THORPE, ELSA S. STROTMEYER, MARY E. WINGER, JANE A. CAULEY, TREVOR J. RICHARD KLEIN, MARIA F. LOPES-VIRELLA, W. TIMOTHY GARVEY, TIMOTHY ORCHARD, Pittsburgh, PA LYONS, DCCT/EDIC RESEARCH GROUP, Stillwater, OK, Oklahoma City, OK, Type 1 diabetes is associated with a markedly increased fracture risk Columbia, SC, Charleston, SC, Birmingham, AL, Belfast, Ireland though the reason is uncertain. Therefore we evaluated risk factors for Plasma homocysteine (tHcy) has been positively associated with carotid falls, fall injuries and fractures in the Pittsburgh Epidemiology of Diabetes intima-media thickness (IMT) in non-diabetic populations and in a few cross- Complications Study, a historical prospective cohort study of childhood sectional studies of diabetic patients. We investigated the prospective onset type 1 diabetes diagnosed at Children’s Hospital of Pittsburgh in association between tHcy and progression of common and internal carotid 1950-80. Subjects were enrolled in 1986-88 and followed biennially. Falls IMT over a 6-year period in type 1 diabetes. tHcy was measured in plasma and fall injuries in the past year and ever fracturing after age 20 years were obtained in 1998-2000 from patients (n=599) from the Epidemiology of Diabetes collected in 2 follow-up surveys over 4.0+0.5 years after the 18 year exam Interventions and Complications (EDIC) study, the observational follow-up Genetics

POSTERS for 405 participants with 110 (27%) falls (47 with >2 falls; 12%), 56 (14%) phase of the Diabetes Control and Complications Trial (DCCT). Common and Epidemiology/ fall injuries and 179 (44%) fractures. Demographic and anthropometric internal carotid IMT were determined by B-mode ultrasonography. Plasma characteristics, medical conditions and diabetes comorbidities were also tHcy [median and interquartile range: 6.2 (5.1, 7.5) µmol/L] signifi cantly collected at the 18 year exam. Participants with falls were older than those correlated with age, diastolic blood pressure, renal dysfunction and smoking without falls (aged 50+8 vs. 46+7 years), with similar older ages for fall (all p<0.05). In unadjusted models, common and internal carotid IMT correlated injuries (51+8 vs. 46+7 years) and fractures (49+8 vs. 45+7 years; all p<0.05). with increasing quartiles of tHcy at EDIC years 6 (1998-2000) and 12 (2004- Forward stepwise logistic regression modeled odds ratio (OR) of outcomes. 2006) (Figure 1; p<0.01), though not signifi cantly when adjusted for covariates. Longer diabetes duration was signifi cantly associated with outcomes and Multivariate logistic regression revealed no signifi cant associations between adjusted for in analyses as were sex and high A1C. Higher BMI (OR=1.1; increasing quartiles of tHcy or the 6-year change in common and internal 95%CI: 1.0-1.1) and worse vibration threshold score at the great toe (OR=1.1; carotid IMT (highest vs. lowest quintile) when adjusted for covariates. Thus, 95%CI: 1.0-1.2) were related to falls while distal symmetric polyneuropathy plasma tHcy is associated with increased carotid IMT at EDIC years 6 and 12, was related to >2 falls (OR=4.2; 95%CI: 1.2-15.0) and fall injury (OR=2.6; but not with IMT progression, in type 1 diabetes. 95%CI: 1.1-6.5). Nephropathy (OR=2.2; 95%CI: 1.2-3.8) was associated with fracture, while proliferative retinopathy (OR=0.56; 95%CI: 0.33-0.96) was a protective factor. Further adjustments did not alter results. Findings suggest that neuropathy is associated with falls while nephropathy correlates to fractures in middle-aged adults with type 1 diabetes. Further exploration of these potential pathways is warranted in order to develop preventive strategies for falls and fractures. Supported By: ADA (1-04-JF-46); R01DK034818; Epidemiology of Diabetes Complications

1443-P Obesity and Risk of Diabetic Kidney Disease: A Mendelian Randomi- zation Study JENNIFER TODD, RANY SALEM, EMMA FAGERHOLM, NIINA SANDHOLM, CAROL FORSBLOM, PER-HENRIK GROOP, JOEL N. HIRSCHHORN, JOSE C. FLOREZ, Boston, MA, Cambridge, MA, Helsinki, Finland Obesity has been posited as an independent risk factor for diabetic kidney disease (DKD); however, epidemiologic studies have produced confl icting results, and establishing causality from observational data is diffi cult. Because obesity has a strong heritable component (heritability estimates ranging 40-70%), a Mendelian randomization approach, which exploits the random assortment of gene variants during meiosis, can be leveraged to assess the causal nature of obesity on the development of DKD. We used a weighted genetic risk score (GRS) as an instrument to test the relationship of body mass index (BMI) with DKD, using 32 loci associated with BMI and weighting each risk allele by its published effect size, in each of 3 cohorts of participants with type 1 diabetes (T1D) with and without DKD (n=6049). Supported By: NIH

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1445-P 1447-P Beta-Cell Function Is Associated with Gastrointestinal Symptoms Prevalence of Advanced Liver Fibrosis and Nonalcoholic Steato- in Type 2 Diabetic Patients hepatitis Diagnosed by Noninvasive Methods in Chilean Type 2 YUN HUANG, MINXIA ZHANG, WENYA LI, JINHUA WANG, JI HU, Suzhou, China Diabetic Patients To investigate the association between beta cell function and CONSUELO GALLEGO, JUAN P. VALDERAS, SERGIO URIBE, CRISTIAN TEJOS, gastrointestinal (GI) symptoms in type 2 diabetic patients, we consecutively CRIS TO BAL SERRANO, ALVARO HUETE, FRANCISCO BARRERA, JESSICA LIBER- recruited 453 diabetic patients with diabetes duration more than 5 years into ONA, PILAR LABBE, TERESA QUIROGA, PABLO IRARRAZABAL, MARCO ARRESE, the study. Fasting c-peptide was adopted to assess beta cell function in the Santiago, Chile present study. Patients filled out questionnaires of gastroparesis cardinal Patients with Type 2 Diabetes (T2D) are at risk for developing end-stage symptom index (GCSI) to evaluate GI symptoms and the hospital anxiety and liver disease due to the co-existence of nonalcoholic steatohepatitis (NASH). depression scale (HADS) to objectify symptoms of anxiety and depression. A Alternative noninvasive methods to the liver biopsy have been validated for GCSI score ≥1.90 indicated defi nite symptoms of gastroparesis. One hundrend assessing the severity of nonalcoholic fatty liver disease (NAFLD). Data on and twenty patients with histories of GI diseases were excluded from the prevalence of advanced fi brosis and NASH evaluated by these methods is present study, leaving 71 (21.3%) patients with symptoms related to diabetic scarse. gastroparesis. Compared to patients with GCSI scores <1.90, those with We performed a longitudinal cohort study in 109 consecutive T2D patients. GCSI scores ≥1.90 had remarkably lower levels of c-peptide (1.72±0.89 vs. The presence of cirrhosis or advanced fi brosis was evaluated by magnetic 2.08±1.23, P=0.01 ) and higher prevalence of depression (40.9% vs. 18.3%, resonance imaging (MRI), Fibrotest® (BioPrective) and NAFLD fi brosis score P<0.0001). In multivariate analysis, after adjustments for age, sex, BMI, (Angulo P. et al. Hepatology 2007). NASH was evaluated by Actitest and HbA1c, current smoking and drinking status, anxiety and depression, fasting cytokeratin 18 (CK-18). Inclusion criteria were Type 2 DM, age older than c-peptide was still signifi cantly associated with symptoms of gastroparesis 55 years, alcohol consuming less than 15 gr in women and 30 gr in men, (odds ratio,0.67 [0.48-0.94]; P=0.021). Furthermore, linear regressions also absence of other hepatic diseases or exposition to hepatotoxic agents. Data showed in the patients with at least one GI symptom, fasting c-peptide was expressed as mean and 95% CI. was independently and negatively related to GCSI scores (standardized 60% were women, age was 60.7 years, (59.8-61.7) BMI was 29.7 kg/ regression coeffi cient, -0.26; P=0.0005). In conclusion, in the present study, m2 (28.8-30.6), diabetes duration was 7 years (5.8-8.2), HbA1c was 7.4 % symtoms of gastroparesis affect approximately 20% of type 2 diabetic (7.1-7.7). 68.8% had hepatic steatosis and 5.5% had hepatic cirrhosis in patients and might be linked to the deterioration of beta cell function. MRI. 3.6% had advanced fi brosis by Fibrotest Score and 7.3% by NAFLD Supported By: Natural Science Foundation of Jiangsu Province (SBK201340560) Score. 13.7% had positive at least one method. 12.1 % patients had Actitest positive and 21.1 % had CK-18 level higher than 246 U/L. 27.7% had positive 1446-P at least one. Patients with advanced fi brosis were older than subjects Glycemic Control and Long-term Vascular Risks in Patients Treated without fi brosis (64.9 [62.1-67.8] vs. 60.9 [59.2-61 years, p <0.001). There with Insulin and Incretin-based Therapy were not differences between patients with or without fi brosis or NASH in SANJOY K. PAUL, KERENAFTALI KLEIN, JAMES W. SHAW, JENNIE H. BEST, BMI, diabetes duration and HbA1c. Brisbane, Australia, Princeton, NJ, Seattle, WA We found a high frequency of advanced hepatic fi brosis and NASH in This longitudinal cohort study compared the glycemic effectiveness of 2TDM patients. There were not clinical features able to predict the presence of these conditions. At least a 13.7% of these patients are in high risk to Genetics insulin- (INS) and incretin-based drugs, and the effect of changes in HbA1c POSTERS (A1c) on macrovascular events (CVE) in patients (pts) with T2DM. develop liver failure and hepatocellular carcinoma. Regular screening for Epidemiology/ Pts (n=21436) who received fi rst prescription (index) of INS (n=11973), liver disease in T2DM patients older than 55 years may be warranted. DPP4 inhibitor (n=4944), exenatide twice daily (EBID, n=1384) or EBID+INS Supported By: CONICYT (n=3135) between 2005 and 2009 were followed for ≥3 y under the same drug regimen. Data on demographics and 6 mo measures of A1c over 2 y 1448-P were extracted from the GE Healthcare Database. Functional and Symptomatic Pulmonary Impairment Is Associated Median follow-up was 3.8 y. EBID- and DPP4-treated pts had similar with Albumin/Creatinine Ratio (ACR) in Type 2 Diabetes: Findings sustained A1c reduction >0.5% during 2 y; INS-treated pts had no clinically from the Hispanic Community Health Study/Study of Latinos (HCHS/ meaningful change in A1c (Table). EBID+INS group (gr) achieved better A1c SOL) control compared to INS. After 2 y post index, 4.8%, 4.3%, 8.5% and 6.8% of OANA L. KLEIN, LARISSA AVILES-SANTA, CAI JIANWEN, HAROLD COLLARD, AL- pts in DPP4, EBID, INS and EBID+INS gr had CVE respectively. In pts with no KA KANAYA, ROBERT KAPLAN, GREGORY L. KINNEY, ELIANA MENDES, LEWIS CV disease history, adjusting for age, sex, ethnicity, smoking, renal disease, SMITH, GREGORY TALAVERA, DONGHONG WU, MARTHA DAVIGLUS, San MET and SU use, baseline BMI and A1c, compared to INS gr, pts in DPP4, Francisco, CA, Bethesda, MD, Chapel Hill, NC, New York, NY, Aurora, CO, Miami, FL, EBID and EBID+INS gr with A1c consistently <7.5% over 2 y had lower CV risk Chicago, IL, San Diego, CA by 42%, 58% and 44% (all p<0.01), respectively. In pts with A1c ≥7.5%, CV Diabetes mellitus (DM) has been associated with lung dysfunction, but risk was lower by 33% and 65% (p<0.05) in DPP4 and EBID gr, respectively, this is unknown in Hispanics/Latinos. The impact of DM microangiopathy compared to INS. (i.e. ACR) on lung impairment has not been studied. Complete data on 14,176 Incretin-based drugs, compared to INS, achieved signifi cant reductions in Hispanics/Latinos from HCHS/SOL, ages 18-74 years, recruited through multi- A1c and CV risk, and CV risk reduction was independent of A1c control. stage probability sampling, were used to compare lung function [forced vital capacity (FVC), forced expiratory volume in one second (FEV1)] and symptoms DPP4 EBID INS EBID+INS [dyspnea score (perception of breathlessness)] between individuals with Age at index [year, mean(SD)] 58 (11) 56 (11) 57 (12) 56 (10) DM (stratifi ed by ACR) and without. Analyses were performed separately for Baseline A1c [%, mean(SD)] 7.4 (1.4) 7.2 (1.4) 7.7 (1.6) 7.6 (1.5) adults without and with lung disease (self-reported asthma, COPD), using survey linear regression with sampling weights. Type 2 DM was defi ned by Duration of follow-up [year, median (IQR)] 3.5 (2.9, 4.3) 3.7 (2.3, 4.8) 3.6 (2.6, 4.5) 4.2 (3.1, 5.3) lab tests, medication use, or self-report. Reduction in A1c at 6 month [%, mean (CI)] 0.64 (0.60, 0.68) 0.63 (0.57, 0.70) 0.17 (0.15, 0.20) 0.33 (0.29, 0.38) For adults with DM/macroalbuminuria vs. non-DM/normoalbuminuria: Reduction in A1c at 1 year [%, mean (CI)] 0.64 (0.61, 0.69) 0.65 (0.58, 0.71) 0.11 (0.09, 0.13) 0.28 (0.24, 0.32) FVC was 15% and 10% lower for individuals with and without lung disease, Reduction in A1c at 2 years [%, mean (CI)] 0.53 (0.49, 0.56) 0.54 (0.47, 0.60) 0.03 (0.01, 0.05) 0.25 (0.20, 0.29) respectively; FEV1 was 6% lower and dyspnea score was 2.5 fold higher. The impairment in lung measures was 2 fold higher in individuals with DM/ Overall Hazard Ratio (CI) for CVE 0.60 (0.49, 0.74) 0.39 (0.26, 0.59) Reference 0.66 (0.63, 0.81) macroalbuminuria vs. DM/microalbuminuria (Table). Supported By: Therapeutic Innovations (Australia) Hispanics/Latinos with DM show functional and symptomatic pulmonary impairment, which is associated with ACR. Further studies to investigate the progression of pulmonary impairment in DM are needed.

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prescribed sulfonylureas, glimepiride and gliclazide, on kidney outcomes in Pulmonary Values in Participants With/Without Lung Disease (Adjusted). type 2 diabetic patients. Without lung disease (n=11552) With lung disease (n=2624) In this retrospective cohort study, a total of 4486 patients treated with Non-DM with DM with 30 DM with Non-DM with DM with DM with either glimepiride or gliclazide for more than 2 years between 2008 and 2012 ACR<30 ≤ACR≤300 ACR>300 ACR<30 30≤ACR≤300 ACR>300 were followed for up to 5.5 years (median 4.7 years). We used a propensity (n=9124) (n=470) (n=129) (n=1919) (n=135) (n=29) score derived on baseline characteristics to match 1427 people treated FEV1 (L), mean 3.11 (3.10-3.13) 3.01 (2.95-3.07) 2.91 (2.83-2.99) 2.99 (2.96-3.02) 2.83 (2.72-2.93) 2.58 (2.31-2.84) with glimepiride with 1427 treated with gliclazide. We then compared the incidences of end-stage renal disease (ESRD) and sustained doubling of p-value Ref <0.001 <0.001 Ref 0.005 0.003 creatinine to above 132.6 µmol/l (1.5mg/dl) in these two groups. FVC (L), mean 3.83 (3.81-3.84) 3.61 (3.54-3.68) 3.46 (3.33-3.59) 3.77 (3.74-3.80) 3.50 (3.37-3.63) 3.22 (2.89-3.56) In the matched cohort with 12,123 person-years of follow-up, there was p-value Ref <0.001 <0.001 Ref <0.001 0.002 no signifi cant difference between groups in the risks of ESRD (reference Dyspnea score, 0.41 (0.34-0.49) 0.73 (0.53-0.94) 1.01 (0.45-1.57) 0.71 (0.47-0.94) 1.21 (0.71-1.71) 1.83 (1.00-2.67) group=glimepiride, hazard ratio [HR] 0.53; 95% confi dence interval [CI], mean 0.25 to 1.12) or doubling of creatinine (HR 0.67; 95% CI 0.39−1.12), although p-value Ref 0.002 0.04 Ref 0.04 0.008 there was a trend toward higher risks in the glimepiride group. Subgroup analyses showed that compared to glimepiride, gliclazide was signifi cantly associated with lower risks of ESRD and doubling of creatinine in patients 1449-P with preserved renal function (estimated glomerular fi ltration rate [eGFR] 2 Quality of Care and Information for Patients with T2DM: EMR Use ≥60 mL/min/1.73 m ), good glycemic control (glycated hemoglobin A1c and Patient Outcomes in Primary Care [HbA1c] <7%), and older subjects (≥62 years). MEHUL DALAL, JEFFREY FRIMPTER, JOHN STEWART, BRYAN JOHNSTONE, In conclusion, there was no signifi cant difference in the clinical outcomes ALEKSANDRA VLAJNIC, TERRY DEX, Bridgewater, NJ, Quebec, QC, Canada of kidney disease for people treated with glimepiride versus gliclazide. Physicians can achieve NCQA Recognition (DRP) when certain proportions However, gliclazide seemed to protect against renal complication progression of their patients meet quality measures. Understanding performance and in certain patients with type 2 diabetes. evaluation of quality metrics may help to interpret research of practice patterns and patient outcomes in primary care management of T2DM. 1451-P We used Diabetes FORWARD (DF), a large practice-based research Effect of Breastfeeding on Early Postnatal Growth of Offspring network focused on T2DM patients and their providers across the U.S., Exposed and Unexposed to Gestational Diabetes In Utero to examine how many provider sites met DRP criteria in 2012 and 2013. IZZUDDIN ARIS, SHU E. SOH, MYA THWAY TINT, SEANG MEI SAW, VICTOR Analyses were of sites contributing ≥20 T2DM patients to DF and sites with RAJADURAI, KENNETH KWEK, KEITH GODFREY, MICHAEL MEANEY, PETER ≥5 patients taking basal insulin. Patients were 18-75 yr with T2DM diagnosis GLUCKMAN, FABIAN YAP, YAP SENG CHONG, YUNG SENG LEE, Singapore, for ≥12 months, under the provider’s care for ≥12 months before the end of Singapore, Southampton, United Kingdom, Quebec, QC, Canada, Auckland, New the analysis year. Zealand In 2012 and 2013, 40-45% of DF sites had ≥20 T2DM patients (1,063 and Infants on prolonged breastfeeding are known to grow slower during 1,509 total patients), and 35-47% met basal insulin criteria (166 and 358 the fi rst year of life. It is still unclear if such effects are similar in offspring Genetics

POSTERS patients). Across all analyses, zero sites achieved 75 points to meet DRP, exposed to gestational diabetes (GDM) in-utero. We studied the effect of Epidemiology/ however we could not distinguish lack of performance from lack of EMR breastfeeding on postnatal growth from birth till 24 months of age amongst notation. DRP mean and median scores varied but were generally low. offspring exposed and unexposed to GDM. The Growing Up in Singapore Clinical indicators from lab tests, such as A1c and BP, were performed and Towards healthy Outcomes cohort undertook maternal 75g 2-hour oral recorded frequently compared to examination for complications. glucose tolerance tests at 26-28 weeks of gestation. GDM was diagnosed This analysis suggests opportunities to improve the quality of care and using WHO criteria (fasting or 2-hr plasma glucose concentrations of patient records related to diabetes management in U.S. primary care. greater than 7.0 or 7.8 mmol/L respectively). In 1152 singleton offspring, Further analyses may identify additional areas of unmet need. measurements included weight and length at birth, 3 weeks, and 3, 6, 9, 12, Table. Analysis of Primary Care EMR Records against NCQA DRP Quality 15, 18 and 24 months of age. To categorize breastfeeding status, a measure Measures. of breastmilk-months (<4 or ≥4 breastmilk-months) was derived from breastfeeding questionnaires. Conditional z-score growth models were used NCQA DRP Measure, Proportion of Sites with ≥20 Sites with ≥5 Patients Patients Threshold (DRP points) Patients with T2DM Using Basal Insulin to assess the effect of breastfeeding on early postnatal growth stratifi ed by GDM status. Correcting for potential confounders, offspring of non-GDM 2012 2013 2012 2013 mothers breastfed for at least 4 months demonstrated signifi cantly slower (n=32) (n=40) (n=20) (n= 34) conditional weight [B(95%C.I):-0.43(-0.62,-0.25)], length [-0.24(-0.43,-0.05)] HbA1c >9.0%, ≤15% (12 points) 23 (72%) 24 (60%) 5 (25%) 4 (12%) and BMI [-0.25(-0.45,-0.06)] z-score growth in the fi rst 12 months of life, HbA1c <8.0%, ≥65% (8) 20 (63%) 18 (45%) 7 (35%) 3 (9%) compared to those who were breastfed for less than 4 months. Offspring HbA1c <7.0%, 40% (5) 27 (84%) 16 (40%) 4 (20%) 4 (12%) ≥ of GDM mothers breastfed for at least 4 months however, demonstrated BP ≥140/90 mmHg, ≤35% (15) 22 (69%) 34 (85%) 13 (65%) 25 (74%) BP <130/80 mmHg, ≥25% (10) 32 (100%) 27 (68%) 10 (50%) 21 (62%) signifi cantly faster conditional BMI z-score growth [0.45(0.06,0.84)] during LDL ≥130 mg/dL, ≤35% (10) 16 (50%) 40 (100%) 19 (95%) 34 (100%) the fi rst 6 months of life compared to those breastfed for less than 4 months. LDL <100 mg/dL, >50% (10) 3 (9%) 12 (30%) 9 (45%) 9 (26%) Our study suggests that unlike offspring of non-GDM mothers, prolonged Eye examination, ≥60% (10) 3 (9%) 0 0 0 breastfeeding appears to have a greater infl uence on adiposity growth for Foot examination, ≥80% (5) 2 (6%) 1 (3%) 0 0 offspring of GDM mothers. This observed effect may represent a critical Nephropathy assessment, ≥85% (5) 0 1 (3%) 4 (20%) 2 (6%) window of opportunity to reduce future obesity risk. Tobacco cessation assistance, ≥85% (10) 1 (3%) 0 1 (5%) 0 Supported By: NMRC Overall DRP Score, mean (SD) 49.5 (17.7) 41.2 (18.7) 29.8 (21.3) 24.5 (12.5) Median, Range 49.0, 15-70 44.5, 10-70 29.0, 0-70 25.0, 0-47 1452-P Number of Sites Meeting ≥6 measures 14 (44%) 11 (28%) 3 (15%) 0 Heart Rate and the Risk of Diabetic Retinopathy Supported By: Sanofi SANGMO HONG, HEE YOON CHO, JUN GOO KANG, JEONG-TAEK WOO, SEI HYUN BAIK, MOON SUK NAM, KWAN WOO LEE, YOUNG SEOL KIM, YONGSOO 1450-P PARK, Gyeonggi, Republic of Korea, Seoul, Republic of Korea, Chuncheon, Republic Comparing Kidney Outcomes in Type 2 Diabetes Patients Treated of Korea, Incheon, Republic of Korea, Suwon, Republic of Korea with Gliclazide and Glimepiride Objectives: Previous studies have reported that heart rate might be a clinical indicator of overall risk of diabetic retinopathy in diabetic patients. YONG-HO LEE, CHAN JOO LEE, EUN YEONG CHOE, SEHEE PARK, JAEHYUN BAE, Higher heart rate could also indicate autonomic dysfunction and might be GYURI KIM, YU JUNG YUN, BYUNG-WAN LEE, CHUL WOO AHN, BONG SOO related with poor autoregulation of retinal vessel. The aim of this study CHA, HYUN CHUL LEE, BEVERLEY BALKAU, EUN SEOK KANG, Seoul, Republic of was to evaluate the resting heart rate as a clinical indicator of developing Korea, Villejuif, France Although sulfonylureas are widely used oral glucose-lowering drugs in diabetic retinopathy in type 2 diabetic patients. type 2 diabetes, its impact on long-term major kidney outcomes remains Methods: We analyzed 1398 patients of type 2 diabetes without diabetic unclear. Here, we investigated the effects of the two most commonly retinopathy at enrollment from a prospective cohort study (Korea National

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Diabetes Program database). Diagnosis and staging of retinopathy was made based measure adapted from the Telephone Interview for Cognitive Status. by 7-fi eld fundoscopic examination and according to The Early Treatment Outcome was time to persistent diffi culty in an ADL/IADL in the following 2 Diabetic Retinopathy Study staging system, respectively. surveys. Analyses were adjusted for demographic characteristics, body mass Results: Subjects were followed for a mean of 4.1±1.4 years. Among 1398 index, and other co-morbid conditions. Proportional hazards survival analysis patients, 88 patients developed new diabetic retinopathy. The cumulative was used to calculate the hazard ratios (HR) ratios for the association of incidence of retinopathy was 6.3 % and the incidence density was 1.6 diabetes with and without CI on subsequent ADL/IADL diffi culty. (95% CI=1.3-1.9) cases per 100 patient-years. Patients who developed At baseline, 19% of respondents had CI. Respondents with CI were more new retinopathy had higher HbA1c (8.1±1.7 vs. 7.5±1.7, p=0.002), higher likely to develop persistent diffi culties in ADL/IADLs over 8 years compared microalbuminuria (34.7% vs. 20.3%, p=0.003), and higher resting heart to those without CI (50% vs. 32%); the adjusted HR was 1.46 (p<0.001). rate (RHR) (81±12 vs. 78±11 p=0.004). Patient with RHR ≥ 90 increased Separately, the rate of developing ADL diffi culties was 39% vs. 26%, 2.08 times (95% CI= 1.214-3.551, p=0.008) than patient with RHR < 90 in HR=1.39 (p<0.01), and IADL diffi culty was 45% vs. 28%, HR=1.55 (p<0.001). the Cox proportional hazard models with adjusted for age, sex, the duration Subsample analysis of respondents with HbA1c measurements showed of diabetes, waist circumference, systolic blood pressure, diastolic blood similar results. pressure, HbA1c, HDL-C, eGFR, and albumin/creatine ratio. Cognitive impairment is common among diabetic patients and is associated Conclusions: These data suggest that RHR might be a novel clinical with increased risk of functional decline over 8 years. Early cognitive indicator of developing diabetic retinopathy in type 2 diabetes, the effect of screening and interventions are needed to ameliorate the increased risk of which is independent of other conventional risk factors. functional decline associated with cognitive impairment. Supported By: Korea Healthcare Technology R&D Project 1455-P 1453-P Are Type 2 Diabetes Patients Treated Intensively Enough from the Decrease in the Incidence of Renal Placement Therapy for DM in Onset of the Disease? ARETAEUS2 Study Results The Netherlands LESZEK CZUPRYNIAK, ELEKTRA SZYMANSKA-GARBACZ, MACIEJ PAWLOWSKI, PETER R. VAN DIJK, ANNEKE KRAMER, SUSAN J.J. LOGTENBERG, ANDRIES J. MALGORZATA SARYUSZ-WOLSKA, JERZY LOBA, PAWEL BIJOS, Lodz, Poland, HOITSMA, KITTY JAGER, NANNE KLEEFSTRA, HENK J.G. BILO, Zwolle, Nether- Kutno, Poland lands, Amsterdam, Netherlands, Leiden, Netherlands Since 2010, clinical guidelines have recommended intensive treatment Diabetes mellitus (DM) is considered the main cause of end stage renal of type 2 diabetes (DM2) from the moment of diagnosis and less intensive disease (ESRD) in many countries. In general, its frequency is estimated regimens in patients with more advanced disease. In 2012 we conducted to be about 40% of ESRD and would be expected to rise in parallel with a cross-sectional nationwide study assessing DM2 treatment effi cacy at the prevalence of DM. Aim was to investigate trends in incidence and various stages of the disease. Patients with DM2 (n=15,643) were enrolled prevalence of DM as cause of renal replacement therapy (RRT) for ESRD in at primary and secondary care clinics. Treatment results were analysed in the Netherlands in the period 2000-2012. three groups according to diabetes duration: less than 2, 2-10, and over 10 Using the RENINE-database, the incidence and prevalence of all Dutch years (tables). Glucose control was better in the patients with the disease individuals initiating RRT having DM as primary diagnosis were obtained. duration <10 years than in those with long-standing diabetes. However, The age- and gender adjusted incidence and prevalence were calculated. effective strategies to improve results of multifactorial intervention in all Genetics

Trends in time were analysed with Joinpoint regression. diabetes patients are urgently needed as fewer than 10% of subjects reach POSTERS The prevalence of DM in the Dutch general population (GP) increased all treatment goals. Epidemiology/ from approximately 500.000 in 2000 to 893.000 in 2011. The number of individuals who started DM related RRT remained stable: 17.4 per million population (pmp) in 2000 and 19.1 pmp in 2012 with an annual percentage change (APC) of 0.8% (95%CI -0.4;2.0). However, for RRT due to T1DM the incidence decreased from 7.3 pmp in 2000 to 3.5 pmp in 2012 with an APC of -4.8% (95%CI -6.5;-3.1). For T2DM it increased from 10.1 pmp in 2000 to 15.6 pmp in 2012 with an APC 3.1% (95%CI 1.3;4.8). The incidence of RRT due to unknown or missing causes of renal failure increased from 21.2 pmp to 28.5 pmp. The prevalence of RRT for DM increased at a lower rate after 2009: APC 1.0% (95%CI -0.4;2.5) versus 5.8% (95%CI 5.6;6.1). Compared to a non-DM reference population, patients on RRT due to T1DM and T2DM had an increased mortality, age and gender adjusted hazard ratios: 1.8 (95%CI 1.7;2.0) and 1.4 (95%CI 1.3 - 1.4). Compared to the period of 2000-2004, patients initiating RRT in 2005-2009 had a lower mortality, age and gender adjusted hazard ratios: 0.8 (95%CI 0.7;0.8). The incidence of RRT for DM is stable over the last decade refl ecting a decrease for T1DM and an increase for T2DM. Taken together with a steady increase in prevalence of DM in the GP this suggest that physicians may be more successful in the prevention of diabetes related ESRD.

1454-P Functional Decline among Adults with Diabetes and Cognitive Im- pair ment PEARL G. LEE, JINKYUNG HA, LILLIAN MIN, TANYA GURE, CHRISTINE CIGOLLE, CAROLINE S. BLAUM, WILLIAM H. HERMAN, Ann Arbor, MI, Columbus, OH, New York, NY Nearly a quarter of U.S. middle-aged and older adults have Type 2 diabetes, and many of them also have cognitive impairment (CI). Diabetes and CI are each independently associated with increased risk of functional limitations. Long-term risk of functional limitations due to co-morbid diabetes and CI remains unclear. We hypothesized that diabetic adults with CI have higher risk for functional decline compared to without CI. We analyzed data from the 2002 - 2010 Health Retirement Study, a nationally representative health survey conducted biennially. Sample included 1,254 adults aged ≥51 years responded to the 2003 HRS supplement Diabetes Mailout Survey - all reported diabetes diagnosis and no instrumental Supported By: Teva Pharmaceuticals Poland or basic activities of daily living (ADL/IADL) diffi culties; 848 respondents also had HbA1c measured. Cognition was assessed using a performance-

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1456-P but not SIF or WMH remained signifi cantly associated with lower DSST. These Socioeconomic Deprivation Independently Predicts Painful Diabetic results suggest that psychomotor slowing may be more strongly infl uenced by Neuropathy in Type 2 Diabetes changes in gray matter, rather than white matter, and by glycemic control rather ADRIAN H. HEALD, SIMON G. ANDERSON, RAM P. NARAYANAN, NAGARAJ S. than other vascular conditions. It remains to be determined whether improving MALIPATIL, GEORGE DUNN, HUGH ROBERTS, LUMA KHALID, Manchester, United glycemic control can prevent or delay psychomotor slowing by improving gray Kingdom, Salford, United Kingdom, Macclesfi eld, United Kingdom, Crewe, United matter health in key brain regions. Kingdom, Peshawar, Pakistan Supported By: NIDDK (DK089028) Objective: Painful peripheral neuropathy in people with type 2 diabetes 1458-P is a disabling complication. We explored associations of this condition with Fracture Risk in Type 2 Diabetes and Trabecular Bone Score socioeconomic deprivation. PETER JACKULIAK, JURAJ PAYER, Bratislava, Slovakia Design: The validated Townsend index of socioeconomic deprivation was Diabetes is associated with increased risk of fracture, although type examined in 15388 (41% female) patients and related to the prevalence of drug 2 diabetes is characterized by normal bone mineral density (BMD). Thus, treated painful diabetic neuropathy. We also analysed prescription trends. diabetes may be associated with a reduction of bone strength that is not Results: Treatment for neuropathic pain was initiated in 3266 (21.2%) of refl ected in the measurement of BMD. It is very problematic to measure the patients. Those on treatment were older [68.2 (95% CI 67.8-68.7) vs. 66.6 bone quality in daily practice. Trabecular Bone Score - TBS iNsight® is one (66.4-66.8) years] than those not on treatment. There was no difference in of these tools, now available for routine clinical practice, that allows for HbA1c (7%, 55 mmol/mol). refi nement of micro architecture and fracture risk, independent of BMD. There were signifi cant differences between the groups for Townsend Objective: TBS evaluation of increased fracture risk in T2DM versus deprivation index, with a greater proportion (30.6% vs. 22.8% of patients control group of patient without DM. with treated neuropathic pain) having a score of ≥1 (2=83.9, p<0.0001). Patients and Methods: Retrospective study, 56 postmenopausal women Multivariate logistic regression analyses indicated that each unit patients with T2DM and 61 women patient without DM or IGT. We evaluated the increment in Townsend index associated with a 6% increased odds of ability of lumbar spine TBS to account the increased risk of fractures in T2DM. requiring neuropathic pain treatment [odds ratio (95%CI) 1.06 (1.05-1.08), Results: Mean age of the patients with T2DM was 67.5 ± 9.1, mean BMI p<0.0001] independent of 5 year age band, BMI, gender, systolic BP, eGFR , 29.7 ± 6.1. Diabetes was associated with higher BMD - the T-score of LS was HbA1C and total cholesterol. -0.8 ± 1.5 and of the HIP -0.7 ± 1.3, while in the group without DM T-score Conclusion: A higher level of socioeconomic deprivation predisposes to of LS was -1.2 ± 1.5, and of the HIP -1.1 ± 1.1. Fractures occurred in 16.3% severe neuropathic pain in diabetes neuropathy requiring pharmacological patients with T2DM (13,3% in patient without DM, p<0.05). The diabetic intervention. Targeted allocation of healthcare resources to this group may patient has lower lumbar spine TBS (1.172 ± 0.133). Least squares mean offer clinical benefi t. (LSM) for BMD were signifi cant greater in women with T2DM than without, whereas LSM for TBS-LS was signifi cant lower in T2DM. The adjusted odds ratio for a measurement in the lowest versus highest tertile was less than 1 for BMD (all p<0.001), but was increased for TBS-LS (OR 2.41). TBS was a BMD-independent predictor of fracture in those with diabetes. Conclusion: TBS together with BMD helps to provide better information Genetics

POSTERS about real bone status and bone micro architecture in patients with T2DM. Epidemiology/ TBS is a promising tool to identify patient with T2DM in higher risk of osteoporotic fracture. To identify these patients in daily clinical practice is the basic for effective treatment.

1459-P Incidence, Characteristics, and Impact of Hypoglycemia in Type 2 Diabetic Patients with Intensifi ed Glycaemic Control in Clinical Practice—2-Year Prospective Follow-up of the DiaRegis Cohort Study DIETHELM TSCHÖPE, PETER BRAMLAGE, CHRISTIANE BINZ, MICHAEL KREKLER, ANSELM K. GITT, DIAREGIS STUDY GROUP, Bad Oeynhausen, Germany, Mahlow, Germany, Munich, Germany, Ludwigshafen, Germany There is a need for contemporary data on the incidence, characteristics, 1457-P prevalence and fi nally prognostic impact of hypoglycaemia. In DiaRegis 3058 Psychomotor Slowing in Middle-aged Adults with Type 1 Diabetes patients had a known status after 2 years of follow-up (80.3%); 75 patients Is Associated with Focal Gray Matter Atrophy and Poorer Metabolic (2.5%) died. The incidence of hypoglycaemia was 17.8% for the two year Control follow-up with a mean of 5.4±5.8 episodes per patient, and was independent CATERINA ROSANO, HOWARD J. AIZENSTEIN, KAREN NUNLEY, TREVOR J. from Glucose control (HbA1c, fasting and postprandial plasma glucose), but ORCHARD, JUDITH SAXTON, CHRISTOPHER RYAN, Pittsburgh, PA was more frequent in those indicating to have a high degree of blood glucose Psychomotor slowing is the most common neurocognitive complication in variability. Positive predictors of hypoglycaemia were HFat baseline (OR 1.66; patients with Type 1 Diabetes. Although risk factors for psychomotor slowing in 95%CI 1.20-2.29) and insulin use after baseline (OR 4.03; 95%CI 3.05-5.33). In these patients are not well known, they have been extensively studied in elderly contrast, the use of DPP-4 Inhibitors was associated with a signifi cant 31% populations without diabetes and include higher burden of vascular disease, relative risk reduction (OR 0.69; 95%CI 0.53-0.89). Episodes of symptomatic white matter hyperintensities and gray matter atrophy. To address this, we hypoglycaemia requiring help were predicted by age > 65 years (OR 2.09; studied 93 adults with childhood-onset type 1 diabetes (mean age and duration: 95%CI 1.10-3.98), male gender (OR 1.99; 95%CI 1.09-3.64), anamnestic 48.9 and 40.8 years) participating in the Pittsburgh Epidemiology of Diabetes HF at baseline (OR 2.40; 95%CI 2.07-16.70) and reporting any episodes of Complications Study since 1989. Psychomotor speed (Digit Symbol Substitution anamnestic hypoglycaemia (OR 5.88; 95%CI 2.07-16.70). Macro-vascular Test (DSST), number of correct symbols in 90 seconds) was measured in 2010- events overall (new MI, stroke and PAD) were more frequent in those reporting 11 concurrently with gray matter volume (GMV, via voxel-wise morphometry), severe episodes of hypoglycaemia (OR 3.39 for macro-vascular events overall brain white matter hyperintensities (WMH),vascular risk factors/conditions and 5.28 for new MI). Micro-vascular events (retinopathy, nephropathy, (stroke, lipids and blood pressure levels, current and averaged since 1989) and neuropathy, and amputation) were more frequent in those with non-severe glycemic control (HbA1c current and historic, skin intrinsic fl uorescence (SIF)). episodes of hypoglycaemia (OR 1.92; 95%CI 1.49-2.49). Blood glucose target Analyses accounted for diabetes duration and complications (retinopathy, achievement (HbA1c < 7%), free of weight gain and hypoglycaemia was less peripheral neuropathy, cardiac autonomic neuropathy, nephropathy).Lower often achieved in patients with long standing diabetes (OR 0.64; 95%CI 0.54- DSST correlated with smaller GMV in basal ganglia, sensorimotor cortices 0.76), HF (OR 0.76; 95%CI 0.49-0.92), sulfonylurea (OR 0.74; 95%CI 0.60-0.91) and temporal lobe, including hippocampus (p < .05 corrected for multiple and insulin use (OR 0.50; 95%CI 0.37-0.67). comparisons using Threshold-Free Cluster Enhancement), higher WMH Hypoglycaemia is frequent and associated with an increased co-morbidity (r=-.285, p=.009) and higher SIF(r=-.279, p=.007). Results were similar after burden as well as micro- and macro-vascular complications. adjustment for duration or complications. In multivariable models, smaller GMV Supported By: Bristol-Myers Squibb

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1460-P Table 1. Combined Low-Risk Lifestyle Factors and GDM Risk. Prevalence and Severity of Periodontal Disease in Type 2 Diabetes Low-risk group Percentage of No. of Relative 95% CI Population 95% CI Mellitus and the Infl uence of Metabolic Parameters Pregnancies in GDM Risk† Attributable JOAO SILVA, DIANA CORREIA, MAFALDA MARCELINO, ANA LOPES, NICHOLAS Group Events Risk‡ FERNANDES, ANA FERREIRA, TIAGO TROLES, ANDREIA DOMINGUES, DOLORES 3 factors in low-risk category 20.3% 112 0.59 0.48, 0.71 35.4% 25.1, 44.9 PASSOS, LUIS LOPES, HENRIQUE LUIS, NUNO SILVA, JOÃO MENDES, JOÃO (current non-smoker, moderate/vigorous CASTRO, Lisbon, Portugal physical activity ≥150 min/week, AHEI- Periodontal Disease (PD) is a chronic infl ammatory disease of the 2010 diet score in upper 2 quintiles) supporting teeth structures, highly prevalent (10% of adults) and can lead All 4 factors in low-risk category 16.3% 71 0.48 0.38, 0.61 47.5% 35.6, 56.6 to premature tooth loss. Diabetes Mellitus (DM) is a major risk factor and (current non-smoker, moderate/vigorous increases the susceptibility to Periodontitis approximately 3-fold. physical activity ≥150 min/week, AHEI- This study aimed to assess an association between metabolic status and 2010 diet score in upper 2 quintiles, and the extent of periodontitis among patients with Type 2 DM (T2DM). BMI<25.0 kg/m2) Single center, randomized trial with T2DM patients. In the day of the AHEI: Alternate Healthy Eating Index. evaluation, biometric parameters were measured and blood analyses were † Relative risk was estimated from generalized estimating equation models and adjusted for age, carried out for HbA1c, HDL, LDL, Triglycerides and glucose. Periodontal parity, family history of diabetes, history of infertility, race/ethnicity, questionnaire period, total clinical parameters were measured by a computerized periodontal probe. energy intake, and alcohol intake. PD was classifi ed according to clinical attachment loss (CAL): initial (CAL ‡ The population attributable risk is the percentage of GDM cases in the population that are the- 1-2mm), moderate (3-4mm) and severe (≥5mm). Variables were analyzed by oretically attributable to the non-adherence to a particular factor. Chi-Square Tests and Multivariable Regression with a signifi cance level of Supported By: NIH 5%. A total of 90 individuals were observed: 70 male (77,8%), mean age of 64,3 & 1462-P years (± 9,95), BMI of 29,1kg/m2 (±4,42), waist circumference of 103,4cm, Vitamin D Status and Diabetes: Meta-analyses of Randomized HbA1c of 6,69% (±0,95), duration of T2DM was 11,3 years (±8,66), and 84% Intervention Studies had Dyslipidemia. Patients had in average 21,4 teeth (±7,1), 98,1% of teeth PHILIPPE AUTIER, CECILE PIZOT, MATHIEU BONIOL, PATRICK MULLIE, PETER had bleeding on probing, 11,1% had suppuration and 100% had dental plaque. BOYLE, Lyon, France CAL ranged from 0 to 11 mm. PD was present in 98% of T2DM patients: 55% Observational research has associated higher serum concentrations had initial PD, 30% moderate and 15% severe. of 25-hydroxyvitamin D (25[OH]D) with a reduced incidence of diabetes. There is an association between metabolic control (HbA1c) and the A systematic review and meta-analysis was undertaken of intervention severity of PD (p<0,001) but not with the duration of T2DM (p=0,415). From studies in subjects 18 or more years of age that examined the infl uence of multivariable analysis it was found that regardless metabolic control, diabetic vitamin D supplementation on glucose metabolism. patients had a higher risk of develop PD if they were obese (p<0,001), had A systematic search was conducted of randomized trials that reported higher waist measure (p<0,001) and Dyslipidemia (p=0,025). results of vitamin D supplementation on glycosylated haemoglobin (HbA1c), We conclude that patients with T2DM had a high prevalence of PD and fasting plasma glucose (FPG), fasting plasma insulin (FPI), and a homeostasis its severity is related with current glycemic control. Obesity, high waist model assessment of insulin resistance (HOMA-IR). Summary differences of Genetics POSTERS measure and Dyslipidemia are a risk factor for PD even with a good glycemic biomarker concentration between intervention and placebo group over the Epidemiology/ control. trial period were computed. A total of 17 (n=1533 subjects), 23 (n=2390), 14 (n=1452), and 20 (n=2046) randomized trials (RTs) were found for the four endpoints respectively which EPIDEMIOLOGY—NUTRITION reported biomarker values at baseline and end of study. Summary differences between intervention and control groups were: -0.01% [-0.24 ; 0.23] for the percentage of haemoglobin under the form of HbA1c, -0.01 [-0.38 ; 0.36] mmol/L Guided Audio Tour: Nutritional Issues in Diabetes (Posters: 1461-P to for FPG, 0.42 [-32.21 ; 33.04] pmol/L for FPI, and -0.08 [-1 ; 0.84] for HOMA- 1468-P), see page 15. IR. Sensitivity analyses did not suggest different results for patients with or without diabetes, according to trial duration, or according to supplement dose. For all four biomarkers, the I2 statistics was 0%, indicating that there was no & 1461-P heterogeneity in results between RTs included in each meta-analysis. Adherence to Healthy Lifestyle before Pregnancy and Reduced Risk These fi ndings show that Vitamin D supplementation has no impact of Gestational Diabetes on four major biomarkers of glucose metabolism. These results suggest CUILIN ZHANG, DEIRDRE TOBIAS, JORGE CHAVARRO, WEI BAO, SYLVIA LEY, that associations between low vitamin D status and glucose metabolism DONG WANG, FRANK B. HU, Bethesda, MD, Boston, MA disorders found in observational studies essentially refl ect physiological It is pivotal to identify key modifi able factors of gestational diabetes (GDM) events leading to diabetes but indicate that low Vitamin D status is not the for the prevention of this increasingly common pregnancy complication. cause of diabetes. We prospectively assessed joint effect of pre-pregnancy healthful lifestyle factors (i.e. maintaining a healthy body weight, consuming a healthy diet, exercising regularly, and not smoking) on GDM risk based on 20,136 & 1463-P singleton births from 14,437 participants free of chronic disease in the Milk Intake Is Not Causally Associated with Diabetes — A Mendelian Nurses’ Health Study II. Randomization Study in 97,811 Danish Individuals Incident fi rst time GDM was reported in 823 pregnancies. The combination HELLE KIRSTINE M. BERGHOLDT, BOERGE G. NORDESTGAARD, CHRISTINA of being a nonsmoker, engaging in ≥150 minutes per week of moderate ELLERVIK, Naestved, Denmark, Copenhagen, Denmark to vigorous physical activity, and having healthful dietary pattern was In meta-analyses of observational studies intake of milk is associated with associated with a 41% lower risk of GDM compared to all other pregnancies reduced risk of diabetes, but whether this association is causal is unknown. (RR=0.59, CI=0.48, 0.71). Additionally having a pre-pregnancy body mass We investigated whether increased milk intake observationally and causally index <25 kg/m2 was associated with a 52% lower risk of GDM compared is associated with reduced risk of diabetes. to all other pregnancies (RR=0.48, CI=0.38, 0.61). Compared to pregnancies We included 97,811 individuals from 3 Danish population studies (the that did not meet any of the healthy lifestyle factors, those meeting all four Copenhagen City Heart Study(N=8,731), the Danish General Suburban criteria had an 83% lower GDM risk (RR=0.17, CI=0.12, 0.25). An estimated Population Study(N=14,833), and the Copenhagen General Population 48% of all GDM pregnancies could have been avoided if women adhered to Study(N=74,247)). all four pre-pregnancy lifestyle factors (95% CI=36%, 57%). Information on milk intake was self-reported. Information on diabetes In conclusion, nearly half of GDM events may be preventable through was obtained from the national Danish Patient Registry and the national adherence to healthy lifestyle practices before pregnancy. Causes of Death Registry in the period from 1977 to 2013 combined with self reported information on diabetes and diabetes treatment. Observational estimates of milk intake (quintiles, yes/no and type) and diabetes were obtained using Cox-regression adjusted for sex, age, physical activity, smoking, alcohol, lipid lowering therapy, hypertension, body mass index, and education.

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We used the LCT-13910 C/T genetic variant in a Mendelian randomization years in fully adjusted models (OR per SD = 0.73; p = 0.02, Figure), with design, as the genotype CC is associated with lactose intolerance and stronger associations in females, normoglycemics, and Hispanics despite lifelong reduced milk intake. nonsignifi cant interaction terms. In contrast, trans 16:1n-7 was not associated No consistent signifi cant observational associations were found between any outcomes in fully adjusted models. In conclusion, these results support milk intake and any diabetes, type 1 diabetes or type 2 diabetes. Milk intake a role for dairy foods in reducing T2DM risk. was lowest among people with the genotype CC compared to the genotypes Supported By: BBDC; DFC; NHLBI TC and TT (median glasses/week (interquartile range): CC=3(0-7), TC=5(0- 10), TT=5(0-10); P= 2*10-59). Logistic regression analysis using a Mendelian randomization design showed no signifi cant associations between LCT-13910 C/T genotypes and risk of any diabetes, type 1 diabetes or type 2 diabetes. Odds ratios(95% CI) comparing TT/TC with CC were 1.13(0.71-1.79) for type 1 diabetes and 0.96(0.86-1.08)) for type 2 diabetes. In conclusion, increased milk intake is not associated with reduced risk of diabetes, observationally or causally through lactose intolerance. Supported By: Danish Dairy Research Foundation

& 1464-P Plasma Fatty Acid Concentrations Vary Seasonally in Persons with Type 2 Diabetes DAWN C. SCHWENKE, JOHN P. FOREYT, EDGAR R. MILLER, REBECCA S. REEVES, MARA Z. VITOLINS, BIOMARKERS OF OXIDATIVE STRESS SUBGROUP OF THE LOOK AHEAD RESEARCH GROUP, Phoenix, AZ, Houston, TX, Baltimore, MD, Winston-Salem, NC Dietary saturated (SFA), cis-monounsaturated (MUFA), and trans-fatty & 1466-P acids (TFA) adversely and polyunsaturated fatty acids (PUFA) favorably Plasma Branched-Chain Amino Acids, Insulin Metabolism, and associate with cardiovascular disease (CVD) risk. Seasonal variation in Incident Type 2 Diabetes—The Insulin Resistance Atherosclerosis plasma fatty acids (FA) may help explain higher CVD risk in winter and has Study (IRAS) not been studied in persons with type 2 diabetes. We assessed seasonal CHRISTINE LEE, STEVEN M. WATKINS, LYNNE E. WAGENKNECHT, CARLOS variation in plasma SFA, MUFA, PUFA and 18-carbon TFA in persons in two LORENZO, STEVEN M. HAFFNER, ANTHONY J. HANLEY, Toronto, ON, Canada, Look AHEAD sites (Baltimore, n =120; Houston, n=185). Look AHEAD was a Sacramento, CA, Winston-Salem, NC, San Antonio, TX, Houston, TX multi-center controlled trial of intensive lifestyle intervention for weight loss Branched-chain amino acids (BCAAs) appear to be markers of the versus control in overweight/obese adults (aged 45-76) with type 2 diabetes. inhibitory action of insulin on amino acid release by skeletal muscle. Percentage women (56 %) and minorities (19 % black, 8 % Hispanic) were Recent evidence has suggested that plasma BCAAs, i.e., valine, leucine similar to Look AHEAD study-wide. At baseline (2002-2004), clinical values and isoleucine, are associated with insulin resistance and the risk of type Genetics

POSTERS were measured, nutrients estimated from the Look AHEAD food frequency 2 diabetes. However, little is known about their roles in β-cell function and Epidemiology/ questionnaire, physical activity assessed by accelerometry, and SFA, MUFA, insulin clearance. We investigated the associations of BCAAs with insulin PUFA, and TFA concentrations measured in plasma collected fasting. Dates sensitivity (SI), acute insulin response (AIR), metabolic clearance of insulin for peak FA values and peak-to-trough ratios (PTR) were estimated from (MCRI) and incident diabetes in 685 non-diabetic participants in the IRAS. models including sine/cosine functions; interaction with site was tested and Plasma BCAAs were measured by mass spectrometry. SI, AIR and MCRI found not signifi cant. In cross-sectional multivariable models adjusting for were determined from frequently sampled intravenous glucose tolerance demographics, body mass index, sampling time, plasma insulin, statin use, tests. We used multivariable-adjusted linear regression to examine the and total plasma FA, seasonal variation was found for plasma SFA [peak cross-sectional associations of plasma BCAAs with SI, AIR and MCRI, and June 2, PTR 1.05 (CI 1.02, 1.07) p<0.0001], MUFA [peak July 3, PTR 1.07 (CI logistic regression to assess associations with incident diabetes at 5-year 1.03, 1.11) p=0.0007], PUFA [peak Dec 14, PTR 1.06 (CI 1.03,1.09) p=0.0003], follow-up. Covariates included age, sex, ethnicity, alcohol intake, smoking, and TFA [peak Dec 24, PTR 1.20 (CI 1.04,1.39) p=0.042]. Adjusting for diet physical activity, BMI, energy intake and protein intake. All plasma BCAAs (total energy, dietary fat, SFA, oleic acid, PUFA, and TFA) and physical were inversely associated with SI [β= -0.0024 (-0.0035, -0.0013) for valine, activity did not alter results. Results showed seasonal variation in plasma FA β = -0.0028 (-0.0046, -0.00091) for leucine, β = -0.0077 (-0.012, -0.0037) for with adverse values for SFA and MUFA in summer compared with adverse isoleucine], and MCRI [β= -0.0024 (-0.0033, -0.0015) for valine, β = -0.0030 values for TFA and benefi cial values for PUFA in winter. Further work will be (-0.0045, -0.0015) for leucine, β = -0.0082 (-0.012, -0.0049) for isoleucine, all needed to determine if seasonal variation in plasma FA contributes to higher p<0.001]. Plasma BCAAs were directly associated with the risk of incident CVD morbidity and mortality in winter. diabetes [odds ratio (OR) per 1 SD increase of valine: 1.30 (1.022, 1.65) Supported By: NIH (R01HL70300) for valine, OR for 1 SD increase of leucine: 1.33 (1.028, 1.72), OR for 1 SD increase of isoleucine: 1.33 (1.041, 1.69), all p<0.05]. Plasma BCAAs were & 1465-P not associated with SI-adjusted AIR. This study suggests that higher levels Pentadecanoic Acid (15:0), a Biomarker of Dairy Food Intake, Is of plasma BCAAs predict the risk of incident diabetes, and are independently Inversely Associated with Incident Type 2 Diabetes and Its Under- associated with lower insulin sensitivity and clearance, but not with β-cell lying Disorders function, in a high risk population. INGRID D. SANTAREN, STEVEN M. WATKINS, ANGELA D. LIESE, LYNNE E. WAGENKNECHT, MARIAN REWERS, STEVEN M. HAFFNER, CARLOS LORENZO, 1467-P ANTHONY J. HANLEY, Toronto, ON, Canada, Sacramento, CA, Columbia, SC, Winston- Salem, NC, Aurora, CO, San Antonio, TX WITHDRAWN Growing evidence suggests that saturated and trans fatty acids (FAs) in dairy foods may play a role in the observed protective effects of dairy on type 2 diabetes (T2DM) risk. This study investigated the associations of dairy biomarkers, pentadecanoic acid (15:0) and trans-palmitoleic acid (trans 16:1n-7), with incident T2DM and underlying traits in the tri-ethnic multi-centre Insulin Resistance Atherosclerosis Study (IRAS) (n=659). Diabetes status was assessed via oral glucose tolerance tests. Frequently sampled intravenous glucose tolerance tests measured insulin sensitivity (SI) and β-cell function (Disposition Index, DI). Serum FAs were quantifi ed using gas chromatography. Logistic and linear regression models were adjusted for demographic, lifestyle, and dietary variables. We found that 15:0 was positively associated with log SI (β = 0.84; p = 0.03) and log DI (β = 2.21; p = 0.02), as well as a 27% decreased incident diabetes risk after 5

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smoking was a signifi cant effect modifi er for initiation. Smokers with PDM were as likely to initiate breastfeeding compared with NDM (odds ratio (OR) 1.1, 95% confi dence interval: 0.7-1.7); smokers with GDM were more likely to initiate breastfeeding compared with NDM (OR: 1.4 (1.1-1.7)). Non-smokers with PDM (OR: 0.7 (0.6-0.9)) or GDM (OR: 0.9 (0.7-0.9)) were less likely to initiate compared with NDM. For continuation, women with PDM were less likely to continue breastfeeding compared with NDM (OR: 0.7 (0.6-0.9)). These national data indicate breastfeeding initiation and continuation rates were lowest among women with PDM compared with women with GDM or NDM. Breastfeeding initiation varied by diabetes and current smoking, which may refl ect differences in prenatal breastfeeding education.

1470-P Reasons for Not Initiating or Continuing Breastfeeding Differ by Maternal Diabetes Type REENA OZA-FRANK, ADAM BARTLEY, Columbus, OH Breastfeeding initiation and continuation rates have been shown to differ by diabetes type, however, the corresponding reasons for not initiating and/ or continuing breastfeeding remain unknown. Our objective was to examine & 1468-P reasons for not initiating and/or continuing breastfeeding by diabetes type. Does Knowing One’s Glycemic Status Make a Difference in Macro- We used data from the Pregnancy Risk Assessment Monitoring System nutrient Intake? (PRAMS) (2009-2011), a survey among women with a recent live birth and BARBARA BARDENHEIER, MARY COGSWELL, EDWARD W. GREGG, DESMOND including data from 16 states and New York City. Women who did not E. WILLIAMS, ZEFENG ZHANG, LINDA S. GEISS, Atlanta, GA initiate breastfeeding were asked to check all the reasons that applied We sought to determine how nutrient intake differs by those who aware for not initiating breastfeeding. Women who initiated breastfeeding were of their glycemic status and those not. We used 24-h dietary recalls and asked to check all the reasons that applied for not continuing breastfeeding other data from 5,045 non-pregnant adults aged over 20 years from the at 2-4 months postpartum. Among n=12613, 8.9% of respondents reported 2005-2010 National Health and Nutrition Examination Survey and stratifi ed gestational diabetes mellitus (GDM) and 1.7% reported pregestational analyses by sex and glycemic status. Estimates of intakes were adjusted diabetes mellitus (PDM). Among GDM and no diabetes (NDM), the three most for within individual day-to-day variation by using measurement error common reasons for not initiating breastfeeding were the same: “I didn’t models and also for age, race/ethnicity, body mass index, weekday, and want to” (44% and 48%, respectively), “I didn’t like breastfeeding” (27% and total caloric intake, if not already included. SEs and 95% CIs were assessed 30%), and “I had other children to take care of” (25% and 19%). Although using jackknife replicate weights. Diagnosed diabetes and prediabetes the top two reasons for PDM were similar (49% and 34%), the third most were self-reported; undiagnosed diabetes and prediabetes were defi ned common response among PDM was “I was sick or on medicine” (30%). The Genetics

by no self-report and fasting glucose (FPG) >126 mg/dL or A1C >6.5% and three most common reasons for not continuing breastfeeding were similar POSTERS FPG 100-125 mg/dL or A1C of 5.7-6.4%, respectively. Factors assessed were among GDM, NDM, and PDM: “I thought was not producing enough milk” Epidemiology/ total caloric intake, sugar, carbohydrates (CHO), fi ber, protein, fat, and total (46%, 45%, 53%, respectively), “Breast milk alone did not satisfy my baby” cholesterol; differences with p<0.05 are reported. Men with diagnosed (37%, 37%, 35%), and “My baby had diffi culty latching or nursing” (32%, diabetes (n=1,014) daily consumed less sugar (mean: 111.2 vs. 130.4g) and 31%, 28%). The primary reasons for not initiating/continuing breastfeeding CHO as a percent of intake (45.6 vs. 47.2%) while consuming more protein were similar regardless of diabetes type, indicating breastfeeding education (mean: 99.2 vs. 95.2g), total fat, and mono- and poly-unsaturated fat (mean: and promotion activities for the whole population are appropriate for women 99.4 vs. 93.1g; 37.2 vs. 34.0g; 21.2 vs. 19.1g) than men with undiagnosed with diabetes. However, PDM women may perceive their chronic condition diabetes (n=224). Women with diagnosed diabetes (n=1,036) daily consumed as a barrier to breastfeeding, refl ecting a specifi c educational need in this less sugar (mean: 90.6 vs. 105.7g) and CHO as a percent of intake (49.0 vs. population. 50.8%) while consuming more protein (mean: 69.9 vs. 64.2g) than women with undiagnosed diabetes (n=137). No signifi cant differences were found 1471-P among those with prediabetes diagnoses and those not. Lower consumption Exclusive Breastfeeding Rates Lowest among Women with Gesta- of sugar and total CHO among people with self-reported diabetes indicates tional Diabetes healthy dietary behavior. Men aware of their diabetes consumed signifi cantly REENA OZA-FRANK, ADAM BARTLEY, Columbus, OH more fat, albeit healthier fats, than those unaware. Our study suggests that The Healthy People 2020 (HP2020) objective for exclusive breastfeeding screening and subsequent knowledge of glycemic status may favorably through 3 months of age is 46.2%, however, there is no previous data on affect some dietary patterns for those with diabetes. exclusive breastfeeding through 3 months by maternal diabetes status. Therefore, our objective was to determine rates of and associations 1469-P between exclusive breastfeeding and maternal diabetes. We used data Differences in Breastfeeding Initiation and Continuation by Maternal from the Pregnancy Risk Assessment Monitoring System (PRAMS) (2009- Diabetes Status 2011) to examine rates of and associations between exclusive breastfeeding REENA OZA-FRANK, ADAM BARTLEY, Columbus, OH and maternal diabetes, including data from 30 states and New York City. Regional data indicate differences in breastfeeding initiation by maternal Associations between exclusive breastfeeding by maternal diabetes were diabetes status. Whether these observations are consistent among a U.S. assessed using chi-squared tests and multivariable logistic regression. sample of women is unknown, as are rates of continued breastfeeding after Among n=57574 women who initiated breastfeeding, 8.9% reported delivery. gestational diabetes mellitus (GDM) and 1.6% reported pregestational We used data from the Pregnancy Risk Assessment Monitoring System diabetes mellitus (PDM). At 3 months postpartum, exclusive breastfeeding (PRAMS) (2009-2011) to examine rates of breastfeeding initiation and rates were 29%, 24% and 21% among no diabetes mellitus (NDM), PDM, and continuation (for at least 2 months) by maternal diabetes status, including GDM, respectively (χ2 p<0.01). In adjusted analyses, women with GDM (odds data from 30 states and New York City. Differences in breastfeeding by ratio (95% confi dence interval): 0.78 (0.68-0.89)) were signifi cantly less likely maternal diabetes were assessed using chi-squared tests and multivariable to breastfeed exclusively for 3 months compared with NDM. There were no logistic regression. Among n=96039, 8.8% reported gestational diabetes signifi cant differences in exclusive breastfeeding between PDM and NDM mellitus (GDM) and 1.7% reported pregestational diabetes (PDM). Initiation (0.83 (0.65-1.07)) or PDM and GDM (0.94 (0.71-1.25)). Women with GDM and continuation rates were similar among GDM and no diabetes mellitus were signifi cantly more likely to introduce liquids other than breast milk (i.e. (NDM) (81.6% vs. 81.8%, p=0.79, respectively; 69.2% vs. 70.4%, p=0.3). formula, water, juice, tea, or cow’s milk) by 3 months (78%) compared with Initiation (78.1%) and continuation (64.1%) rates were consistently lower women with NDM (70%) and PDM (75%) (p<0.01). Although national data among PDM compared with NDM. Rates of initiation among GDM compared indicate breastfeeding initiation rates among GDM were as high as NDM, to PDM were similar (p=0.05), although continuation rates were higher this study indicates fewer women with GDM exclusively breastfeed through among GDM compared to PDM (p=0.02). In adjusted analyses, current 3 months compared with NDM and had exclusive breastfeeding rates similar

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to women with PDM. Additionally, women with GDM introduce liquids other is regulated enzymatically rather than through the diet, with insulin resist- than breast milk more frequently by 3 months than other women, indicating ance. different infant feeding patterns that may impact infant growth. Supported By: CDA; CIHR; BBDC; OGS

1472-P 1474-P Dietary Patterns and Associations with Metabolic Risk Factors in Associations of Total, Bioavailable, and Free 25(OH)D Concentrations South Asians with Metabolic Syndrome in an Aboriginal Canadian Community MEGHANA D. GADGIL, CHERYL A.M. ANDERSON, NAMRATHA R. KANDULA, SUDABA MANSURI, ALAA BADAWI, DAVID E. COLE, STEWART B. HARRIS, ALKA M. KANAYA, San Francisco, CA, San Diego, CA, Chicago, IL MARY MAMAKEESICK, JONATHON MAGUIRE, PHILIP W. CONNELLY, BERNARD South Asians are at high risk of type 2 diabetes and dietary patterns ZINMAN, ANTHONY J. HANLEY, Toronto, ON, Canada, London, ON, Canada, Sandy may infl uence this risk. South Asians aged 40-84 years without known Lake, ON, Canada cardiovascular disease were enrolled in a community-based cohort called the Accumulating evidence suggests that vitamin D may play a role in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) etiology of metabolic syndrome (MetS); however, limited studies have been study. A validated food frequency questionnaire, fasting and 2-hour post- conducted in Aboriginal populations. Recent research on bone mineral challenge blood samples were collected. We used principal component density and renal osteodystrophy suggests that bioavailable 25(OH)D may analysis with varimax rotation to determine dietary patterns, and sequential be a superior biomarker for vitamin D metabolism, although detailed studies linear regression models to determine associations with metabolic factors. have yet to be pursued in MetS. We analyzed the associations of total, Data from 892 participants was used (47% female). We identifi ed 3 major bioavailable and free 25(OH) D with MetS in a First Nations population in dietary patterns: Western (34%), Sweets and Refi ned Grains (SRG, 34%), and Ontario. A cross-sectional analysis was conducted within the Sandy Lake Fruits and Vegetables (33%). The Western pattern was consumed more by Health and Diabetes Project (2003-2005). A total of 390 participants (> age men, smokers, and those who often eat out (>2 times/wk) (p<0.01). Compared 12 y) were assessed for serum total, bioavailable and free 25(OH)D, fasting to the Fruits and Vegetables pattern, the SRG was associated with higher plasma glucose and insulin, and anthropometric and lifestyle variables. HOMA-IR (p=0.03) and lower HDL (p=0.02) in Model 1 (adjusted for age, The 2009 harmonized criteria (Alberti et al 2009) were used to defi ne sex, study site and total caloric intake), and the Western diet a higher BMI MetS. Multivariate logistic regression analyses were conducted adjusting (p=0.01) and LDL (p=0.04) in Model 1, and higher waist-hip ratio (p=0.01) for sociodemographic and lifestyle confounders. The prevalence of MetS in Model 2 (further adjusted for income, education, alcohol and exercise). was 47%. Those with MetS were signifi cantly older and had higher BMI (Table). Both Western and SRG diet patterns are associated with metabolic vs. with those without MetS (both p <0.001). There was a decreased risk risk factors, and may be potential targets for risk reduction. (OR=0.71, 95% CI 0.55, 0.92) of MetS per standard deviation (SD) increase in baseline total 25(OH)D after adjustment for sex, age, season, sun exposure Mean (95%CI) *p<0.05. and parathyroid hormone (PTH). Also, signifi cant interactions were found Reference Pattern: Sweets and Refi ned Grains Sweets and Refi ned Grains Western Western between total, bioavailable and free 25(OH)D and both BMI and PTH levels Fruits and Vegetables (Model 1) (Model 2) (Model 1) (Model 2) (p < 0.05). Decreased risks of MetS per SD increase in total, bioavailable BMI (kg/m2) 0.56 [-0.14,1.26] 0.34 [-0.44,1.11] 0.92* [0.19,1.64] 0.63 [-0.18,1.44] and free 25(OH)D were found after adjustment for covariates in those with higher BMI (> 25 kg/m2) and those with higher PTH levels (> 55 pg/mL) (all p <

Genetics WHR 0.02* [0.01,0.03] 0 [-0.01,0.01] 0.02* [0.01,0.03] 0.02* [0.01,0.03]

POSTERS 0.001). However, there were no signifi cant associations in those with lower Epidemiology/ HOMA-IR 1.13* [0.11,2.15] 0.40 [-0.69,1.48] 0.86 [-0.20,1.93] 0.88 [-0.25,2.02] BMI or lower PTH levels. In summary, a signifi cant inverse association was Triglycerides (mg/dL) 0.16 [-11.25,11.57] -3.49 [-16.24,9.27] 2.88 [-8.94,14.69] 1.94 [-11.30,15.19] found between serum total 25(OH)D and MetS prevalence. These results HDL (mg/dL) -2.45* [-4.41,-0.49] -1.47 [-3.65,0.72] -0.25 [-2.29,1.78] -0.4 [-2.67,1.87] support a potential role for vitamin D status in the etiology of MetS. Fasting Glucose (mg/dL) 1.17 [-2.76,5.10] -0.61 [-4.98,3.76] 2.59 [-1.49, 6.67] 3.24 [-1.32,7.80] Supported By: CIHR Supported By: NIH (1R01HL093009) 1475-P Nutritionist Involvement in Care, Use of Carbohydrate Counting, 1473-P and Their Association with Dietary Intake among Individuals with Lower Serum Non-Esterifi ed Eicosapentaenoic Acid (EPA) Is T1DM in China Associated with Insulin Resistance: PROspective Metabolism and LINDSAY M. JAACKS, WEI LIU, JAMIE CRANDELL, MICHELLE MENDEZ, LINONG ISlet Cell Evaluation (PROMISE) Cohort JI, WAYNE ROSAMOND, ELIZABETH J. MAYER-DAVIS, Chapel Hill, NC, Beijing, LUKE W. JOHNSTON, SHEENA KAYANIYIL, CHRISTINE LEE, STEWART B. HARRIS, China RAVI RETNAKARAN, BERNARD ZINMAN, RICHARD P. BAZINET, ANTHONY J. The contribution of nutrition education and diabetes nutrition therapy to HANLEY, Toronto, ON, Canada, London, ON, Canada self-management among individuals with T1DM in China is unknown. The Although high total serum non-esterifi ed (free) fatty acids (NEFA) levels 3C Study was an epidemiological study of the cost, care and coverage of are a risk factor for type 2 diabetes (T2DM), the contribution of individual T1DM in China. Data presented are from the 3C Nutrition Ancillary Study, a NEFA to T2DM is unclear. While EPA has potent anti- infl ammatory and anti- follow-up study conducted 1.6 ± 0.2 yr after the 3C Study. Meeting with a lipotoxic effects, limited data exist on the association of EPA in the NEFA nutritionist and carb counting were assessed by an interviewer-administered pool, which is thought to be enzymatically regulated, with the underlying questionnaire and dietary intake by 3, 24-hr recalls. Associations between disorders of T2DM. Our aim, therefore, was to study the association of EPA nutrition education and dietary intake were estimated using analysis of with insulin resistance (IR) and beta-cell dysfunction. covariance. Participants (n = 100; 54% male) were 41.7 ± 16.3 yr old; diabetes Serum samples of 484 adults at-risk for diabetes in the PROMISE cohort duration 11.8 ± 9.7 yr. Forty-eight percent of participants reported that they were analyzed for EPA using thin-layer-chromatography with gas-liquid- had “ever” met with a nutritionist; only 1 had met with a nutritionist in chromatography coupled to fl ame-ionization detectors. Glucose and insulin the past year. Sixty-four percent of all participants had been taught carb were measured from an oral glucose tolerance test. IR was assessed using counting, and the majority (56%) had been taught by physicians. Only 19% HOMA-IR and the Matsuda index (ISI), while the insulinogenic index over of participants who were taught carb counting ever use this tool. After HOMA-IR (IGI/IR) and the Insulin Secretion Sensitivity Index 2 (ISSI-2) adjustment for confounding by age and occupation, participants who had determined beta-cell function. Regression model covariates included sex, met with a nutritionist had higher iron and egg intakes compared to those age, ethnicity, BMI, and family history of T2DM. who had not (Table). In this sample of individuals with T1DM in China there is EPA was signifi cantly negatively correlated with BMI (r = -0.11, p = 0.02) little nutritionist involvement in continuing diabetes education and very few and positively correlated with age (r = 0.18, p < 0.0001). EPA as a percent of participants practice carb counting. total NEFA (%EPA) was signifi cantly associated with ISI (beta [95% CI] = 0.45 [0.10, 0.79]) and with HOMA-IR (beta = -0.50 [-0.85, -0.15]) in the adjusted regression models. Similarly, EPA concentration was signifi cantly associated with ISI (beta = 0.10 [0.003, 0.21]) and with HOMA-IR (beta = -0.16 [-0.26, -0.05]). While there was a signifi cant bivariate correlation of %EPA with both IGI/IR and ISSI-2 (r = 0.11-0.15, all p < 0.01), there was no signifi cant association with these outcomes (p > 0.23) in adjusted regression models. These results suggest a potential role for EPA in the NEFA pool, which

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1477-P Table. Estimated Mean (Standard Error) Nutrient and Food Group Intakes, Adjusted for Age and Occupation, Across Groups of Nutrition Education Relationship between Abdominal Obesity and Manifestation of Risk Among Individuals with T1DM in China. Factors for the Metabolic Syndrome in Japanese: A 5-Year Cohort Study Using Data from Local Resident Health Check-up Programs Ever met with a nutrition- Carb Counting ist YUTAKA MORI, HIDEAKI KOMIYA, KAZUNORI UTSUNOMIYA, Komae, Japan, Utsunomiya, Japan, Tokyo, Japan * * Yes No P Taught and Taught but Never P Objective: To explore the relationship between abdominal obesity (AO) sometimes use never use taught and the risk factors for metabolic syndrome (MS) during a 5-year period. Energy 1553 (59) 1628 (56) 0.38 1331 (114) 1624 (54) 1631 (64) 0.06 Methods: The study enrolled 3,126 subjects who participated in local health (kcal/day) check-up programs in both 2006 and 2011. MS was diagnosed based on the Fat 36.2 (1.2) 35.6 (1.2) 0.72 37.0 (2.4) 36.8 (1.1) 34.2 (1.3) 0.31 JASSO criteria, and the following analyses were performed with adjustment (% kcal) for age and sex. 1) 902 subjects with no risk factors including AO in 2006 and Carb 46.6 (1.2) 47.5 (1.2) 0.64 45.8 (2.5) 46.8 (1.2) 48.0 (1.4) 0.68 172 subjects with only AO in 2006 were compared for incidence of risk factors (% kcal) for MS 5 years later to clarify the effect of AO on risk factors for MS. 2) 1,535 Protein 16.8 (0.4) 15.8 (0.4) 0.13 15.9 (0.9) 16.2(0.4) 16.5 (0.5) 0.77 AO (-) subjects without high blood pressure in 2006 were divided into those (% kcal) who became AO (+) and those who remained AO (-) 5 years later and were Fiber 7.6 (0.4) 7.4 (0.4) 0.72 7.0 (0.7) 7.7 (0.4) 7.4 (0.4) 0.67 compared for incidence of high blood pressure to clarify the relationship (g/1000 kcal) between the onset of AO and the risk factors for MS. Again, 2,074 AO (-) subjects without IFG were divided into those who became AO (+) and those Iron 11.9 (0.4) 10.5 (0.4) 0.007 11.0 (0.8) 10.9 (0.4) 11.6 (0.4) 0.51 (mg/1000 who remained AO (-) 5 years later and were compared for incidence of IFG. kcal) Results: 1) Those found to be AO (+) at baseline had a signifi cantly higher incidence of high blood pressure and IFG, compared to those found to be Rice 81 (7.9) 78 (7.5) 0.81 81 (15) 71 (7.2) 90 (8.7) 0.24 AO (-) at baseline, with no signifi cant difference in incidence of high TG/ (g/1000 kcal) low HDL-C, regardless of baseline AO status. 2) The incidence of high blood Vegetables 274 (21) 241 (20) 0.26 275 (41) 258 (19) 249 (23) 0.85 pressure 5 years later was signifi cantly higher in those who became AO (+) 5 (g/1000 kcal) years later at 69.9% than in those who remained AO (-) 5 years later (21.8%). Fruit 42 (8.8) 55 (8.4) 0.32 46 (18) 48 (8.2) 51 (9.9) 0.95 Again, the incidence of IFG was signifi cantly higher 5 years later in those who (g/1000 kcal) became AO (+) at 5.6% than in those who remained AO (-) (2.9%). However, Red meat 47 (4.9) 41 (4.7) 0.38 31 (9.7) 46 (4.6) 45 (5.4) 0.36 IFG was lower in incidence than high blood pressure in those who remained (g/1000 kcal) AO (-) and those who became (+) 5 years later. Conclusions: It is suggested Eggs 37 (3.1) 27 (2.9) 0.03 45 (6.1) 28 (2.8) 31 (3.4) 0.05 that the risk factors for MS increase with aging, but are accelerated in the (g/1000 kcal) presence of AO and that blood pressure may be a risk factor more sensitive *Pr > F from analysis of covariance, adjusted for age and occupation. to AO than fasting plasma glucose.

Supported By: NIH; Sanofi Genetics

1478-P POSTERS Relationship between Clinical Characteristics and Vegetable Epidemiology/ 1476-P Intake in Japanese Patients with Type 2 Diabetes: Analysis from Plasma Trace Elements and Preeclampsia in Type 1 Diabetes: A Japan Diabetes Complications Study Prospective Study CHIKA HORIKAWA, CHIEMI KAMADA, RYOTA OKUMURA, SHIRO TANAKA, ARPITA BASU, YONGXIN YU, ALICIA J. JENKINS, ALISON NANKERVIS, KRISTIAN SACHIKO TANAKA, YASUO OHASHI, ATSUSHI ARAKI, HIDEKI ITO, YUKIO YOSHI- HANSSEN, HANNE SCHOLZ, TORE HENRIKSEN, BJORG LORENTZEN, SATISH MURA, HIROHITO SONE, Niigata, Japan, Tokushima, Japan, Kyoto, Japan, Tokyo, K. GARG, KATHRYN MENARD, SAMAR HAMMAD, JAMES SCARDO, JOHN Japan STANLEY, CHRISTOPHER ASTON, TIMOTHY J. LYONS, Stillwater, OK, Belfast, It is well known that high vegetable intake reduces the risk of diabetes. Ireland, Sydney, Australia, Melbourne, Australia, Oslo, Norway, Aurora, CO, Chapel We recently reported that increased vegetable intake was associated Hill, NC, Charleston, SC, Spartanburg, SC, Oklahoma City, OK with reduced incident stroke and diabetic retinopathy. However, evidence Preeclampsia (PE) affects approximately 5% of all pregnancies, but its of a relationship between clinical characteristics and vegetable intake in prevalence is increased several-fold in the presence of pre-gestational Asian patients with diabetes is sparse, unlike in Western countries. We type 1 diabetes mellitus (T1DM). Plasma trace elements have been shown investigated these associations in a nationwide study of 1,516 patients with to modulate oxidative stress. Elements, such as manganese, selenium and type 2 diabetes aged 40-70 y whose HbA1c levels were ≥6.5%, originally zinc are essential for fetal growth, and act as antioxidants. In non-diabetic part of the Japan Diabetes Complications Study. Nutrition and food women, higher levels of copper and iron and lower levels of manganese, intakes were assessed by the food frequency questionnaire based on food selenium and zinc have been associated with PE in case-control studies. We groups. Other evaluations included a physical examination, blood pressure investigated the longitudinal changes in selected trace elements in T1DM measurement, neurological/ophthalmological examination, and laboratory pregnancy in women with and without subsequent PE. Plasma levels of tests that included HbA1c, fasting plasma glucose/insulin/C-peptide, serum trace elements (copper, iron, manganese, selenium and zinc) were measured lipids/creatinine/urea nitrogen and urine analyses. Physical activity and using inductively coupled plasma mass spectroscopy (ICP-MS) during the smoking status were determined by a detailed questionnaire. Mean daily fi rst (mean ± SD, 12.2 ± 1.9 weeks), second (21.6 ± 1.5 weeks), and third vegetable intake in quartiles ranged from 134 to 561 g in men and from 142 (31.5 ± 1.7 weeks) trimesters of pregnancy. We studied 23 T1DM women to 550 g in women. HbA1c, BMI, triglycerides, and systolic blood pressure who developed PE, and 24 T1DM women who remained normotensive. were well controlled. In male patients, serum triglyceride levels in patients We also studied 21 non-diabetic (non-DM) normotensive pregnant women in the 2nd, 3rd, and 4th quartiles of vegetable intake compared with the 1st as reference controls. All study visits took place before the onset of PE. In quartile (Q1: 105.0 mg/dl, Q2: 106.5 mg/dl, Q3: 105.0 g/dl, Q4: 94 ml/dl, trend women with T1DM who developed PE vs. those who remained normotensive, p<0.01) showed a signifi cant reduction. However, no signifi cant association no signifi cant differences were observed in trace elements at any trimester, was observed in female patients. Additionally, there was a signifi cant except that plasma zinc was higher at the fi rst trimester (p<0.05). Secondary relationship between high vegetable intake and low smoking ratio in analyses in T1DM women who did not develop PE versus non-DM women both men and women (Q1: 55.0%, Q2: 44.6%, Q3: 47.0%, and Q4: 35.0%, revealed signifi cantly higher copper and manganese at the third trimester, trend p<0.01; Q1: 16.5%, Q2: 8.7%, Q3: 5.7%, and Q4:6.6%, trend p<0.01, and higher plasma selenium at both fi rst and third trimesters (all p<0.05). respectively). In conclusion, we suggested that high dietary vegetable intake These fi ndings persisted after adjustment for covariates.In our longitudinal is associated with low serum triglyceride levels in male patients and a low study, higher plasma zinc, only at the fi rst trimester was associated with smoking ratio in both men and women. subsequent development of PE in T1DM women. In comparison to non-DM women, normotensive T1DM women tended to have higher levels of copper, manganese and selenium. These preliminary fi ndings deserve further investigation in T1DM pregnancies affected by PE. Supported By: JDRF

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1479-P 1481-P Impact of Sugar from Solid Food or Sugar Sweetened Beverage on Noodle Intake and Abdominal Obesity in Japanese Men and Women Weight Gain TOMOKO NAKAGAMI, JUNKO OYA, SATOSHI SASAKI, YASUKO UCHIGATA, MATHIEU BONIOL, PHILIPPE AUTIER, ALICE KOECHLIN, MARIA BOTA, CECILE Tokyo, Japan PIZOT, MAGALI BONIOL, PATRICK MULLIE, CHRIS ROBERTSON, PETER BOYLE, A low-carbohydrate diet, which is expected to correct hyperinsulinemia Lyon, France, Glasgow, United Kingdom and prevent obesity or diabetes, has recently attracted much attention. High Diabetes is associated with overweight and obesity. Intake of sugar, intake of white rice is known to increase the risk of diabetes in Japanese particular sugar sweetened beverages (SSB), has been held to be a contributor women. Little is known about the relation of noodle, another staple food to weight gain. It is not clear whether sugar intake from SSB induces greater in Japan, to obesity a known risk factor of diabetes. This study examined weight gain than sugar from solid food. A systematic review and analysis of the association of noodle intake to obesity in Japanese men and women. intervention studies of solid sugar intake and SSB on weight gain in adults Subjects were 2,101 middle-aged men and 1,281 women without a history and children undertaken based on estimation of the impact of 100g of sugar of diabetes who participated in health screening. Dietary information from intake per day on weight gain (in kg) between baseline and end of study the previous month was obtained by a brief-type self-administered dietary enabling inclusion of several arms per study. The impact of adjustment for questionnaire for Japanese. In men, there was a signifi cant positive effect energy intake on risk was evaluated. A total of 26 studies (with 72 arms) of noodle intake on waist circumference (Wc) after adjusting for age, alcohol evaluated the impact of SSB on weight change in adults. A signifi cant intake, smoking, physical activity at leisure time and work, medications association of sugar intake was found (0.69 kg increase (95%CI (0.29; 1.09) for hypertension and dyslipidemia, eating speed, and dietary fi ber intake per 100 g/day of sugar from SSB). In children fewer studies were performed (beta for 1 cm: 0.025, p=0.014) in the linear regression model. In contrast, (7 studies, 15 arms) and a similar, although non-signifi cant, association was the signifi cant effect of noodle intake remained neither on body mass found (0.84 kg increase (-0.34, 2.01) per 100 g/day of sugar from SSB). After index nor on % body fat after adjustment for confounding factors. Multiple adjusting for energy, the association was no longer signifi cant in adults logistic regression analysis adjusting for age, alcohol intake, smoking, (p=0.21) nor children (p=0.08). In studies of sugar from solid food in adults, physical activity at leisure time and work, medications for hypertension a signifi cant association of sugar intake was also found (0.60 kg increase and dyslipidemia, eating speed, and dietary fi ber intake showed that the (0.14, 1.06) per 100 g/day of sugar from SSB). After adjusting for energy, the odds ratios and 95% confi dence intervals for abdominal obesity (Wc ≥90 association was no longer signifi cant in adults (p=0.58). Too few studies in cm = top Wc quartile in men) against the 2nd, 3rd, and top noodle intake children (four) were available. No impact of study duration was identifi ed in quartiles (<27.8, 27.8-42.4, 42.5-62.7, ≥64.8 g/1000 kcal) were 0.96 (0.57- meta-regression in adults neither for SSB (p=0.19) nor sugar from solid food 1.61), 1.20 (0.73-1.97), and 1.83 (1.12-2.99), respectively, compared to the 1st (p=0.11). Studies with a parallel group exhibited higher weight gain, but this quartile in men (p for linear trend=0.010). In women, there was no signifi cant did not affect the lack of interaction between SSB intake and sugar. The relationship between noodle intake and each of three obesity indices. The increase of weight gain associated with sugar intake is driven by the energy increased noodle intake is associated with abdominal obesity in Japanese content of sugar rather than the source. Hence, population measures to men, but not in women. This may in part refl ect a sex difference of preference reduce risk of diabetes via consumption of sugar should not only be directed behavior for foods among modern Japanese population. at SSB but at all sources of sugar and energy. Supported By: Japan Diabetes Society Genetics

POSTERS 1480-P 1482-P Epidemiology/ Long-term Reduction of Weight and Antidiabetic Medication by A Mediterranean-type Nutrition Intervention Program in Greek Protein-Rich Meal Replacement in Type 2 Diabetes Patients—A Municipalities for Patients with Cardiometabolic Diseases (Food Randomized, Controlled Trial 4Health Study) KERSTIN KEMPF, BABETTE GÄRTNER, RUDOLF KEIL, SILKE ULLMANN, STEPHAN MARIA CHASAPIDOU, THEMISTOKLIS TZOTZAS, IOANNIS PAGKALOS, KONSTAN- MARTIN, Düsseldorf, Germany, Grevenbroich, Germany TINOS TZIOMALOS, KONSTANTINA PAPADIMITRIOU, Thessaloniki, Greece Formerly, we demonstrated in a randomized-controlled trial that a 12- The purpose of this prospective, randomized, controlled nutrition week long protein-rich meal replacement (PRMR) program was successful intervention study is to evaluate the impact of a 6-month balanced in reducing HbA1c, weight and antidiabetic medication in type 2 diabetes Mediterranean-type diet on cardiovascular risk factors in Greek adults with mellitus (T2DM) patients. Now we investigate if these improvements could known cardiometabolic (CM)diseases (Food4Health study). We present here be maintained long-term. preliminary results for 384 patients from a total of 8000 estimated to fi nally 80 T2DM patients had been randomized into two groups. The group with participate in the study, recruited from 50 randomly selected municipalities the stringent diet regime (n=43) replaced in week 1 three, in week 2-4 two in Greece. From these 384, 79.9% had obesity, 19% type 2 DM, 55.1% and in week 5-12 one main meal by 1g PRMR (Almased-Vitalkost, Almased hyperlipidemia, 50.6% hypertension and 14.6% cardiovascular disease Wellness GmbH, Bienenbüttel, Germany) per kg normal body weight. The (CVD), e.g. coronary disease or stroke. All subjects were randomized into moderate group (n=37) replaced two meals in week 1-4 and one until week 2 groups and followed for 6 months. The intervention group (I) received a 12. Afterwards participants did not have to but were allowed to continue Mediterranean healthy diet personalized in calories and nutrients according PRMR for the next 9 months. Clinical parameters were compared at baseline to the patient’s diseases, and was followed monthly by a dietitian, whereas and after one year using the Chi square, Mann Whitney, and Wilcoxon the control group (C) did not receive any dietary counseling. Measurements: signed rank test. BMI, %Body Fat (%BF) by BIA, waist circumference(W), serum lipids Baseline values (61% men, age 59 ± 11 years) did not differ signifi cantly (TC,TG,LDL-C,HDL-C), Fasting plasma glucose (FPG), HBA1c (only in diabetic between groups. 76% of participants completed the 1-year follow up and patients), Systolic (SBP) and Diastolic (DBP) blood pressure. A total of 316 maintained a signifi cant lower weight (mean reduction from 113 ± 18 kg to patients [181 group (I) and 135 group(C)], aged 58±4, 0 y, 77,5% women, age 100 ± 16 kg in the stringent group and from 111 ± 17 kg to 101 ± 16 kg in and sex-matched, fi nally completed the study. Anthropometric and metabolic the moderate (both p<0.0001)), although the percentage of participants with parameters before and after intervention in group (I) and percentage of higher weight loss was signifi cantly higher in the stringent group (≥ 10 kg: 50 signifi cant mean difference (in parenthesis) between groups (I) and (C) were vs. 30%; 5-10 kg: 36 vs. 37%; 0-5 kg: 14 vs. 30%; p=0.003). Just one person as follow: BMI: 33.7 ±5.6 vs. 32.5±5.4, (-4.0%,p<0.001), BF%: 39.4±8.4 vs. of the moderate group demonstrated weight gain. In both groups body mass 38.2±9.0,(-2.8%,p<0.05), (W):106.7±14.1 vs. 102.5±12.7cm (-4.1%,p<0.001), index, waist and hip circumference, systolic and diastolic blood pressure as LDL-C: 137.0 vs. 121.7 mg/dl (-7.9%,p=0.05), FPG :107.6 vs. 100.8 mg/dl well as antidiabetic medication remained signifi cantly reduced, e.g. at 1 year (-7.1%,p<0.001), SBP: 125.6 vs. 123.0 mmHg (-5.1%,p<0.05). In conclusion, follow up 30% in the stringent group (vs. 49% at baseline) and 33% in the preliminary data from this nutrition intervention study suggest that a well moderate group used insulin therapy (vs. 56%). balanced Mediterranean-type diet is able to reduce several metabolic risk In sum, both diet regimes with PRMR demonstrate a long-term effect on factors in Greek patients with CM diseases. weight reduction and antidiabetic medication in T2DM patients, although Supported By: National Strategic Reference Framework with the stringent diet regime the effects seem to be stronger. Supported By: Almased Wellness GmbH

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1483-P Characteristics of Routine, Periodic Fasting Behavior in Coronary Angiography Patients BENJAMIN D. HORNE, DONALD L. LAPPÉ, JOSEPH B. MUHLESTEIN, ANNA FRENCH, HEIDI T. MAY, STACEY KNIGHT, TAMI L. BAIR, JEFFREY L. ANDERSON, Salt Lake City, UT Background: Routine, periodic fasting associated with lower risk of diabetes and coronary artery disease (CAD) in two cohorts of coronary angiography patients. The frequency, duration, and purpose of fasting was not investigated, thus this study evaluated how and why patients engage in fasting. Methods: Patients evaluated for CAD between February, 2013, and December, 2013, were surveyed at the time of angiography for fasting behavior (N=446). Diagnosis of type-II diabetes, presence of CAD (≥70% stenosis in ≥1 coronary artery), and other measures were collected electronically. Results: In those reporting routine fasting (n=91; 20.4%), the primary purpose was religious (n=78; 85.7%), while lack of appetite (n=4), weight management (n=3), medical problems (n=2), cleansing fast (n=2), and habit (n=2) were also reported. Because lifetime fasting experience in patients with non-religious purpose (n=24) was <5 years, they were excluded. In Supported By: NIH/NCATS (TL1TR000155); NIDDK (R01DK076648) N=422, age averaged 60.0±13.2 years in fasters and 60.6±11.3 years in non-fasters (p=0.44), while 20.5% and 30.0% were females (p=0.09). Half & 1485-P of fasters drank water while fasting. The usual maximum duration of fasting Urinary Bisphenol A-Glucuronide (uBPA-G) and Metabolic Health at was ≥24 hours (n=6), 20-24 (n=31), 13-19 (n=18), ≤12 (n=22), and unknown Baseline in the French Prospective Cohort Study D.E.S.I.R. (n=1). Fasting was associated with lower risk of diabetes (15.4% vs. not DIANNA J. MAGLIANO, FANNY RANCIERE, JEREMIE BOTTON, REMY SLAMA, fasting: 27.6%, adjusted odds ratio [OR]=0.49, 95% CI=0.26, 0.96; p=0.027), MARIE ALINE CHARLES, MARLENE LACROIX, GAELLE GUSTO, BEVERLEY and with lower CAD risk (75.3% vs. 84.6%, adjusted OR=0.57, CI=0.29, 1.14; BALKAU, Prahran, Australia, Villejuif, France, Grenoble, France, Toulouse, France, La p=0.11). Fasting associated best with lower CAD risk in those fasting 20-24 Riche, France hours 2-11 times per year, while fasting for as few as 13-19 hours per episode Bisphenol A (BPA) is widely used in epoxy resin linings of food and was associated with incrementally lower diabetes risk for increasing fasting beverage containers. Evidence linking exposure of BPA to elevated glucose, frequency. No association was found for lifetime number of years of fasting HbA1c and other metabolic markers in humans begins to accumulate. The with diabetes or CAD. main metabolite of total BPA is BPA-glucuronide (BPA-G), a conjugated form Conclusions: Routine, periodic fasting may provide health benefi ts when of BPA (~57% of total BPA), but unconjugated (bioactive) and sulphated practiced about once per month or more for 13-24 hours at a time. These Genetics BPAs also exist. The relevance of these forms of BPA to evaluate exposure POSTERS data validate prior reports and support further research on the health and risk for humans is poorly understood. We examined whether BPA-G is Epidemiology/ effects of fasting. associated with markers of metabolic disease. Cross-sectional analyses of urinary BPA-G (uBPA-G) in a random sample of the French population-based D.E.S.I.R. study conducted were undertaken. Participants were 599 adults EPIDEMIOLOGY—OTHER aged 30 to 65 years. BPA-G and creatinine concentrations were measured in urine samples collected at baseline (1994-1996). uBPA-G was measured using liquid chromatography coupled to tandem mass spectrometry UPLC/MS/MS. Guided Audio Tour: Life Course Issues in Diabetes—From Vaccinations, Regression models with uBPA-G corrected for creatinine level were adjusted to Pregnancy, and Beyond (Posters: 1484-P to 1491-P), see page 13. for age, sex and education level. The sample had a mean age of 47±10 years and included 53% women. The median concentration of BPA-G was 5.7 ng/ & 1484-P ml (5.2 ng/mg creatinine). uBPA-G was higher in women than men (7.26 ng/ Maternal Glucose Mediates the Association between Maternal mg vs. 3.58 ng/mg creatinine, p<0.001). Levels were not associated with BMI and Neonatal Adiposity: The Healthy Start Study age (β coeff: -0.129, p=0.227). In adjusted models, uBPA-G concentrations ALLISON BUTI, SARAH SCHMIEGE, TESSA L. CRUME, JACOB E. FRIEDMAN, were not associated with glucose, HbA1c, BMI, or insulin in men (β coeffs: DANA DABELEA, Aurora, CO 0.019, 0.187, -0.068, -0.004, all p>0.05, respectively), nor in women: (-0.371, Maternal pre-pregnant BMI is associated with childhood obesity in -0.565, 0.009, -0.003, all p>0.05, respectively). There were no signifi cant epidemiological studies. It was suggested that this association is due in part associations of uBPA-G with any of the standard metabolic markers. More to specifi c intrauterine effects, but the responsible mechanisms are unclear. research on metabolites of BPA as well as prospective studies are required We conducted a multiple mediator path analysis to simultaneously test the to disentangle the relationship of BPA with chronic metabolic diseases such effects of fi ve hypothesized mediators in a pre-birth cohort of 981 mother- as diabetes and obesity. infant pairs (Figure below). Pre-pregnant BMI was obtained from medical Supported By: Société Francophone du Diabète records or self-reported. Neonatal fat mass (FM) was measured within 2 days after birth by air displacement plethysmography. Maternal insulin, & 1486-P glucose, triglycerides (TG), free fatty acids (FFA), and TNF-alpha levels Placental Abruption and Type 2 Diabetes Risk in Women: The Danish were measured fasting between 25 and 32 weeks of gestation. Maternal Birth Registry, 1980-2010 insulin resistance was calculated using HOMA-IR. The total effect of BMI on TAMARRA JAMES-TODD, GRETE SKØTT PEDERSEN, JENNIFER STUART, LAUST neonatal FM was 0.013 (p < 0.01). The pathway including maternal HOMA-IR HVAS MORTENSEN, JANET RICH-EDWARDS, ANNE-MARIE NYBO ANDERSEN, and fasting glucose accounted for 23% of the total effect (p < 0.01) while all Boston, MA, Odense, Denmark, Copenhagen, Denmark other pathways were not signifi cant. These data suggest that part of the Placental abruption is defi ned as premature complete or partial separation association between maternal and offspring obesity is due to intrauterine of the placenta before delivery. Two distinct pathways are thought to be effects: increased maternal insulin resistance and increased glucose involved_acute infl ammation or vascular dysfunction and chronic infl ammation. availability to the fetus, which infl uences neonatal FM accretion. Our data The latter process is a precursor of type 2 diabetes (T2DM) and may signal implicate maternal glucose as a potential fetal programming pathway. future risk of T2DM. The purpose of this study was to determine the extent to which having a pregnancy complicated by a placental abruption is associated with subsequent risk of T2DM in women. We used data from all singleton deliveries to Danish women registered in the Danish Medical Birth Registry during the period from 1980-2010. Placental abruption was defi ned as having an ICD-8 and ICD-10 codes for placenta abruption, placenta previa, or antepartum hemorrhage. T2DM was defi ned as having an ICD-8 code of 250 or ICD-10 code

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of E11. We considered maternal age, education, ethnicity, and immigrant status than 50% risk reduction of diabetes. A prospective study is warrant to as potential confounders. We used Cox proportional hazards models to estimate examine the impact of hepatitis B vaccination in prevention of diabetes. age-adjusted and fully-adjusted hazards ratios (HR) and 95% confi dence intervals. We stratifi ed by immigrant status. In age-adjusted models, having had & 1489-P a placental abruption was associated with a 1.40 increased risk of developing Undiagnosed Diabetes Is Associated with Higher Risks of Cardio- T2DM (95% CI: 1.18-1.63). The association was stronger in immigrants than metabolic Profi les Compared with Known Diabetes: Implication for native-born Danish (age-adjusted HR for immigrants: 1.70; 95% CI: 1.13-2.53) the Screening of Diabetes in Younger Adults compared to (age adjusted HR: 1.40; 95% CI: 1.18-1.66). Adjustment for socio- YONG-HO LEE, JAEHYUN BAE, SEHEE PARK, GYURI KIM, YU JUNG YUN, BYUNG- demographic factors attenuated the overall association. These results indicate WAN LEE, CHUL WOO AHN, BONG SOO CHA, HYUN CHUL LEE, EUN SEOK KANG, that having a placental abruption could signal a woman’s increased risk of T2DM, Seoul, Republic of Korea particularly in immigrant women. If replicated, future studies should evaluate Although diabetes is one of the most common and rapidly increasing whether women who experience a placental abruption would benefi t from chronic metabolic disorders which cause serious complications and mortality, lifestyle interventions to reduce future risk of T2DM. more than 30% of patients with diabetes are undiagnosed according to Supported By: NIH (5K12HD051959) the Korea National Health and Nutrition Examination Survey (KNHANES), a nationwide, population-based study regularly conducted by Centers for & 1487-P Disease Control and Prevention. We investigated the characteristics of Changes in Lifetime Risk of and Years Lost due to Diabetes in the cardiometabolic profi les among subjects with undiagnosed diabetes (UD). United States: 1986-2011 Nationally representative samples of 28071 subjects aged ≥20 years EDWARD W. GREGG, XIAOHUI ZHUO, YILING J. CHENG, K.M. VENKAT NARAYAN, from the KHNANES 2008−2011 were categorized as having normal glucose ANN L. ALBRIGHT, TED THOMPSON, Atlanta, GA (n=19461), impaired fasting glucose (n=5771), UD (n=713), or known diabetes Lifetime risk of diagnosed diabetes has been previously estimated to be 33% (KD, n=2126). Blood pressure, anthropometric, and laboratory indices were for men and 38% for women. We examined the impact of recent increases in examined. Hyper-LDL-cholesterolemia was individually evaluated by 2004 diabetes incidence and decreases in mortality rates on lifetime risk and years Adult Treatment Panel III guidelines. lost to diabetes among Americans. We used National Health Interview Survey Among those with diabetes, prevalence of UD were markedly increased and linked mortality data from 1986 through 2011 on 1,092,549 sampled adults (46% vs. 18%, P<0.001) in younger adults (<50 years) compared to older to estimate the age-, sex, and race/ethnicity specifi c incidence of diagnosed adults (≥60 years), indicating signifi cant discrepancies between younger diabetes and all-cause mortality. Incidence and mortality rates were incorporated and older population. Subjects with UD showed signifi cantly higher into a Markov chain model to calculate the lifetime diabetes risk and years lost obesity profi les (waist circumference and BMI), increased levels of total due to diabetes between 3 cohorts: 1986-1989; 1990-1999; 2000-2011. Lifetime and LDL cholesterol, and more hypertensive comparing to other groups. In risk at age 20 was 41.7% (95% CI, 40.5 - 42.9%) for men and 41.1% (95% CI, 40.1 addition, higher proportion of subjects with male, current smoking, and low -42.3%) for women, representing a 20 percentage point increase in men (from physical activity were observed in people with UD. While the prevalence 21.6% to 41.7%) and 13 percentage point increase in women (from 27.8% to of hypertension was higher in subjects with KD, those with UD had more 40.8%) between 1985-89 and 2000-2011. Lifetime risk increased in all sex, race/ people of undiagnosed hypertension (14% vs. 6%, P<0.001). The prevalence ethnic groups, with the largest increase among non-Hispanic Blacks, for whom of hyper-LDL-cholesterolemia was also increased in the group of UD (54% Genetics

POSTERS lifetime risk at age 20 was 46.3% (95% CI, 44.2 - 48.8) for men and 56.9% (95% vs. 46%, P<0.001). Epidemiology/ CI, 56.1 - 57.7%) for women in 2000-2011. For the average adult diagnosed at age Therefore, early and intensive screening for diabetes should be stressed in 40,the number of years lost due to diabetes decreased from 7.4 (95% CI, 5.7 - 9.5) public healthcare policies to reduce the elevated burden of cardiometabolic to 5.8 (95% CI, 4.4 -7.0) years in men and from 7.4 (95% CI, 6.5 - 8.1) to 6.8 years risks in the younger population with undiagnosed diabetes. (95% CI, 6.7 - 7.0) in women. However, because of the increasing prevalence of diabetes, the average number of years lost to diabetes for the U.S. population & 1490-P increased by 49% in men and 44% in women. About nine-tenths of the increase Serum Adipocyte Fatty Acid-binding Protein Is Related to the in lifetime risk was attributed to increased incidence while one-tenth was due Development of Metabolic Syndrome in Japanese Male Workers to greater longevity of non-diabetic persons.The continued increases in diabetes AKIKO HATA, YOSUKE SHIKAMA, NANAKO AKI, CHISATO KOSUGI, HIROYA incidence combined with declining mortality rates have increased lifetime KOBAYASHI, MASASHI MIYOSHI, TAKAYUKI NAKAO, AYAKO TAMURA, TAKAKO probability of diabetes, and for the average person with diabetes, led to more ICHIHARA, TAKAKO MINAGAWA, YUMI KUWAMURA, TOSHIO MATSUMOTO, years spent with diabetes but fewer years of life lost to the disease. MAKOTO FUNAKI, Tokushima, Japan Adipocyte fatty acid-binding protein (A-FABP/FABP4) is abundantly & 1488-P expressed in mature adipocytes and presumably secreted into the plasma Hepatitis B Vaccination Reduces the Risk of Diabetes by 50% from these cells. Emerging evidence suggests that FABP4 may be involved in a JEAN HUANG, HORNG-YIH OU, JAMES LIN, RUDRUIDEE KARNCHANASORN, development of insulin resistance and metabolic syndrome (MetS). However, WEI FENG, RAYNALD SAMOA, LEE-MING CHUANG, KEN C. CHIU, Duarte, CA, prospective cohort study to prove their causative relationship is still limited. Tainan, Taiwan, Kansas City, KS, Taipei, Taiwan The aim of the present study is to investigate an association between serum Liver plays a key role in glucose and insulin metabolism. It is well concentration of FABP4 and incidence of MetS in Japanese male workers. established that liver disease is associated with an increased risk for Here we report a prospective occupational-based study, which has been diabetes mellitus. We examined the risk of diabetes based on the serological conducted since 2008 in Japan. A total of 365 male workers without MetS testing for hepatitis B. aged 20 to 60 years were followed up prospectively (mean follow-up period We used the sample set from the participants of the NHANES 2005-2010. of 3.1years). We included only adult subjects (≥18 y/o) with both fasting plasma glucose The age-adjusted incidence of MetS signifi cantly increased with and hepatitis B status available. Subjects with established diabetes were increasing tertile of serum FABP4 levels at baseline (≤ 7.75, 7.76-11.06, and excluded from the study. Diabetes was defi ned as fasting plasma glucose ≥11.10ng/ml, P for trend<0.01). In multivariate analyses after adjusting for ≥ 126 mg/dL. Logistic regression analysis was used to calculate the odds age, BMI, smoking habits, alcohol intake, and regular exercise, the hazard ratio (OR) with 95% confi dence intervals (95%CI) with consideration of the ratio of MetS was 3.27 [95% confi dence interval:1.19 to 8.97, P=0.02] in the following covariates: age, gender, BMI, race/ethnic group, current smoking, highest tertile, when compared with the lowest tertile. Additionally, the alcohol consumption, education, poverty index, and physical activity. categorical variable of adiponectin and FABP4 was stratifi ed by the median This study consisted of 7,142 subjects without a prior history of diabetes. value. In stratifi ed analysis, the multivariate adjusted risk of MetS was Among them 1,412 subjects were noted to be successfully vaccinated with higher in subjects with high FABP4/high adiponectin (2.75 [0.73 to 10.41]) or hepatitis B as noted with positive hepatitis B surface antibody and negative low FABP4/low adiponectin (2.04[0.48 to 8.60]), and signifi cantly higher in hepatitis B core antibody. Diabetes was noted 16 subjects (1.13%) in subjects subjects with high FABP4/low adiponectin (5.11[1.49 to 17.57, P=0.01]) than with hepatitis B vaccination and 325 subjects (5.67%) without vaccination. The that in subjects with low FABP4/high adiponectin. OR for diabetes was 0.19 (95%CI: 0.11-0.32). After adjustment for age, gender, Our fi ndings suggest that increased serum concentration of FABP4 is a and BMI, the OR for diabetes was 0.43 (95%CI: 0.25-0.73). After adjustment risk factor for the incidence of MetS in Japanese male workers. Measuring for all covariates, the OR for diabetes was 0.48 (95%CI: 0.28-0.82). serum levels of both FABP4 and adiponectin may be useful to predict an Our study shows the subjects with hepatitis B vaccination are much less onset of MetS in this population. likely to be diabetic. Thus, hepatitis B vaccination is associated with more Supported By: Grants-in-Aid for Scientifi c Research; Knowledge Cluster Initiative

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1493-P & 1491-P Comorbidities in Patients with Lipodystrophy Risk of Pancreatitis, Pancreas Cancer among Patients with Diabetes REBECCA J. BROWN, KAREN LUTZ, ELAINE K. COCHRAN, JEAN L. CHAN, PHILLIP MARIA BOTA, PETER BOYLE, Lyon, France GORDEN, Bethesda, MD, San Diego, CA Concerns have been raised on the potential association between incretin- Lipodystrophy (LD) is a rare, heterogenous condition characterized by related therapies for type 2 diabetes and the risk of developing pancreatitis. adipose tissue defi ciency and ectopic lipid deposition in liver and muscle. LD Most recently, the debate has extended to the potential for the potential is often associated with severe metabolic abnormalities leading to signifi cant incretin-induced pancreatitis resulting in an increased risk of pancreas morbidity and early death, but due to the condition’s rarity, characterizing cancer. As background to this issue, the association between diabetes and these comorbidities is diffi cult. An ongoing study at the NIH has the largest pancreatitis and pancreas cancer was investigated. cohort of LD patients treated for metabolic abnormalities with metreleptin, Meta-analyses were undertaken, following PRISMA guidelines, of a recombinant analogue of human leptin, at a single center (N=72, July 2011). the potential associations between (i) diabetes and pancreas cancer: Inclusion criteria included LD, low leptin, and at least 1 of: diabetes, fasting (ii) diabetes and risk of pancreatitis; and (iii) pancreatitis and risk of insulin ≥30 µU/mL, or triglyceride (TG) ≥200 mg/dL. We describe the baseline pancreatic cancer. The aim was to shed light on the presence, strength and medical conditions of this population to better understand the severity of magnitude of this complex series of associations. Analysis was restricted to these comorbidities. Enrolled patients were 83% female; 61% Caucasian; prospective epidemiological studies for diabetes and pancreas cancer but all mean age = 23.7 y (54% <18 y); 44% congenital generalized LD, 28% familial observational studies were included in other analyses. partial LD, 22% acquired generalized LD, and 6% partial LD; mean fasting P a t ie n t s w i t h diab e t e s h a v e an in c r e a s e d r is k o f p an c r e a s c an c e r [S R R =1. 6 8 , leptin = 2.6 ng/mL; mean A1c = 8.2%; mean TG = 1041 mg/dL. Patients had a 95% CI (1.56, 1.82)] (based on 28 prospective studies) and of being diagnosed high burden of comorbid conditions often at a young age (Figure), with >80% with pancreatitis [SRR=1.90, 95% CI (1.56, 2.33)] (8 studies). Pancreatitis, having diabetes, liver disease, or hypertriglyceridemia. The majority (88%) in all its forms and irrespective of having diabetes, bears an increased risk of patients were receiving ≥1 antidiabetes agent (mean insulin dose 711 of going on to develop pancreas cancer [SRR=10.52, 95% CI (6.34, 17.47)] U/d [N=33]); 50% were receiving ≥1 lipid-lowering medication. This study (27 studies) although patients specifi cally with chronic pancreatitis have an highlights the frequency of serious and chronic medical conditions at a young even greater risk of pancreas cancer [SRR=13.24, 95% CI (5.66, 30.96)] (9 age in patients with generalized and partial LD. studies). There are important limitations of these meta-analysis including inconsistent criteria for diagnosing pancreatitis and, consequently, a large degree of unexplained variability between individual study fi ndings. It can be concluded that patients with diabetes have an increased risk of pancreatitis and also an increased risk of pancreas cancer although whether this is mediated through pancreatitis remains an open question.

1492-P Gender Difference in the Association between Food Insecurity and Insulin Resistance among U.S. Adults: NHANES, 2005-2010 YONG-MOON MARK PARK, JUNXIU LIU, SETH A. BERKOWITZ, QINGWEI HU, Genetics POSTERS

KYUNGDO HAN, ANDREW ORTAGLIA, ANGELA LIESE, ROBERT MCKEOWN, Epidemiology/ Columbia, SC, Boston, MA, Seoul, Republic of Korea Food insecurity refers to limited or uncertain ability to acquire nutritionally appropriate food. We tested hypotheses that food insecurity would have differential associations with insulin resistance by BMI and gender, in a Supported By: Bristol-Myers Squibb/AstraZeneca representative U.S. population. A total of 5,585 adults≥20 years (2,782 men and 2,803 women) without 1494-P diabetes were included in our fi nal analysis from the 2005-2010 National Youth with Type 2 Diabetes (T2D) Have More Vitamin D Defi ciency Health and Nutrition Examination Survey (NHANES) data. Insulin resistant than Youth with Type 1 Diabetes (T1D): The Pediatric Diabetes individuals were defi ned as those who had a homeostasis model assessment Consortium (PDC) of insulin resistance (HOMA-IR) ≥ 2.5. We categorized respondents as having JAMIE WOOD, FIDA BACHA, STEVEN M. WILLI, EDA CENGIZ, WILLIAM V. full, marginal, low, and very low food security using a validated scale. TAMBORLANE, BRIGID GREGG, GEORGEANNA J. KLINGENSMITH, DESMOND A. The prevalence of insulin resistance was highest in those with very low SCHATZ, KATRINA RUEDY, ROY W. BECK, CRAIG KOLLMAN, CRYSTAL CONNOR, food security (33.6 % in men and 22.5 % in women) in a normal weight group, HEIDI HARO, Los Angeles, CA, Houston, TX, Philadelphia, PA, New Haven, CT, Ann whereas in an overweight/obese weight group it was highest in those with Arbor, MI, Aurora, CO, Gainesville, FL, Tampa, FL marginal and low food security in men (74.1 %) and in women (66.1 %), Vitamin D defi ciency is common in youth with diabetes. To compare the respectively. Insulin resistance increased in both normal weight women (P frequency of vitamin defi ciency in youth with T1D and T2D, 25-hydroxy =0.001) and overweight/obese women (P < 0.001) as food security decreased, vitamin D (25OHD) levels were measured in 172 youth with T1D and 323 with but no linear trend was found in men. In multiple logistic regression analyses T2D 10−<21 years old enrolled in the PDC. very low food security, compared to full food security, was associated with Vitamin D defi ciency (<21 ng/ml) occurred in 48% of T2D vs. 17% of T1D insulin resistance in normal weight men (Odds ratio (OR), 95% confi dence youth, and insuffi ciency (21-<29 ng/ml) in 30% vs. 38%, respectively. The interval (CI): 3.14 (1.32-7.47)), and marginal food insecurity was associated median levels of 25OHD were lower in the T2D youth (21 ng/ml) than the T1D with increased odds of insulin resistance in overweight/obese men (OR, youth (29 ng/ml; unadjusted p-value<0.001, adjusted for site, race/ethnicity 95% CI: 2.13 (1.24-3.69)), after adjusting for age, race, smoking, drinking and age p-value=0.11). alcohol, physical activity, education, income, total energy intake, and total Although non-Hispanic, white youth with T2D and T1D had comparable fat intake. In women, no signifi cant association was found. levels of 25OHD, Hispanic and Black youth with T2D had lower levels than Food insecurity is associated with insulin resistance in NHANES did Hispanic and Black youth with T1D (Figure 1). The median 25OHD levels in participants without diabetes, and these effects vary by BMI and gender. both the T2D (15-34 ng/mL) and T1D (range 24-33 ng/mL) groups had a wide Future studies should evaluate whether improving food security status can range across the 8 PDC sites. In both groups, youth ≥18 years had the lowest also improve metabolic parameters and reduce diabetes risk. median 25OHD level (19ng/ml and 26 ng/ml respectively). T2D youth in this cohort had lower levels of vitamin D than T1D youth, as did Hispanic/Black youth, and older youth. Variation by site likely refl ects geographic variation in sun exposure and race/ethnicity. All youth with diabetes should have vitamin D status evaluated to optimize bone health, as well as potential benefi ts on glycemic control.

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(FH1); 3) mild: no fi rst-degree relative with diabetes(FH0). SUDAAN software was used to perform all weighted statistical analyses, with P <0.05 considered statistically signifi cant. The age and sex adjusted prevalence of diabetes was 32.7%(95%CI: 26.4- 39.7%) in risk category of FH2, 20.1%(95%CI: 18.2-22.1%) in risk category of FH1, and 8.4%(95%CI: 7.9-8.9%) in risk category of FH0, respectively (P trend <0.0001). The calculated Homa-IR, Matsuda ISI, delta I30/G30 among the three categories showed signifi cant trending changes, with the most negative effects in FH2. Multivariate Logistic regression analysis showed that relative to people in risk categories of FH0, the odds of having diabetes for people in risk categories of FH2 and FH1 were 6.16(95%CI: 4.46-8.50) and 2.86(95%CI: 2.41-3.39) times higher, respectively, after adjustment for age, sex, blood pressure, BMI, waist circumference, geographic regions, and education levels. Supported By: Novo Nordisk A/S; DK020572 Family history of diabetes has a signifi cant, independent, and graded association with the prevalence of diabetes in Chinese population. 1495-P Supported By: Chinese Medicine Association Prevalence and Risk Factors of Diabetes Mellitus in Jaffna District, Sri Lanka 1497-P SIVARATHY AMARASINGHE, SANDRASEGARAMPILLAI BALAKUMAR, VASAN- Frequency of Self-Monitoring of Blood Glucose (SMBG) and A1C THY ARASARATNAM, Jaffna, Sri Lanka Levels in Youth with Type 2 Diabetes (T2D): Data from the Pediatric A community based cross sectional descriptive study was undertaken Diabetes Consortium (PDC) T2D Registry Consortium (PDC) T2D to determine the prevalence and risk factors for diabetes mellitus (DM) in Registry people above 18 years of Jaffna District, Sri Lanka during the period of 2011 MICHAEL J. HALLER, EDA CENGIZ, WILLIAM V. TAMBORLANE, SANI ROY, APIS- to 2012. Overnight fasting blood sample was obtained from 511 subjects ADAPORN THAMBUNDIT, ROY W. BECK, CRAIG KOLLMAN, KATRINA RUEDY, to measure the fasting plasma glucose (FPG) using enzymatic colorimetric CRYSTAL CONNOR, BRUCE BUCKINGHAM, BRIGID GREGG, INAS THOMAS, Gainesv- assay. Anthropometric measurements were recorded and interviewer ille, FL, New Haven, CT, Philadelphia, PA, Tampa, FL, Stanford, CA, Ann Arbor, MI administrated questionnaire was employed. Physical activity was assessed It is well established that more frequent SMBG is associated with lower using International physical activity questionnaire. The prevalence of DM A1c levels in children with T1D. However, the relationship between SMBG (FPG ≥7.0 mmol/L) was 16.4% (95% CI: 13.3-9.9) and it was 19.6% (14.6- and A1c in youth with T2D has not been determined. We examined the 25.4) in males and 13.9% (10.1-18.5) in females. Of the total diabetics, 27.4% relationship between SMBG and A1c in 444 youth with T2D in the PDC T2D was previously undiagnosed. The prevalence of pre-diabetes (FPG<6.1- registry at 8 pediatric diabetes centers. Clinical characteristics included 7.0mmol/L) was 7.4%. Prevalence of dysglycemia (DM and pre-diabetes) mean age 16.2 ± 2.5 years; 66% female; 85% Black or Hispanic; 62% utilized was 23.9% (95% CI: 20.2-27.8). Prevalence of DM was higher among the public health insurance; 71% of parents with a high school education or less; Genetics

POSTERS smokers (26.3%) than the non-smokers (15.2%, p=0.032). Prevalence of 76% with family income <$50,000; and 96% with BMI >85%. A1c (%) was Epidemiology/ DM was higher among inactive subjects (21.8%) compared with active ≥ 9 in 28%, 8-<9 in 9%, 7-<8 in 13%, 6-<7 in 23%, and <6 in 27% of the ones (13.9%, p=0.034). In the fi nal multivariable model adjusted for age, cohort. high waist hip ratio (WHR>0.9 in male, >0.85 in female) and central obesity Patients treated with metformin alone (n=144; mean ± SD A1c 6.5 ± 1.5%) (waist circumference for male ≥90cm, female ≥80cm), people with family had a median of 2 SMBG tests per day (only 18% tested >3 times a day) history of DM were 3.5 times more likely to develop DM compared to the and there was no signifi cant association between A1c and SMBG frequency people without family history of DM (2.073-5.925). Likewise subjects with (p=0.12). In patients treated with insulin (n= 217; mean A1c 8.8 ± 2.6%), high WHR had 2 times DM risk than the normal subjects (1.205-3.644). median frequency of SMBG (3 tests per day with only 8% testing >4 times a Association of DM with the central obesity was marginally signifi cant in the day) was greater than in patients with metformin alone (p<0.001). There was fi nal adjusted model (p=0.057). Effects of age categories greater than 65, also no signifi cant association between A1c and SMBG frequency within 50-64 and 35-49 years on DM were 12.6 (4.195-38.022), 7.3 (2.712-19.803) this subgroup (p=0.81) or in the entire cohort (p=0.20). A1c increased with and 3.8 (1.387-10.820) higher compared to the age category 18-34 years duration of diabetes for those using insulin, but not in those treated with respectively. It was concluded that 1 out of 4 people in Jaffna has either DM metformin alone (unadjusted p<0.001 and 0.44 respectively). or pre-diabetes and the risk of developing DM is increased with age, positive The frequency of SMBG does not appear to infl uence A1c levels in youth family history of DM and high WHR. with well-controlled T2D being treated with metformin alone. Glycemic Supported By: Medical Faculty Research Fund control deteriorates over time in children with T2D who require insulin, despite increases in SMBG frequency. However, the limited number with >4 test/ day could account for the lack of correlation. These data suggest that new 1496-P treatment strategies, which could include more frequent blood testing, are Risk Categories of Family History of Diabetes and Prevalence of needed to improve clinical outcomes in youth with poorly-controlled T2D. Diabetes in Chinese Population: The Results from the 2007-2008 Supported By: Novo Nordisk A/S; DK020572 China National Diabetes and Metabolic Disorders Study ZHAOJUN YANG, JINGPING ZHANG, JIANZHONG XIAO, XIAOYAN XING, JUMING LU, JIANPING WENG, WEIPING JIA, LINONG JI, ZHONGYAN SHAN, 1498-P JIE LIU, HAOMING TIAN, QIUHE JI, DALONG ZHU, JIAPU GE, LI CHEN, XIAOHUI Classifi cation of Depression Symptoms in Youth with Type 1 and GUO, ZHIGANG ZHAO, QIANG LI, ZHIGUANG ZHOU, NA WANG, LIXIANG LIN, Type 2 Diabetes in the Pediatric Diabetes Consortium (PDC) WENYING YANG, CHINA NATIONAL DIABETES AND METABOLIC DISORDERS JANET SILVERSTEIN, EDA CENGIZ, WILLIAM V. TAMBORLANE, STEVEN M. STUDY GROUP, Beijing, China, Guangzhou, China, Shanghai, China, Shenyang, WILLI, GEORGEANNA J. KLINGENSMITH, SATYA SHANMUGHAM, JAMIE China, Taiyuan, China, Chengdu, China, Xi’an, China, Nanjing, China, Urumqi, China, WOOD, FIDA BACHA, JOYCE M. LEE, MARIA J. REDONDO, ROY W. BECK, CRAIG Jinan, China, Henan, China, Harbin, China, Changsha, China, Fuzhou, China KOLLMAN, CRYSTAL CONNOR, KATRINA RUEDY, Gainesville, FL, New Haven, CT, Several reports have shown that the risk of diabetes mellitus increases Philadelphia, PA, Aurora, CO, Stanford, CA, Los Angeles, CA, Houston, TX, Ann Arbor, with number of affected relatives in western population.The aim of the study MI, Tampa, FL was to investigate the association between different risk categories of family Psychological issues, especially depression, are associated with poor history of diabetes and prevalence of diabetes in Chinese population. adherence to the diabetes regimen and poor metabolic control as well as The analysis was based on the national-representative sample (n=46,239) high levels of markers of vascular infl ammation. The Children’s Depression from the 2008 China Diabetes and Metabolism Disorders Study. The family Inventory 2 (CDI2) was completed by 612 youth (253 with T1D, 359 with T2D) history of diabetes of each subject were collected, and an oral glucose age 10-17 years enrolled in the PDC. Frequency of depression symptoms and tolerance test and levels of fasting and post-load glucose and insulin were association with type of diabetes and demographic factors were evaluated. performed. The risk categories of family history of diabetes was defi ned as Treatment by a psychiatrist, behavioral therapist or psychologist within follows: 1) high: at least 2 generations of fi rst-degree relatives with diabetes the past year occurred in 4% of T1D and 10% of T2D youth. Symptoms (FH2); 2) moderate: only 1 generation of fi rst-degree relative with diabetes of depression were identifi ed on the CDI2 in 13% and 22% of children,

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A390 EPIDEMIOLOGY—OTHERCATEGORY respectively (p=0.004; Table) and were elevated or very elevated for 7% tolerance test (GTT) and insulin tolerance test (ITT) were performed at 2 and 12%, respectively. Among T1D youth, CDI2 depressive symptoms were and 3 weeks after initiation of the Western diet, respectively. For GTT, mice associated with lower family income (p=0.02) and there was a trend for were fasted overnight before being injected intraperitoneally with glucose higher symptoms among patients with higher BMI percentile and higher (1 g/kg). Blood glucose was determined with an UltraTouch glucometer using HbA1c that was not statistically signifi cant. There were no apparent trends whole blood taken from cut tail tips immediately before and at 10, 20, 30, among the T2D youth and there was no association of CDI2 scores with race/ 60, 90, and 120 min after glucose injection. Mice treated with phthalate ethnicity in either group. exhibited a trend of increased glucose intolerance compared with the This study underscores the need for regular screening for depression for control mice. In addition, fasting blood glucose levels at the baseline (0 min) DM youth and appropriate referral when needed. were signifi cantly higher in phthalate-treated mice than in the control mice (97.9±2.1 vs. 84.3±5.3 mg/dl, P=0.034). ITT was performed on non-fasted mice by injection of insulin (1.5U/kg). In response to insulin, both group of mice showed a deeper and longer-lasting fall in blood glucose levels. The baseline level of non-fasting blood glucose (at 0 min on ITT) was higher in the phthalate-treated group (159.2±6.0 vs. 145.2±3.6 mg/dl), although the difference did not reach a signifi cant level (P=0.086). These data suggest that phthalates promote the development of type 2 diabetes. Supported By: Novo Nordisk A/S; DK020572 Supported By: NIH

1499-P 1501-P Findings at Diagnosis of Type 1 Diabetes (T1D) and Type 2 Diabetes Global Estimates of the Prevalence of Impaired Glucose Tolerance (T2D): The Pediatric Diabetes Consortium (PDC) for 2013 and Projections to 2035 GEORGEANNA J. KLINGENSMITH, STEVEN M. WILLI, EDA CENGIZ, JAMIE LEONOR GUARIGUATA, DAVID R. WHITING, UTE LINNENKAMP, JESSICA BEAG- WOOD, WILLIAM V. TAMBORLANE, JOYCE M. LEE, HEIDI HARO, ROY W. BECK, LEY, JONATHAN SHAW, Brussels, Belgium, Chatham, United Kingdom, Mel bourne, CRAIG KOLLMAN, KATRINA RUEDY, CRYSTAL CONNOR, Aurora, CO, Philadelphia, Australia PA, New Haven, CT, Los Angeles, CA, Ann Arbor, MI, Tampa, FL Diabetes is a serious and increasing global health burden. Impaired glucose We present the clinical fi ndings in youth with T1D and T2D at diagnosis tolerance puts people at high risk of developing diabetes. Estimates of the from the eight diabetes centers of the PDC allowing a comparison of the prevalence of impaired glucose tolerance (IGT) are essential for allocating demographic and clinical characteristics of these two populations. resources towards the primary prevention of diabetes. Diagnosis data were collected at diagnosis in 484 children with T1D, 10.0- We conducted a literature search of studies reporting the age-specifi c 18.8 years of age and at enrollment in 453 youth with T2D, 10.0-19.8 years prevalence for IGT and used the Analytic Hierarchy Process to systematically at diagnosis, (diabetes duration: median 2.1 years (0.0-10.2). The diagnosis select studies to generate estimates for 219 countries and territories. of T2D required: weight at diagnosis >85%ile and negative diabetes Estimates for countries without available source data were modelled from autoantibodies, or no insulin for > 6 months or C-Peptide > normal fasting pooled estimates of countries that were similar in regard to geography, value. Youth < 10 years were excluded to minimize age as a confounder. ethnicity, and economic development. Logistic regression was applied to Genetics

Youth with T2D were signifi cantly older than T1D youth and more likely to generate smoothed age-specifi c prevalence estimates for adults 20-79 years POSTERS be female (Table). Youth with T2D were much less likely to be non-Hispanic which were then applied to population estimates for 2013 and 2035. Epidemiology/ white, have a parent who graduated from college (29% vs. 66%) and have a A total of 116 data sources were considered and 78 included, representing family income >$50,000 (25% vs. 70%). Children with T2D were dramatically 63 countries. In 2013, 316 million adults 20-79 years (6.9%) had IGT; this more likely to be morbidly obese (49% with BMI >99%ile for age) than those number is expected to rise to 471 million (8.0%) by 2035. Most people with with T1D, although 7% of the T1D youth were obese or morbidly obese IGT live in low- and middle-income countries and these will experience the (BMI≥95%ile). The p-values for all characteristic comparisons were <0.001. greatest increase in cases of diabetes over the next 22 years. The very different SES characteristics of T2D youth vs. the T1D youth The new estimates of IGT in adults confi rm the large burden of people at point out the much more socially vulnerable position of children with T2D in high risk of diabetes, especially in developing countries. the U.S. suggesting greater resources may be needed to provide adequate health care to this population. 1502-P The Association between Disability Retirement and Socioeconomic Status among Danish Employees with Diabetes BRYAN CLEAL, HARALD HANNERZ, KJELD POULSEN, LARS L. ANDERSEN, Gentofte, Denmark, Copenhagen, Denmark It is important to determine whether, and to what extent, the increasing prevalence and earlier onset of type 2 diabetes mellitus impacts on the workforce. In this study we examine relative rates of disability retirement among employees with diabetes in Denmark stratifi ed according to socio- economic status. The study uses a database obtained by the linkage of four national population registries, including the Danish National Diabetes Registry. The study population is all employees in Denmark who were 20-59 years old and registered in the diabetes register at baseline (1 January 2001). These Supported By: Novo Nordisk A/S; DK020572 people were followed in our national registries until 31 December 2010. The clinical endpoint was disability retirement during follow-up. 1500-P 29,210 (16,855 men; 12,355 women) were included in the analysis. Phthalates Promote the Development of Type 2 Diabetes in a Hyper- The follow-up yielded 3163 cases (10.8%) of disability retirement. Using lipidemic Mouse Model Professionals as reference, excess fraction analysis suggests 47% of cases WEI ZHOU, WEIBIN SHI, Charlottesville, VA observed in the study period could have been avoided if all groups were Phthalates are one of the most manufactured industrial chemicals subject to the same risks as Professionals. worldwide and used to produce plastic materials, medical devices and The results show liability for early retirement among people with diabetes cosmetics. Limited epidemiological studies have associated serum or is especially acute for employees in lower socio-economic groups. Given the urinary phthalate metabolites with the prevalence of type 2 diabetes or observed excess fraction is 47%, the fi ndings highlight the gains to be had related phenotypes. However, direct evidence is still missing. To determine from better utilising the workplace as an arena in which to support people the potential infl uence of phthalates on glucose homeostasis, one group of with diabetes in the management of the condition. female B6.Apoe-/- mice were started with the Western diet together with phthalate (100 mg/kg/d, Sigma) at 6 weeks of age and the other group was fed the Western diet without phthalate. Bis-(2-ethylhexyl) phthalate was administered in drinking water at a daily dosage of 100 mg/kg. Glucose

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pmol/ml at 24 mos. Across time points, there was a negative correlation of Rate Ratios (RR) with 95% CI for Disability Retirement in Denmark among peak C-peptide level with A1c level (Spearman r=-0.22 to -0.47, p=0.08 for 3 Employees with Diabetes. mo and p<0.01 for 6-24 mos) as well as insulin-dose adjusted A1c (IDAA1c) SOCIO-ECONOMIC GROUP N CASES RR 95% CI level (Spearman r=-0.41 to -0.65, p<0.001 across all time points). Changes in Legislators, senior offi cials and managers 1,032 62 0.88 0.67-1.17 peak C-peptide levels from previous visits also were moderately correlated Professionals 3,630 228 1,00 — with changes in A1c levels from previous visits (Spearman r=-0.28 to -0.49, p<0.05) and with changes in IDAA1c levels (Spearman r=-0.27 to -0.47, Technicians and associate professionals 5,206 382 1.22 1.03 - 1.44 p<0.05). However, longitudinal data showed that the A1c from a previous Workers in occupations that require skills at a basic level 14,632 1,653 2.02 1.76 -2.32 visit did not predict the change in C-peptide at the subsequent visit, and Workers in elementary occupations 4,710 838 3.27 2.82 - 3.78 likewise peak C-peptide from a previous visit did not predict the change in A1c levels at the next visit. In summary, while moderate correlation was found between C-peptide 1503-P levels and A1c and IDAA1c over the fi rst 2 years after diagnosis of T1D, Early Predictors of Stimulated C-Peptide in Persons with Type 1 changes in A1c or C-peptide levels could not be predicted from data at Diabetes (T1D) previous time points. LINDA A. DIMEGLIO, PEIYAO CHENG, ROY W. BECK, CRAIG KOLLMAN, KATRINA Supported By: HD41890-10, HD41906-10, HD41908-10, HD-41918, HD56526 RUEDY, BRUCE A. BUCKINGHAM, STUART A. WEINZIMER, ROBERT SLOVER, ANDREW A. BREMER, TANDY AYE, Indianapolis, IN, Tampa, FL, Stanford, CA, New 1505-P Haven, CT, Aurora, CO, Nashville, TN Twins Concordant for Type 1 Diabetes in the T1D Exchange A variety of interventions have been attempted to preserve endogenous KELLEE M. MILLER, DAVID M. MAAHS, DEANNA W. ADKINS, SUREKA BOLLE- insulin secretion in persons with T1D. Prior studies have assessed mixed- PALLI, LARRY A. FOX, JOANNE HATHWAY, ANDREA K. STECK, ROY W. BECK, meal tolerance test (MMTT) stimulated c-peptide (CP) parameters ~10 wks MARIA J. REDONDO, Tampa, FL, Aurora, CO, Durham, NC, Jacksonville, FL, Boston, after diagnosis (dx). CP assessments more proximate to dx might aid in MA, Houston, TX prediction of beta cell loss over time. Using data from the TrialNet-DirecNet The T1D Exchange clinic registry provides a unique opportunity to study that evaluated the effectiveness of intensive management (inpatient evaluate differences in diabetes onset, management, and glycemic control hybrid closed-loop control followed by outpatient sensor-augmented pump between twins concordant for type 1 diabetes (T1D). Most recent HbA1c, therapy) initiated within 7 days of T1D dx compared to standard care, we along with several diabetes management factors, were compared between examined which clinical factors at dx predicted 90-min MMTT CP at baseline 32 concordant pairs of twins (64 participants) who were between the ages (BL 5.7±1.2 days after dx), 2wks, and 6wks after dx. We also studied whether of 7 and 62 years (83% <18 years of age) with T1D duration of at least 1 year. trajectories of CP changes during this early period were predictive of CP at Seventeen (53%) of the twin pairs were self-reported as monozygotic twins 1 and 2yrs. (MZT), 13 (41%) as dizygotic twins (DZT), and 2 (6%) were unknown. Data from 67 participants aged 7-45 yrs were analyzed. Since the study The median (25th, 75th percentile) absolute difference in age of diagnosis intervention did not affect CP measurements, data from intervention and was 1.0 year (0.0, 4.0) among MZT (p=0.24) and 3.0 years (2.0, 4.0) among control groups were pooled for analysis. DKA at dx, higher BL A1c, lower DZT. Time of diagnosis of T1D differed by less than 2 years in 65% of MZT Genetics BL CP were each associated with greater increases in CP from BL-2wks and

POSTERS compared with 23% of DZT. The median (25th, 75th percentile) absolute Epidemiology/ BL-6wks; in multivariable analyses only lower BL CP remained signifi cant. difference in HbA1c was 0.4% (0.2%, 0.9%) among MZT compared with Age and number of autoantibodies (AAb) at dx (multiple vs. none/one) were 0.8% (0.2%, 1.2%) among DZT (p=0.28). Characteristics of twin pairs who not predictive. did and did not differ in HbA1c by 0.5% are compared in the table. BL, 2wk, and 6wk CP signifi cantly correlated with 1 and 2yr CP (all The time between diagnoses for MZT was less compared with DZT. When p<0.001), with the greatest relationship between 6wk and 1yr CP (r=0.66). comparing twin pairs who did and did not differ by 0.5% in HbA1c, the type Older age was a signifi cant predictor of 2yr CP (r=0.44). Early CP changes of twin, difference in age of diagnosis, and differences in SMBG per day (BL-2wks and BL-6wks) were not signifi cantly related to 1 or 2yr CP. In seemed to play a role. Since MZT share most of their genes while DZT share multivariable regression analyses, greater BL and 6wk CP, and older age 50% on average, these results suggest a large genetic contribution in age at were independently predictive of greater 1 and 2yr CP, whereas AAb number, diagnosis and also in metabolic control. A1c, and DKA at dx were not. DKA, A1c and CP measurements near the time of clinical T1D dx relate Monozygotic Twins Dizygotic Twins both to early beta cell function and longer-term endogenous insulin Difference in HbA1c ≥ Difference in Difference in HbA1c ≥ Difference in production measures. CP measures obtained close to dx also correlate to 0.5% between Twin Pairs HbA1c 0.5% between Twin Pairs HbA1c those observed later. Early MMTTs could be used in assessing responses to N=7 N=10 N=8 N=5 beta cell preservation therapies. Absolute Difference in Age at Diagnosis 1.0 (1.0, 14.0) 0.5 (0.0, 2.0) 3.5 (2.0, 5.0) 1.0 (1.0, 4.0) Supported By: HD41890-10, HD41906-10, HD41908-10, HD-41918, HD56526 (years) -median (25th, 75th percentile) Different Gender between DZT Twin Pairs NA NA 5/8 4/5 1504-P Different Insulin Delivery Method (injec- 1/10 2/10 0 0 Relationship of Glycemic Control and C-Peptide Levels 2 Years tions vs. pump) between Twin Pairs Following Diagnosis of T1D Absolute Difference in SMBG tests/day 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 1.0 (1.0, 2.0) 1.0 (0.0, 1.0) BRUCE A. BUCKINGHAM, PEIYAO CHENG, ROY W. BECK, CRAIG KOLLMAN, -median (25th, 75th percentile) KATRINA RUEDY, STUART A. WEINZIMER, ROBERT SLOVER, ANDREW A. BREMER, WILLIAM V. TAMBORLANE, JACK FUQUA, Stanford, CA, Tampa, FL, New Absolute Difference in Total Daily Insulin/ 0.34 (0.24, 0.39) 0.34 (0.24, 0.39) 0.25 (0.10, 0.89) 0.29 (0.15, 0.29) Haven, CT, Aurora, CO, Nashville, TN, Indianapolis, IN Kg /day -median (25th, 75th percentile) Prior studies have suggested that better glycemic control may help Occurrence of at least 1 DKA event in 0 0 1/8 0 preserve endogenous insulin secretion in individuals with type 1 diabetes past 12 months differed between (T1D). To address whether this association is true in the fi rst 2 years following twin pairs diagnosis of T1D, we analyzed data from a randomized trial conducted by the DirecNet and TrialNet Study Groups that evaluated the effectiveness of intensive management (inpatient hybrid closed-loop control followed 1506-P Nonalcoholic Steatohepatitis in Patients with Type 2 Diabetes by outpatient sensor-augmented pump therapy) initiated within 7 days of Mellitus diagnosis of T1D compared with standard care. OANA ALBAI, ROMULUS TIMAR, BOGDAN TIMAR, Timisoara, Romania In 6 8 s tud y p ar ticip ant s wit h positive islet or T1D associated au toantibodies Nonalcoholic steatohepatitis (NASH), type 2 diabetes mellitus (DM) and (age 7 to 45 yrs, mean 13.3±5.7 yrs, 24 female), mixed meal tolerance tests metabolic syndrome (MS) have at least one common pathogenic mechanism: (MMTTs) were performed at 2 and 6 weeks and at 3, 6, 9, 12, 18 and 24 mos visceral obesity and concomitant insulin resistance.We included 423 type after T1D diagnosis and Hemoglobin A1c (A1c) was measured at each visit 2 DM patients, 176 men and 247 women, mean age 58.4 ± 7.6 years. Were starting with 6 wks. excluded: subjects with alcohol consumption, with a history of viral hepatitis, Gradual decline in C-peptide levels was observed over the 2 yrs from a autoimmune hepatitis, or other forms of chronic liver disease. Tha aim of median peak value of 0.90 pmol/ml at 3 mos to a median peak value of 0.25 our study was to investigate the NASH prevalence and the association

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A392 EPIDEMIOLOGY—OTHERCATEGORY between glycemic control (by measuring HbA1c). The secundary endpoint: We conducted a retrospective cohort study of adult patients with diabetes the relationship between NASH and other cardiovascular risk factor discharged from an academic medical center between 1/1/2004 and (CVR): obesity, dyslipidemia, hypertension (AHT). NASH was diagnosed by 12/31/2012. Diabetes was defi ned by ICD-9-CM code 250 or documentation ultranonography. The fi brosis degree was established using the FibroScan. of a diabetes-specifi c medication upon admission. Index discharges were NASH prevalence in the study group was 68%, being higher in women: excluded for patient age <18 years, transfer to another hospital, inpatient 78.5%, respectively 58.5%. The main characteristics of the two patient death, outpatient death within 30 days of discharge, or discharge from an groups (with NASH and without NASH) are shown in Table 1. obstetric service. We constructed a predictive model for all-cause ER by multivariable logistic regression (DERRI). Parameter with NASH without NASH p Among 17,595 patients, there were 3,996 ER (22.7%). Out of 43 variables BMI (kg/m2) 33.4 ± 5.8 28,9 ± 5.1 <0.0001 (ES) examined, 13 statistically signifi cant predictors of ER were retained (p<0.05): WC (cm) 107 ± 16.1 100.7 ± 14.9 <0.0001 (ES) race, e.g., black vs. white (OR 1.15 [1.03-1.28] 95%CI), education, e.g., no high school vs. college degree (1.48 [1.29-1.70]), insurance, e.g., none vs. private HbA1c (%) 8.1 ± 1.9 7.6 ± 1.8 0.028 (S) (0.68 [0.54-0.85]), employment, e.g., disabled vs. employed (2.41 [2.05- TC (mg/dl) 204.2 ± 41.9 178.6 ± 28.8 <0.0001 (ES) 2.82]), home zip code <5 miles from hospital (1.72 [1.57-1.88]), pre-admission TG (mg/dl) 209.8 ± 113.4 161 ± 75.3 0.0005 (ES) insulin (1.39 [1.28-1.52]), statin (0.82 [0.76-0.89]), or steroid use (1.67 [1.46- HDLc (mg/dl) 39.7 ± 1.8 44 ± 2 <0.0001 (ES) 1.91]), number of microvascular complications (1.26 [1.18-1.34]), number of macrovascular complications (1.26 [1.21-1.32]), urgent or emergent vs. LDLc (mg/dl) 117.2 ± 38.9 103 ± 36.4 <0.0001 (ES) elective admission (1.52 [1.36-1.69]), log (admission serum creatinine, mg/dl) ASAT (U/L) 30.2 ± 13.8 28.6 ± 24.5 0.555 (NS) (1.28 [1.20-1.37]), and admission hematocrit, per 5% (0.86 [0.83-0.88]). The ALAT (U/L) 38.6 ± 26.7 32.3 ± 16.1 0.022 (S) model has good discrimination (C-statistic 0.72) and calibration (Goodness- SAT (mmHg) 152.6 ± 44.1 134.2 ± 31.5 <0.0001 (ES) of-fi t Test p=0.41). ER risk in the highest tertile was 40%, accounting for 58% of all ER. Based on the ADVANCE risk engine, we ascertained within the study The DERRI is valid for predicting ER risk of diabetic patients and may be group that the CVR in patients with type 2 DM and NASH is 2.5 higher than useful to target discharge support resources to those at higher risk. in those with type 2 DM without NASH: 25.8%, versus 10.4%. For the patients with DM, achieving and maintaining optimal glycemic control is the best way to prevent NASH. To prevent CVR, the therapeutic 1509-P strategy in NASH has two goals: to reduce visceral fat and to improve insulin Endogenous Sex Hormones and Glucose in South Asians: The resistance. MASALA Study BELINDA NEEDHAM, CATHERINE KIM, BHRAMAR MUKHERJEE, PRAMITA BAGCHI, FRANK STANCZYK, ALKA KANAYA, Ann Arbor, MI, Los Angeles, CA, San 1507-P Francisco, CA Metabolic Risk Factors Substantively Mediate Familial Risk of Type South Asians are at high risk for diabetes. Although prior studies have 2 Diabetes linked endogenous sex hormones (estradiol [E2], testosterone [T], and sex SRIDHARAN RAGHAVAN, BIANCA PORNEALA, JOSÉE DUPUIS, JAMES B. MEIGS, hormone binding globulin [SHBG]) to diabetes risk in other race/ethnic Boston, MA Genetics

groups, no previous studies have examined this association among South POSTERS Background: Parental history of Type 2 diabetes mellitus (T2D) is a Asians. Epidemiology/ strong determinant of T2D risk; however, familial T2D risk is not completely We used data from the Metabolic Syndrome and Atherosclerosis in explained by genetic risk, BMI, or lifestyle factors like diet and exercise. South Asians Living in America (MASALA) pilot study. Respondents were We hypothesize that metabolic risk factors substantively mediate T2D risk aged 45-84 and free of cardiovascular disease. We used multivariable attributed to parental history of T2D. regression to examine the association between endogenous sex hormones Methods: Metabolic risk was estimated using corrected insulin response (log-transformed) and fasting glucose and 2-hour glucose in sex-stratifi ed (CIR= Ins120 / Glu120×[Glu120 - 70]; where Glu120 is the 120 minute post- models adjusted for age and visceral and hepatic adiposity. Women using oral-glucose challenge value in mg/dL), homeostatic model assessment estrogen therapy and those with diabetes were excluded from analyses. The - insulin resistance (HOMA-IR= Glu×Ins/405; fasting insulin and glucose analytic sample included 59 women and 45 men. values in mg/dL), or a score of 0 to 4 metabolic syndrome components (MSS). As shown in the table, lower levels of SHBG and higher levels of We studied initially non-diabetic participants of the Framingham Offspring bioavailable T (bioT) were associated with increased diabetes risk in Study and tested risk across 0 (n=1965), 1 (n=370), or 2 (n=26) parents with women, whereas lower levels of SHBG and lower levels of total T were T2D using logistic regression of incident T2D (265 incident cases over median associated with increased diabetes risk in men. Adjustment for adiposity follow-up of 13 years) in models that accounted for sibling correlation and attenuated most of these associations; the relationship between SHBG and adjusted for age, sex and a count of 62 common T2D genetic risk alleles. fasting glucose in women, and SHBG and 2-hour glucose in men, remained The proportion of T2D risk mediated by metabolic factors was estimated by signifi cant. Results were consistent with prior research, which suggests comparing the logistic regression coeffi cients for parental history with and that endogenous sex hormones are a risk factor for diabetes across multiple without adjustments for CIR, HOMA-IR, and MSS (% mediated = 1 - βadj / race/ethnic groups. βunadj). Results: Among non-diabetic Offspring HOMA-IR (p=0.002) and MSS Association between SHBG or T (Predictor) with Fasting Glucose or 2-Hour (p=0.002), but not CIR, were statistically associated with greater number Glucose (Outcome). of parents with T2D. Metabolic factors mediate 11% of incident T2D risk SHBG, Women SHBG, Men Total T, Women Total T, Men BioT, Women BioT, Men associated with parental history of T2D even with adjustment for T2D genetic β-coeffi cient β-coeffi cient β-coeffi cient β-coeffi cient β-coeffi cient β-coeffi cient risk alleles, corresponding to a reduction in the odds ratio for incident T2D (95% confi dence (95% confi dence (95% confi dence (95% confi dence (95% confi dence (95% confi dence interval) interval) interval) interval) interval) interval) from 2.13 to 1.96 (unadjusted for genetic risk) or 1.99 to 1.84 (adjusted for genetic risk) per diabetic parent after inclusion of metabolic covariates. Fasting glucose Conclusions: Metabolic risk partially, substantively mediated T2D risk Age-adjusted -2.95 -2.28 0.70 -2.04 2.35 -1.66 related to parental history, even accounting for genetic risk. Metabolic risk (-4.95, -0.95) (-4.30, -0.26) (-1.31, 2.70) (-4.06, -0.02) (0.35, 4.36) (-3.68, 0.36) factors account in part for risk of T2D associated with parental T2D. Fully adjusted -2.77 -1.72 0.76 -1.44 1.97 -1.06 (-4.78, -0.76) (-3.75, 0.30) (-1.25, 2.77) (-3.56, 0.58) (-0.04, 3.98) (-3.08, 0.96) 1508-P 2-hour glucose Predicting Hospital Readmission Risk with a Novel Tool: The Age-adjusted -3.06 -3.20 -1.60 -2.60 0.04 -2.00 Diabetes Early Readmission Risk Index (DERRI) (-5.06, -1.06) (-5.22, -1.18) (-3.60, 0.41) (-4.62, -0.58) (-1.96, 2.05) (-4.02, 0.02) DANIEL J. RUBIN, MARIE E. MCDONNELL, DEBORAH B. NELSON, HUAQING Fully adjusted -1.98 -2.54 -0.97 -1.73 -3.37 -1.15 ZHAO, SHERITA H. GOLDEN, Philadelphia, PA, Boston, MA, Baltimore, MD (-3.99, 0.03) (-4.56, -0.52) (-2.99, 1.05) (-3.75, 0.29) (-6.83. 0.08) (-3.17, 0.87) Hospital readmission within 30 days of discharge (early readmission, ER) is a high-priority quality measure and target for cost reduction. A method to Supported By: NIDDK (U01DK048489, K23HL080026, R01DK083297) predict ER risk in diabetic patients is lacking.

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1510-P 1512-P Antibodies Against Oral Microorganisms and Hyperglycemia Factors Affecting the Decline in Incidence of Diabetes in the Dia- ANWAR T. MERCHANT, DEEPIKA SHRESTHA, CANDRA CHAISSON, YOUN-HEE betes Prevention Program Outcome Study (DPPOS) CHOI, LINDA J. HAZLETT, JIAJIA ZHANG, Columbia, SC, Daegu, Republic of Korea RICHARD F. HAMMAN, EDWARD S. HORTON, ELIZABETH L. BARRETT-CONNOR, There is emerging evidence that the effect of periodontal disease on systemic GEORGE A. BRAY, COSTAS A. CHRISTOPHI, JILL CRANDALL, JOSE C. FLOREZ, outcomes may be associated with the type of oral microorganisms. The aim of RONALD B. GOLDBERG, STEVEN E. KAHN, WILLIAM C. KNOWLER, JOHN M. this study was to evaluate the relation between serum antibody titers against LACHIN, MARY BETH MURPHY, ELIZABETH M. VENDITTI, Aurora, CO, Boston, MA, 19 selected oral microorganisms and hyperglycemia. Data from NHANES III San Diego, CA, Baton Rouge, LA, Rockville, MD, Bronx, NY, Miami, FL, Seattle, WA, were used including participants aged 40 years or older who had complete Phoenix, AZ, Memphis, TN, Pittsburgh, PA serum IgG antibody data against 19 oral microorganisms. The 19 antibody The Diabetes Prevention Program Outcomes Study (DPPOS) is a follow- titers were grouped into 4 categories using cluster analysis: Orange-Red, up to the Diabetes Prevention Program (DPP), a randomized clinical trial of Yellow-Orange, Orange-Blue, and Red-Green, named after the predominant intensive lifestyle (ILS) and metformin (MET) compared with placebo (PLB) microbes represented in the groups using Socransky’s classifi cation scheme for on prevention of diabetes. We explored why diabetes incidence rates in the oral microbes. Linear regression models weighted for complex survey design PLB and MET groups decreased compared to the rates observed in the ILS were used to evaluate associations of fasting blood glucose, fasting insulin, group during the fi rst 7 years of DPPOS and during the fi rst 3 years of DPP. and HbA1c and antibody cluster scores adjusting for potential confounders. Participants in PLB and MET groups were offered group ILS prior to starting A one unit higher Orange-Red cluster score was associated with 0.57 mg/dl DPPOS and 57% and 58% respectively attended some of these sessions. Two higher fasting blood glucose (p-value=0.01), and a one unit higher Orange-Blue hypotheses were explored: ‘effective intervention’ (changes in weight and cluster score was associated with 0.02% lower HbA1c (p-value=0.03) after other factors due to ILS) using Cox and Poisson regression, and ‘exhaustion multivariable adjustment. Antibody clusters against oral microorganisms were of susceptibles’ using changes in mean genetic score (34 risk variants). associated in opposite directions with HbA1c. This fi nding may lead to early Compared to DPP, DPPOS diabetes incidence rates were lower in PLB identifi cation of persons at risk of developing hyperglycemia, and provide a (-42%) and MET (-25%), whereas rates were higher in ILS (+31%). Adjustment metric to monitor periodontal treatment. for changes in multiple risk factors (weight, activity, dietary fat, waist Association between Cluster Scores and Fasting Blood Glucose, Fasting Insu- circumference, alcohol, smoking, antidepressant use, depression score, lin, and HbA1c. statin use, meeting goals score) did not explain the lower DPPOS rates of diabetes development in PLB (HRadjusted=0.541, p<0.0001) and MET Orange-Red Red-Green Yellow-Orange Orange-Blue (HRadjusted=0.758,p=0.009), whereas weight gain (alone) explained the Beta coeffi cient Beta coeffi cient Beta coeffi cient Beta coeffi cient higher rates in ILS (HRadjusted=1.035, p=0.755). The average genetic risk (p-value) (p-value) (p-value) (p-value) score of those remaining without diabetes declined more in the MET and PLB Fasting Blood Glucose, 0.79 (0.0002) -0.04 (0.8627) -0.22 (0.3633) -1.05 (0.0005) groups than in the ILS group, consistent with ‘exhaustion of susceptibles’. Crude No other published long term clinical trial follow-up of high risk persons Fasting Blood Glucose, 0.57 (0.0107) -0.09 (0.6523) -0.01 (0.9677) -0.60 (0.0881) identifi ed a similar pattern of lower rates in the PLB groups following Multivariable Adjusted cessation of active intervention. Fasting Insulin, Crude 0.14 (0.0171) 0.05 (0.3527) -0.07 (0.2690) -0.25 (0.0125) Results are consistent with ‘exhaustion of susceptibles’ for the change Genetics in incidence rates, but not with effects of offering group ILS to all persons POSTERS Fasting Insulin, 0.10 (0.0610) 0.05 (0.2703) -0.04 (0.4431) -0.20 (0.0502) Epidemiology/ Multivariable Adjusted before the start of DPPOS. Thus ‘effective intervention’ did not explain the lower diabetes rates in DPPOS among PLB and MET groups compared with HbA1c, Crude 0.02 (0.0005) 0.001 (0.9285) -0.003 (0.6011) -0.04 (<0.001) DPP. HbA1c, 0.01 (0.1023) -0.001 (0.8228) 0.005 (0.4651) -0.02 (0.0262) Supported By: NIH/NIDDK Multivariable Adjusted Supported By: ADA (1-13-MUl-08) 1513-P Abdominal Obesity, Metabolic Syndrome, and the Risk of Chronic 1511-P Kidney Disease in Japanese Males and Females The U-shaped Association between Body Mass Index and the Risk MASARU SAKURAI, JUNJI KOBAYASHI, YASUO TAKEDA, SHIN-YA NAGASAWA, of Future Proteinuria Independent of Glycemic Status JUNICHI YAMAKAWA, JUNJI MORIYA, HIROSHI MABUCHI, Uchinada, Japan, SHINICHIRO UEHARA, TOMOSHIGE HAYASHI, KYOKO K. SATO, SHIGEKI KINU- Kanazawa, Japan HATA, GINJI ENDO, KEIKO OUE, HIROSHI KAMBE, KANJI FUKUDA, Osaka, Japan Obesity is a representative risk factor for chronic kidney disease (CKD). It is not fully understood whether body mass index (BMI) is associated Hemodynamic and hormonal changes caused by excess weight and abdominal with the risk of future proteinuria independent of glycemic status. Study fat may increase the risk of CKD. Obesity-related metabolic abnormalities subjects consisted of 9902 Japanese men aged 40 to 55 years with normal such as hypertension, dyslipidemia, and diabetes mellitus also affect CKD estimated glomerular fi ltration rate (≥60 ml/min/1.73m2) and not proteinuria progression. The prevalence of obesity is lower in Asian individuals, and it is who were not taking hypoglycemic or hypertensive medications at entry. not clear which has a stronger effect on CKD progression: obesity itself or the Proteinuria was defi ned as 1+ or higher on urine dipstick. Normal glucose metabolic abnormalities caused by obesity. We examined the relationships tolerance (NGT) was defi ned as the fasting plasma glucose (FPG) was <100 among abdominal obesity, obesity-related metabolic abnormalities, and the mg/dl and hemoglobin A1C (A1C) was <6.5%. Impaired fasting glucose (IFG) prevalent risk of CKD in a general Japanese population. In 2008, a total of was defi ned as the FPG was ≥100 and <126 mg/dl and A1C was <6.5%. Type 8,539 men and women (age, 40-64 years) underwent health examinations. 2 diabetes was defi ned as the FPG was ≥126 mg/dl or A1C was ≥6.5%. BMI The presence of abdominal obesity, high blood pressure, dyslipidemia, and was categorized as <18.0, 18.0-19.9, 20.0-21.9, 22.0-23.9, 24.0-25.9, 26.0- high fasting plasma glucose levels was assessed according to the Japanese 27.9, and 28.0 kg/m2. During the 11-years follow-up period, we confi rmed criteria of metabolic syndrome. The estimated glomerular fi ltration rate ≥ 2 2168 cases of proteinuria. The association between BMI and incident (eGFR, mL/min/1.73 m ) was calculated by the modifi ed MDRD equation proteinuria was U-shaped. Incidence rates of proteinuria as incidence per for the Japanese, and participants with an eGFR of <60 and/or proteinuria 1000 person-years were 34.8, 25.8, 23.4, 24.9, 28.4, 34.4, and 43.1 for BMI were defi ned as having CKD. A total of 19% of the subjects had CKD. The of <18.0, 18.0-19.9, 20.0-21.9, 22.0-23.9, 24.0-25.9, 26.0-27.9, and ≥28.0 kg/ age- and sex-adjusted rate ratios for CKD across the number of metabolic m2, respectively. In Cox proportional-hazards analysis, both higher and lower abnormalities (0, 1, 2, and 3) were 1.00 (reference), 0.97 (0.83-1.15), 1.30 BMI were associated with an increased risk of the future proteinuria. After (1.08-1.56), and 1.49 (1.13-1.96) for participants without abdominal obesity adjustment for glycemic status (NGT, IFG, type 2 diabetes), age, systolic and 1.06 (0.75-1.52), 1.55 (1.24-1.93), 1.72 (1.39-2.12), and 2.81 (2.21-3.56) for blood pressure, alcohol consumption (non-drinkers, 0.1-16.4, 16.5-42.7, ≥42.8 obese participants, respectively. An interaction between abdominal obesity g ethanol per day), regular physical activity (yes, no), and smoking status and the number of complicated metabolic abnormalities was observed in the (current, past, or non-smokers), the hazard ratios of proteinuria were 1.49 association with the presence of CKD (p for interaction = 0.017). In conclusion, (95% CI 1.14-1.94), 1.11 (0.93-1.32), 1.00 (reference), 1.04 (0.91-1.18), 1.15 accumulation of metabolic abnormalities, rather than abdominal obesity (1.01-1.32), 1.33 (1.13-1.55), and 1.57 (1.30-1.89) for BMI of <18.0, 18.0-19.9, itself, increases the risk of CKD in relatively lean Japanese individuals and 20.0-21.9, 22.0-23.9, 24.0-25.9, 26.0-27.9, and ≥28.0 kg/m2, respectively. In that the presence of obesity accelerates the progression of CKD in patients conclusion, the association between BMI and the risk of future proteinuria with metabolic abnormalities. was U-shaped independent of glycemic status.

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1514-P 1516-P Prepregnancy Predicted Vitamin D Status and Risk of Gestational Lower Risk of Mortality in Patients with Type 2 Diabetes Using Diabetes: A Prospective Cohort Study Insulins Detemir or Glargine Compared to NPH: A Propensity Score WEI BAO, YIQING SONG, DEIRDRE K. TOBIAS, FRANK B. HU, SJURDUR F. OLSEN, Matched Nationwide Register Study in Finland JORGE E. CHAVARRO, CUILIN ZHANG, Rockville, MD, Boston, MA, Copenhagen, SARI MAKIMATTILA, FABIAN HOTI, SOLOMON CHRISTOPHER, JARI HAUKKA, Denmark PASI KORHONEN, TERO SAUKKONEN, Espoo, Finland Accumulating evidence suggests that the pre-conception period is likely Cardiovascular diseases and hypoglycemia increase mortality in insulin a critical time window for the prevention of gestational diabetes mellitus treated patients with type 2 diabetes (T2D). Risk of mortality in patients (GDM). Emerging evidence from both in vitro and in vivo studies supports using long-acting insulins detemir (IDet), glargine (IGla), or NPH insulin a pivotal role of vitamin D in regulating glucose homeostasis. However, (NPH) was evaluated in a nationwide retrospective database study 2006- the relation of pre-pregnancy vitamin D status with GDM etiology is 2009. Date and cause of death were obtained from the Finnish Causes uncertain due to sparse human data. We prospectively evaluated the of Death Register. Data on insulin usage were obtained from the Finnish association between pre-pregnancy predicted 25-hydroxyvitamin D (25(OH) Prescription Register. Prescription bias is minimized by government-funded D) scores and risk of GDM among women who were free of prior GDM or reimbursement of all insulins, and by lack of preference between long-acting pre-pregnancy chronic disease in the Nurses’ Health Study II from 1991 insulins in guidelines. to 2001. Pre-pregnancy predicted 25(OH)D scores were computed using There were 23 751 long-acting insulin naïve T2D patients, and 2 078 previously validated regression models that included major determinants deaths in nine ICD-10 categories. Insulin exposure periods were defi ned of vitamin D status (race/ethnicity, ultraviolet B fl ux, physical activity, body based on the amount purchased and the estimated average daily dose of mass index [BMI], vitamin D intake, and alcohol consumption). Relative risks each drug for a specifi c patient. A propensity score matched cohort analysis (RRs) and 95% confi dence intervals (CIs) were estimated using log-binomial was performed: among 9 363 patients there were 620 deaths; most common models with generalized estimating equations. During 10 years of follow- categories were circulatory n=275, neoplasms n=183, digestive n=42, up, we documented 861 incident GDM pregnancies from 21,323 singleton respiratory n=29. Increase in age, female gender and use of short-acting pregnancies. In the multivariable model adjusting for age, parity, family insulin increased the mortality risk. The adjusted risk of all-cause mortality history of diabetes, and smoking, the RR (95% CI) comparing the highest with was 61% (hazard ratio [HR] 0.39, 95% CI 0.30, 0.50) lower during use of IDet, lowest quartile of pre-pregnancy predicted 25(OH)D score was 0.35 (0.29- and 45% (HR 0.55, 95% CI 0.44, 0.69) lower during use of IGla vs. NPH. In 0.43) (P for linear trend < 0.001). The association was signifi cantly stronger comparison to IGla, IDet had a signifi cantly (HR 0.71, 95% CI 0.54, 0.93) lower among women with a BMI ≥ 25 kg/m2 than those with a BMI < 25 kg/m2; risk for mortality. For the deaths related to circulatory system and neoplasm, the RRs (95% CIs) were 0.24 (0.12-0.48) and 0.61 (0.46-0.82), respectively (P the adjusted risk during use of IDet compared to NPH were 58% (HR 0.42, for interaction < 0.001). The association was not signifi cantly modifi ed by 95% CI: 0.28, 0.61) and 77% (HR 0.23, 95% CI: 0.14, 0.40) lower, respectively, other pre-pregnancy GDM risk factors, including age, parity, family history of and during use of IGla compared to NPH 35% (HR 0.65, 95% CI: 0.47, 0.91) diabetes, or physical activity. In conclusion, pre-pregnancy predicted vitamin and 65% (HR 0.35, 95% CI: 0.22, 0.54) lower, respectively. D status was inversely and strongly associated with the risk of incident In conclusion, in T2D the risk of all-cause mortality and risk of death GDM, particularly among women with a higher BMI. related to circulatory system or neoplasms were lower during the use of IDet Supported By: NICHD/NIH or IGla compared to NPH. Supported By: Novo Nordisk A/S Genetics POSTERS 1515-P Epidemiology/ Association between Marital Status and Treatment Durability in 1517-P Patients with Type 2 Diabetes Treated with Glucagon-like Peptide 1 Effect of Lifestyle Interventions on Changes in Glycemic Indicators Receptor Agonists: The SWEET Study among High Risk Adults with Normal Glucose Values: A Systematic YOSHINOBU KONDO, URU NEZU, YUICHIRO INOUE, YUKO MIYAZAKI, SAHO Review and Meta-analysis HOSOKAWA, SHINOBU SATOH, YASUO TERAUCHI, Kanagawa, Japan, Okinawa, XUANPING ZHANG, GIUSEPPINA IMPERATORE, WILLIAM THOMAS, JINAN Japan SAADDINE, LINDA S. GEISS, MOHAMMED K. ALI, ROBERTO LOBELO, KERI NORRIS, Previous studies reported that family support is benefi cial for diabetes HEATHER DEVLIN, STEPHANIE GRUSS, BARBARA BARDENHEIER, PYONE CHO, management. However, the association between marital status and diabetes ISABEL GARCIA, UMA MUDALIAR, EDWARD W. GREGG, Atlanta, GA treatment durability is not clarifi ed. We investigated the effect of marital It is unclear whether lifestyle interventions (LI) are effective in reducing status on diabetes treatment durability in patients with type 2 diabetes risk of pre-diabetes (DM) among high risk adults with normal glucose levels (T2D) in this retrospective cohort study using medical chart reviews. Totally, (NGL). We conducted a systematic review to assess the effectiveness of 155 T2D patients treated with glucagon-like peptide 1 receptor agonists LI to change glycemic indicators (GI) among adults (age ≥ 18 years) with (GLP-1-RA) with available marital status information were included. The NGL but with other DM risk factors. We identifi ed randomized controlled primary endpoint was the difference in the duration of maintaining HbA1c trials with a follow-up interval ≥ 6 months published before April 2013 < 7.0% after GLP-1-RA treatment initiation between married (n = 103, 66%; that examined LI, including physical activity (PA), dietary (D), behavioral (B) lived with spouse) and single groups (n = 52, 34%). Baseline characteristics interventions, or their combinations. A random-effect model was used in were similar between groups, except for a higher rate of eating out (1.2 ± 1.5 pooling intervention effects. times/week vs. 2.4 ± 2.1 times/week, p < 0.001) and corner store use (0.8 ± We identifi ed 165 studies with 57318 participants. Results are summarized 1.2 times/week vs. 2.2 ± 2.5 times/week, p < 0.001) in the single group. The in Table 1. Pooled effects for PA, D, PA+D, and PA+D+B interventions duration of maintaining HbA1c < 7.0% was longer in the married group than compared to usual care showed signifi cant decreases in fasting glucose (FG), in the single group (335.4 ± 29.6 days vs. 202.7 ± 41.7 days, p = 0.01). As fasting insulin (FI), and body weight (p<0.05 for each). PA and D combined per Kaplan-Meier analysis based on defi ning an event as diabetic control interventions also improved A1 C levels signifi cantly (-0.08[-0.13, -0.02]). deterioration and reaching HbA1c ≥ 7.0%, treatment durability was better in Interventions with a D component had a stronger effect on weight than PA- the married group (log-rank test, p = 0.01). Cox hazard analysis also showed only interventions; however, intervention effects on FG and FI were similar a 48% decrease in HbA1c deterioration risk, even after adjusting for age, across different intervention modalities. gender, body mass index, duration of diabetes, baseline HbA1c, and beta In adults with NGL, PA, D, B interventions or their combinations can cell function as assessed by the CPR index (fasting C-peptide × 100/fasting achieve signifi cant improvements in weight, FG, and FI, thus reduce risk of plasma glucose; relative risk, 0.52; 95% confi dence interval, 0.32 to 0.86, progression to pre-DM. p = 0.01). These fi ndings indicate that marriage and living with spouse is benefi cial for diabetes treatment durability in T2D patients. Single patients are at a higher treatment failure risk and require care because they lack family support.

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A395 EPIDEMIOLOGY—OTHERCATEGORY

lower, by 22%: 44 (25)% vs. 56 (41)% in patients with higher bilirubin levels Table 1. Lifestyle Interventional Effect: Meta-analyses Results. [QII-IV] (p 0.0004). [BxS] was signifi cantly reduced (-23%) in low-bilirubin Weight Fasting Glucose Fasting Insulin patients: 22.6 (16.6)% vs. 29.4 (19.1)% in [QII-IV] (p 0.0005). Low-bilirubin Change (kg) (mmol/L) (µU/ml) patients also had higher [BxS] loss rates: 1.42 (0.43) %/year vs. 1.27 (0.54) Stuides Pooled Effect: Stuides (sample Pooled Effect: Stuides Pooled Effect: %/year in [QII-IV] (p 0.0040), and poorer glycemic control, as refl ected by (sample size) mean (95%CI) size) mean (95%CI) (sample size) mean (95%CI) current HbA1c levels: 7.9 (1.2)% (63 (10) mmol/mol) vs. 7.5 (1.3)% (59 (10) PA vs. Usual 19 (2092) -1.36 29 (3105) -0.13 19 (2486) -1.96 mmol/mol) in [QII-IV] (p 0.0004). By contrast, the two groups did not differ Care (-1.84, -0.88) (-0.18, -0.09) (-2.83, -1.09) in age; gender; ethnicity; diabetes duration; glucose-lowering therapies; BP- D vs. Usual 9 (2659) -4.05 15 (3630) -0.16 9 (2661) -1.31 lowering or other cardiovascular drugs; waist circumference; blood pressure, Care (-5.93, -2.17) (-0.23, -0.10) (-2.24, -0.38) or hepatic steatosis. Lower bilirubin levels are linked to more severe insulin resistance, -cell PA+D vs. 17 (1952) -3.87 19 (2043) -0.16 14 (1504) -2.26 β Usual (-5.62, -2.11) (-0.27, -0.05) (-3.42, -1.10) function loss, and poorer glycemic control in T2DM. The mechanisms Care underlying these adverse associations warrant further investigations. PA+D+B vs. 16 (7887) -2.11 22 (11203) -0.15 7 (489) -2.33 Usual Care (-3.12, -1.09) (-0.30, -0.001) (-4.38, -0.27) 1520-P Comparison of Objective Physical Activity between Participants Supported By: CDC from the Diabetes Prevention Program Outcomes Study (DPPOS) and from the National Health and Nutrition Examination Survey 1518-P (NHANES) Change in CT-Measured Abdominal Subcutaneous and Visceral but BONNY ROCKETTE-WAGNER, KRISTI L. STORTI, DANA DABELEA, SHARON L. Not Thigh Fat Areas Predict Future Insulin Sensitivity EDELSTEIN, HERMES FLOREZ, PAUL W. FRANKS, MARIA G. MONTEZ, JEREMY AMY W. LIU, STEVEN E. KAHN, TOMOSHIGE HAYASHI, WILFRED Y. FUJIMOTO, POMEROY, ANDREA M. KRISKA, Pittsburgh, PA, Aurora, CO, Washington, DC, MARGUERITE J. MCNEELY, DONNA L. LEONETTI, EDWARD J. BOYKO, Cleveland, Miami, FL, Malmö, Sweden, San Antonio, TX, Phoenix, AZ OH, Seattle, WA, Osaka, Japan The Diabetes Prevention Program (DPP) lifestyle intervention had a Greater intra-abdominal fat area (IAFA) predicts a decline in insulin physical activity (PA) goal of 150 min/wk of moderate-vigorous PA (MVPA) sensitivity (IS) over 10 years, but not known is if a recent change in IAFA that was encouraged for all participants after the DPP ended. Objective PA or other fat depots is related to this outcome. We determined if changes was assessed in DPPOS by accelerometer (ACL) >10 years after DPP ended, in CT-measured fat depots over 5 & 10 years predict change in 10 year IS. at which point the participants (who started with impaired glucose tolerance) We followed 357 nondiabetic Japanese-Americans (mean age 51 years, BMI either developed diabetes (DM) or remained at high risk for DM (HR). 24.1, 54% male) with the following measured at baseline and 10 years: BMI; DPPOS participants (n=1794) from all but 3 sites wore an ActiGraph ACL CT-measured IAFA and subcutaneous abdominal fat at the umbilicus level with 1580 participants having usable data (≥4 days of ≥10 hrs. of wear time (SAFA) and thigh fat (STFA) areas; and oral glucose tolerance testing. IS was in uniaxial mode). Mean values by age/sex group for time spent in MVPA, assessed with HOMA-IR or Matsuda Index (MI). Linear regression analysis light PA (LPA) and sedentary behavior (SED) were examined between the was used to estimate associations between IS (HOMA-IR or MI) at 10 years DPPOS cohort and a U.S. representative sample (NHANES 2003-06) with

Genetics and 10 year fat depot changes while adjusting for covariates. Models (Table)

POSTERS comparable ACL data. We hypothesize that DPPOS participants (HR & DM) Epidemiology/ showed statistically signifi cant associations between baseline IAFA and would have more PA and less SED than relatively comparable NHANES IAFA Δ and 10 year HOMA-IR (Model 1) and MI (Model 2). Of the remaining individuals (impaired fasting glucose & DM), respectively. fat depots, baseline SAFA and SAFA Δ were signifi cantly associated with Compared to NHANES individuals, DPPOS participants with comparable HOMA-IR (Model 3) and SAFA Δ only with MI (Model 4). Similar results were DM status/age/gender engaged in more min/day of MVPA (Figure 1) but not seen with 5-year fat depot changes. We conclude that 10 year increase in more LPA or less SED (not shown). IAFA and SAFA is associated with decline in IS independent of baseline Higher MVPA in the DPPOS relative to the NHANES cohort suggest that IAFA. A paradoxical negative association was seen between baseline SAFA the activity intervention remained successful. The lack of a difference in and HOMA-IR only (Model 3). However, these results do not support an SED may relate to the absence of a SED goal in DPP. association between change in IS and STFA or STFA Δ.

Supported By: NIH (P30DK017047)

1519-P Supported By: 1R01DK091345-01A1 Lower Serum Bilirubin Levels Linked to Decreased Insulin Sensi- tivity, Greater and Faster β-Cell Function Loss, and Poorer Glycemic 1521-P Control in T2DM Factors Associated with Discontinuation of Sulfonylurea Therapy MICHEL P. HERMANS, SOUMAÏLA CAMARA, SYLVIE A. AHN, MICHEL F. ROUS- in Type 2 Diabetes Patients Who Initiate Insulin SEAU, Brussels, Belgium, Paris, France ALEX Z. FU, PEDRO LAIRES, KRISTY IGLAY, YING QIU, Washington, DC, Whitehouse Bilirubin is a natural antioxidant and cytoprotective heme catabolite. Station, NJ Higher levels of serum bilirubin are associated with decreased risk of T2DM. Sulfonylureas (SUs) represent a common treatment for type 2 diabetes This study assesses the impact of low bilirubin levels on insulin sensitivity, (T2DM), but they are associated with hypoglycemia, weight gain, and β-cell function, and glycemic control in patients with long-standing T2DM. possibly cardiovascular events. The purpose of this study is to evaluate 425 T2DM patients (mean age (SD): 67 (11) years; diabetes duration factors associated with SU discontinuation after insulin initiation. Pts ≥21 16 (10) years) were divided in 2 groups according to total serum bilirubin years old with a T2DM diagnosis between 2005 and 2012 were identifi ed levels: a low-bilirubin group, corresponding to the 1st quartile [QI] (n=106; using the GE electronic medical records database. Index date was defi ned mean bilirubin 0.35 (0.06) mg/L), and a group composed of the remaining as the fi rst insulin prescription (Rx) between 2006 and 2011. Pts were 3 quartiles [QII-IV] (n=319; mean bilirubin 0.65 (0.21) mg/L). In all patients, required to be on SU at the index date. Pts were excluded if they did not insulin sensitivity [S]; unadjusted -cell function [B]; residual -cell function β β have medical records available ≥12 months before and after index date, adjusted for [S] (expressed as [BxS], the hyperbolic product), and annual were receiving insulin in the 12 months prior to index date, or had type 1 [BxS] loss rates were determined using HOMA. diabetes mellitus, other forms of secondary diabetes or gestational diabetes BMI, fat mass, and atherogenic dyslipidemia measures were signifi cantly mellitus. Treatment with other diabetes medications in addition to SU and higher in low-bilirubin patients, whose insulin sensitivity was signifi cantly

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A396 EPIDEMIOLOGY—OTHERCATEGORY insulin were permitted in this study. SU discontinuation occurred when the -0.30 to 0.22, I2=45%), insulin secretion (HOMA–B: MD, 1.64; 95%CI, -25.94 gap between the end date of current SU Rx supply and the start date of to 29.22, I2=40%), or A1c (MD, -0.05; 95%CI, -0.12 to 0.03, I2=55%) compared subsequent SU supply was ≥90 days apart. Multivariate logistic regression with controls. Four RCTs reported on progression to new diabetes and found was performed to identify factors associated with SU discontinuation vs. no effect of vitamin D (OR, 1.12; 95%CI, 0.87 to 1.44, I2=0%). Adverse events continuation. A total of 8,185 pts were selected, with mean age 64 years and were rare and similar across treatment groups, and there was no evidence 49% were male. 60.4% discontinued their SU Rxs within 1 year, with a median of publication bias. Evidence from available trials shows no effect of vitamin time from insulin initiation to SU discontinuation of 88 days. In the logistic D3 supplementation on insulin resistance, glycemic control, or diabetes regression, baseline diagnosed hypoglycemia (OR=2.29 [95% CI 1.03, 5.10]; prevention. Defi nitive conclusions from the available evidence to-date are p=0.04) and baseline HbA1c (OR=1.04 [95% CI 1.01, 1.06]; p=0.004) were limited, however, due to the degree of heterogeneity and variable risk of identifi ed as factors associated with SU discontinuation. Additional factors bias. included BMI (<25 vs. ≥30 kg/m2: OR=1.23 [95% CI 1.03, 1.46]; p=0.03), use of 3rd generation SU (OR=0.86 [95% CI 0.78, 0.95]; p=0.002), and chronic renal 1524-P disease (OR=1.34 [95% CI 1.07, 1.67]; p=0.01). In conclusion, multiple factors, New Use of SU as Add-on Therapy to Metformin Is Not Associated including effi cacy and hypoglycemia, are associated with discontinuation of with Weight Changes (Zodiac-39) SU treatment after insulin initiation. HENK J.G. BILO, RAIZA WEVER, NANNE KLEEFSTRA, SEBASTIAAN HOUWELING, KORNELIS VAN HATEREN, KLAAS GROENIER, GIJS W. LANDMAN, Zwolle, 1522-P Netherlands, Groningen, Netherlands Risk Factors Associated with Treatment Discontinuation and Down- Increases in weight after starting glucose lowering agents are undesirable Titration in Type 2 Diabetes Patients Treated with Sulfonylureas and included as surrogate end-points in randomized trials. Patients in KRISTY IGLAY, YING QIU, CHUN-PO STEVE FAN, ZHIYI LI, JACKSON TANG, randomized trials differ from patients treated in daily practice. We aimed PEDRO LAIRES, Whitehouse Station, NJ, New York, NY to study effects of starting individual sulphonylureas (SUs), pioglitazone and Sulfonylurea (SU) therapy can be discontinued or down-titrated for reasons insulin, on top of metformin, on weight and HbA1c in patients with T2DM in such as hypoglycemia or weight gain. A retrospective cohort study using daily practice. the MarketScan database was conducted to identify risk factors associated Changes in body weight and HbA1c up to 5-years follow-up were studied with therapy changes (ie, discontinuation or down-titration). in a prospective observational primary care cohort with a ‘new-user design’. Patients (pts) were included when the following criteria were satisfi ed: fi rst In the Netherlands over 85% of patients are treated in primary care. SU prescription (Rx) (index date) between 2009 and 2011, ≥18 years of age on Medication and clinical data were collected annually, changes in weight and the index date, and ≥ 1 year continuous enrollment pre- and post-index. Pts HbA1c were estimated using linear mixed models, adjusted for gender, age with type 1, gestational or secondary diabetes, insulin use before the index and diabetes duration. date, or ≥ 2 SUs on the index date were excluded. Therapy changes were From a total of 82,167 patients, 3805 and 803 patients were identifi ed who determined during the 1 year post-index period. Discontinuation occurred received oral and insulin add-on therapy. Prior to add-on therapy, patient had a when the gap between the end date of current SU fi ll and the start date of HbA1c of 7.1%. Within and between groups, no relevant effects on weight and subsequent fi ll was ≥ 90 days apart. Down-titration occurred when an SU HbA1c were present the 5 years after treatment intensifi cation (see table). fi ll had a lower equivalent dose than that on the index date. The Kaplan- This study shows that for the majority of patients treated in the Genetics

Meier method was used to estimate 3- and 6-month therapy change rates. Netherlands, initiation of individual SUs or insulin, on top of metformin, POSTERS Cox regression was used to identify risk factors associated with therapy strict glycaemic control can be maintained without clinically relevant weight Epidemiology/ changes in hazard ratios (HRs). changes. These results are opposite to commonly held opinions regarding 104,082 pts were included, of which 55,233 (53.1%) experienced therapy effects of sulfonylureas on weight. changes in the 1-year post-index period. 3- and 6-month therapy change Table 1. Baseline Data and Estimation of Mean Differences During 1 (Δ rates were 23.2% and 38.9%, respectively. Major risk factors associated 1-0) and 5 year (Δ 5-0) Follow-up for Weight and HbA1c in the Different with therapy changes were post-index hypoglycemic events (discontinuation Treatment Regimens. HR= 1.78 [1.68, 1.90], p<.01; down-titration HR=2.79 [2.40, 3.23], p<.01) and concomitant use of insulin (discontinuation HR= 1.48 [1.40, 1.57], p<.01; down- Treatment Metformin Metformin Metformin Metformin Metformin Metformin Metformin regimen Gliclazide Glibenclamide Glimepiride Tolbutamide Pioglitazone Insulin titration HR=1.82 [1.56, 2.11], p<.01). Other risk factors include younger age, use of 2nd generation SUs, prior cardiovascular conditions and liver disease. Age 65.3[±12.6] 61.2 [±11.7] 62.1 [±12.1] 60.7 [±11.4] 61.8 [±11.5] 59.2 [±12.1] 57.2 [±11.8] In conclusion, more than half of type 2 diabetes pts who newly initiated baseline SU therapy experienced discontinuation or down-titration within 1 year (Years) following treatment initiation. Insulin use and hypoglycemic events elevated Weight (Kg) 87.6[±17.8] 91.7 [±18.5] 91.2 [±19.5] 91.2 [±17.7] 90.1 [±17.8] 91.5 [±16.5] 91.0 [±17.8] the risk of therapy changes. baseline HbA1c (%) 6.7 [±0.9] 7.1 [±1.1] 7.2 [±0.9] 7.1 [±1.1] 7.1 [±1.1] 7.1 [±1.3] 7.2 [±1.3] 1523-P baseline Effect of Vitamin D Supplementation on Improving Glycemic Control Δ 1-0 (n. 5446) (n.574) (n.47) (n.1046) (n.1568) (n.78) (n.195) and Preventing Diabetes: A Systematic Review HbA1c (%) -0.1 [-0.1-0.09] -0.2 [-0.3,-0.1] -0.1 [-0.4, 0.2] -0.2 [-0.3, -0.2] -0.2 [-0.2, -0.1] -0.4 [-0.7, 0.01] -0.2 [-0.5,0.1] JENNIFER C. SEIDA, JOANNA MITRI, ISABELLE N. COLMERS, SUMIT R. MAJUMDAR, MAYER B. DAVIDSON, ALUN L. EDWARDS, DAVID A. HANLEY, Weight (Kg) (n.5421) (n.565) (n.50) (n.1043) (n.1564) (n.70) (n.202) ANASTASSIOS G. PITTAS, LISA TJOSVOLD, JEFFREY A. JOHNSON, Edmonton, -0.7 [-0.8, -0.5] +0.4 [0.1, 0.8] -0.4 [-2.1,1.3] +0.3 [0.1, 0.7] +0.3 [0.1, 0.5] +0.6 [-0.5, 1.5] +1.4 [0.6,2.1]] AB, Canada, Boston, MA, Los Angeles, CA, Calgary, AB, Canada Δ 5-0 (n.866) (n.101) (n.15) (n.157) (n.228) (n.25) (n.38) Observational studies report consistent associations between low vitamin HbA1c (%) -0.1 [0.01, 0.2] -0.2 [-0.4, 0.1] +0.3 [-0.4, 0.9] +0.09 [-0.1, 0.3] -0.1 [-0.2, 0.1] +0.3 [-0.4, 0.9] +0.1 [-0.4,0.5] D concentration and hyperglycemia and increased risk of type 2 diabetes, but results of randomized controlled trials (RCTs) are mixed. We systematically Weight (Kg) (n.863) (n.105) (n.15) (n.157) (n.226) (n.18) (n.38) reviewed RCTs that report on the effects of vitamin D supplementation -0.9 [-1.5, -0.3] +1.2 [-0.7, 3.1] -2.7 [-8.0, 2.6] -0.6 [-2.0, 0.9] -0.7 [-1.9, 0.6] +2.6 [-2.1, 7.3] +0.2 [-3.3,3.7] on glucose homeostasis or diabetes prevention. We searched MEDLINE, EMBASE, SCOPUS, Cochrane Database of Systematic Reviews, Science Citation Indices, trial registries, and grey literature through to June 2013. 1525-P Trials that compared vitamin D3 supplementation with placebo or a non- Intensive Lifestyle Modifi cation Reduces Cardiometabolic Events vitamin D supplement in adults with normal glucose tolerance, prediabetes, in Young South Asians: Diabrisk-Sri Lanka Trial or type 2 diabetes and that reported outcomes of interest (insulin resistance JANAKA KARALLIEDDE, MAHEN WIJESURIYA, LAKSHA VASANTHARAJAH, [HOMA–IR] and secretion [HOMA–B], glycemic control [A1c], incident MARTIN GULLIFORD, GIANCARLO VIBERTI, LUIGI GNUDI, London, United Kingdom, diabetes, or adverse events) in English were eligible. Two reviewers collected Colombo, Sri Lanka data and assessed trial quality using the Cochrane Risk of Bias tool. Random There is an increasing incidence of type 2 diabetes mellitus (T2DM) and effects models were used to estimate mean differences (MD) and odds related cardiovascular disease (CVD) in young South Asian subjects. T2DM ratios (OR). Thirty-fi ve trials (43,407 patients) with variable risk of bias were and CVD share common antecedents. The effect of lifestyle modifi cation included. Across the spectrum of baseline glucose tolerance, vitamin D had (LSM) on the prevention of cardio-metabolic disease in young urban South no signifi cant effects on insulin resistance (HOMA–IR: MD, -0.04; 95%CI, Asian subjects is unknown.

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Diabrisk-SL was a 4 year randomised controlled clinical trial to compare self-reported general health (Table). Mean A1C was higher at registration an intensive 3 monthly LSM (I-LSM) with a less intensive 12 monthly LSM as was prevalence of basal insulin therapy; treatment with multiple OADs (LI-LSM) for a primary composite cardio-metabolic endpoint of T2DM, was less common. A1C change was numerically greater in AA patients at hypertension, dyslipidaemia, cardiovascular disease and albuminuria, in 3, 6, and 9 months, and a higher proportion reported nocturnal and severe healthy subjects aged 5 to 40 years with at least 2 of the following risk hypoglycemia as a signifi cant problem (Table). factors: raised body mass index, raised waist circumference, family history T h e r e p r e s e n t a t i v e n u m b e r o f A A p a t ie n t s in D F s u g g e s t s hig h e r r e c r ui t m e n t of T2DM and physical inactivity. The trial was performed in Colombo, Sri is possible in studies where it has traditionally been unsuccessful. Despite Lanka between 2010 to 2013. Of the 4606 at risk subjects randomized younger age, higher baseline A1C and insulin use suggest T2DM is more 3,685 (48% males) qualifi ed for the intention to treat analysis. Each subject advanced in AA patients. Greater concern about hypoglycemia is likely received individualised LSM advice aimed at reducing weight, improving diet related to experience with T2DM medication including basal insulin. and increasing physical activity 3 monthly (I-LSM) or 12 monthly (LI-LSM). Table. Clinical and Demographic Features of AA and W Patients. Metabolic endpoints were diagnosed by ADA criteria. There were no signifi cant baseline differences in anthropometric, clinical Characteristic AA W P-value (n = 276) (n = 1,510) and demographic measures between groups [I-LSM (n=1807, mean ± SD age, 22.4±10 yrs.) and LI-LSM (n=1878 age, 22.4±9.8 yrs.]. Age, mean (SD), years 54.6 (11.7) 61.1 (11.6) 0.0001 In both groups improvements were observed in metabolic, lipid, Female, n (%) 197 (71.4) 743 (49.2) 0.0001 infl ammatory and haemodynamic measures. The cumulative incidence BMI category, n (%) of the primary end point was n=270 in I-LSM vs. n=302 in LI-LSM, a 10% < 25 kg/m2 12 (4.4) 99 (6.8) 0.0090 25 to < 30 kg/m2 53 (19.3) 336 (23.0) (95% CI 2%-17%) relative risk reduction (RRR), which was independent of 2 baseline age, gender, blood pressure and glucose (p=0.01). Similarly there 30 to < 35 kg/m 82 (29.9) 432 (29.5) 35 to < 40 kg/m2 55 (20.1) 309 (21.1) was a signifi cant 28% RRR (95%CI 3%-46%) with I-LSM in the development ≥ 40 kg/m2 72 (26.3) 287 (19.6) of T2DM (p=0.03). Our results demonstrate for the fi rst time that in a young at risk South Education level, n (%) 117 (42.4) 527 (34.9) 0.0003 Some high school/graduate 82 (29.7) 405 (26.8) Asian population individualised intensive LSM signifi cantly reduces the Some college Associate/Bachelor degree 44 (15.9) 321 (21.3) development of cardio-metabolic disease. Some post-graduate work/degree 29 (10.5) 246 (16.3) Supported By: IDF; Diabetes Association of Sri Lanka Missing 4 (1.4) 11 (0.7) General health (patient’s view), n (%) 0.0001 1526-P Excellent 6 (2.2) 44 (2.9) Different Angiotensin Receptor Blockers and Diabetes Risk: A Very good 50 (18.1) 357 (23.7) Nationwide Cohort Study Good 107 (38.8) 698 (46.3) CHIA-HSUIN CHANG, YI-CHENG CHANG, LI-CHIU WU, JOU-WEI LIN, LEE-MING Fair 86 (31.2) 326 (21.6) Poor 27 (9.8) 84 (5.6) CHUANG, MEI-SHU LAI, Taipei, Taiwan Aim: Angiotensin receptor blockers (ARBs) have been shown exert various OADs, n (%) 0.0001 peroxisome proliferator-activated receptor -γ gamma (PPARγ) binding 0 51 (18.5) 123 (8.1)

Genetics 1 91 (33.0) 489 (32.4)

POSTERS activity and insulin-sensitizing effects. In this study, we aimed to compare

Epidemiology/ 2 108 (39.1) 691 (45.8) the effects of different ARBs on diabetes risk. ≥ 3 26 (9.4) 207 (13.7) Methods: A nationwide cohort study was conducted by analysing the Taiwan National Health Insurance Database. A total to 492,530 subjects Basal insulin, n (%) 68 (24.6) 237 (15.7) 0.0003 A1C at registration, mean (SD), % 7.97 (1.84) 7.22 (1.43) 0.0001 who started initial ARBs treatment were identifi ed from January, 2004 to December, 2009. Newly diagnosed diabetes was defi ned based on A1C change from baseline, mean (SD), % International Classifi cation of Diseases code, ninth revision. Cox proportional 3 months (n = 934) −0.3 (51.9) −0.17 (1.1) 0.2798 6 months (n = 619) −0.17 (1.6) −0.03 (1.2) 0.3166 regression was used to estimate the risk of diabetes associated each ARB 9 months (n = 581) −0.22 (1.3) −0.03 (1.3) 0.3310 using losartan as the common reference. Results: During 1,771,173 person-years of follow-up, 65,358 incident Signifi cance of severe hypoglycemia, n (%) Signifi cant 31 (11.7) 72 (4.9) 0.0001 Not signifi cant 234 (88.3) 1,401 (95.1) 0.0001 diabetes cases are identifi ed. Olmesartan initiators have signifi cantly Signifi cance of nocturnal hypoglycemia, n (%) Signifi cant 43 (16.2) 97 (6.6) higher risk of developing diabetes (crude hazard ratio, 1.35; 95 % confi dence Not signifi cant 222 (83.8) 1,375 (93.4) interval [CI], 1.29-1.40). The association remains signifi cant after adjustment for baseline characteristics and mean daily dose (HR, 1.07; 95% CI, 1.03- Supported By: Sanofi 1.12). After excluding those followed for less than one year, the increase in diabetes risk are more pronounced, (HR, 1.48; 95% CI, 1.41-1.55; adjusted 1528-P HR, 1.09; 95% CI, 1.05-1.14). The risks were consistent across all subgroups. Prevalence of Missed Doses of Oral Agents for Diabetes among U.S. Similar results were observed using a more strict defi nition of diabetes Patients with Type 2 Diabetes combining both diabetes diagnosis and anti-diabetic treatment. However, SWAPNIL RAJPATHAK, ROSE LORENZO, CATHERINE WLODARCZYK, JEFFREY telmisartan was not associated with reduced diabetes risk. VIETRI, North Wales, PA, New York, NY Conclusions: Among all ARBs, olmesartan may be associated with higher Medication adherence in type 2 diabetes (T2D) is known to be suboptimal, risk of diabetes mellitus. Our data suggest differential effects of ARBs on but the usual prevalence of missing a dose of oral antidiabetic medication diabetes risk beyond a class effect. (OAD) has not been quantifi ed. We conducted a survey among patients who self-reported physician diagnosis of T2D within the Lightspeed Research 1527-P survey panel, using quotas by age, gender, race, and type of drug regimen Demographics, Clinical, and Treatment Patterns in African (oral monotherapy, oral-only polytherapy, or polytherapy combining oral Americans (AA) with T2DM in Primary Care (PC) and injectable medications) to ensure representativeness of the adult U.S. THERESA L. CHO, MANUEL J. QUINONES, TERRY DEX, MEHUL DALAL, JEFFREY T2D population (n=2,031). Mean age of the study population was 58.5 years FRIMPTER, JOHN STEWART, ROBERT CUDDIHY, ALEKSANDRA VLAJNIC, Ventura, with 45.1% women and mean duration of diabetes of 10.6 years. Sample CA, Anaheim, CA, Bridgewater, NJ, Quebec, QC, Canada weighting incorporated age and type of drug regimen using fi gures from the AA patients are underrepresented in T2DM trials, and real-world demo- 2012 National Health and Wellness Survey. Results suggest that 30.3% of graphic and clinical data are sparse. We used Diabetes FORWARD (DF), a U.S. adults with T2D using an OAD missed or took less than the prescribed large practice-based research network focused on T2DM patients and their dose in the prior 4 weeks. Approximately 50% reported missing ≤ 2 doses providers across the U.S., to compare characteristics of AA and White (W) in the prior month, but others had important treatment gaps; 10% who patients with T2DM in PC. Eligible patients were aged ≥ 18 years with a missed indicated missing ≥ 10 doses, and 5% reported missing ≥ 20 doses. diagnosis of T2DM. In addition, 23% of those who missed a dose in the prior 4 weeks indicated Of 2,195 patients enrolled from March 2012–November 2013, 1,786 were their most recent dose was missed within last 2 days, and more than half included in this analysis. AA patients (15.4%) were younger, more likely to missed a dose within the last 5 days, suggesting that the prevalence of be female, and had a higher BMI. They were also more likely to receive missed doses is likely underestimated. Missed doses were most often Medicaid (26.1% AA vs. 6.9% W), have a lower education level, and poorer attributed to forgetting (36.1%), while 29.7% patients missed a dose on

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A398 EPIDEMIOLOGY—OTHERCATEGORY purpose. The most commonly indicated reason for intentional skipping was 1531-P concern about hypoglycemia (~15%). These results illustrate that missing Regional Variation in Fasting and Hypoglycemia Experiences in doses of OAD is common among U.S. patients with T2D, and that patient MOSAIc Study Patients with T2DM Taking Insulin self-reports are likely underestimated even when assessed via anonymous JOHN SEEGER, AMANDA R. PATRICK, WILLIAM SHRANK, JERRY AVORN, questionnaire. NITEESH CHOUDHRY, JENNIFER M. POLINSKI, Boston, MA, Woonsocket, RI Supported By: Merck & Co., Inc. Patients taking insulin while fasting may be at risk of hypoglycemia. Globally, patterns of insulin use during fasting have been incompletely 1529-P studied. Prevalence and Features of Adult-Onset Autoimmune Diabetes in MOSAIc is a 2-year observational study in 18 countries in 5 regions to the United Arab Emirates (UAE) identify factors associated with insulin intensifi cation in patients with ERNESTO MADDALONI, NADER LESSAN, ALIA AL TIKRITI, PAOLO POZZILLI, T2DM already taking insulin. We present baseline data on 3070 patients’ MAHA T. BARAKAT, Rome, Italy, Abu Dhabi, United Arab Emirates beliefs about and experiences with hypoglycemia and fasting, drawn from The UAE has one of the highest prevalence of diabetes in adults worldwide. the Experience with Insulin Therapy and the Hypoglycemia and Fasting However data on autoimmune diabetes, including Latent Autoimmune Questionnaires. Diabetes in Adults (LADA), is lacking. Of possible insulin regimens, 61% of patients used basal insulin alone. To describe the features of adult-onset autoimmune diabetes in the UAE Mean age was 61, 50% were male, and mean T2DM duration was 12 (±8) we carried out a cross-sectional study on diabetic subjects attending a major years. 68% reported hypoglycemia <1 per month, 25% reported 1-2 episodes diabetes centre in Abu Dhabi. Records of 17391 subjects with age range at per month, and 7% reported weekly episodes. Frequent (≥1 episode / week) diagnosis 30-70 years and available relevant antibody data were analysed. hypoglycemia was most common in North America and North Africa / Middle LADA was diagnosed according to standard criteria: no insulin therapy for at East and least common in Europe and Southeast Asia. Fasting behaviors least 6 months after diagnosis and presence of at least one autoantibody to also varied by region, with fasting occurring in 74% of North Africa/Middle islet cell antigens GAD65 (GADA) or anti-IA2. Eastern patients and only 7% of European patients. There were signifi cant 439 (2.5%) patients were identifi ed as LADA and 36 (0.2%) as classical type differences across regions in the frequency of and discussion with providers 1 diabetes in adults (antibody positivity and insulin therapy since diagnosis). about hypoglycemia and fasting, even after adjusting for age, gender, T2DM Compared to age matched type 2 diabetes LADA patients showed lower age duration, education, and insulin use. Whether these beliefs and behaviors at diagnosis, BMI, waist circumference and systolic blood pressure, but higher are related to the frequency of hypoglycemic episodes will be assessed over HbA1c [table]. Patients positive for GADA vs. IA2 positive showed a more the 2-year study. aggressive form of LADA with a higher prevalence requiring insulin (52.3% vs. 24.6%, p <0.001) and an earlier mean age at diagnosis (44.2 ± 9.5 years vs. 46.2 Region (N) >1 Hypo- ≥1 Hypo- Worry Believe Confi dent Fast for Discuss glycemic glyemic about insulin can avoid religious fasting with ± 9.2, p=0.005) but with no signifi cant differences in HbA1c values. episode / episode / hypoglycemia causes hypoglycemia or other physician (%, Prevalence of autoimmune diabetes in adults is low in the UAE if month (%) week (%) (%) hypoglycemia (%) reasons (%) of those compared to Europe, U.S. or China but with clinical features suggesting a (%) fasting) more aggressive form of disease. Europe (579) 24 4 29 15 78 7 68

Type 2 Diabetes LADA Type 1 Diabetes P Middle East / North 41 13 45 38 68 74 71 Genetics POSTERS

n=16917 n=439 n=35 Africa (425) Epidemiology/ T2D vs. LADA LADA vs. T1D T2D vs. T1D North America (486) 42 11 31 12 84 20 34 Age at diagnosis, mean ± SD (years) 46.8 ± 9.6 45 ± 9.5 42.7 ± 12.2 <0.001 Ns 0,01 South and Central 3093724822051 America (348) Disease duration, mean ± SD (years) 9.7 ± 7.5 10.4 ± 7.0 3.2 ± 1.6 <0.022 <0001 <0.001 Southeast Asia (1232) 29 4 25 23 72 15 72 BMI, mean ± SD (Kg/m2) 31.4 ± 6.2 30.7 ± 6.2 27.5 ± 5.1 0.023 0.004 <0.001 P value comparing <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 Waist Circumference, mean ± SD (cm) 100.7 ± 12.5 99.5 ± 14.1 90.2 ± 12.6 0.043 <0.001 <0.001 regions, univariable HbA1c, mean ± SD (%) 8.5 ± 2.1 8.8 ± 2.1 10.0 ± 2.5 0.002 0.001 <0.001 P value comparing <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 Total Cholesterol, mean ± SD (mmol/L) 4.8 ± 1.2 4.9 ± 1.2 5.0 ± 1.1 Ns Ns Ns regions, multivariable Systolic BP, mean ± SD (mmHg) 131.2 ± 20.7 127.5 ± 20.3 119.9 ± 20.1 <0.001 0.034 0.001 Supported By: Eli Lilly and Company (F3Z-MC-B010) Diastolic BP, mean ± SD (mmHg) 72.8 ± 10.4 72.7 ± 10 69.1 ± 7.3 Ns 0.04 0.035 Subjects requiring insulin therapy, n (%) 5504 (32.5) 208 (47.4) 35 (100.0) <0.001 <0.001 <0.001 1532-P Uncharted Territory: Michigan Medicaid Claims Analysis for Diabetes Surveillance 1530-P MICHELLE BYRD, ERIKA GARCIA, DAWN CRANE, ROBERT L. WAHL, SARAH LYON-CALLO, Lansing, MI WITHDRAWN About 1.1 million Michigan adults have diabetes. Michigan’s Medicaid programs serve a vulnerable adult population at risk for diabetes. Medicaid claims analysis provides a unique and powerful perspective on key components of health care. We report on indicators of diabetes burden and health care utilization using Medicaid claims. This study was a surveillance of adults 18-64 years using Michigan Medicaid claims. Diabetes cases were defi ned based on an adaptation of the 2012 Health Plan Employer Data Information Set (HEDIS®) criteria. Surveillance of diabetes prevalence and diabetes-related treatment and procedures by demographic characteristics and geography was conducted for each year 2007 through 2012. Diabetes prevalence among the Michigan adults served by Medicaid programs was 9.6% for 2012. Of 83 counties, 46 had diabetes prevalences greater than the prevalence among Michigan Medicaid benefi ciaries (Figure). Among adults with diabetes, only 4.7% had at least one diabetes self-management education session. The emergency department visit rate was 117 per 100 persons with diabetes.

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Medicaid claims are a robust data source for diabetes surveillance. This The sample population (n=4106) consisted of 867 Pima Indians (PI) from surveillance will provide more information on the burden of diabetes among Southwestern United States and 3239 Asian Indians (AI) surveyed in the low-income populations in Michigan. Diabetes intervention programs Centre for cArdiometabolic Risk Reduction in South-Asia Surveillance Study and messaging may be better targeted towards these citizens based on in Chennai, India. All subjects had glucose and insulin measured after an 8-10 diabetes-related health care utilization. hour fast and 30 min after a 75g glucose challenge. We estimated proportions with normoglycemia (NG), isolated impaired fasting glucose (iIFG), isolated impaired glucose tolerance (iIGT), and IFG+IGT defi ned by ADA guidelines. We compared β-cell function [oral disposition index, DIo = (ΔI0-30 /ΔG0-30) x (1/ fasting insulin)] and IR (HOMA-IR) between glycemic categories. PIs were younger (PI: mean 27.4 ± SD 6.6, AI: 39.5 ± 11.7 years) and had greater BMI (PI: 33.6 ± 8.1, AI: 25.7 ± 4.8 kg/m2). Percent NG (PI: 64%, AI: 66%) and IFG+IGT (PI: 7%, AI: 5%) varied less compared to % iIFG (PI: 5%, AI: 17%) and iIGT (PI: 18%, AI: 4%). After adjusting for age and BMI, AIs had higher fasting glucose (mean 100 ± SE 0.5; PI: 90 ± 1 mg/dL, p<.0001) and 30 min glucose (159 ± .8; PI: 147 ± 2 mg/dL, p<.0001) but PIs had higher 120 min glucose (127 ± 2; AI: 118 ± 1 mg/dL, p<.0002). The biggest % difference in age- and BMI- adjusted DIo was between iIFG and IFG+IGT for PIs (-53%) and NG and iIGT for AIs (-52%), while the biggest % differences in HOMA-IR were between NG and iIFG (PI: +67%) or iIGT (AI: +77%). Differences in β-cell function and IR between these ethnic groups suggest potentially varied pathways to diabetes. Longitudinal studies might shed further light on differences in pathophysiology.

1535-P Geographic Patterns of Patient Demographics and Insulin Usage: A Global Perspective from the MOSAIc Study JENNIFER M. POLINSKI, ANTHONY ZAGAR, MARTHA M. FUNNELL, AHMED HASSOUN, WILLIAM SHRANK, BRADLEY H. CURTIS, Boston, MA, Indianapolis, IN, Ann Arbor, MI, Al-Madinah, Saudi Arabia, Woonsocket, RI, Carmel, IN Among patients with type 2 diabetes (T2DM), insulin intensifi cation to 1533-P achieve glycemic targets occurs less often than clinically indicated. The The Impact of Timing of Insulin on the Incidence of Macrovascular MOSAIc study is a multi-national, prospective observational cohort study Complications designed to identify patient, physician, and health care environment JANICE C. ZGIBOR, LICHUAN TU, SHIHCHEN KUO, MELISSA SAUL, FRANCIS X. factors that infl uence insulin intensifi cation among patients with T2DM Genetics

POSTERS SOLANO, WEI-HSUAN LO-CIGANIC, KRISTINE RUPPERT, Pittsburgh, PA and to quantify relationships between these factors and long-term clinical Epidemiology/ It is unclear if timing of insulin initiation impacts the incidence of macro vascular outcomes. Extensive demographic, clinical, and psychosocial data at the complications (MVCs) in people with type 2 diabetes. Administrative data from patient and physician level are collected at baseline and regular intervals the University of Pittsburgh Medical Center between 1/1/2003-1/1/2013, in 2,834 during a 24 month follow up period. T2D patients were analyzed. The association between longitudinal patterns of In total, 4543 patients within 222 physician practices across 18 countries treatment and glycemic control and the incidence of MVCs was explored. Insulin are participating. Select characteristics for countries enrolling the most initiation was the fi rst record of insulin use following the fi rst A1C≥7% (baseline). patients are presented below. Across geographies the average age of Group-based trajectory models identifi ed 3 insulin use groups: No Insulin (NI), patients on a starting insulin therapy was 61years (±11) and 50% female. We Later Insulin Initiation (LI) ~ 5 years after baseline, and Earlier Insulin Initiation present selected characteristics at enrollment. These data highlight notable (EI)-within 1 year of baseline. 5 trajectory groups for A1C patterns over time were differences in patient characteristics across countries that may contribute identifi ed: (1) remained stable at 7%; (2) remained stable at 8%; (3) started high to the likelihood of insulin intensifi cation and subsequent clinical outcomes. (>11%) and decreased to near 7%; (4) started at 8.5% and increased to >10%; (5) These include wide variations in obesity rates between East Asian and remained in poor control (>11.5%). MVCs were defi ned by ICD-9 and CPT codes Western countries and disparities in the use of insulin mixtures compared to and included coronary heart disease (CHD), cerebrovascular disease (CBVD), and the more widely-used basal therapies. At study enrollment, the use of basal peripheral vascular disease (PVD). bolus approaches is rare. There were 1,914 NI, 500 LI, and 420 EI patients. The NI group was the oldest (mean=61 yrs) with the lowest baseline A1C (mean=8.7%), while the Duration of Most Body Mass Basal Mixed Basal + LI was the youngest (mean=54 yrs) with a higher baseline A1C (mean=8.9%). Diabetes recent Index insulin insulin short-acting (years) HbA1c (% ) > 30kg/m2 Alone Alone insulin The EI group had the highest baseline A1C (mean=9.2%) and had the most prevalent diabetes complications. The unadjusted incidence of MVCs (i.e., Argentina 13.1 ± 9.6 8.1 ± 1.8 52% 54% 23% 4% overall, CHD, CBVD, or PVD) was highest in NI (48.4, 44.1, 14.6, 20.8%), China 10.9 ± 7.3 7.5 ± 1.8 4% 28% 21% 0% followed by EI (15.1, 11.7, 2.3, 8.1%), and lowest in LI (4.0, 3.5, 2.1, 5.0%). Germany 13.7 ± 8.2 6.5 ± 2.3 47% 45% 45% 4% Compared with NI, EI and LI were associated with a signifi cantly lower India 11.4 ± 7.6 8.6 ± 1.7 22% 45% 41% 1% risk of MVCs (adjusted hazard ratios for all events ranged from 0.13-0.29 for EI; 0.05-0.69 for LI). Among those with an A1C≥7%, NI experienced a higher Japan 13.6 ± 8.7 7.6 ± 1.3 6% 66% 11% 1% incidence than insulin users. Among insulin users, EI patients experienced Saudi Arabia 10.6 ± 7.3 9.1 ± 2.4 59% 71% 22% 0% a higher incidence compared to LI patients. A more proactive approach to USA 12.3 ± 8.3 7.9 ± 1.4 56% 61% 12% 5% glycemic control could reduce the incidence of diabetes complications. Supported By: Sanofi 1536-P 1534-P Prevalence of Diabetes and Prediabetes in Asian Indians in the U.S. The Tale of Two Indians: A Comparison of β-Cell Function and and India: The MASALA and CARRS Studies Insulin Resistance between Pima Indians and Asian Indians UNJALI P. GUJRAL, K.M. VENKAT NARAYAN, RAJENDRA PRADEEPA, MOHAN LISA R. STAIMEZ, MOHAN DEEPA, MOHAMMED K. ALI, VISWANATHAN MOHAN, DEEPA, MOHAMMED K. ALI, RANJIT M. ANJANA, NAMRATHA KANDULA, VIS- ROBERT L. HANSON, Atlanta, GA, Chennai, India, Phoenix, AZ WANATHAN MOHAN, ALKA KANAYA, Atlanta, GA, Chennai, India, Chicago, IL, San Contributions of β-cell dysfunction to diabetes development in high-risk, Francisco, CA ethnic populations are not fully understood. We compared β-cell function Asian Indian (AI) immigrants have a higher prevalence of type 2 diabetes among two ethnicities at high risk for diabetes and insulin resistance (IR): (DM) than the general U.S. population. Migration to developed countries is Pima Indians, a population with a high mean body mass index (BMI), and associated with higher DM risk; however it is unclear if U.S. AIs’ risk differs Asian Indians, a population with relatively low mean BMI. from AIs in urban India.

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We assessed the age-specifi c prevalence of DM and preDM in two AI 1538-P populations aged ≥40 years: n=2,305 in Chennai, India from the Centre for Cross-National Variation in Physicians’ Characteristics and Their cArdiometabolic Risk Reduction in South-Asia study (CARRS, 2010-2011); Goals for Patients Taking Insulin: Evidence from the MOSAIc Study n=757 from the Mediators of Atherosclerosis in South Asians Living in America JING XIE, SHUICHI SUZUKI, XAVIER COS, AHMED HASSOUN, IKIRO MATSUBA, study (MASALA, 2010-2013). DM was defi ned as use of diabetes medication JENNIFER M. POLINSKI, Boston, MA, Tokyo, Japan, Barcelona, Spain, Al-Madinah, or fasting glucose ≥ 126 mg/dl or 2 hour glucose ≥ 200 mg/dl; preDM: fasting Saudi Arabia glucose 100-125 mg/dl and/or 2 hour glucose 140-199 mg/dl. Variations in physicians’ characteristics, their practice environments and Mean age and BMI were 51 ± 9 and 26 ± 5 kg/m2 in CARRS and 56 ± 9 and their patients’ characteristics may contribute to insulin intensifi cation in 26 ± 4 kg/m2 in MASALA, respectively. Age-adjusted DM prevalence was patients with type 2 diabetes (T2DM) over time. higher in CARRS than in MASALA (overall: 38% vs. 24%; Men: 36% vs. 27%; The MOSAIc study is a multi-national, prospective observational cohort Women: 42% vs. 23% (p< 0.01 for each). In contrast, age-adjusted preDM study designed to identify factors that infl uence insulin intensifi cation prevalence was lower in CARRS than in MASALA (overall: 24% vs. 33%(p among patients with T2DM. In total, 222 physicians and 4,543 patients are <0.01); Men: 21% vs. 35% (p< 0.01); Women 25% vs. 29% (p=0.12). These participating across 18 countries in 5 regions. Already, 134 (60%) physicians patterns were consistent across age and sex groups, but differences by age have completed the physician demographic survey and described their were more pronounced in women (Figure). HbA1c treatment goals for each of their patients (N=135). DM prevalence was 40% higher in urban India compared to the U.S., Most clinicians are male (64%) and over 1/3 are ages 50-59. Across regions, while preDM prevalence was 30% lower. These fi ndings challenge popular physicians report signifi cant differences in both the overall number and the paradigms about the impact of migration on DM risk. number of patients with T2DM that they treated in the last month, adjusting for physicians’ characteristics. North American and Southeast and East Asian physicians on average treat more patients per month than physicians in other regions. Physicians’ long-term goals for patients’ glycemic control are similar across regions, after adjustment for both physician and patient characteristics, including patients’ HbA1c levels at enrollment. Longitudinal data from MOSAIc will better clarify the patient- and physician- specifi c factors that predict insulin intensifi cation and glycemic control. Region (Number of Years Number of Patients Patients Patient Target HbA1c Minutes Physicians) experience Diabetes treated with T2DM visits due level for spent with treating Education last month treated last to T2DM patients each patient patients with Meetings month in last 6 over next to manage T2DM attended, per months two years (% T2DM care year hbg) Europe (37) 17±8 4±3 388±256 189±223 2.6±2.2 6.8±1.0 31±24 Middle East/ North 20±8 4±2 357±204 190±212 2.2±1.6 6.9±1.0 22±15 Africa (13) Genetics

North America (26) 20±9 4±6 411±198 141±113 2.2±1.4 6.7±0.7 24±13 POSTERS Epidemiology/ South/Central 12±10 4±3 154±105 110±79 2.5±1.9 6.9±0.7 38±20 America (15) Supported By: NIH (1R01HL093009) Southeast and 15±10 11±18 443±293 334±263 3.3±2.1 6.7±0.9 29±22 East Asia (43) 1537-P Univariable P 0.06 0.04 0.004 0.0007 <.0001 0.0002 <.0001 Correlation between Glucose Intolerance and Histological Severity Multivariable P 0.59 0.09 0.005 0.003 0.17 0.28 0.35 in Nonalcoholic Fatty Liver Disease Supported By: Eli Lilly and Company (F3Z-MC-B010) SATOKO OHMI, MASAFUMI ONO, YUICHI NISHI, SEIKI HIRANO, MAKOTO TSUGITA, HIROSHI TAKATA, KUMIKO YOSHIMURA, SHUNSKE MORI, YOSHIO TERADA, TOSHIJI SAIBARA, SHIMPEI FUJIMOTO, Nankoku, Japan 1539-P While the association of the prevalence of non-alcoholic fatty liver Plasma 25-Hydroxyvitamin D Concentration and Carotid Intima- disease (NAFLD) with impaired glucose metabolism has been reported, the Media Thickness among Middle-aged and Elderly Chinese Urban association between the severity of NAFLD and glucose tolerance remains Residents to be clarifi ed. We investigated the association between histological LING LI, QING BO MA, YAO GUANG SONG, AN SONG, MIN YA LU, YAN LI, YONG severity and clinical factors. The glucose tolerance of 135 Japanese patients TANG, PING LU REN, JUN YA ZHU, SHA SHA ZANG, XUAN YI LIU, Shijiazhuang, diagnosed as NAFLD by histological fi ndings of liver biopsy specimen China, Jinan, China was examined using 75g OGTT. According to Matteoni’s classifi cation, Low levels of 25-hydroxyvitamin D [25(OH)D] have been reported to be patients were divided to 4 groups [M1~4, M1,2: simple steatosis; M3,4: associated with many cardiovascular disease (CVD) risk factors. Previous steatohepatitis (NASH)]. Based on the OGTT data, patients were classifi ed data on the relationship between 25(OH)D and carotid intima-media as normal (N), impaired glucose tolerance (I), and diabetes (D); insulinogenic thickness (CIMT) is controversial and the mechanism is unknown. Besides, index (IGI) and QUICKI were calculated as indices of insulin secretion and the evidence from the Asian population is limited. We aimed to evaluate insulin sensitivity, respectively. Stepwise multiple logistic regression the association between 25(OH)D and CIMT among middle-aged and analysis using the classifi cation of glucose tolerance (N vs. I or D) as a elderly Chinese Urban Residents. A total of 696 participants were enrolled dependent variable and IGI, QUICKI, sex, BMI, and age as independent in our study. Fasting lipids, glucose, insulin, infl ammatory markers were variables revealed that IGI (β=-0.350), QUICKI (β=-0.229), and age (β=0.232) measured. Fasting 25(OH)D was assessed from stored serum samples.The are the factors predicting glucose intolerance (R2=0.234) and that insulin CIMT were measured of all the subjects. Baseline cross-sectional data such secretion is most important, fi ndings that accord with glucose intolerance as sex, age, smoking and drinking status were also analysed. The median as high as 90.4% in patients with impaired insulin secretion defi ned as <40 of serum 25(OH)D was 26.45nmol/l in the subjects, and percentages of µU/mg IGI. While IGI did not differ among M1~4, QUICKI was greater in M1 25(OH)D defi ciency and insuffi ciency were 89.7 and 8.8%, respectively. than that in the other groups, indicating that histological severity may affect Consistent with our hypothesis, the serum level of 25(OH)D was inversely insulin sensitivity. Stepwise multiple regression analysis using QUICKI as associated with CIMT (P<0.01). Compared with the highest quartile of a dependent variable and Matteoni’s classifi cation, sex, BMI, and age as 25(OH)D (≥35.64nmol/L), the odds ratio for having abnormal CIMT in the independent variables shows that BMI (β=-0.443), M1 vs. M2~4 (β=-0.180), lowest quartile (≤13.01nmol/L) was 4.319 (95%CI 2.011-9.276, P<0.05) after and age (β=-0.297) are factors predicting insulin sensitivity (R2=0.163). These adjustment for multiple confounders, but the association was attenuated fi ndings indicate that impairment of insulin secretion is the most important by futher controls of IL-6, TNF-α and CRP and had no signifi cance (P>0.05). factor to predict glucose intolerance and that the severity of histological Backward logistic regression analyses showed that 25(OH)D was negtively fi ndings independently affects insulin sensitivity in NAFLD. associated with CIMT and vitimin D defi ciency was a risk factor of subclinical atherosclerosis (OR 0.649, 95%CI 0.453-0.930, P<0.05). Vitamin D defi ciency is common in middle-aged and elderly Chinese urban residents. Vitamin D

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status was negatively associated with CIMT, suggesting that vitamin D may 1542-P play a role in the development of atherosclerosis. The anti-infl ammatory and Food Insecurity and Cost-related Medication Underuse as Barriers immune modulatory properties of vitamin D provide possible mechanisms by to Glycemic Control in Diabetes which impact on the progression and severity in atherosclerosis. SETH A. BERKOWITZ, JAMES B. MEIGS, STEVEN J. ATLAS, DEBORAH J. WEX- LER, Boston, MA 1540-P Addressing socioeconomic barriers to glycemic control is an emerging Longitudinal Patterns of Stages of Change for Exercise and Lifestyle strategy for diabetes care, but it is not clear which factors to target. We Intervention Outcomes tested the hypothesis that food insecurity (FI), an inability to access LUOHUA JIANG, BEN ZHANG, JANETTE BEALS, CHRISTINA MITCHELL, SPERO nutritious food consistently, and cost-related medication underuse (CRMU) MANSON, YVETTE ROUBIDEAUX, College Station, TX, Aurora, CO, Rockville, MD were forms of economic insecurity that would identify a group at increased Purpose: To examine the transition patterns of stages of change (SoC) risk of poor glycemic control. for regular exercise over time among individuals participating in a lifestyle We contacted a stratifi ed random sample of adult (age > 20 years) diabetes intervention project and to investigate the association between longitudinal patients (type 1 or 2) in 4 clinics associated with a primary care network, patterns of SoC and lifestyle intervention outcomes. from 6/15-9/15, 2013. Patients completed previously validated instruments Methods: We analyzed data from the Special Diabetes Program for Indians to assess FI and CRMU using standard scoring. Unadjusted analyses Diabetes Prevention (SDPI-DP) Program, a lifestyle intervention program to evaluated the association of FI and CRMU with poor glycemic control (last prevent diabetes among American Indian and Alaska Natives (AI/ANs). A Hemoglobin A1c[HbA1c] > 9.0%). We then fi t multivariable logistic regression total of 1,344 participants completed the project questionnaires at baseline, models, adjusted for age, gender, race/ethnicity, health insurance, diabetes post-curriculum, and one year. Latent class analysis (LCA) was conducted duration, Charlson comorbidity score, and diabetes medications, and tested to identify the longitudinal patterns of SoC for regular exercise reported at for interaction by insulin use. Multivariable analyses were clustered by clinic the three time points. An improved 3-step approach was used to investigate using generalized estimating equations. the associations between latent class membership and behavioral changes Completed surveys were obtained from 412 patients (62% response rate); after the intervention. 19% reported FI and 28% reported CRMU. Compared to those without FI Results: Three latent classes were identifi ed: Pre-action, Transition, and or CRMU, both FI (22% vs. 8%, p=.002) and CRMU (21% vs. 8%, p<.001) Maintenance classes. The participants in the Transition class moved from pre- were associated with poor glycemic control. In multivariable models, both action stage at baseline to action or maintenance stage post-intervention. FI (adjusted OR 1.78, 95% CI 1.21-2.60) and CRMU (adjusted OR 1.93, 95% Compared to the other two classes, those in the Transition class had the CI 1.07-3.97) were associated with poor glycemic control. Non-signifi cant greatest improvements in physical activity and weight outcomes at both (p>0.05) insulin use interaction terms suggested that FI and CRMU were time points post-baseline. Furthermore, at year 1 assessment, the Transition associated with poor glycemic control in both those treated with insulin and and Maintenance classes had less attenuation than the Pre-action class in oral medications only. the improvements they had achieved initially in all the outcome variables. The high prevalence of food insecurity and cost-related medication Conclusions: LCA methods are useful in identifying longitudinal patterns underuse are important to consider in optimizing diabetes care, given the of readiness to change exercise behavior. Three latent classes were found in key role of diet and medication adherence in diabetes self-management. this study. The Transition class, where stage progression occurred, had the Further research should evaluate whether improving FI or CRMU improves Genetics diabetes control. POSTERS highest magnitude in positive behavioral changes. Epidemiology/ Supported By: ADA (7-12-CT-36); Indian Health Service; NIDDK Supported By: NRSA (T32HP10251); Ryoichi Sasakawa Fellowship Fund

1541-P 1543-P Double Diabetes in Saudi Arabia: A New Entity or an Underestimated Biochemical Bone Turnover Markers and Their Correlation with Condition? Body Mass Index in Patients with Type I Osteoporosis and Type 2 RIM BRAHAM, AUS AL ZAID, RANIA AHMED, MONTHER ZITOUNI, SAMIA Diabetes SOBKI, FAHD AL SABAAN, Riyadh, Saudi Arabia RALUCA NAN, ADRIAN CURSARU, RAMONA MARIA DRAGUT, EMILIA RUSU, While in general it is relatively easy to distinguish whether a child or CRISTINA TEODORESCU, MADALINA MUSAT, GABRIELA RADULIAN, Bucharest, a teenager has type 1 or type 2 diabetes mellitus (DM); in some cases Romania however, young people can display elements of both types of diabetes, a This study was designed to evaluate the levels of bone-specifi c biochemical condition commonly known as double diabetes (DD). This new entity has not markers of turnover and their relationship with body mass index in patients been studied in young Saudis before. The aim of this study therefore was to with type I osteoporosis and type 2 diabetes. A transversal study that determine the frequency and clinical characteristics of DD in young people evaluated 125 patients with postmenopausal osteoporosis: 49 patients with presenting with diabetes in Saudi Arabia. type 2 diabetes and 76 patients without diabetes (control group); Control This retrospective descriptive study included 312 young (12-20 years group was matched for age and sex. The variables analyzed were sex, of age) newly diagnosed diabetic patients admitted to a major institution age, body mass index (BMI), magnesium, calcium, phosphorus, cholesterol, over a four year period (2009-2012). Family history of diabetes (fi rst degree), trygliceride, fasting glucose, serum levels of osteocalcin, serum crosslaps and physical (BMI) and laboratory data for HbA1c, basal C-peptide level and 25(OH)D. The mean age of patients was 65,8±8,3 years. Women with type 2 diabetes autoantibody response (anti-GAD, anti-IA2 and anti-ICA) were diabetes osteocalcin was 15,82±6,77 ng/ml and crosslaps 0,257±0,14 ng/ml. collected and analyzed. Controls: osteocalcin 21,12±9,75 ng/ml and crosslaps 0,393±0,22 ng/ml. Based on the autoantibody response (Ab+ or Ab-) and C-peptide secretion Among these parameters there was statistically signifi cant difference (β+ for fasting level 0.4-2.1 ng/ml andβ- if < 0.4 ng/ml), patients were (p<0,05). Diabetic group had lower plasma 25(OH) than nondiabetic patients categorized into 4 groups: group1 (type 1a): Ab+ β- (21%); group 2 (type 1b): D (21,3 vs. 22,8 ng/ml) but not signifi cant. In univariate analysis 25 (OH)D Ab- β-(9%), group 3 (double diabetes, DD): Ab+ β+(31%) and group 4 (classic correlates negativ with serum trigyceride (r=-0.224) and osteocalcin and type 2 DM): Ab- β+(39%). crosslaps correlate positiv with magnesium. There was no statistically The mean age of presentation in patients with DD was 15.1 years with sex signifi cant difference in BMI. Level of crosslaps was signifi cantly lower in ratio of 1,2. Subjects with DD presented with DKA in 41% of the cases, and the underweight patients than overweight patients (0,15 vs. 0,41) and the 61% had positive family history of diabetes. The mean BMI in this group was level of osteocalcin was signifi cantly lower in the underweight patients 28.3 Kg/m2 with 64% of the patients with overweight or obesity. Only 32% than normal weight patients (12,3 vs. 21,9) (p<0,05). Patients with diabetes of these patients required insulin on follow up. showed signifi cantly reduced levels of osteocalcin and serum crosslaps Our fi ndings suggest that DD accounts for approximately one third of cases in comparison with contol group. Our results confi rm previous studies of young subjects presenting with diabetes in Saudi Arabia. We conclude demonstrating low bone turnover in patients with type 2 diabetes and this therefore that it is important to identify patients with double diabetes since thing should be taken into account when we talk about the management that will help the clinician decide on the appropriate therapeutic approach of patients with type 2 diabetes. Also underweight patients require more to be undertaken. attention regarding the skeleton.

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1544-P Frequency of Administration of Antidiabetic Drugs According to the GFR Level in Type 2 Diabetes Patients ATHANASIA K. PAPAZAFIROPOULOU, ANASTASIOS G. KOUTSOVASILIS, ANTHI KOKOLAKI, MARINA KARDARA, ALEXIS SOTIROPOULOS, MARIA BABOURDA, PARASKEVI VERGIDOU, DIMITRIOS M.D. GOUGOURELAS, STAVROS BOUS- BOULAS, STAVROS PAPPAS, Nikaia, Greece The number of Type 2 Diabetes patients suffering chronic kidney disease (CKD) is signifi cant and continuously increasing. Thus, the antidiabetic treatment needs to be regulated according to the level of the glomerular fi ltration rate (GFR). The aim of this study is o estimate the use frequency for antidiabetic drugs according to GFR level. The study included 255 (135 men) T2DM who were admitted in the Diabetes Center of our Clinicduring the period September - December2013. Plasma creatinine level was recorded in all the study’s patients, as well as somatometric parameters, HbA1c and antidiabetic treatment. Patients were classifi ed into four groups according to their GFR level (Group 1≥90, Group 2=60-89, Group 3=30-59 and Group 4<30 mL/min/1.73 m2). The mean age of the study’s participants was 68.7±10.1 years, diabetes Supported By: FORTE (FAS20061512); Swedish Research Council/Medical Research duration was 14.2±7.9 years and HbA1c was 7.3±1.1%. In Group 1 (n=123) Council (MCU106179474) the frequency of the antidiabetic treatment was: 29.3% (36 patients) for insulin, 20.3% (25) for sulfonylureas, 79.7% (98) for metformin, 0.8% (1) 1546-P for pioglitazone, 0.8%(1) for meglitinides, 35% (43) for DPP-4s and 6.5% (8) Treatment Persistence and Switch in German Patients with Type 2 for GLP-1 analogues. In Group 2 (n=86), 43%(37) for insulin, 25.6% (22) for Diabetes Mellitus (T2DM) after Initiating Basal Insulin sulfonylureas, 74.4% (64) for metformin, 2.3% (2) for pioglitazone, 4.7% (4) ENGELS CHOU, FRANZ-WERNER DIPPEL, HSING-WEN CHUNG, Bridgewater, NJ, for meglitinides, 32.6% (28) for DPP4s and 2.3%(2) for GLP-1 analogues. In Berlin, Germany, King of Prussia, PA Group 3 (n=37), 43.2% (16) for insulin, 10.8% 4) for sulfonylureas, 54.1% (20) Treatment persistence (PST) is related with improved glycemic control. A for metformin, 8.1% (3) for pioglitazone, 2.7% (1) for meglitinides and 43.2% retrospective cohort study compared PST among different basal insulins (BIs) (16) for DPP4s. In Group 4 (n=3), 33.3% (1) for insulin, 33.3% (1) for metformin in adult T2DM patients initiating glargine (GLA), detemir (DET), or NPH (Index; and 33.3% (1) for DPP4. 2008-2010). Patients with offi ce visits ≥ 1 year pre-(baseline,BL)/2 years post- The results of this study show that the GFR level, which is a reliable marker BI initiation were identifi ed from a representative German database. PST, of renal function, is taken into account for the choice of the most appropriate defi ned as duration from BI initiation to change of Index insulin, was evaluated antidiabetic treatment. The only difference was in Group 3 (GFR=30-59 mL/ by Kaplan-Meier curve and adjusted by Cox regression for BL characteristics; min/1.73 m2) for the use of DPP-4s. further evaluated by patient segments: combination of BI and oral drugs (BOT) Genetics

or bolus insulin (ICT). A1c was reported when available. Switch pattern was POSTERS Epidemiology/ 1545-P evaluated after patients discontinued their study BI (i.e., not persistent). Mean Achieving Healthy Behaviour Goals Reduces 10-Year Risk of age was 66 years for patients initiating GLA (n=2,996), 62 for DET (n=1,005), Developing Diabetes and 65 for NPH (n=3,237). In BOT, 65% GLA patients had an over two-year GRÁINNE H. LONG, INGEGERD JOHANSSON, MARGARETA NORBERG, PATRIK PST vs. 53% in DET and 59% in NPH (p<0.001; Hazard Ratio (95% Confi dence WENNBERG, EVA FHÄRM, OLOV ROLANDSSON, SIMON J. GRIFFIN, REBECCA K. Interval) =1.5 (1.28-1.76) and 1.2 (1.06-1.33), respectively). Of patients who SIMMONS, LARS WEINEHALL, Cambridge, United Kingdom, Umeå, Sweden discontinued Index BI, the BL/last A1c values before change were 8.9%/8.2% Intensive behavioural interventions reduce incidence of type 2 diabetes (GLA), 8.8%/8.5% (DET), and 8.3%/8.1% (NPH); over 75% switched to basal- in people with impaired glucose tolerance. It is unclear if the same risk bolus (ICT) or premix (CT); when change occurred within BI class, 59% DET reduction might be realised if individuals in the general population met similar and 77% NPH initiators changed to GLA. In ICT, ≥84% patients had an over behavioural goals. Västerbotten Intervention Programme (VIP) is a population- 2-year PST across BI groups (p=0.536). Of patients who discontinued BI, the based health promotion strategy in Northern Sweden incorporating an oral BSL/last A1c before switch were 8.9%/8.0% (GLA), 8.2%/8.1% (DET), and glucose tolerance test, clinical measures and diet and physical activity 8.4%/7.8% (NPH); 44-49% switched within BI, 9-13% switched to premix, and questionnaire. In a cohort analysis including 32,120 VIP participants aged 35-39% stayed on ICT. GLA had a better PST than DET/NPH in BOT. Patients 35-55 years we quantifi ed the association between achievement of six who discontinued BI in BOT and ICT, a good proportion of patients across BI behavioural goals - BMI <25 kg/m2, moderate physical activity, non-smoker, groups changed to ICT/CT. A BI treatment with comparable effectiveness and fat intake <30% of total energy, fi bre intake ≥15g/4,184kJ and alcohol intake once daily injection such as GLA can improve treatment persistence. ≤10g/day - and diabetes incidence using Poisson regression. Median (IQR) Supported By: Sanofi follow-up was 9.9 (0.3) years; 2211 individuals (7%) developed diabetes. Only 22% of VIP participants met 5 or 6 goals. Diabetes incidence was inversely 1547-P associated with the number of behavioural goals achieved (Figure 1. p-value Plasma Soluble DPP4 Levels and Metabolic Syndrome for trend 0.001). Compared to individuals who achieved 6 goals, in adjusted ≤ YUKIKO MORI, KUNIMASA YAGI, NAOTO YAMAAKI, KAORU NAKANO, TAKUYA models diabetes incidence was 2.90 (95% CI 1.93 to 4.36) times higher OKAMOTO, YUKO SAIKI, KENGO WADA, EIKO KITAMOTO, AZUSA OBATAKE, in participants meeting 0 or 1 health goal at baseline. Interventions that SATOKO OKAZAKI, KENKI RYU, YOSHIYU TAKEDA, MASAKAZU YAMAGISHI, promote achievement of behavioural goals in the general population could Kanazawa, Japan signifi cantly reduce the burden of diabetes-related morbidity and mortality. Dipeptidyl peptidase 4 (DPP4) is a ubiquitously expressed transmembrane glycoprotein. Substantial DPP4 activity is found in plasma as a soluble DPP4 (sDPP4). Recent studies have reported that sDPP4 is a novel adipokine and a biomarker for obesity and metabolic syndrome. Since previous studies looked at relatively small numbers of subjects, we examined the relationship between plasma sDPP4 levels and metabolic syndrome related parameters on relatively large numbers of subjects. There were 181 people (M131/F50, age 59±15 years old, BMI 25.0±4.7kg/m2, FBS 130±48mg/dl, HbA1c (NGSP) 6.8±1.5%). We studied 109 diabetic and 72 non-diabetic subjects. sDPP4 levels positively correlated with age (p=0.018, r2=0.031), BMI (p=0.044, r2=0.023), waist circumference (p=0.023, r2=0.032), FBS (p<0.0001, r2=0.22) and HbA1c (p<0.0001, r2=0.27), and negatively correlated with diastolic blood pressure (dBP) (p=0.035, r2=0.049), TC (p=0.028, r2=0.029), LDL-C(p=0.036, r2=0.048). In 131 subjects we measured hepatic function, visceral fat area, adiponectin, and leptin. sDPP4 levels

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correlated positively with AST (p=0.0005, r2=0.14), ALT (p<0.0001, r2=0.26), (as markers of PCOS) was 2% in Delhi and 0.9% (CI 0.4%-1%) overall, γGTP (p=0.0001, r2=0.17), adiponectin (p=0.0040, r2=0.080), and leptin while either oligomenorrhea or hirsutism was 16.8%. PCOS markers were (p=0.00029, r2=0.066). In addition, sDPP4 correlated positively with visceral associated with increased odds of having diabetes, hypertension, elevated fat area (p=0.045, r2=0.17) in non-diabetic subjects. We looked at 47 subjects waist and elevated BMI (Table 1). Population based data from two Indian who had data available over the previous four years. sDPP4 correlated with cities suggest a high prevalence of PCOS among Indian women which may increased levels in FBS (p=0.025, r2=0.14), and correlated with decreased have implications for cardiovascular risk. levels in dBP (p=0.023, r2=0.13) and HDL-C (p=0.049, r2=0.11). Table 1. Cardio-metabolic Risk of Women with PCOS Symptoms (Oligomenor- These results demonstrated that sDPP4 is associated with metabolic rhea and/or Hirsutism). syndrome as an adipokine as was previously reported. A signifi cant correlation Hirsutism Oligomenorrhea PCOS [Hirsutism Hirsutism or with increased liver enzymes also suggested an association between sDPP4 [Ferriman- [period lasting l and oligomenorrhea and fatty liver. The changes in DPP4 over four years are associated with an Gallway score onger than 35 oligomenorrhea] § increase in blood glucose and a decrease in HDL-C and dBP. of >6] days or less than 8 periods in a year] 1548-P OR CI OR CI OR CI OR CI Periodontal Microorganisms and Oral Hygiene in Type 1 Diabetes Diabetes mellitus 1.2 0.7 – 1.8 1.7 1.2 – 2.4 1.3 0.4 – 4.6 1.5 1.1 – 2.1 ANWAR T. MERCHANT, GEORGES J. NAHHAS, R. PAUL WADWA, JIAJIA ZHANG, (self reported or LONNIE JOHNSON, DAVID M. MAAHS, FRANZISKA K. BISHOP, RICARDO TELES, newly diagnosed) ELAINE MORRATO, Columbia, SC, Aurora, CO, Cambridge, MA Hypertension 1.2 0.6 – 2.3 1.8 1.1 – 2.9 5.2 0.3 - 93.7 1.7 1.1 – 2.5 We evaluated the relation between periodontal microorganisms and (self reported or oral hygiene measures in youth with type 1 diabetes (T1DM). Youth with newly diagnosed) T1DM (N=54) treated at the Barbara Davis Center, Aurora, CO from 2009- Waist circumference 1.4 0.9 – 2.1 1.8 1.3 – 2.4 0.37 0.1 - 1.6 1.8 1.4 – 2.3 2011 completed questionnaires on oral and general health, received oral (≥85cm) examinations, and provided subgingival plaque samples. Counts of 41 Waist to hip ratio 1.1 0.8 – 1.6 1.3 0.9 – 1.7 0.78 0.3 - 2.1 1.2 0.9 – 1.6 microorganisms, obtained by DNA-DNA hybridization, were classifi ed into (≥0.85) 4 groups using cluster analysis, and organism z-scores summed to obtain cluster scores. Clusters names were based on Socransky’s method where BMI (≥25) 1.8 0.5 – 5.8 3.8 1.2 – 12.8 2.8 1.2 – 6.5 2.8 1.2 – 6.5 orange and red indicate periodontal disease: Cluster 1 (Blue-Other), Cluster 2 LDLc (≥130) 1.5 0.9 – 2.3 1.05 0.7 – 1.5 1.6 0.5 - 5.3 1.2 0.9 – 1.6 (Orange-Green), Cluster 3 (Red-Orange), Cluster 4 (Yellow-Other). Participants Triglycerides (≥150) 0.7 0.4 – 1.1 1.5 1.1 – 2.1 0.24 0.03 - 1.8 1.2 0.9 – 1.6 were 15 years old (mean), 52% female, and 72% white; 78% visited a dentist Wealth index 2.6 1.7 – 3.9 1.2 0.9 – 1.8 8.8 1.9 – 39.8 1.7 1.3 – 2.2 within 2 years, 54% brushed 2+ times a day, and 46% fl ossed 7+ times per (divided in tertiles week; 21% sites had bleeding on probing (indicating gingivitis); none of lowest to highest) the participants had pocket depth ≥3 mm (indicating periodontal damage). *OR – Odds Ratio; CI – Confi dence Intervals. Cluster scores were positively correlated with gingival index (measuring §women with neither symptoms are the reference. gingivitis), and plaque index (measuring oral hygiene), but not calculus Genetics

POSTERS index. Tooth brushing frequency was negatively correlated with all clusters, Supported By: R24TW007988 Epidemiology/ especially Clusters 1 and 2. This population had low levels of periodontal disease. It may be possible for youth with T1DM to maintain good oral health 1550-P through regular oral hygiene practices and visits to the dentist. Association between Infl ammation, Insulin Resistance, and Bio- Spearman Correlation between Microorganisms, Cluster Scores, and Measures logical Variation in Hemoglobin A1c in U.S. Non-Diabetic Adults of Oral Hygiene. SHUQIAN LIU, JAMES M. HEMPE, ROBERT MCCARTER, VIVIAN FONSECA, New Cluster 1 Cluster 2 Cluster 3 Cluster 4 Orleans, LA, Washington, DC (Blue Other) (Orange Green) (Red Orange) (Yellow Other) Studies indicated that protein glycation including hemoglobin A1c (A1c) No. of teeth with bleeding 0.11 0.12 0.39* 0.34* formation may be associated with infl ammation and insulin resistance (HOMA-IR). The hemoglobin glycation index (HGI) measures biological Percent teeth with bleeding 0.09 0.11 0.38* 0.33* variation in A1c due to factors other than blood glucose concentration. This Gingival Index 0.35* 0.35* 0.46* 0.43* analysis used data from the National Health and Nutrition Examination Plaque Index 0.31* 0.32* 0.46* 0.49* Survey (1999-2008) to test the hypothesis that HGI is associated with Calculus Index 0.07 0.09 0.00 -0.07 infl ammation and insulin resistance. A subsample of 897 were randomly selected from 8968 subjects ≥20 y old without diabetes for deriving a Frequency of tooth brushing/week -0.38* -0.30* -0.16 -0.14 linear regression equation (A1c = 0.019× FPG (mg/dl) + 3.5). After excluding Frequency of fl ossing/week -0.28* -0.09 -0.21 -0.13 subsamples and observations with missing data or acute infection, a total Supported By: ADA (7-11-CT-27) of 4,513 NHANES participants were fi nally included. HGI were calculated (HGI=observed A1c - predicted A1c) for 4513 subjects by inserting FPG and A1c into the formula. Polymorphonuclear leukocyte (PMNL) count, monocyte 1549-P count, C-creative protein (CRP), and serum ferritin were used as biomarkers Prevalence of Polycystic Ovarian Syndrome (PCOS) and Its of infl ammation. HOMA-IR was divided into quartiles. Association with Cardiometabolic Risk Factors in Reproductive For the entire population, PMNL (β: 0.034, 95% CI: 0.009, 0.059) and Age Women in Delhi and Chennai, India monocytes (β: 0.056, 95% CI: 0.014, 0.099), but not CRP (β: 0.005, 95% CI SAMARA RIFKIN, KAVITA SINGH, ELI KAMARA, ROOPA SHIVASHANKAR, -0.005, 0.015) or ferritin (β: -0.001, 95% CI: -0.018, 0.015), were independent MOHAN DEEPA, SHIVAM PANDEY, MOHAMMED K. ALI, K.M. VENKAT NARAYAN, predictors of HGI after adjustment for covariates (age, gender, race, DORAIRAJ PRABHAKARAN, VISWANATHAN MOHAN, NIKHIL TANDON, triglycerides, hemoglobin level, mean corpuscular volume, and red cell Nashville, TN, New Delhi, India, New York, NY, Chennai, India, Atlanta, GA distribution width) plus BMI or HOMA-IR. There was an interaction effect Women with PCOS may have higher cardiometabolic risk. Data on the between BMI and HOMA-IR (P=0.039). After stratifi cation by BMI categories prevalence of PCOS and its association with cardiometabolic risk factors (BMI<25, 25-29.9, >=30 kg/m2), HOMA-IR was no longer associated with HGI in India are scarce. We measured the prevalence of PCOS markers in a among obese subjects (P=0.476); whereas, HOMA-IR had signifi cant negative representative sample (n=1927) of reproductive age women (20-50 years) association with HGI among normal (P<0.011) and overweight subgroups (P in Delhi and Chennai, CARRS (Centre for Cardiometabolic Risk Reduction) <0.0001). We conclude that HGI is associated with infl ammation biomarkers; cohort. PCOS was defi ned by oligomenorrhea (based on cycle duration and however, the relationship with insulin resistance is infl uenced or partly frequency in non-lactating premenopausal women) and hirsutism, (self- determined by body adiposity. report using pictures of 9 body parts used to calculate the modifi ed Ferriman- Supported By: 1R01HL110395-01 Gallway score). The associations between PCOS and cardiometabolic risk factors were examined with multivariate logistic regression. The prevalence of oligomenorrhea and hirsutism were 11.6% (CI 10% -13%) and 6.6% (CI 5%-8%), respectively. The prevalence of both oligomenorrhea and hirsutism

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A404 EPIDEMIOLOGY—OTHERCATEGORY

1551-P 1553-P Prevalence of Type 2 Diabetes in Indigenous Population from the Exposure to Bisphenol A and the Risk of Type 2 Diabetes in the East and Southeast Regions of Mexico French Prospective Cohort Study D.E.S.I.R. AIDA JIMENEZ-CORONA, LOURDES FLORES-LUNA, CARLOS PANTOJA- FANNY RANCIÈRE, JÉRÉMIE BOTTON, RÉMY SLAMA, MARIE ALINE CHARLES, MELENDEZ, ENRIQUE O. GRAUE-HERNANDEZ, Mexico City, Mexico OLIVIER LANTIERI, MARLÈNE Z. LACROIX, BEVERLEY BALKAU, DIANNA J. Ethnic differences in the prevalence of type 2 diabetes (T2DM) may relate MAGLIANO, DESIR STUDY GROUP, Villejuif, France, Grenoble, France, La Riche, to differences in susceptibility and lifestyle. We determined the prevalence France, Toulouse, France, Melbourne, Australia of T2DM in indigenous (IND) and non-indigenous (NIND) populations from There are accumulating animal and human data linking exposure to 2 population-based studies carried out in the East (Tlaxcala Study) and endocrine disruptors such as bisphenol A (BPA) and type 2 diabetes (T2D). Southeast (Comitan Study) regions of Mexico. A total of 1439 IND and However, all of the human studies supporting this association are cross- 1923 NIND individuals aged 20-105 years were examined. Subjects were sectional, making causality diffi cult to establish and further, the reports are considered IND by self-report or if they spoke an IND language. T2DM was somewhat confl icting. We investigated the relation between exposure to defi ned as fasting serum glucose >7.8 mmol/l or 2-hour post load serum BPA and the risk of developing T2D in the French prospective cohort study glucose >11.1 mmol/l or previous diagnosis. D.E.S.I.R. (Data from the Epidemiological Study on the Insulin Resistance Age-sex adjusted prevalence of T2DM was 11.1% (95%CI 9.5-12.8) in the Syndrome). Based on a case-cohort design, this study examined data from IND people and 21.1% (95%CI 19.3-23.1) in the NIND people. Prevalence of 754 participants, aged 30-65 years at baseline, including the 201 incident T2DM by age and BMI (age-sex adjusted) is shown in the table. In multiple cases of T2D over the 9-year follow-up. Urinary BPA-glucuronide (uBPA-G), logistic regression, the prevalence of T2DM (OR= 0.63, 95%CI 0.52-0.77) the main metabolite of BPA, was assessed as a proxy of BPA exposure, in was signifi cantly lower in IND compared with NIND people after adjustment samples collected at baseline in 1994-1996, using liquid chromatography for age, sex, BMI and study. In addition, subjects with overweight and coupled to tandem mass spectrometry (LC/MS-MS). The association obesity had 1.51 (95%CI 1.20-1.90) and 1.70 (95%CI (1.31-2.19) times the risk between uBPA-G concentrations corrected for urinary creatinine level and of having T2DM compared with subjects with normal weight. the risk of T2D was analyzed using Cox regression models adjusted for Longitudinal data from our study such as diet and exercise will permit potential confounders (age, sex, education level, body mass index, family us to estimate the incidence of T2DM in these two populations and also to history of diabetes, smoking status, physical inactivity...). The median confi rm the large differences between IND and NIND Mexican populations. concentration of uBPA-G was 5.7 ng/ml (5.2 ng/mg creatinine). Compared to those in the lowest uBPA-G tertile, participants in the upper uBPA-G T2DM prevalence (%) T2DM prevalence (%) tertiles were not at higher risk of developing T2D, adjusted hazard ratios (95%CI) in IND subjects (95%CI) in NIND subjects (95% CI) tertile 2: 1.04 (0.72-1.48); tertile 3: 0.98 (0.68-1.41). Urinary BPA-G Age (years)<40 3.0 (2.6-4.4) 6.0 (4.8-7.6) concentrations did not predict the development of T2D in this cohort after 40-49 7.1 (5.8-8.5) 11.9 (10.3-13.8) adjustment for confounders. This is the fi rst study to assess BPA exposure 50-59 13.9 (12.0-15.9) 22.3 (20.4-24.4) and incident T2D. More research on the relevance of the uBPA-G biomarker is needed. Other longitudinal studies are required to better understand the >=60 25.3 (22.2-28.7) 37.5 (34.6-40.6) relation between BPA exposure and the development of chronic metabolic Normal BMI 6.0 (4.9-7.6) 15.5 (13.0-18.4) diseases such as T2D. Supported By: Francophone Diabetes Society Genetics Overweight 13.3 (11.2-15.8) 21.4 (18.8-24.1) POSTERS Obesity 18.5 (15.4-22.1) 22.5 (19.4-25.9) Epidemiology/ 1554-P Type 2 Diabetes Is Associated with Increased Incidence of 1552-P Hospital Admission and Mortality from Liver Disease in a National Childhood Obesity Is Associated with Increased Odds of Type 2 Retrospective Cohort Study Diabetes in Morbidly Obese Women (but Not Men) SARAH H. WILD, CHRISTOPHER D. BYRNE, LLABORATION SCOTTISH- RANDI STØRDAL LUND, JØRAN HJELMESÆTH, JENS K. HERTEL, Tønsberg, SOUTHAMPTON DIABETES AND LIVER DISEASE CO, Edinburgh, United Kingdom, Norway Southampton, United Kingdom There is some evidence that, as compared with adult-onset obesity, Increasing evidence suggests that liver disease is more common in people childhood debut of obesity is associated with increased risk of type 2 with type 2 diabetes. However, the impact of type 2 diabetes on hospital diabetes (T2D). We aimed to investigate whether childhood-onset (age 0-11 admissions and mortality attributable to all liver diseases is uncertain. The years) and adolescent-onset (age 12-20 years) of obesity were associated aim of this retrospective cohort study was to investigate the relationship with higher odds for T2D in morbidly obese patients ≥ 40 years than adult- between type 2 diabetes and liver disease incidence using routine data in a onset obesity (age >20 years), and to examine whether possible associations retrospective cohort study of a population of 5 million people between 2001 differed by gender. A total of 2239 morbidly obese consecutive patients and 2010. We used the population-based Scottish diabetes register derived from the Morbid Obesity Registry at Vestfold Hospital Trust in Norway were from primary and secondary care electronic records linked to hospital included in the analyses. All patients were examined by physicians and T2D admission and death records. We compared combined incidence rates of was classifi ed according to the ADA criteria. To assess the odds of prevalent liver-related hospital admission and mortality for all liver diseases (liver T2D as a function of obesity onset we applied logistic regression models disease events), identifi ed by International Classifi cation of Disease codes in adjusted for age, gender, family history of diabetes and current adult waist people with type 2 diabetes and people without diabetes between 35 and 84 circumference and BMI, with adult-onset obesity as the reference category. years of age for the period 2001-2010. Incidence rates were age-standardised Mean (SD) age, current BMI and waist circumference was 50.8 (7.9) years, to the European standard population and age-adjusted incidence rate ratios 43.3 (5.9) kg/m2 and 130.0 (13.8) cm, respectively. Sixty-fi ve % were females, (IRR) were estimated using Poisson regression. In total, there were 22922 32 % had T2D and 35 % reported a family history of diabetes. Of the 2239 incident liver disease events among people without diabetes and 3045 patients, 27 %, 18 % and 55 % reported childhood-onset, adolescent-onset among people with type 2 diabetes of which approximately 65% occurred and adult-onset obesity, respectively. Women had a higher prevalence of among men in each group. Incidence of liver disease events among the adolescent-onset obesity compared to men (20 % vs. 14 %). Adjusted OR non-diabetic population was 6.8 and 3.3/10,000 person years for men and (95% CIs) from the regression analyse revealed that neither childhood- (1.19 women respectively. IRR (95% confi dence intervals) for incident liver disease (0.95-1.48)) nor adolescent-onset (1.04 (0.80-1.36)) obesity was associated events associated with type 2 diabetes were 1.93 (1.84-2.03) for men and with increased odds for T2D in adulthood compared to adult-onset obesity. 2.56 (2.39-2.73) for women. Further adjustment for socio-economic status However, we observed signifi cantly higher odds for T2D in adulthood among only modestly attenuated IRRs. These fi ndings suggest that type 2 diabetes women who became obese during childhood (1.36 (1.02-1.81)) compared with makes an important contribution to the burden of hospital admissions and those who became obese during adulthood (p=0.03). This pattern was not mortality attributed to liver disease. observed for men. In conclusion, early onset of obesity is associated with Supported By: Scottish Government; NHS Research Scotland increased odds for T2D in morbidly obese women ≥ 40 years, but not in men.

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A405 EPIDEMIOLOGY—TYPECATEGORY 1 DIABETES

1555-P EPIDEMIOLOGY—TYPE 1 DIABETES Difference in Clinical Characteristics According to Age of Onset in Korean Patients with Newly Diagnosed Type 2 Diabetes MIN-YOUNG CHUNG, JIN-OOK CHUNG, Gwangju, Republic of Korea Guided Audio Tour: Hot Issues in Type 1 Diabetes (Posters: 1557-P to The aim of this study was to assess how metabolic and cardiovascular 1564-P), see page 15. profi les may differ depending on age at onset in Korean patients with newly diagnosed type 2 diabetes. Six hundred and fi fty-eight type 2 diabetic patients & 1557-P with newly diagnosed type 2 diabetes (M: 340, F: 318; mean age: 54.1 ± 13.7 Sugars Intake and Type 1 Diabetes Risk: The Diabetes Autoimmunity years) were recruited. All subjects were assessed for the metabolic profi les, Study in the Young cardiovascular risk factors and microvascular complications. Patients were MOLLY M. LAMB, BRITTNI FREDERIKSEN, JENNIFER SEIFERT, MIRANDA grouped according to age at diagnosis: < 30 years, 30-39 years, 40-49 years, KROEHL, MARIAN REWERS, JILL M. NORRIS, Aurora, CO 50-59 years, 60-69 years, and ≥70 years. There was a strong inverse linear Sugars intake may increase insulin production, thus stressing the beta relation between body mass index (BMI) and age at diagnosis (P <0.001). In cells and increasing islet autoimmunity (IA) and type 1 diabetes (T1D) risk. 2 addition, the prevalence of obesity (BMI ≥ 25 kg/m ) showed the inverse The Diabetes Autoimmunity Study in the Young (DAISY), which prospectively linear association with age at diagnosis (P < 0.05). Glycated hemoglobin follows children at increased genetic risk for T1D, previously reported that (HbA1c), fasting plasma glucose, triglyceride, and estimated glomerular glycemic index was associated with progression to T1D in children with fi ltration rate (eGFR) showed the inverse linear association with age of IA. We now explore which nutrients or foods specifi cally infl uence this onset (all P < 0.001), while the prevalence of hypertension, retinopathy, association in DAISY with longer follow-up. We examined records for 1,885 cardiovascular autonomic neuropathy (CAN) and brachial-ankle pulse DAISY children (mean follow-up: 9.8 years) with dietary data, 143 of whom wave velocity (baPWV) showed the positive linear association with age at developed IA (positive for autoantibodies to insulin, GAD65 or IA-2 twice diagnosis ( P < 0.001, P < 0.05, P < 0.001, and P < 0.001, respectively). In the in succession), and 40 of whom progressed to T1D. Diet was collected multivariate model, age of onset was independently associated with BMI (β annually via food frequency questionnaire. We calculated intake (g/day) = -0.255, P < 0.001), HbA1c (β = -0.198, P < 0.001), triglyceride (β = -0.177, P of fructose, sucrose, lactose and total sugars. We also calculated servings < 0.01), eGFR (β = -0.263, P < 0.001), the prevalence of CAN (β = 0.116, P < per week of sugar-sweetened carbonated or non-carbonated beverages, 0.05), and baPWV (β = 0.363, P < 0.001). Our results showed that younger beverages sweetened with non-nutritive sweetener, and juice. Sugars age of onset is more associated with metabolic disturbance, while older intake variables were analyzed as time-varying covariates for association age of onset is more associated with vascular disturbance in patients with with IA development. For association with progression to T1D in IA positive newly diagnosed type 2 diabetes. Furthermore, this study suggests that age children, we examined sugars intake at IA development. In separate survival of diabetes onset is a continuous risk rather than a threshold risk for diabetic models adjusted for total calories, food frequency questionnaire type (parent metabolic and vascular disturbances. or self-report), HLA-DR genotype (high risk = HLA-DR 3/4 vs. low/moderate risk = all other HLA-DR genotypes), T1D family history, and ethnicity, none 1556-P of the sugars intake variables were associated with IA development. Effect of Comorbid Depression on the Use of Preventive Services in Increased fructose intake (HR: 1.53, CI: 1.04-2.24), and total sugars intake Patients with Diabetes (HR: 2.42, CI: 1.45-4.02) were associated with T1D development in children Genetics

POSTERS SAUMITRA V. REGE, BRIAN J. QUILLIAM, Kingston, RI with IA. Greater sugar-sweetened beverage intake was associated with T1D Epidemiology/ The prevalence of depression is higher in patients with diabetes. Preventive development in children with IA who had the high risk HLA-DR genotype (HR: services are aimed at better management of diabetes. There is a paucity of 1.82, 95% CI: 1.30-2.56) but not in those with low/moderate risk HLA-DR research regarding the receipt of these diabetes related preventive services genotypes. Sugars, especially fructose, may infl uence the fi nal stages of the in patients with depression. T1D development process. This study aims to explore the impact of comorbid depression on the receipt of preventive services in diabetic patients with and without depression. & 1558-P We used data from the Medical Expenditure Panel Survey (2008-2011) Fetal Exposure to Maternal Type 1 Diabetes Is Associated with for our analysis. We identifi ed diabetes and use of preventive services (A1C Reduced Insulin Secretory Function in Adult Offspring tests, diabetic foot exams, eye exams, blood cholesterol check, infl uenza SUK CHON, LILA-SABRINA FETIA, EUGENE SOBNGWI, JEAN-PIERRE RIVELINE, vaccination, routine medical checks) in the previous year by utilizing the JEAN-LOUIS NGUEWA, BAZ R. BAZ, SIMÉON P. CHOUKEM, PHILIPPE BOUDOU, Diabetes Care Survey. Depression was examined by utilizing a combination SAMY HADJADJ, ETIENNE LARGER, ALFRED PENFORNIS, MICHEL MARRE, of self-reports and diagnostic codes. We assessed demographic and clinical JEAN-FRANCOIS GAUTIER, Seoul, Republic of Korea, Paris, France, Yaounde, characteristics of diabetic patients with and without depression. Logistic Cameroon, Poitiers, France, Besançon, France regression was used to study the effect of comorbid depression on use of In utero exposure to maternal hyperglycemia is one of the important diabetes preventive services in the previous year. All the estimates were risk factors for type 2 diabetes (T2D) development in offspring. We weighted according to the U.S. non institutionalized population. previously reported that it is associated with an insulin secretory defect There were 4668 survey respondents who suffered from diabetes. Of these, in a small number of offspring. To avoid the confounding effect of genetic 25.87% suffered from depression. After controlling for various demographic predisposition for T2D, we proposed to evaluate maternal type 1 diabetes and clinical characteristics, we observed signifi cant differences in use of as a model of fetal hyperglycemia. We aimed to investigate whether fetal some preventive service by diabetic patients with and without depression. exposure to maternal T1D is associated with insulin secretory dysfunction in Patients with depression were 19% more likely (AOR 1.19, 95% CI 1.01 - 1.44) adult offspring in a larger cohort. to get A1C test in the previous year. Similarly patients with depression were Oral glucose tolerance test (75 g) was performed in 44 offspring of T1D 26% more likely (AOR 1.26, 95% CI 1.06 - 1.57) to get a diabetic foot exam mothers (cases) and 47 offspring of T1D fathers (controls) recruited from and 24% more likely (AOR 1.24, 95% CI 1.03 - 1.47) to get a blood cholesterol six diabetes centers. Insulin secretion index and insulin sensitivity index check. In contrast, diabetes patients with depression are 20% less likely(AOR were assessed by insulinogenic index (IGI, Δ insulin 0-30 / Δ glucose 0-30) 0.80, 95% CI 0.63 - 0.98) to undergo a routine medical checkup. and Matsuda index respectively. Insulin secretion related to insulin We found that comorbid depression in diabetes is associated with a sensitivity status was estimated by disposition index (IGI*Matsuda Index). signifi cantly higher use of some preventive services. Anthropometric measurements and DEXA scan to assess percent body fat mass were performed. Clinical characteristics were similar in cases and controls: age 25.3 ± 6.2 (SD) vs. 25.0 ± 5.6 years; sex ratio (F/M) 25/19 vs. 25/22: body fat mass 24.9 ± 8.7 vs. 24.0 ± 9.9 % ; birth weight 3322 ± 518 vs. 3348 ± 396 grams. Insulinogenic index was lower in cases: 9.3 (median) (5.2-14.7 Q1-Q3) vs. 12.3 (7.0-17.3) µUI/mmol (p=0.074). This was signifi cant after adjustment for age, sex, body mass index and body fat mass (p=0.025). Insulin sensitivity was similar in cases and controls. Disposition index was signifi cantly lower in cases than controls (p=0.024). In multiple linear regression analysis adjusted for covariates, cases had a signifi cantly reduced disposition index (P=0.024), but insulin sensitivity index did not differ between the two groups.

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A406 EPIDEMIOLOGY—TYPECATEGORY 1 DIABETES

In conclusion, we confi rm that fetal exposure to maternal type 1 diabetes is donors had a history of alcohol abuse noted in their clinical record as associated with reduced insulin secretion with respect to insulin sensitivity compared to only 4 (11%) of the control donors. Isolated islets from both in adult offspring. groups contained similar amounts of the infl ammatory markers IL-6, MCP- 1 and Tissue Factor, whereas IL-8 in average was signifi cantly higher in & 1559-P islets from the autoantibody-positive group. Staining for CD45 revealed Incidence of Diabetes in U.S. Youth by Type, Race/Ethnicity, and infl ammatory cells in all donors to some extent, but no signifi cant difference Age, 2008-2009 between the groups. There was no sign of insulitis in any of the donors. JEAN M. LAWRENCE, GIUSEPPINA IMPERATORE, DAVID J. PETTITT, DANA In conclusion, we found no evidence of increased infl ammation in the DABELEA, BARBARA LINDER, ELIZABETH J. MAYER-DAVIS, SCOTT ISOM, pancreas from subjects carrying at least one diabetes-related autoantibody. CATHERINE PIHOKER, DEBRA A. STANDIFORD, SANTICA M. MARCOVINA, RALPH Ongoing analyses will reveal if subsets of infl ammatory cells in the pancreas B. D’AGOSTINO, JR., SHARON H. SAYDAH, FOR THE SEARCH FOR DIABETES IN may be altered. Notably, it is possible that events not related to T1D, (e.g. YOUTH STUDY GROUP, Pasadena, CA, Atlanta, GA, Santa Barbara, CA, Aurora, CO, excessive alcohol intake as may be suggested from our data) and subclinical Bethesda, MD, Chapel Hill, NC, Winston-Salem, NC, Seattle, WA, Cincinnati, OH pancreatitis may be the cause of autoantibodies in some cases. The SEARCH for Diabetes in Youth Study has reported diabetes (DM) incidence rates for 2002-2005 and trends in incidence of type 1 DM (T1D) & 1561-P for non-Hispanic white (NHW) youth aged < 20 yrs. from 2001-2009. Data Taurine Transporter Gene Expression in Peripheral Mononuclear from SEARCH centers in California, Colorado, Ohio, South Carolina, and Blood Cells of Type 1 Diabetic Patients Washington State were used to calculate incidence per 100,000 person GIUSEPPE SEGHIERI, LORIA BIANCHI, ZALEIDA NAPOLI, ROBERTO ANICHINI, years (PY) and 95% confi dence intervals for 2008-2009 by age, sex, race/ ALESSANDRA DE BELLIS, ILARIA CAMPESI, FLAVIA FRANCONI, Pistoia, Italy, ethnicity, and clinical DM type. We then applied these rates to the age-, Sassari, Italy sex- and race/ethnic-specifi c U.S. census estimates to calculate numbers Taurine (Tau) has a protective role against the oxidative stress of high of U.S. youth newly-diagnosed in 2009. From a denominator of over 10 glucose levels, and additionally plays a pivotal role in the retinal function. Tau million PY, we identifi ed 2,945 youth with DM (T1D n= 2,199; type 2 DM is more concentrated in the intracellular than in the extracellular milieu due [T2D] n=613; other n=133). Ascertainment completeness was 98.8% (98.4- to the action of a specifi c transporter (TauT), which is represented in retinal 99.2%) for T1D and 91.8% (89.0-94.6%) for T2D. Among children aged < 10 epithelial cells where is down-regulated by high glucose concentrations. yrs., 94% developed T1D. Among youth 10-14 yrs., non-Hispanic Blacks (NHB) Since TauT was found increased in blood mononuclear peripheral cells and American Indians (AI) were more likely to develop T2D than T1D; by ages (MPC) of type 2 diabetic patients, especially if exempt from retinopathy, 15-19 yrs., only NHW youth were more likely to be diagnosed with T1D than this study was aimed at evaluating the relationship between TauT, HbA1c T2D. We estimated that in 2009, 18,436 U.S. youth were newly-diagnosed and some markers of oxidative stress or of endothelial function in MPCs of with T1D (12,945 NHW, 3,098 Hispanic, 2,070 NHB, 276 API, and 47 AI) and type 1 diabetic patients with or without retinopathy. TauT gene expression 5,089 with T2D (1097 NHW, 1635 Hispanic, 1981 NHB, 222 API, and 154 AI). measured by real-time PCR analysis in MPCs and represented as arbitrary Incidence of DM varies by age and race/ethnicity. NHW youth are more likely units was on average signifi cantly higher in 30 type 1 diabetic patients than to have T1D across all age groups, whereas the incidence of T2D is higher in 30 age-and-sex matched controls (4.29±0.77(SD) vs. 3.89±0.66;p=0.03) than that of T1D for older minority youth. and was signifi cantly related to HbA1c (r=0.41;p=0.02) and inversely with Genetics

Incidence (95% Confi dence Interval) /100,000 Youth <20 Yrs. by DM Type, diabetes duration (r=-0.42; p=0.02). TauT was signifi cantly related to POSTERS Race/Ethnicity, and Age. symmetric-dimethyl-arginine (r=0.41; p=0.02), and inversely to plasma Epidemiology/ homocysteine (r=-0.38; p=0.04) while no relation was present with plasma T1D, 0-4 yrs T1D, 5-9 yrs T1D, 10-14 T1D, 15-19 T2D, 5-9 yrs T2D, 10-14 T2D, 15-19 yrs yrs yrs yrs malondialdehyde (r=0.07; p=NS). Ratio TauT/Tau was signifi cantly lower in patients with retinopathy (n=12; 0.084±0.029), compared to those who N Total Cases 355 720 797 327 42 276 294 were unaffected (n=18; 0.106±0.054; p=0.01) while there was no difference Total 14.6 29.6 32.0 12.4 1.7 11.1 11.1 in mean plasma or cell Tau levels between controls and diabetics, with or (13.1, 16.2) (27.5, 31.8) (29.9, 34.3) (11.1, 13.8) (1.3, 2.3) (9.8, 12.5) (9.9, 12.4) without retinopathy. In conclusion TauT gene expression is higher in MPCs of NHW 19.1 38.3 39.2 14.6 0.6 3.7 4.6 type 1 diabetic patients, is inversely related to diabetes duration and directly (16.9, 21.6) (35.1, 41.7) (36.1, 42.6) (12.8, 16.7) (0.3, 1.2) (2.9, 4.9) (3.7, 5.8) to worse metabolic control and to some markers of endothelial dysfunction. Hispanic 10.3 19.9 26.7 10.1 1.5 14.2 20.5 Finally, TauT/Tau is signifi cantly lower in patients with retinopathy, (7.9, 13.4) (16.4, 24.2) (22.5, 31.6) (7.7, 13.4) (0.7, 3.0) (11.3, 17.9) (16.8, 24.9) hypothesizing a possible selective protective role of TauT against the NHB 9.1 21.6 23.7 11.2 6.1 34.4 20.5 development of this duration related microvascular complication. (6.4, 12.8) (17.2, 27.1) (19.1, 29.3) (8.4, 15.0) (4.0, 9.3) (28.8, 41.1) (16.5, 25.5) Supported By: Fondazione Cassa di Risparmio di Pistoia e Pescia Asian/Pacifi c 7.0 8.3 6.5 4.8 1.5 9.5 9.3 Islander (API) (3.8, 13.1) (4.7, 14.7) (3.4, 12.3) (2.4, 9.9) (0.4, 5.4) (5.5, 16.1) (5.5, 15.7) & 1562-P American Indian 1.8 7.0 12.5 1.0 4.9 26.0 36.5 Type 1 Diabetics Have Lower Volumetric Bone Mineral Density (0.3, 9.7) (2.8, 17.4) (6.3, 24.9) (0.1, 7.1) (1.7, 14.4) (16.1, 42.1) (25.0, 53.2) and Strength in Femoral Bone Subfraction Determined by Three- dimensional Quantitative Computed Tomography Supported By: CDC; NIDDK TOMOYASU FUKUI, TSUTOMU HIRANO, TAKASHI NAGAI, KATSUNORI INAGAKI, Tokyo, Japan & 1560-P Several previous studies have reported osteoporosis measured by Characterization of Human Organ Donors Carrying Diabetes-related dual-energy X-ray absorptiometry (DXA) in younger patients with type 1 Serum-Autoantibodies diabetes (T1D). DXA, however, is unsuitable for precise measurements of ANNA WIBERG, SOFIE INGVAST, OLLE KORSGREN, OSKAR SKOG, Uppsala, Sweden bone geometry and strength because of the limitations of two-dimensional Among patients newly diagnosed with type 1 diabetes (T1D), auto- (D) imaging. Our group used 3D quantitative computed tomography (QCT) antibodies targeting beta cell antigens are detected frequently. These to obtain more precise information about bone fragility in T1D. Seventeen antibodies are used as diagnostic and predictive markers of T1D, but it is not male T1D patients aged from 19 to 48 years and eighteen age-matched known whether they have any pathogenic effect. nondiabetic males (C) were studied. Patients with diabetic nephropathy In recent efforts to understand the pathology of the pancreas prior to T1D (proteinuria and eGFR<60) were excluded. In QCT examination, T1D onset, biobanks of pancreatic and other tissues have been established. In patients had a signifi cantly lower cortical volumetric bone mineral density this study we describe the characteristics of the autoantibody positive organ (vBMD) in the femoral neck, signifi cantly lower total vBMD and cortical donors collected within the Nordic Network for Islet Transplantation. cross-sectional area (CCSA, an estimator of compression strength) in the Starting in 2007, 948 donors have been screened in Uppsala for antibodies inter-trochanter , and signifi cantly lower CCSA in the femoral shaft .Bone against IA2 and GAD65. Of these, 35 (3.7%) were positive for GAD65 and 2 strength estimated by the bucking ratio (an index of cortical instability) of (0.2%) also for IA2. Mean age was 53±16 years. Pancreas morphology and the inter-trochanter was signifi cantly higher in T1D. Serum bone formation clinical data were compared to 35 age- and sex-matched controls without and the following markers of bone quality were comparable between T1D diabetes-related autoantibodies. and C: bone-specifi c alkaline phosphatase, N-terminal propeptide of type There was no signifi cant difference in pancreas weight, BMI or HbA1c Iprocollagen, osteocalcin, pentosidine, and homocysteine. However, IGF-1 between the groups. Interestingly, 11 (31%) of the autoantibody positive values were signifi cantly lower in T1D than in C (130±35 vs. 158±34 mg/dl).

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A407 EPIDEMIOLOGY—TYPECATEGORY 1 DIABETES

Serum IGF-1 values were positively correlated with the total vBMD of the BMI), log PAT was signifi cantly associated with decreased GIR in males (β= neck and the serum bone formation markers (r=0.49~0.71, respectively) in -4.12 ±SE 1.90, p=0.033), but not in females (β= 1.15 ±SE 1.79, p=0.521; p for T1D. Early onset of diabetes (<20 years) and long disease duration (ə15years) interaction = 0.027). The relationship between log PAT and GIR did not differ were not associated with any of the QCT measurements. This study is the by diabetes status (p=0.791). fi rst investigation by sensitive QCT measurement to demonstrate that young Gender differences in deposition and metabolic regulation of PAT could and middle-aged T1D patients have lower vBMD together with cortical play an important role in IR. instability of the inter-trochanter. Low IGF-1 might be a causative factor for Supported By: ADA (7-13-CE-02) osteoporosis in T1D. 1565-P & 1563-P Ketoacidosis at Diagnosis of Type 1 Diabetes: An Italian Survey, Trends in Life Expectancy for Those with Type 1 Diabetes in Sweden 2005-2012 DENNIS J. PETRIE, PHILIP M. CLARKE, THOMAS LUNG, ANDREW J. PALMER, VALENTINO CHERUBINI, EDLIRA SKRAMI, SARA STERNARDI, ANTONIO IANNILLI, ANN-MARIE SVENSSON, BJÖRN ELIASSON, Melbourne, Australia, Tasmania, FLAVIA CARLE, ROSARIA GESUITA, STUDY GROUP FOR DKA IN ITALY, Ancona, Australia, Gothenburg, Sweden Italy Those with type 1 diabetes mellitus (T1DM) have reduced life expectancy To analyze the distribution of diabetic ketoacidosis (DKA) in children at compared to the general population but attempts to quantify the size of the diagnosis of type 1 diabetes in Italy. gap and examine changes over time are rare. To quantify improvements in Incidence data were collected from 19 Italian pediatric diabetes centers medical care we sought to determine life expectancy (LE) in people with (9 population-based registers and 10 clinic-based databases). Date of T1DM in Sweden and examine how this has changed from 2002-2011 relative birth, date of diabetes, gender, venous pH and HCO3 were obtained from to the general population. all incident cases between 1/1/2005 and 12/31/2012. DKA was defi ned This study is based on a large dataset comprising of health records from according to ISPAD criteria: absent (pH≥7.30 and/or HCO3>15 mmol/L), mild the Swedish National Diabetes Register (NDR) linked with death records. (7.1≤pH<7.30) and severe (pH<7.1). A polynomial multiple logistic regression Abridged period life tables for those with T1DM in Sweden aged 20 years analysis was performed to evaluate the effect of time trend (grouped in two- and older were derived for rolling 3-year time intervals from 2002-2004 till year periods), and the role of age class (0-4; 5-9; 10-14; ≥15 years), residence 2008-2011 using Chiang’s method with 5 year age intervals (plus an open- (Sardinia vs. other Italian regions), and gender, on the risk of DKA. ended interval for 80 years and older). Bootstrap techniques were used to Overall 2355 subjects with type 1 diabetes mellitus were recruited; 50.5% derive 95% Confi dence Intervals (CI) for the life expectancy at each age. from registries with 28% of missing data on pH and/or HCO3. Among 2026 There were 27,062 persons aged 20 years and older identifi ed in the NDR evaluable, the overall percentage of severe and mild DKA resulted of 12% as living with T1DM in Sweden and at risk of death at some point between (95%CI: 11 - 14%) and 30% (95%CI: 28 - 32%), respectively. Mild DKA risk 2002-11 inclusive, contributing 188,609 person years of follow-up and 1,964 signifi cantly decreased over time; children aged 0-4 years were found at deaths. In those with T1DM, the remaining LE at aged 20 in 2002-04 was 47.2 higher risk of both severe and mild DKA than the other age classes; children (95%CI: 46.0-48.3) and 52.1 years (95% CI: 51.0-53.5) for men and women living in Sardinia were at signifi cantly lower risk of mild DKA; males resulted respectively which had increased to 50.2 years (95% CI: 49.8-50.8) and at signifi cant lower risk of severe DKA (Table 1). These results highlight 53.2 years (95% CI: 51.6-53.6) respectively for males and females for 2009- the need of continuing surveillance and of developing new strategies for Genetics

POSTERS 11. Overall the life expectancy gap at age 20 between those with T1DM preventing DKA. Epidemiology/ versus the general population changed from 11.3 and 11.9 years in men and Effect Estimate of Time Trend, Age, Residence, and Gender on the Risk of women respectively in 2002-04 down to 9.8 and 10.8 for men and women DKA at Diabetes Diagnosis. respectively in 2009-11. DKA Severe vs. Absent DKA Mild vs. Absent From 2002-11 the life expectancy of those with T1DM in Sweden has increased substantially with the greatest gains seen for males. These Variables OR 95% C.I. p OR 95% C.I. p improvements have closed the life expectancy gap with the general population Diagnosis period 0.97 (0.85-1.11) 0.69 0.89 (0.81-0.98) 0.02 in absolute terms and are likely due to improvements in care for type 1 diabetes (from 2005 to 2012) and its related conditions plus increases in access to improved care. Age class 5 - 9 vs 0.36 (0.25-0.52) <0.01 0.57 (0.43-0.75) <0.01 Supported By: NHMRC (1028335) 0 - 4 years Age class 10 - 14 vs 0.49 (0.34-0.69) <0.01 0.69 (0.53-0.91) 0.01 & 1564-P 0 - 4 years Association of Pericardial Adipose Tissue with Insulin Resistance Age class >15 vs 0.41 (0.23-0.74) <0.01 0.49 (0.31-0.76) <0.01 Is Modifi ed by Gender: The Coronary Artery Calcifi cation in Type 1 0 - 4 years Diabetes Study (CACTI) Residence 0.53 (0.28-1.00) 0.05 0.56 (0.36-0.87) 0.01 AMY C. ALMAN, STEVEN R. SMITH, ROBERT H. ECKEL, JOHN E. HOKANSON, BRANT (Sardinia vs. other) R. BURKHARDT, JANET K. SNELL-BERGEON, Tampa, FL, Winter Park, FL, Aurora, CO Gender 0.68 (0.52-0.90) 0.01 0.88 (0.72-1.07) 0.19 Insulin resistance (IR) is associated with accelerated atherosclerosis and (Males vs. Females) is increased in those with type 1 diabetes (T1D) compared to those without (non-DM). While obesity is a known risk factor for IR, the association between pericardial adipose tissue (PAT) and IR in those with T1D is unclear. 1566-P PAT surrounds the coronary arteries and has been shown to be associated Positive GAD Antibody Seroconversion Accompanied by Deteriora- with coronary heart disease due to its increased metabolic activity and tion of Insulin-Secretory Ability after Insulin Therapy Initiation: A paracrine effects. Possible Correlation with Immunity to Insulin Data for this report came from a substudy of the CACTI cohort in which CHIHO SUGISAWA, SHOTARO SATO, FUMIKO OTSUKA, MATSUO TANIYAMA, hyperinsulinemic-euglycemic clamps were performed on 87 subjects (40 Kanagawa, Japan with T1D, 47 non-DM; mean age 45 ±8, 45% male) randomly selected from We investigated the clinical features of three patients with type 2 participants at the 6-year follow-up exam. PAT volume was measured from diabetes who showed positive seroconversion for GAD antibodies (GADA). EBCT scans taken at the 6-year exam. Four subjects were excluded from In addition, we conducted a literature review for similar cases and compared PAT volume measurement due to inconsistencies in the available scans. the clinical characteristics. PAT volume was not normally distributed and was log transformed. Linear Case 1 is a 64-year-old (y/o) woman diagnosed with diabetes at age 44, regression was used to examine the association between log PAT and when GADA were negative. She was started on insulin at age 49. Her insulin- glucose infusion rate (GIR) during the last 30 minutes of the fi nal clamp secretory ability was maintained but declined twelve years later, when she stage (insulin infusion of 40 mU/m2/min), a measure of insulin sensitivity. became positive for GADA (1.6 U/ml). Case 2 is a 75 y/o woman with a 38-year Interaction terms for sex and diabetes status with PAT were also examined. history of diabetes. She was started on insulin at age 60 when GADA were The median PAT volume was higher in males compared to females (49.9 negative. Fourteen years later, her insulin-secretory ability disappeared and vs. 26.2 cm3, p<0.001), although it did not differ by diabetes status (T1D: she became positive for GADA (4.3 U/ml). Case 3 is an 81 y/o man with a 39- 36.2 vs. non-DM: 31.0 cm3, p=0.36). The GIR was lower in T1D compared to year history of diabetes. He was started on insulin at age 73. His glycemic non-DM (5.8 ±3.6 vs. 13.4 ±5.8 mg/kg FFM/min, p<0.001). After adjustment control deteriorated and he became positive for GADA (29.8 U/ml), with a for covariates (age, diabetes status, hypertension, HDL cholesterol, and reduction in his insulin-secretory ability. All three patients had high titers of

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A408 EPIDEMIOLOGY—TYPECATEGORY 1 DIABETES insulin antibodies (IA) when GADA became positive. The characteristics of sample included 89 women 18-45 years of age, with diabetes durations IA were similar to those of IAA. ranging from 13-18 years. In the subgroup with C-peptide measured at Among 25 type 2 diabetes cases showing GADA seroconversion, diagnosis (n=49), TNF-α level at 13-18 years duration was independently we found 16 (6 males and 10 females) that were followed up for β-cell associated with both a lower residual C-peptide and worse 10-year mean function. All were elderly, had a long history of diabetes and relatively long total glycosylated hemoglobin (GHb). In addition, in the entire group, TNF-α history of insulin therapy. All showed positive GADA seroconversion after levels were higher with longer duration of disease, and disease duration insulin therapy initiation. Insulin-secretory ability was maintained in most modifi ed the association of TNF-α with both 10-year mean GHb (positive patients at insulin therapy initiation and deteriorated after positive GADA association in women with longer durations; no association in women with seroconversion. All the nine patients who underwent IA assays showed shorter durations) and daily caffeine intake (positive association in women high IA titers. GADA titers were low in most cases. A clinical syndrome with shorter durations; no association in women with longer durations). has emerged in which positive GADA seroconversion occurs after insulin There was an inverse association with renal function. TNF-α level was not therapy initiation in patients with type 2 diabetes. Our fi ndings suggest associated with insulin dose, blood glucose self-monitoring, BMI, or physical that immunity to insulin may trigger autoimmunity to islet antigens with activity. This study provides a unique analysis of TNF-α in long-standing type accompanying β-cell dysfunction. 1 diabetes. Less residual C-peptide at diagnosis appears to be associated with a more pro-infl ammatory profi le years later, independent of glycemic 1567-P control. As higher TNF-α levels were associated with worse renal function, A Novel Method to Measure GFR in People with Type 1 Diabetes efforts to decrease the infl ammatory milieu may be benefi cial. DAVID M. MAAHS, LANE BUSHMAN, BECKY KERR, SAMUEL L. ELLIS, KIM Supported By: ADA (1-05-CR-35); NIH (K12HD055892, R01DK036904, UL1RR MCFANN, ALEXIS BOUFFARD, FRANZISKA K. BISHOP, NHUNG NGUYEN, PETER 029879) ANDERSON, Aurora, CO A major barrier in diabetic kidney disease research is a convenient and 1569-P accurate means to quantify glomerular fi ltration rate (GFR), especially for Estradiol in Premenopausal Women With and Without Type 1 Dia- GFR >60 ml/min/1.73m2 when current estimating equations are inaccurate. betes (T1D) Our objective was to compare GFR measured by iohexol clearance using LINA SALEH HASSAN, KIRSTIE K. DANIELSON, Chicago, IL dried blood spots (DBS) versus plasma (gold standard). We hypothesized that Prior research has found varying estradiol levels in women with T1D GFR-DBS would be comparable to plasma and superior to GFR estimating compared to controls. We therefore analyzed total and bioavailable equations. estradiol (luteal phase) in premenopausal women with T1D (n=89; age=18- GFR was measured by iohexol clearance over 4 hours in plasma and DBS 50 years; duration=13-18 years) and age/race matched controls (n=76) using and as estimated by the CKD-EPI equations in 31 studies in T1D adults multivariable regression (accounting for matching), testing for confounders (age 30±12 yrs, 50% male, T1D duration 20±10 yrs, BP=116/70 mmHg, ACR (e.g., BMI, reproductive history) and effect modifi cation by T1D status. 38±57 mg/g). Bland-Altman plots were generated to analyze agreement and Mean total and bioavailable estradiol levels did not differ by T1D status. directionality of bias between measurements. However, only in women with T1D, total estradiol was positively associated The gold standard GFR measured by plasma iohexol was 84.1±12.5 ml/ with number of potential ovulatory years (years since menarche minus years min/1.73m2, which compared well with DBS (84.1±15.1 ml/min/1.73m2 on hormonal contraceptives/pregnant/breastfeeding; see Figure). Further, Genetics

(p=1.0), bias of 0.06±6.9, 95% CI: -13.4-13.5, Figure). In contrast, GFR cystatin upon stratifying all women into either < or > the median of 9 years ovulating, POSTERS C (91.5±16.7 ml/min/1.73m2, p=0.009, bias: -7.3±14.7 [95% CI: -36.2-21.5]); compared to controls, women with T1D had signifi cantly lower estradiol in Epidemiology/ GFR serum creatinine (119.7±16.5 ml/min/1.73m2, p<0.0001, bias: -35.5±11.8 <9 years group (β=-43.2 pg/ml, p=0.04), and signifi cantly higher estradiol [95% CI: -58.8-12.3]); and GFR both (100.3±16.8 ml/min/1.73m2, p<0.0001, in >9 years group (β=53.9 pg/ml, p=0.04). Age or years since menarche bias: -16.2±12.7 [95% CI: -41.1-8.8]) were less comparable and more biased. could not replace years ovulating in the model. In summary, estradiol was GFR by iohexol in DBS may improve upon convenience (by self collection) lower in women with T1D with fewer ovulatory cycles, and higher in those and accuracy compared with current approaches to detect early change in with more cycles. This may explain the confl icting results on estradiol in GFR in people with T1D. T1D. Given the complex effects of insulin on ovarian function, research is needed to elucidate the potentially different mechanisms affecting estradiol production in T1D versus nondiabetic women.

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1568-P Lower Residual C-Peptide at Type 1 Diabetes Diagnosis and Poor 10- Year Glycemic Control Independently Predict Higher Pro-infl amma- tory Tumor Necrosis Factor-alpha at 13-18 Years Diabetes Duration KIRSTIE K. DANIELSON, REBECCA S. MONSON, TAMARA J. LECAIRE, Chicago, IL, Madison, WI While cytokines play a role in the etiology of type 1 diabetes, cytokines in the chronic phase of type 1 diabetes are less understood. This study evaluated the association of tumor necrosis factor-α (TNF-α) at prolonged Supported By: ADA (1-05-CR-35); NIH (K12HD055892) disease duration with C-peptide at diagnosis, long-term glycemic control, disease duration, and current diabetes management, renal function, and modifi able health behaviors such as body mass index (BMI), diet, and physical activity, using multivariable regression. Data were collected and TNF-α measured during an ancillary study to the longitudinal Wisconsin Diabetes Registry Study, a population-based cohort of incident type 1 diabetes. The

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A409 EPIDEMIOLOGY—TYPECATEGORY 1 DIABETES

1570-P Validating Insulin Sensitivity Prediction Equations in Type 1 Diabetes LINDSEY M. DUCA, BRYAN C. BERGMAN, GREGORY L. KINNEY, DAVID M. MAAHS, KRISTEN J. NADEAU, MARIAN J. REWERS, IRENE E. SCHAUER, RACHEL M. SIPPL, JANET K. SNELL-BERGEON, Aurora, CO, Denver, CO People with type 1 diabetes (T1D) have reduced insulin sensitivity (IS), which correlates with coronary artery calcifi cation. The gold standard measurement of IS, a hyperinsulinemic-euglycemic clamp, is costly and time- consuming. IS prediction equations from the SEARCH Study (eIS-SEARCH), the Pittsburgh Epidemiology of Diabetes Complications Study (eIS-EDC), and the Coronary Artery Calcifi cation in Type 1 diabetes study (eIS-CACTI) were applied to independent populations for validation. Study participants were 25 premenopausal women (T1D n=12, non-diabetic [Non-DM] n=13) with a mean ± SD age of 33 ± 8 years and 56 (T1D=17, Non- DM = 39) adolescent boys and girls with a mean ± SD age of 15 ± 2 years who completed a three stage (4, 8, and 40 mU/m2/min in adults and 8, 16 and 80 mU/m2/min in adolescents) hyperinsulinemic-euglycemic clamp. The mean glucose infusion rate (GIR [mg/kg/FFM/min]) during the fi nal stage was used as a measure of skeletal muscle IS, and was compared to estimated IS based on each of the above three studies using Spearman correlation coeffi cients. Supported By: ADA (7-11-CT-27) As shown in the table, eIS-CACTI signifi cantly correlated with GIR in both T1D and non-DM adults as well as non-DM adolescents. The eIS-SEARCH signifi cantly correlated with GIR in the non-DM adolescents. 1572-P These data suggest that prediction equations developed in the CACTI Associations of Nuclear Magnetic Resonance-determined Lipo- study can broadly applied to patients with and without type 1 diabetes using protein Subclasses with Carotid Intima-Media Thickness in Type 1 common clinical measures. Diabetes: A Prospective Study ARPITA BASU, ALICIA J. JENKINS, YING ZHANG, JULIE A. STONER, RICK L. KLEIN, MARIA F. LOPES-VIRELLA, W. TIMOTHY GARVEY, TIMOTHY J. LYONS, DCCT/EDIC RESEARCH GROUP, Stillwater, OK, Oklahoma City, OK, Charleston, SC, Birming ham, AL, Belfast, Ireland We investigated the prospective associations of nuclear magnetic resonance- determined lipoprotein subclass profi les (NMR-LSP) and conventional lipid levels with carotid intima-media thickness (IMT) in type 1 diabetes. NMR- LSP and conventional lipid profi les were measured in an available subset (no

Genetics signifi cant differences in clinical characteristics vs. non-participating subjects) POSTERS

Epidemiology/ of Diabetes Control and Complications Trial (DCCT) participants (n=455; men=246; women=209) at study entry (‘baseline’, 1983-89), and were related to carotid IMT determined by ultrasonography during the observational follow- up of DCCT, the Epidemiology of Diabetes Interventions and Complications (EDIC) study, in EDIC ‘year 12’ (2004-2006). Associations between NMR- LSP, conventional lipids levels and IMT were examined by multiple linear regression following adjustment for HbA1c, diabetes duration, body mass index, albumin excretion rate, DCCT randomization group, and smoking status, stratifi ed by gender. In men, we observed signifi cant positive associations of DCCT baseline NMR-based LDL subclasses (total IDL/LDL and large LDL) and Supported By: ADA (1-10-JF-50, 7-11-CD-08) conventional LDL-C, with common and/or internal carotid IMT, which persisted in adjusted analyses (p<0.05). Signifi cant inverse associations of mean HDL diameter and large HDL concentrations, and positive associations of small 1571-P LDL, and conventional total cholesterol and triglyceride levels, with common Oral Microbial Profi le and BMI in Youth with Type 1 Diabetes and/or internal carotid IMT (p<0.05) were also found, but these did not persist GEORGES J. NAHHAS, R. PAUL WADWA, ELAINE MORRATO, JIAJIA ZHANG, in adjusted analyses. No signifi cant associations were observed in women. LONNIE JOHNSON, FRANZISKA K. BISHOP, RICARDO TELES, LINDA J. HAZLETT, Our data suggest that NMR-LSP can reveal some associations of lipoprotein DAVID M. MAAHS, ANWAR T. MERCHANT, Columbia, SC, Aurora, CO, Cambridge, MA characteristics with future disease with regard to common and internal carotid We explored the relationship between oral microbial profi le and BMI in IMT in men. Thus, NMR-LSP may add value in identifying men with type 1 youth with type 1 diabetes (T1D). diabetes at high risk for vascular complications. Dental plaque data from 105 youth (< 20 years old) with T1D were collected Supported By: NIH at the Barbara Davis Center in Colorado, 2009-2011. Samples were assessed by DNA-DNA hybridization for counts of 41 microbes. Four clusters were obtained by cluster analysis and summary scores were calculated by adding- 1573-P up z-scores of all microbes within each cluster. BMI z-scores were defi ned as Predictors for Vascular Disease Hospitalisations in Young Adults normal (<85%) or overweight (≥85%). with Childhood Onset T1DM: Insights from 20 Years of Follow-up On average, participants were 15 years old and had T1D for 8 years; 73% MATTHEW N. COOPER, MARTIN I. DE BOCK, TIMOTHY W. JONES, ELIZABETH A. were white, 51% females and 37% overweight. There were no differences DAVIS, West Perth, Australia, Perth, Australia in levels of HbA1c (mean, 9%), fasting blood glucose (mean, 195 mg/ There is evidence to suggest that improvements in the management of dL), or daily teeth brushing (54%) and fl ossing (46%) between normal and T1DM over the last 2 decades have been associated with a change in the overweight participants. Cluster 2 contained Actinomyces and the majority epidemiology of microvascular and macrovascular complications. of Socransky’s orange complex organisms (Fusobacteria). Cluster 3 harbored The Western Australian paediatric diabetes database was established in those of the red complex (P. gingivalis, T. forsythia and T. denticola) and 1987 and serves a population of 2.4 mil. (<99% ascertainment for T1DM <16 some Streptococci. Red and orange complexes indicate periodontal disease. years). Patient data from 3 monthly clinical visits are stored prospectively. Cluster scores were not signifi cantly different; however, overweight All patients with T1DM >18 years of age by Dec 2011 were included in the participants had qualitatively lower scores for clusters 2 and 3 than normal study. Their paediatric clinical records were linked to all public and private participants. inpatient hospitalisations in Western Australia for vascular disease between No difference was found in the oral microbial composition of normal and Jan 1992 and Jan 2012. overweight youth with T1D. This may be due to the fact that this sample is Of the 1298 eligible patients (50.4% males), 915 were identifi ed in the young, has relatively short T1D duration and good oral hygiene practices. inpatient database. Those not identifi ed had a lower attained age (23.6 vs. 27.5 years, P<0.001), lower paediatric mean HbA1c (8.5% vs. 9.2%, P<0.001)

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A410 EPIDEMIOLOGY—TYPECATEGORY 1 DIABETES and were 30% less likely to be male (P<0.001). For the 915, there were 7,657 group of relatives with no anti-islet antibodies and the controls. A positive patient years (PY) of paediatric data available for analysis against 8,652 correlation between IAA and TPO-Abs levels was noted in the whole group years of follow-up data (after age 18 years); mean duration at end the end of of relatives, as well as in a subgroup with anti-islet antibodies (r=0.549, follow-up was 17.5 years. The overall incidence rates were 3.40/1000 PY for p<0.05 and r=0.567, p<0.05, respectively). retinopathy (n=26), 0.65/1000 PY for dialysis (n=5), 0.52/1000 PY for stroke Conclusions: Our results demonstrated for the fi rst time signifi cantly (n=4), 0.39/1000 PY for myocardial infarction (n=3) and 1.04/1000 PY for higher prevalence of anti-thyroid antibodies and anti-gastric parietal cell atherosclerosis (n=8). antibodies in the fi rst degree relatives of T1D patients, in particular in these Those with vascular disease were 3.4 times more likely to be female (P=0.001), with positive anti-islet antibodies. The fi nding suggest that these subjects more likely to be from a lower socioeconomic background, older (birth year 1980 may be at higher risk of developing not only type 1 diabetes, but also vs. 1984, P<0.001), and have a higher mean paediatric HbA1c (11.0% vs. 9.1%, other autoimmune disorders and should be routinely screen especially for P<0.001). Mean age at diagnosis was similar (9.7 vs. 9.2 years). autoimmune thyroid disease and auto-immune gastritis. These data indicate reduced rates of vascular complications compared to previous reports, confi rm the association between poor glycaemic control 1576-P and the development of vascular complications, and identify females and Age at Menopause in Women with Type 1 Diabetes and Relationship those from a low socio-economic background to be at a higher future risk of with Complications vascular complications. TINA COSTACOU, DEBRA RUBINSTEIN, TREVOR J. ORCHARD, Pittsburgh, PA Data on the age at menopause (MNP) in women with type 1 diabetes 1574-P (T1D) are scarce. Two studies thus far have addressed this issue; the earlier, Differential Effect of Body Mass Index on Glycemic Control in Type conducted among U.S. women diagnosed with T1D at Children’s Hospital 1 Diabetes of Pittsburgh reported a younger MNP age in T1D compared to their sisters YONG-HO LEE, SANG-MAN JIN, MI HYANG KOWN, HYE JIN YOON, EUN SEOK and controls; the more recent study in a large, population based sample KANG, BONG SOO CHA, HYUN CHUL LEE, BYUNG-WAN LEE, JAE HYEON KIM, of Finnish women, suggested no difference in age at MNP by T1D status. Seoul, Republic of Korea We assessed the age at MNP in female participants of the Epidemiology Even in subjects with type 1 diabetes (T1D), optimal amount of muscle of Diabetes Complications study of childhood onset T1D (mean baseline and fat are necessary to maintain glucose uptakes by exogenous insulin age, 28 and diabetes duration, 19 years) and evaluated whether HbA1c and injection. Despite well-established close link between BMI and glycemic diabetes complications at study baseline predicted an earlier MNP up to 22 control in T2D, the association of BMI with glycemic control in T1D remains yrs later. Starting in 2008, female participants were asked to complete a unclear. The aim of study is to investigate the relationship between BMI and reproductive history questionnaire (n=172). Women <45 yrs of age reporting average HbA1c levels during 12 months in subjects with T1D. regular menstrual cycles were classifi ed as pre-MNP, whereas those >55 In this multi-center observational study, we analyzed 624 subjects aged yrs with no menstrual periods as post-MNP. Plasma FSH and estradiol were ≥18 years with T1D from 5 tertiary university hospitals. Mean HbA1c levels assessed in women falling outside this classifi cation and the WISE hormonal examined during 12 months from enrollment and other clinical and laboratory and historical algorithms were used to categorize them as pre- or post-MNP. parameters including c-peptide levels were evaluated. The median age was 50 and T1D duration 41 yrs. Age at menarche was Average age of the study population and duration of diabetes were similar to that observed in the general population (13 yrs). Excluding pre- Genetics

40.2±13.7 and 10.8±8.3 years, respectively. A U-shaped correlation between MNP women <45 yrs (n=33) and surgical MNP (n=25, median age MNP 38 POSTERS Epidemiology/ BMI and mean HbA1c levels was documented by the spline curve. Based on yrs), 56% had reached natural MNP (22%, 51%, 90% and 100% of women this fi nding, subjects were divided into three groups according to the BMI <50, 50-<55, 55-<60 and >60 yrs, respectively; median MNP age 49 yrs). (Group I, <21; Group II, 21-23; Group III, ≥23kg/m2). In the Group I (BMI<21kg/ Dichotomizing MNP age as < or >49 yrs, baseline log albumin excretion rate 2 m ), BMI was negatively correlated with mean HbA1c (r=-0.172, P=0.011), (OR=1.47, p=0.048) predicted earlier MNP age in a model adjusting for age. while positive relationship was observed (r=0.162, P=0.012) in Group III In conclusion, the median age at MNP currently appears a little younger 2 (BMI≥23kg/m ). Mean HbA1c levels were lower and proportion of individuals than the general population (49 vs. 51 yrs) and is weakly predicted by renal with well-controlled glycemia (HbA1c<7%) were increased in the higher complications at study baseline. tertile group among subjects with Group I as well as in lower tertile group Supported By: DK034818-21 among subjects with Group III. After adjustment with additional covariates in the multiple regression model, these associations between BMI and HbA1c 1577-P levels according to the different BMI ranges remained signifi cant. Salivary Infl ammatory Biomarkers Are Associated with Glycemic In subjects with T1D, inverse relationship of BMI with HbA1c levels was Control and Gum Health in Type 1 Diabetes observed in the low BMI group, while positive correlation was shown in the MELANIE N. KUEHL, BRANT R. BURKHARDT, HENRY RODRIGUEZ, AMY C. high BMI group. ALMAN, Tampa, FL Self-monitoring of blood glucose results in better clinical outcomes for 1575-P T1D. Therefore, there is strong rationale to identify non-invasive biomarkers Increased Prevalence of Anti-thyroid and Anti-gastric Parietal predictive of glycemic control. We investigated the association of salivary Cell Antibodies in First-Degree Relatives of Patients with Type 1 infl ammation with glycemic control and oral health. We collected whole Diabetes unstimulated saliva from T1D subjects (n=144) enrolled at the USF Diabetes KATARZYNA SIEWKO, ANNA POPLAWSKA-KITA, BEATA TELEJKO, RAFAL Center. At collection, BMI (mean 27.4 ± 6.3), duration of diabetes (mean MACIULEWSKI, ANNA ZIELINSKA, DANUTA LIPINSKA, AGNIESZKA NIKOLAJUK, 18.4 years ± 12.9), HbA1C (mean 8.3 ± 1.7), race (79.2% white), gender (41% MARIA GORSKA, MALGORZATA SZELACHOWSKA, Białystok, Poland male), and age (mean 35.8 ± 16.5) were recorded. In addition, subjects self- Aim: It is well known that T1D is associated with other autoimmune reported the condition of their gums (ranging from poor to excellent) using a diseases. The aim of this study was to compare the prevalence of various previously validated questionnaire. Cytokine and MMP levels of interleukin auto-antibodies in fi rst-degree relatives of patients with T1D and healthy (IL)-1β, -6, -8, -10, TNF-α, MMP-3, -8, and -9 were determined using a individuals with negative family history of diabetes. multiplexed bead immunoassay via the MAGPIX analytical test instrument Material and Methods: The group studied consisted of 90 relatives and (Luminex). Principal components analysis (PCA) with orthogonal rotation was 60 healthy individuals. Serum concentrations of antibodies to anti-21- used to produce uncorrelated linear components of the cytokine and MMP hydroxylase (21-OH-Abs), anti-gastric parietal cell antibodies (GPC-Abs), variables. Individual cytokines were considered to load highly on a given anti-thyroglobulin antibodies (TG-Abs), anti-thyroid peroxidase antibodies component with factor loads >0.6. Multiple linear (HbA1c) and logistic (gum (TPO-Abs) and anti-TSH receptor antibodies (TSHR-Abs) were measured by health) regression analyses were performed to examine the relationships commercial radioimmunoassay. between the PCA components and HbA1c and gum health (adjusted for age, Results: Positive antibodies against pancreatic islet antigens were found duration of diabetes, BMI, sex, and race; model for HbA1c also adjusted for in 34.4% of the relatives (IAA in 23.3%, GADA in 16.7% and IA-2A in 2.2%) gum health and model for gum health also adjusted for HbA1c). and in none of the controls. Other antibodies (mainly TPO-Abs, TSHR-Abs PCA components 1 (MMP-8 and MMP-9) and 3 (TNF-α) were signifi cantly and GPC-Abs) were detected in 40% of all relatives and in 93.5% of these associated with HbA1c (β=0.28 ±0.14, p=0.045; β=0.31 ±0.14, p=0.029), while with positive anti-islet antibodies. Median levels of 21-OH-Abs, GPC- PCA component 2 (IL-6, IL-1β, and IL-8) was signifi cantly associated with gum Abs, TPO-Abs and TSHR-Abs were signifi cantly higher in the relatives, in health (OR 1.60 95% CI 1.09-2.34, p=0.016). In conclusion, increased salivary particular these with positive anti-islet antibodies, as compared with the infl ammatory burden is associated with decreased glycemic control and oral

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A411 GENETICS—TYPECATEGORY 1 DIABETES

health. Furthermore, saliva may represent a useful future reservoir of novel these observations and to identify additional candidate variants in these noninvasive biomarkers predictive of the progression and control of T1D. two families. Supported By: University of South Florida (to A.C.A.) Supported By: R01DK085212

1580-P GENETICS—TYPE 1 DIABETES Functional Domain of Autoimmune Regulator, AIRE, Modulates INS- VNTR Transcription in Human Thymic Epithelial Cells 1578-P AVIS E. SPARKS, MARY B. BRESLIN, MICHAEL S. LAN, New Orleans, LA Additional Non-HLA Genetic Markers in Children at Increased Risk Autoimmune regulator (AIRE) is a transcription factor that has been for Type 1 Diabetes shown to mediate the expression of numerous target genes for peripheral- ALEXANDRA R. FOUTS, FRAN DONG, SUNA ONENGUT-GUMUSCU, WEI-MIN tissue antigens in thymus, which is thought to play a key role in the CHEN, BRITTNI FREDERIKSEN, JILL M. NORRIS, STEPHEN S. RICH, MARIAN autoimmune tolerance induction. Insulin is one of those peripheral-tissue REWERS, ANDREA K. STECK, Aurora, CO, Charlottesville, VA antigens differentially expressed in the thymus and is modulated by insulin- Diabetes Autoimmunity Study in the Young (DAISY) follows high-risk variable number tandem repeats (INS-VNTR) and AIRE. AIRE is made of children for development of islet autoimmunity (IA) and type 1 diabetes (T1D), various functional domains including HSR, SAND, PHD1 and PHD2. In the providing an opportunity to validate associations reported by genome-wide present study, we engineered twelve AIRE mutants derived from the natural association studies between non-HLA single nucleotide polymorphisms mutation site of the autoimmune polyendocrinopathy type 1 syndrome (APS- (SNPs) and T1D as well as to explore potential associations with pre-clinical 1 also known as APECED) patients. We tested these AIRE mutants against IA. Previously, PTPN22, UBASH3A and C1QTNF6 were associated with IA, INS-VNTR specifi c target. We measured the transcriptional activation of while INS, UBASH3A, C1QTNF6, IFIH1 and rs10517086 (between SEL1L3 and INS-class III-VNTR-luciferase using wild type (WT) or mutant AIRE. The 11 RBPJ) were associated with progression from IA to T1D, in 1700 non-Hispanic AIRE mutants show diminishing INS-VNTR transcriptional activity up to over white (NHW) DAISY participants genotyped for 41 non-HLA SNPs. 90% of the WT AIRE activity except for the mutant 252 that shows higher Here we are reporting the results of genotyping (using ImmunoChip) for activity than the WT AIRE. We also tested the AIRE mutants with WT AIRE 59 non-HLA SNPs (including 18 SNPs previously not typed in DIASY), among together as heterozygous form in regulating INS-class III-VNTR transcription. 303 DAISY NHW subjects with the HLA-DRB1*03/04,DQB1*0302 genotype. Interestingly, mutant 228, 257x, 311fs, 397fs, or 433fs when complexes with Of the 303 subjects, 46 developed IA and 36 progressed to T1D. WT AIRE lost activity in heterozygous form suggests that these mutants In multivariate analyses, adjusting for family history of T1D, we confi rmed function as dominant negative fashion in contrast to the autosomal recessive association between UBASH3A, C1QTNF6, rs10517086 and IA and/or T1D. In nature of APS-1 patients. We showed that AIRE protein forms dimer for INS- addition, IL10 rs3024496 was associated with T1D (HR 1.66, p=0.03) in these VNTR DNA binding. The biotin-labeled class I INS-VNTR probe was used to subjects with HLA-DRB1*03/04,DQB1*0302 genotype, but not in the overall demonstrate physical interaction of AIRE and INS-VNTR probe. Each AIRE cohort. Among the 18 SNPs previously not typed, only CTLA4 rs3087243 was mutant was further analyzed for its ability to form dimer, physical interaction associated with IA (HR 0.61, p=0.03) and showed borderline association with with INS-VNTR DNA probe, and the impairment of functional domain that T1D (HR 0.71, p=0.18). In survival analysis, the cumulative risk of development alters the AIRE protein cellular localization. In summary, we are the fi rst to of IA by 15 years of age was higher in subjects with CTLA4 rs3087243 GG analyze the functional domains of AIRE using a specifi c target gene, INS- Genetics

POSTERS (26%), compared with AA/AG (15%) genotypes (p=0.02); the cumulative risk VNTR that accounts for the differential expression of human insulin gene Epidemiology/ for T1D followed a similar pattern. in thymus. UBASH3A, C1QTNF6, IL10, CTLA4 and rs1051708 contribute independently Supported By: ADA (1-13-BS-101) to development of IA and T1D in children with the highest risk HLA- DRB1*03/04,DQB1*0302 genotype. Interrogation of the non-HLA SNPs in 1581-P larger cohorts is warranted. Permanent Neonatal Diabetes in Polish Population Supported By: JDRF (11-2010-206); NIH/NIDDK (R37DK32493) KAROLINA ANTOSIK, PIOTR GNYS, IZABELA DROZDZ, WOJCIECH FENDLER, AGNIESZKA SZADKOWSKA, AGNIESZKA ZMYSLOWSKA, MALGORZATA MYSLI- 1579-P WIEC, GRAZYNA DEJA, JOANNA NAZIM, WOJCIECH MLYNARSKI, MACIEJ Whole-Exome Sequencing in Families with Latent Autoimmune BORO WIEC, Lodz, Poland, Gdansk, Poland, Katowice, Poland, Krakow, Poland Diabetes of Adults (LADA) Reveals Novel Candidate Loci Permanent neonatal diabetes (PNDM) is a rare disease caused by single KEVIN J. BASILE, ARIELLA SASSON, VANESSA GUY, JUAN C. PERIN, MAHDI gene mutations leading to β cell dysfunction, diagnosed usually in the fi rst SARMADY, STANLEY SCHWARTZ, STRUAN F.A. GRANT, Philadelphia, PA, 6 months of age but in some cases later on even up to the fi rst year. In the Wynnewood, PA current study we searched for mutations in the known PNDM genes and Latent autoimmune diabetes of adults (LADA) has been described by the additionally screened candidate genes (KCNQ1 and FXYD2). World Health Organization (WHO) as a slow-onset form of type 1 diabetes The study group consisted of 55 patients with diabetes diagnosed in the (T1D) resulting from autoimmune destruction of pancreatic beta cells. fi rst year of life, recruited in the ”Polish Registry for Pediatric and Adolescent However, LADA also shares characteristics with type 2 diabetes (T2D), such Diabetes—nationwide genetic screening for monogenic diabetes” in years as adult age onset, non-insulin dependence, and strong association with 2009 - 2013. Screening for mutations within the genes was performed using variants in the T2D-implicated gene, TCF7L2. In order to further clarify the Sanger sequencing. distinction between LADA and other forms of diabetes, we performed whole We identifi ed 4 patients with the mutations in KCNJ11 (A161T, R201C, exome sequencing of members of two families with multiple cases of LADA. R201H, E227K), 1 patients has mutations in ABCC8- P201L, 2 in INS (Y50C, Exome capture was implemented with the Agilent SureSelect All Exon R89C) and 7 were heterozygous for GCK mutation (G72R, G175R, T206M, V4+UTRs target enrichment kit. Data was aligned using NovoAlign. Variant C220X, E221L, S383L, G409S). One patient was a carrier of compound calling and indel detection was performed using the Genome Analysis Toolkit heterozygous mutation (T207M/S383L) in GCK gene. (GATK), following the Broad Institute’s Best Practices. Annotations were In two patients with diabetes and extrapancreatic features there have made using SnpEff. Preliminary analyses excluded members with T1D and been identifi ed compound heterozygous mutation (P444fsdelG/H647R) in considered variants that were common in all cases of LADA for each family, GLIS3 and (H387N) in the FOXP3 gene. No mutations were identifi ed in the but not present in unaffected members, in either family. The lead candidate KCNQ1 and FXYD2 genes. in Family 1, where we sequenced three members with LADA, four members The genetic diagnosis was confi rmed in 31% patients with suspicion of with T1D, and eight unaffected members, is an intronic variant in MNX1. The PNDM diagnosed within the fi rst year of age. Therefore other genes related lead candidate in Family 2, where we sequenced two members with LADA, to development of PNDM as well as candidate genes should be sequenced one member with T1D, and fi ve unaffected members, is an exonic variant in in patients with an unknown genetic aetiology. TRPM6. The exonic variant in TRPM6 results in a M333I substitution and Supported By: NCN Poland (2011/01/M/NZ5/02815, 2011/01/N/NZ5/02758, TEAM- is predicted to be damaging by SIFT algorithms. Both MNX1 and TRPM6 2009-3/7) have been previously implicated in non-autoimmune forms of diabetes according to published literature. Additionally, neither of these variants were present in any family member with T1D. Therefore, from these initial observations, the genetics of LADA in these two families may resemble T2D more than T1D. Further analyses are currently ongoing in order to validate

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A412 GENETICS—TYPECATEGORY 2 DIABETES

1582-P can be assessed for contribution to disease. Further validation coupled with Decreased Expression of Common Gamma-chain Dependent Cyto- deeper phenotypic investigation will help clarify the role of specifi c coding kine Receptors on Peripheral T Lymphocytes of Type 1a Diabetes deletions in T2D susceptibility. Patients and Its Association with Pancreatic Autoantibodies LINDIANE G. CRISOSTOMO, NOEMIA ORII, ROSA FUKUI, DEWTON VASCONCELOS, & 1584-P MARIA ELIZABETH ROSSI DA SILVA, São Paulo, Brazil Cis- and Trans-Regulatory Genetic Contributions to RNA Expression Introduction: The common gamma-chain dependent cytokine family Levels in Skeletal Muscle Tissues in a Founder Population include the interleukins IL-2, IL-4, IL-7, IL-9 , IL-15 and IL-21 and affect the WEN-CHI HSUEH, SAYUKO KOBES, CLINTON C. MASON, KE HUANG, LESLIE J. function of T and B lymphocytes and NK cells. Their role in autoimmune BAIER, ROBERT L. HANSON, Phoenix, AZ diabetes has been suggested but there are few data about the expression Muscle is an important tissue involved in glucose metabolism. of these receptors. Understanding the genetic regulation of transcript expression in muscle may Objective: To investigate the possible relationship between the expression provide insight into T2D etiology. We estimated heritability (h2) of transcript of common gamma-chain cytokine receptors on peripheral T lymphocytes levels in skeletal muscle biopsies obtained from 149 healthy, non-diabetic cells in T1D patients and pancreatic autoantibodies titles. Pima Indians. Transcript levels were measured on the Affymetrix Human Exon Material and Methods: We studied the expression of IL-21R, IL-2Ra (CD25), 1.0 ST Array, resulting in 16,567 core transcripts. Extent of both genome- IL-2Rb (CD122), IL-4R (CD124) and IL-7R (CD 127) on peripheral T lymphocytes wide and gene-specifi c identical-by-descent (IBD) sharing between all pairs of 35 recently diagnosed T1D patients (aged 1-16 yrs) and 25 healthy controls of subjects was estimated based on actual genotypes for ~400,000 SNPs of the same age group, using fl ow citometry. Pancreatic autoantibodies (anti- with Beagle. We defi ned the gene-specifi c region to include SNPs within a GAD and anti-IA2) were assessed by radioimmunoassay. given transcript and 200kb up- and down-stream of its coding region. The Results: All T1D patients had at least 1 positive autoantibody (anti-GAD average relatedness for “unrelated” pairs (mean IBD sharing=0.021) was or anti-IA2), and all control subjects were normoglycemic, with negative comparable to that for 2nd cousins, consistent with a founder population. pancreatic auto-antibodies. T1D patients presented a statistically signifi cant We estimated narrow-sense h2 of each transcript, and partitioned out the decrease in the proportional expression of IL-21R (p ≤0.1), IL-2Ra (p<0.01), IL- contributions of cis- and trans-elements, adjusting for age, sex and the fi rst 2Rb (p ≤ 0.03 ) in CD3 and CD4 T cells , of IL-4R in CD4+ T cells (p=0.03) and principal component from a previous GWAS. Permutation was used to derive of IL-7R in CD3T cells (p=0.03) when compared to controls. the distribution of h2 expected by chance. Observed total h2, and h2 due to cis- Further, there was negative correlation of the proportional expression and trans-elements were all signifi cantly greater than expected (P<0.0001). of IL-4Ra, IL-2Ra and IL-21R in CD4 T cells with anti-GAD65 and anti-IA2 More than a quarter (n=4,324, 26.1%) of transcripts were deemed to have antibodies levels (p<0.02) and of the proportional expression of IL-2Ra and substantial heritability (i.e. h2≥0.3) with a mean of 0.56±0.20. Among these IL-21R in CD3T cells with anti-IA2 (p<0.05). Only the expression of IL-4Ra in transcripts, cis- and trans-elements had similar contributions to total h2 (on CD8 T cells have positive correlation with anti-GAD65 levels (p=0.04). average, 47% and 53% attributable to cis- and trans-elements, respectively). Conclusion: Our data suggest that gamma chain receptors on peripheral T Interestingly, ~31% (n=1,356) of these transcripts’ h2 could be accounted cells signaling is downregulated and its expression is correlated negatively for completely by cis-elements and ~31% (n=1,353) had h2 fully attributed with pancreatic autoantibodies in recent Type 1 diabetes patients. to trans-elements. Taken together, our fi ndings, based on a largest muscle sample to date, suggest that ~1/4 of human skeletal muscle transcripts have Genetics

strong genetic infl uences, and among these, expression quantitative trait POSTERS GENETICS—TYPE 2 DIABETES loci involve both cis and trans effects. Epidemiology/

& 1585-P Guided Audio Tour: Integration of Genomic Findings with Other Data Merging Whole Genome Sequence and Tissue Expression Data to Sources (Posters: 1583-P to 1590-P), see page 15. Identify cis-Acting SNPs that Affect Risk for Type 2 Diabetes and Obesity & 1583-P LESLIE J. BAIER, KE HUANG, PAOLO PIAGGI, YUNHUA MULLER, ANUP NAIR, Identifi cation of Gene Loss of Function Deletions from Dense Exome MICHAEL TRAURIG, SAYUKO KOBES, CLINT MASON, ROBERT L. HANSON, Array Data and Their Role in Type 2 Diabetes CLIFTON BOGARDUS, Phoenix, AZ MATTHIAS THURNER, ANUBHA MAHAJAN, NEIL ROBERTSON, ASHISH KUMAR, To identify functional variants that affect risk for type 2 diabetes or WILLIAM RAYNER, LOUKAS MOUTSIANAS, JUAN FERNANDEZ, FREDRIK obesity, we obtained whole genome sequence (WGS) data on 234 Pima KARPE, COLIN N. PALMER, TIMOTHY D. SPECTOR, MARK I. MCCARTHY, KYLE Indians. All subjects have BMI and oral glucose tolerance test (OGTT) data, J. GAULTON, GOT2D CONSORTIUM, Oxford, United Kingdom, Dundee, United and many also have measures of % body fat (pfat), acute insulin secretion Kingdom, London, United Kingdom (AIR) following an IV glucose bolus, and insulin-stimulated glucose uptake Loss of function (LoF) of gene activity is a major contributor to phenotypic (M) during a hyperinsulinemic euglycemic clamp from a non-diabetic exam. variability and contributes to Mendelian and complex disease. The extent Some non-diabetic subjects also underwent skeletal muscle (N=90) and/or to which LoF events, in particular rare structural deletions, might infl uence percutaneous abdominal adipose (N=69) tissue biopsies, and gene expression type 2 diabetes (T2D), however, is currently unknown. We investigated levels were previously analyzed in these tissues in a larger sample (N~200 exonic deletions that could be discovered using the Illumina HumanExome including these subjects). To date, 4 million SNPs identifi ed by WGS have SNP array. We developed a pipeline for deletion discovery that combines been investigated as potential cis-acting eQTLs in muscle and adipose tissue existing structural variant (SV) calling algorithms (PennCNV, QuantiSNP, (SNPs 400 kb upstream and downstream of each gene were analyzed for CBS) and merges resulting calls together to determine deletion events. We association with expression of that target gene). SNPs providing evidence applied this pipeline to exome chip data from 650 samples whole genome for being cis-acting are currently being analyzed for association with the sequenced as part of the GoT2D project and for which genome-wide calls following metabolic traits: BMI, pfat, 2 hr glucose during an OGTT, AIR and M. were made using GenomeSTRiP. In total, 20 deletions were identifi ed, Expression levels of their target genes are also being analyzed for association 75% of which were also detected in low pass sequencing with a genotype with the same trait. Preliminary results identifi ed cis-acting SNPs for GPR81 specifi city of 99% and sensitivity of 82%. We applied this pipeline to exome and AKR1C3 whose expression has previously been correlated with obesity, chip data from 11,686 UK T2D case and control samples and identifi ed but expression changes had been assumed to be the consequence of the 1,150 deletion sites, 91% of which were rare (MAF<0.01). We tested the obese state, rather than genetically controlled. Rs10773433 was associated 1,150 deletions for association to T2D and found several with signifi cant with both GPR81 expression in adipose tissue (N=69; P=8x10-10) and BMI association after correction for multiple testing (P<4.35x10-5). Among the (N=234; P=0.004 adjusted for age and sex) and GPR81 expression correlated top associated genes were C4ORF40 (P=2.2x10-10, OR=0.44, MAF=0.04, with BMI (N= 192; P< 4x10-5). Rs11252861 was associated with both adipose length=176bp), KIF7 (P=5.41x10-13, OR=0.48, MAF=0.04, length=10,816bp) AKR1C3 expression (N=69; P=1x10-4) and BMI (N=234; P=4x10-4 adjusted for and BAAT (P=4.25x10-10, OR=0.18, MAF=0.01, length=453bp). Both SVs of age and sex) and AKR1C3 expression correlated with BMI (N=192; P <1x10-5). C4ORF40 and KIF7 fully overlap deletions present in the database of genomic Replication in larger samples is ongoing. variants, supportive of these being true deletion events. While the function of C4ORF40 is unknown, KIF7 mutations may cause a syndromic form of diabetes (Bardet-Biedl syndrome). These results show that dense exome arrays can accurately identify low frequency and rare gene deletions that

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A413 GENETICS—TYPECATEGORY 2 DIABETES

& 1586-P & 1588-P A Prospective Metabonomics Analysis Reveals New Pathways In- Age-related DNA Methylation and mRNA Expression Changes in volved in T2D Development Human Pancreatic Islets ABDELILAH ARREDOUANI, LOIC YENGO, MICHEL MARRE, OLIVIER LANTIERI, KARL BACOS, PETR VOLKOV, TASNIM DAYEH, ANDERS H. OLSSON, CHARLOTTE BEVERLEY BALKAU, PHILIPPE FROGUEL, Doha, Qatar, Lille, France, Paris, France, La A. LING, Malmö, Sweden Riche, France, Villejuif, France Increased age is associated with a reduced capacity for insulin secretion Characterization of the metabolic disruptions that precede T2D is critical and an increased risk of type 2 diabetes. Recent studies suggest that for the screening of at risk individuals and hence the implementation of early epigenetic modifi cations such as DNA methylation play a role in the interventions. Currently genetic predictors still fail to grasp the complex development of type 2 diabetes. However, it remains unknown if ageing metabolic etiology of T2D and metabolomics opens new horizons for biomarkers is associated with altered DNA methylation and gene expression patterns discovery. Together, metabolomics and genotyping profi ling should enhance in human pancreatic islets. In the present study we used the Illumina our power for T2D understanding and prediction. The aim of this study was the Infi nium HumanMethylation450 BeadChip and Affymetrix GeneChip® search for T2D at risk metabolites as functional phenotypes and their association Gene 1.0 ST Arrays to investigate the effect of age on the genome-wide with SNPs. We used plasma from 1,214 subjects from a prospective cohort for DNA methylation and gene expression patterns in human pancreatic islets non-targeted metabolomics analysis at baseline and 9 years. For genotyping from 87 non-diabetic donors with an age spanning between 26-74 years. we used the 200,000 SNPs metabochip. We detected 491 named metabolites DNA methylation data of 482,889 sites remained after quality control and from 65 metabolic pathways. With a false discovery rate set at 5% (q<0.05) and the methylation level of 322 of these where signifi cantly associated with after adjusting for BMI, sex and age, 109 metabolites were found to nominally age after correction for multiple testing. These represent 214 individual associate with incident T2D (p<0.05). After adjusting for fasting glucose (FG), genes, including loci previously associated with diabetes. Interestingly, 23 metabolites were signifi cantly associated with incident T2D (p from 3.12E-03 all of the signifi cant methylation sites showed increased DNA methylation to 1.7E-06). Of these, 1-palmitoylglycerol, 1,5-anhydroglucitol, 1-oleoylglycerol, with increasing age. Moreover, based on the annotation of the analyzed mannose, alpha-ketobutyrate and gamma-glutamylphenylalanine showed methylation sites, we found enrichment of signifi cant methylation sites the strongest associations (p from 1.3E-05 to 1.7E-06). When using the on chromosomes 2 and 19 and in the following gene regions; TSS1500 metabolite ratios between y9 and y0, after adjustment for FG, the metabolite (the region 1500 bases upstream of the transcription start site), TSS200 1,5-anhydroglucitol (1,5-AG) showed the strongest association with incident T2D and 1st exon as well as in CpG islands. Seven genes exhibited signifi cant (p=1.2E-09). 1,5-AG is a naturally occurring form of glucose whose blood levels associations for both DNA methylation and mRNA expression with increased are inversely proportional to glucose, and can thus be used as marker for short- age. Of these, 5 showed an inverse relation, with increased methylation and term IGT. Moreover, our analysis revealed a strong association of the metabolite reduced expression. These 5 genes encode for a ribosomal, a zinc fi nger, a mannose with the rs1260326 in the T2D associated GCKR locus (p=8.8E-40). histone, a mitochondrial and a RNA methyl transferase protein, respectively. We found associations of other metabolite ratios with 8 different SNPs outside Together, our study demonstrates that ageing is associated with differential known T2D loci which opens novel genetic hypotheses. In conclusion, prospective DNA methylation in human pancreatic islets. These epigenetic modifi cations metabonomics analyses reveal new pathways involved in T2D development. may contribute to altered gene expression, impaired insulin secretion and Supported By: Qatar Foundation fi nally affect the risk for type 2 diabetes.

Genetics POSTERS & 1587-P Epidemiology/ Genetic Evidence for a Metabolically Obese, Normal Weight Pheno- & 1589-P type That Links Insulin Resistance with Type 2 Diabetes, Hyper- Disturbed Glucose Metabolism and Increased Intramyocellular tension, and Coronary Artery Disease Lipid Content in Healthy Male Carriers of Arg82cys in Cd300lg: A HANIEH YAGHOOTKAR, ROBERT SCOTT, CHARLES C. WHITE, WEIHUA ZHANG, New Genetic Cross-Link between Glucose Homeostasis and Fasting ELIZABETH K. SPELIOTES, PATRICIA B. MUNROE, GEORG B. EHRET, JOSHUA Lipoprotein Profi le C. BIS, CAROLINE S. FOX, MARK WALKER, INGRID B. BORECKI, JOSHUA W. ULLA KAMPMANN, JULIE STOEY, JOERGEN RUNGBY, HANS STOEDKILDE- KNOWLES, LAURA YERGES-ARMSTRONG, CLAES OHLSSON, JOHN PERRY, JOERGENSEN, IVAN BRANDSLUND, CRAMER CHRISTENSEN, TORBEN HANSEN, JOHN C. CHAMBERS, JASPAL S. KOONER, NORA FRANCESCHINI, CLAUDIA OLUF PEDERSEN, CLAUS JUHL, NIELS MOELLER, Aarhus, Denmark, Copenhagen, LANGENBERG, MARIE-FRANCE HIVERT, ZARI DASTANI, BRENT JOHN RICHARDS, Denmark, Vejle, Denmark, Esbjerg, Denmark ROBERT SEMPLE, TIMOTHY M. FRAYLING, Exeter, United Kingdom, Cambridge, United Each of the components of the metabolic syndrome has been scrutinized Kingdom, Framingham, MA, London, United Kingdom, Ann Arbor, MI, Geneva, Switzerland, in GWA-studies with a large number of genetic variants identifi ed. The Stanford, CA, Newcastle upon Tyne, United Kingdom, St. Louis, MO, Baltimore, MD, possibility that the different aspects of the metabolic syndrome share Gothenburg, Sweden, Chapel Hill, NC, Boston, MA, Montreal, QC, Canada overlapping causative genes was recently explored in a whole exome The mechanisms that cause an adverse metabolic phenotype in individuals sequencing study of 2000 Danish individuals. An amino acid polymorphism of normal weight are poorly understood. One proposed mechanism is insulin in CD300LG was associated with low fasting HDL-cholesterol and resistance (IR) that leads to hypertension, coronary artery disease (CAD) and high triglyceride levels. In the present study a metabolic phenotype type 2 diabetes (T2D). We tested whether or not common alleles associated characterization with emphasis on glucose metabolism was performed in with IR infl uence the metabolic outcome of monogenic forms of IR. carriers of the risk-allele in CD300LG. We selected 19 genetic variants associated with fasting insulin based 20 healthy male carriers of the CD300LG rs72836561 CT genotype were measures of IR. We used results from genome wide association studies matched on age and BMI with 20 healthy males with the CC genotype. The of 8 biomarkers of monogenic IR, including adiposity, fatty liver, lipids and metabolic phenotyping included assessment of insulin sensitivity using adiponectin, to group genetic variants by their metabolic phenotype profi le. the hyperinsulinemic euglycemic clamp, intrahepatic lipid content (IHLC) We analysed variants against metabolic diseases using genetic risk scores and intramyocellular lipid (IMCL) were evaluated by MR spectroscopy, and including 12171 T2D cases, 40365 CAD cases and 69828 individuals with beta-cell function was evaluated by an intravenous glucose tolerance test blood pressure measurements. (IVGTT). Based on a hierarchical clustering analysis, 11 variants were associated The two genotype groups were similar with respect to age, BMI, body with a metabolic profi le consistent with a common form of lipodystrophy. composition, HbA1c, and fasting glucose. The CT-group displayed features of A genetic risk score of these 11 IR risk alleles were associated with higher the metabolic syndrome including (i) higher IMCL (0.5 arbitrary units versus triglycerides (per allele β=0.018; p=4x10-29), lower HDL-C (β=-0.020; p=7x10-37), 0.4; p=0.045), (ii) a reduced forearm glucose uptake (p=0.042), (iii) a trend greater hepatic steatosis (β=0.021; p=3x10-4) higher alanine transaminase towards lower M-values; 6.0 mg/kg/min compared to 7.1 (p=0.1), and (iiii) (β=0.002; p=3x10-5), lower SHBG (β=-0.010; p=9x10-13) and lower adiponectin a lower HDL2/HDL3 ratio; 1.49 versus 2.23; p=0.014. No differences were (β=-0.015; p=2x10-26). In contrast the risk alleles were associated with lower observed in IHLC or fi rst-phase insulin secretion during the IVGTT (p=0.15 -8 BMI (β=-0.008; p=7x10 ) and an increased visceral to subcutaneous adipose and p=0.37, respectively). -7 tissue ratio (β=-0.015; p=6x10 ). Individuals carrying > 16 IR risk alleles were CD300LG was recently identifi ed as a gene impacting fasting HDL- -13 -5 at increased risk of T2D (OR 1.36; per allele p=5x10 ), CAD (OR 1.10; p=1x10 ), cholesterol and triglyceride levels and our data demonstrate a new genetic -5 and increased systolic and diastolic blood pressure (0.98, 0.55 mmHg; p=2x10 , cross-link between two major components of the metabolic syndrome; -4 2x10 , respectively), compared to individuals carrying < 10 risk alleles. disturbed glucose and lipoprotein metabolism in carriers of the CD300LG Our results, consistent with a polygenic “lipodystrophy like” phenotype, rs72836561 CT genotype. highlight a potential role of dysfunctional adipose tissue as a driver of IR, Supported By: Lundbeck Foundation T2D, CAD and hypertension.

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A414 GENETICS—TYPECATEGORY 2 DIABETES

& 1590-P & 1592-P GIP and CPPED1 Are Implicated as Novel Type 2 Diabetes Loci Lifestyle and Metformin Ameliorate Insulin Sensitivity Independ- through Integration of TCF7L2 DNA Occupancy and SNP Association ently of the Genetic Burden of Insulin Resistance Risk Variants in Data Diabetes Prevention Program Participants MATTHEW E. JOHNSON, JIANHUA ZHAO, JONATHAN SCHUG, SANDRA MARIE-FRANCE HIVERT, COSTAS A. CHRISTOPHI, PAUL W. FRANKS, KATHLEEN DELIARD, QIANGHUA XIA, VANESSA GUY, JESUS SAINZ, KLAUS H. KAESTNER, A. JABLONSKI, DAVID A. EHRMANN, STEVEN E. KAHN, EDWARD S. HORTON, ANDREW D. WELLS, STRUAN F.A. GRANT, Philadelphia, PA, Santander, Spain TONI POLLIN, KIEREN J. MATHER, LEIGH PERREAULT, ELIZABETH L. BARRETT- The TCF7L2 locus is strongly implicated in the pathogenesis of type 2 CONNOR, WILLIAM C. KNOWLER, JOSE C. FLOREZ, Sherbrooke, QC, Canada, diabetes (T2D). We previously mapped the genomic regions bound by TCF7L2 Rockville, MD, Malmö, Sweden, Chicago, IL, Seattle, WA, Boston, MA, Baltimore, using ChIP-seq in the colorectal carcinoma cell line, HCT116, revealing an MD, Indianapolis, IN, Aurora, CO, San Diego, CA, Phoenix, AZ unexpected highly signifi cant over-representation of GWAS loci associated Despite an initial dearth of insulin resistance (IR)-associated genetic primarily with endocrine (in particular T2D) and cardiovascular traits. In variants, technological and statistical advances have now revealed order to further explore if this observed phenomenon occurs in other cell several loci associated with IR. We constructed a genetic risk score (GRS), lines, we carried out ChIP-seq in HepG2 cells and leveraged ENCODE data composed of 17 established IR variants, and genotyped these variants in for fi ve additional cell lines. Indeed, we found strong evidence for continued 2,713 participants in the Diabetes Prevention Program (DPP), who at baseline enrichment of endocrine and cardiovascular GWAS categories, with were at high risk of progression to Type 2 diabetes. additional support for cancer. Given that only a minority of the predicted In DPP participants, we tested: 1) the association between the IR-GRS and genetic component to most complex traits has been identifi ed to date, plus the insulin sensitivity index (ISI, reciprocal of HOMA-IR) at baseline, and 2) our GWAS-related observations with respect to TCF7L2 occupancy, we the interaction between the IR-GRS and the effect of metformin or lifestyle investigated if restricting association analyses to the genes yielded from interventions on the change in ISI over 1 year. this approach, in order to reduce the constraints of multiple testing, could The IR-GRS was calculated by summing the number of risk alleles (0,1,2) reveal novel T2D loci. When investigating all the known GWAS loci bound by present at the 17 selected variants (median score=20; range 11-29). We TCF7L2 in the shortest gene list, derived from HCT116, the coronary artery tested the effect of IR-GRS on ISI (baseline and 1-year change) using linear disease associated variant, rs46522 at the GIP locus yielded signifi cant regression models after adjusting for age, sex, ethnicity, and BMI (and further association with T2D within DIAGRAM. Furthermore, when we analyzed adjusting for treatment and baseline ISI for the 1-year change models) and tag-SNPs in genes not previously implicated by GWAS but bound by TCF7L2 tested whether the effect differed by intervention arm. within 5kb, we observed signifi cant association of rs4780476 within CPPED1 A higher IR-GRS was associated with lower ISI at baseline (β=-0.013 in DIAGRAM. In conclusion, ChIP-seq data generated with this GWAS- [SE=0.004] for baseline ln(ISI) per risk allele; P=0.0004 in adjusted model). implicated transcription factor provided a biologically plausible method to Over 1 year, ISI improved in metformin (0.19±0.12 to 0.23±0.15, P<0.0001) and limit multiple testing in assessment of genome-wide genotyping data to in lifestyle (0.20±0.14 to 0.27±0.18, P<0.0001) but not in placebo participants implicate novel T2D-associated loci. (0.19±0.13 to 0.19 ±0.12, P=0.28). A higher IR-GRS was associated with less Supported By: Children’s Hospital of Philadelphia improvement or a decline in ISI over 1 year, (β=-0.010 [SE=0.004] for Δln(ISI) at 1-year vs. baseline; P=0.008 – fully adjusted model) with no interaction

detected with intervention arms (p=0.80). Genetics POSTERS

Guided Audio Tour: Clinical Translation of Genetic Findings (Posters: 1591-P In conclusion, a higher IR genetic burden is associated with insulin Epidemiology/ to 1598-P), see page 13. resistance (lower ISI) at baseline in the DPP. The effects of lifestyle and metformin to improve ISI in DPP participants appear independent of this & 1591-P genetic burden. Genetic Variation and Response to Weight, Physical Activity, and Supported By: NIH/NIDDK Diet Change to Prevent Diabetes in the Diabetes Prevention Program NISA MARUTHUR, MICHELLE S. YAU, KATHLEEN A. JABLONSKI, LINDA & 1593-P DELAHANTY, PAUL W. FRANKS, WILLIAM C. KNOWLER, JEANNE M. CLARK, Evaluating the Relationship of Established Obesity-associated VANITA ARODA, ALAN SHULDINER, RICHARD F. HAMMAN, STEVEN KAHN, Genetic Loci on Behavioral Weight Loss and Subsequent Regain: JOSE C. FLOREZ, TONI POLLIN, Baltimore, MD, Rockville, MD, Boston, MA, Malmö, Combined Analyses in the Diabetes Prevention Program and Look Sweden, Phoenix, AZ, Hyattsville, MD, Aurora, CO, Seattle, WA AHEAD Trials Genetic variation may modify the effect of multi-component lifestyle PAUL W. FRANKS, GEORGE D. PAPANDONATOS, QING PAN, NICHOLAS M. interventions on diabetes risk. We evaluated genetic modifi cation of the PAJEWSKI, LINDA DELAHANTY, IGNA PETER, WILLIAM C. KNOWLER, SHAFQAT effect of individual components (change in weight, diet, and physical activity) AHMAD, LYNNE E. WAGENKNECHT, STEVEN E. KAHN, RENA R. WING, KATHLEEN on diabetes risk in the Diabetes Prevention Program (DPP), a randomized A. JABLONSKI, GORDON HUGGINS, JOSE C. FLOREZ, JEANNE M. MCCAFFERY, controlled trial of lifestyle, metformin, and placebo interventions (N=2,994). Malmö, Sweden, Providence, RI, Rockville, MD, Winston-Salem, NC, Boston, MA, Sixty-nine pre-selected SNPs, which had previously demonstrated a New York, NY, Phoenix, AZ, Seattle, WA nominally signifi cant interaction (P<0.05) with the DPP lifestyle intervention Clinically relevant weight loss (WL) is achievable through lifestyle change. (vs. placebo) for diabetes risk, were tested for interaction with 12-month However, weight regain (WR) after initial weight loss remains a common change in weight (%), physical activity (MET-hrs/wk), and daily total fat problem. We investigated if recently discovered genetic variants underlie and saturated fat intake (g/day), with diabetes as the outcome. Using these traits (at 1-4 years post-randomization) in the Diabetes Prevention multivariate Cox proportional hazards models (stratifi ed by treatment arm), Program (DPP; N=1,735) and Look AHEAD (N=3,906), two randomized we identifi ed 37 SNPs impacting the association (P<0.05 for each SNP) of controlled trials of lifestyle-induced weight-loss vs. control. We tested 95 change in weight (7 SNPs), physical activity (16 SNPs), and daily total (7 established obesity-predisposing loci (characterized by 99 single nucleotide SNPs) and saturated (7 SNPs) fat intake at 12 months with diabetes risk. polymorphisms [SNPs] discovered or confi rmed by the GIANT consortium [in These interactions were not signifi cant after Bonferroni correction for review]), with the effect allele defi ned as the BMI raising allele reported by effective number of tests. The strongest statistical interaction (P=0.001) GIANT. Results were derived within each trial and combined by fi xed-effects occurred in the metformin arm for HNF4A rs8116574: For those in the highest meta-analysis. The majority of variants were not associated with either vs. lowest tertile of physical activity change at 12 months, the cumulative WL or WR in the DPP and Look AHEAD, neither directly nor via interactions incidence of diabetes for the GG genotype was 15.6% vs. 24.2% while the with lifestyle. Of all SNPs examined, only one (at MTIF3) modifi ed treatment cumulative incidence of diabetes for the GT/TT genotypes was 31.4% vs. effects on WL at an experiment-wide level of statistical signifi cance (P for 12.2%. Genetic modifi cation of diabetes incidence in response to weight and gene × lifestyle interaction test =4.9×10-5, on 3-year WL), where in both physical activity change at 12 months was most common in the metformin studies combined the GIANT effect allele associated with WL in the lifestyle arm; genetic modifi cation of diabetes incidence in response to change in (P=5.2×10-5) but not the control (P=0.13) arms (i.e., standard of care). None dietary fat intake was most common in the placebo arm. We fi nd that genetic of the tests of gene × treatment interactions on WR was signifi cant after background may differentially affect response to individual components accounting for multiple testing. However, nominally signifi cant interactions of diabetes prevention strategies and provide a foundation for future for a variant at FUBP1-DNAJB4 were observed, where the effect allele development of personalized preventive interventions. tended to be related with faster WR at 2-years post-randomization with Supported By: NIH/NIDDK lifestyle modifi cation and slower WR with control intervention, in the DPP (Pinteraction=0.033) and Look AHEAD (Pinteraction=0.046) trials. This study

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A415 GENETICS—TYPECATEGORY 2 DIABETES

suggests that recently established genetic loci for BMI do not meaningfully in MESA European Americans and with common carotid intima-media determine response to weight loss interventions in people at high risk of or thickness in FHS (p=0.004 and 0.009, respectively, fully adjusted model) was with manifest type 2 diabetes. not confi rmed in other study cohorts. Supported By: NIH/NIDDK A comprehensive burden of common T2D SNPs was not associated with prevalent SCA, despite a detailed phenotypic characterization and a & 1594-P transethnic, multicentric study design. As functional variants at the 62 loci Common Genetic Variants Highlight the Role of Insulin Resistance become known, a genetic basis for shared T2D-CVD risk might become and Body Fat Distribution in Type 2 Diabetes, Independently of apparent. Obesity ROBERT A. SCOTT, TOVE FALL, DOROTA PASKO, ADAM BARKER, STEPHEN J. & 1596-P SHARP, VILMANTAS GIEDRAITIS, MARK WALKER, ROBERT K. SEMPLE, ERIK SLC47A1 Gene rs2289669 G>A Variants Enhance Hypoglycemic INGELSSON, TIMOTHY M. FRAYLING, DAVID B. SAVAGE, CLAUDIA LANGENBERG, Effect of Metformin via Delaying Its Excretion in Chinese Type 2 NICK J. WAREHAM, THE RISC STUDY GROUP, THE INTERACT CONSORTIUM, Diabetes Patients Cambridge, United Kingdom, Uppsala, Sweden, Exeter, United Kingdom, Newcastle RUI HE, DANDAN ZHANG, WEI LU, TAISHAN ZHENG, FANG LIU, WEIPING JIA, upon Tyne, United Kingdom, Stockholm, Sweden Shanghai, China Type 2 diabetes (T2D) typically develops when insulin secretion is The SLC47A1 gene encodes the multi-drug and toxic excretion -1(MATE1) insuffi cient to maintain normoglycaemia in the face of obesity-associated protein, which plays a key role in the transport and excretion of metformin. insulin resistance. We aimed to validate common genetic variants as This study is to clarify the infl uence of variants in SLC47A1 (rs2289669 G→A) instruments for insulin resistance and beta-cell dysfunction, to characterise on metformin pharmacokinetics and the long-term hypoglycemic effect of their association with intermediate metabolic traits, and to investigate their metformin. role in T2D risk among normal-weight, overweight and obese individuals. A total of 220 newly diagnosed type 2 diabetes patients were recruited, We investigated the associations of genetic scores comprising variants genotyped and divided into three groups by SLC47A1 genotypes (G/G, G/A, associated with fasting insulin or early insulin secretion with euglycaemic- A/A). Ten patients in each group were randomly selected for metformin hyperinsulinaemic clamp- and OGTT-based measures of insulin resistance pharmacokinetics. All the participants received metformin oral treatment and secretion, as well as a range of metabolic traits in up to 18,565 and were followed for one year. individuals. We also studied their contribution to T2D risk among normal After one-year follow-up, the decline of HbA1c level was signifi cantly weight, overweight and obese individuals in the InterAct study including greater in subjects with variant genotype (AA) than other two groups 8,124 incident T2D cases. (−2.32% in AA vs. -1.16% in GA, -1.07% in GG, P<0.05). Then taking GG The insulin resistance score was associated with lower insulin sensitivity genotype as the referent, the association between AA genotype and change measured by M/I value (β in SDs per-allele [95% CI]: -0.03 [-0.04,-0.01]; of HbA1c still existed after adjusted for age, sex, BMI, baseline HbA1c and p=0.004). This score was associated with lower BMI (-0.01 [-0.01, -0.00; diabetes duration (P<0.05). Pharmacokinetic parameters of metformin p=0.02), lower DXA-measured gluteofemoral fat-mass (-0.03 [-0.05, -0.02; indicated that patients carrying MATE1 homozygous A had higher area p=1.4x10-6) and with higher ALT (0.02 [0.01, 0.03]; p=0.002) and gamma- under the plasma concentration versus time curve (AUC12h), but lower renal GT (0.02 [0.01, 0.03]; p=0.001). Both the insulin resistance (HR per-allele clearance (CLR) and renal clearance by secretion (CLSR) than other patients Genetics -13

POSTERS [95% CI]: 1.06 [1.04, 1.07]; p=2.0x10 ) and secretion (1.09 [1.07, 1.11]; (all P<0.01). Multivariate lineal stepwise analysis further revealed that Epidemiology/ p=8.0x10-30) scores were associated with incident T2D, and in all BMI strata SLC47A1 genotype was an independent impact factor for urine excretion of (p<1.5x10-4). metformin (P<0.01). Genetic scores for insulin resistance and secretion are valid tools to study In conclusion, SLC47A1 rs2289669 G>A variants improve the hypoglycemic the role of these features in disease processes including T2D. While insulin effect of metformin through slowing its excretion in type 2 diabetes resistance as a cause of T2D is often considered secondary to obesity, the populations. association of the insulin resistance score with lower BMI and adiposity and Supported By: NSFC (81270397, 81070650) with T2D even among individuals of normal weight highlights the role of insulin resistance and body fat distribution in T2D, independently of body size. & 1597-P Combined Infl uence of Genetic Determinants on Sulfonylurea Effi cacy & 1595-P QIAN REN, XUEYAO HAN, XIAOLING CAI, XIUYING ZHANG, LINONG JI, Beijing, A 62 Variant Type 2 Diabetes Genetic Risk Score Is Not Associated China with Markers of Subclinical Atherosclerosis in Multiethnic Cohorts: Eight genes have been shown to infl uence the response to sulfonylureas The Framingham Heart Study (FHS), Genetic Epidemiology Network in previous studies, including CYP2C9, KCNJ11, ABCC8, TCF7L2, IRS1, of Atherosclerosis (GENOA), Multiethnic Study of Atherosclerosis CDKN2A/2B, GCK and KCNQ1. However, limited number of studies had (MESA), and Coronary Artery Risk Development in Young Adults assessed the combined infl uence of these genes on sulfonylurea effi cacy. To (CARDIA) Studies assess the combined effect of multiple susceptibility alleles, we genotyped MARCO DAURIZ, BIANCA C. PORNEALA, XIUQING GUO, LAWRENCE F. BIELAK, eight variants of these genes in a total of 747 diabetic patients enrolled from NEFERTITI H. DURANT, JAMES B. MEIGS, FOR THE FHS, MESA, GENOA AND a double-blind, randomised controlled trial. All the patients had been treated CARDIA INVESTIGATORS, Boston, MA, Los Angeles, CA, Ann Arbor, MI, Birmingham, with glibenclamide for 48 weeks. Treatment failure was confi rmed when AL patients reached the criteria for terminating their participation in the study Type 2 diabetes (T2D) and cardiovascular disease (CVD) arise together (fasting blood glucose level ≥7.0 mmol/l on two consecutive tests 4 weeks from T2D risk factors and subclinical atherosclerosis (SCA). T2D genetic risk after reaching the pre-set maximal dose or maximal tolerated dose). A Cox might act as common ground for the development of both T2D and SCA. regression model was used to evaluate the relationship between genetic We hypothesized that greater T2D genetic risk is associated with higher variants and treatment failure over a period of 48 weeks. We divided all indices of SCA. the patients into three groups according to the mean value and standard In a cross-sectional analysis of up to 9,210 European Americans, 3,773 deviation (SD) of risk allele numbers (Low Group: risk alleles <3, Middle African Americans, 1,446 Hispanic Americans, 773 Chinese Americans Group: risk alleles 3-7, and High Group: risk allele>7). In the initial 4 weeks without known CVD and enrolled in FHS, CARDIA, MESA and GENOA of glibenclamide treatment, participants with more risk alleles seemed to studies we tested the association of a genetic risk score (GRS) comprised of have a less reduction in FPG at the end of 4 weeks (Low Group: 11.7% (6.1- 62 confi rmed T2D single nucleotide polymorphisms (SNPs) with measures of 21.7%), Middle Group: 10.6% (1.2-20.8%), High Group: 7.3% (2.9-15.0%), SCA (coronary artery or abdominal aortic calcium score, internal and common P=0.053). We then analyzed the relationship between treatment failure carotid intima-media thickness, ankle-brachial index). We used ancestry- and combined risk alleles during 48 weeks. After adjusting for sex, age and specifi c linear mixed effect models to account for family relatedness and a BMI, Cox regression showed there were signifi cant association between nested modeling strategy from a genetic-only (GRS adjusted for sex) to a full number of risk alleles and glibenclamide treatment failure (OR=1.352(95%CI CVD risk factor adjusted model. We had 80% power to detect association of 1.009-1.811, P=0.043). Our study demonstrated that the combined drug GRS with at least 0.42% of the variance in any SCA trait; we set signifi cance metabolism and diabetes risk polymorphisms were signifi cantly associated at p-value<0.01 (p=0.05/5, the number of traits analyzed). with the effi cacy of glibenclamide. This approach may have a role in future We found no signifi cant association between the GRS and any SCA trait pharmacogenetic study for common, polygenic diseases. in any of the models. An association with coronary artery calcium score

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A416 GENETICS—TYPECATEGORY 2 DIABETES

1600-P & 1598-P T-cadherin Gene (CDH13) Polymorphisms, Plasma Adiponectin, and Genome-Wide Search for Susceptibility Loci to Diabetic Retinopathy Type 2 Diabetes in Japanese Patients with Type 2 Diabetes ANTHONY NICOLAS, ROBERTE AUBERT, NAIMA MUNOZ-BELLILI, BEVERLEY MINAKO IMAMURA, ATSUSHI TAKAHASHI, MICHIAKI KUBO, SHIRO MAEDA, BALKAU, OLIVIER LANTIERI, GILBERTO VELHO, RONAN ROUSSEL, MICHEL Yokohama, Japan MARRE, FRÉDÉRIC FUMERON, Paris, France, Villejuif, France, La Riche, France Diabetic retinopathy (DR) is one of the leading causes of blindness in Adiponectin is an adipocyte-secreted protein associated with insulin Japanese adults. Several reports have shown familial aggregations of DR sensitivity. T-cadherin is a receptor for high and medium molecular weight or advanced DR among patients with type 1 or type 2 diabetes, suggesting adiponectin. In GWAS, the T-cadherin gene (CDH13) polymorphisms are genetic susceptibility contributes to the development and/or progression associated with circulating adiponectin. The aim of our study was to of DR. However, the genes involved in the susceptibility to DR are still investigate the associations between the genetic variants of CDH13 and unknown. type 2 diabetes and related parameters. To identify novel genetic loci associated with the susceptibility to DR, we Four polymorphisms of CDH13 (rs11646213, rs12051272, rs3865188, performed genome-wide association studies (GWAS) in Japanese patients rs4783244) were genotyped with the KASPAR method in a cohort drawn with type 2 diabetes. We divided patients with type 2 diabetes, registered from the French general population, D.E.S.I.R. (N=5212), and a cohort of in BioBank Japan, into 2 groups; 1) DR cases, defi ned as patients having any type 2 diabetic patients, DIABHYCAR (N=3123). The associations between stages of DR, and 2) controls, who did not have any sign of DR and with long the polymorphisms and continuous quantitative variables were estimated duration of diabetes (≥10 years) or with diabetic nephropathy. We examined by ANCOVA, with adjustments for confounding factors. The associations of 2 independent case-control groups (Study-1; 4,839 DR cases and 4,041 polymorphisms with type 2 diabetes were tested by Chi², Cochrane’s trend controls, Study-2; 693 DR cases and 1,524 controls) for ~7.5 million single test and logistic regression along with multiple adjustments. nucleotide polymorphisms (SNPs) from directly genotyped data (Study-1; CDH13 genotype distributions were different between diabetic and non- Omni-express, Study-2; Illumina 610K) and genotype imputation using diabetic subjects: the odds ratio (95% CI) of type 2 diabetes for minor variants mini-MACH. Results of the 2 GWAS were combined with a meta-analysis were 1.11 (1.04-1.19) (P=0.002), 1.59 (1.06-2.38) (P=0.04), 0.92 (0.87-0.99) using the Mantel-Haenszel method. As a result, we identifi ed 5 SNP loci (P=0.02) and 0.91 (0.86-0.98) (P=0.008) respectively for the polymorphisms associated with DR in Japanese patients with type 2 diabetes (rs8025089 rs11646213, rs12051272, rs3865188 and rs4783244. The rs11646213 variant, -7 on chromosome [Ch]15: p = 3.0 × 10 , Odds ratio [OR] = 1.15, rs12630354 on associated with a higher risk of type 2 diabetes, was also associated with -7 -6 Ch3: p = 4.2 × 10 , OR = 1.15, rs2471299 on Ch7: p = 1.5 × 10 , OR = 1.14, higher BMI (p=0.04) and HbA1c (P=0.006) and lower plasma adiponectin -6 rs2517532 on Ch6: p = 3.9 × 10 , OR = 1.13, rs4240499 on Ch10: p = 4.4 × levels (P=0.03) in the general D.E.S.I.R. population. Conversely, the variants -6 10 , OR = 1.17). A sub-group analysis, excluding patients with simple DR, rs3865188 and rs4783244, associated with a lower risk of type 2 diabetes, has identifi ed 3 loci associated with advanced DR (2,003 DR cases [Study-1] were also associated with lower BMI (P=0.04) and HbA1c (P=0.03) and an -5 and 368 DR cases [Study-2]) (p < 1 × 10 ). None of the association reached to increase in plasma adiponectin levels (p=0.002 and 0.003). -8 genome-wide signifi cance (p < 5.0 × 10 ) in this study. In conclusion, we have In conclusion, CDH13 polymorphisms were associated with type 2 diabetes identifi ed several candidate loci potentially contributing to DR susceptibility, in the French population. This association may be mediated through effects although further studies are required to validate the association of these on BMI and plasma adiponectin. These results must be replicated in further loci with DR. investigations. Genetics POSTERS

Supported By: Grants-in-Aid for Scientifi c Research (C23591361); Ministry of Epidemiology/ Education, Culture, Sports, Science and Technology 1601-P Whole-Exome Sequencing in a Family with Highly Aggregated Type 1599-P 2 Diabetes Identifi es a Candidate Susceptibility Variant Insulin Signaling Genes Exert a Combined Effect on All-Cause DAISUKE TANAKA, KAZUAKI NAGASHIMA, SHINICHI HARASHIMA, NOBUYA Mortality INAGAKI, Kyoto, Japan CLAUDIA MENZAGHI, SIMONETTA BACCI, ANDREA FONTANA, STEFANO RIZZA, Familial clustering of diabetes is frequently observed. However, most BELINDA SPOTO, GIOVANNI TRIPEPI, ANTONELLA MARUCCI, ALESSANDRA Japanese families with highly aggregated type 2 diabetes remain genetically TESTA, MASSIMILIANO COPETTI, FRANCESCA MALLAMACI, SALVATORE DE unexplained. The aim of this study was to investigate the genetic background COSMO, MASSIMO FEDERICI, CARMINE ZOCCALI, VINCENZO TRISCHITTA, San of familial clustering of diabetes using whole exome sequencing. Giovanni Rotondo, Italy, Rome, Italy, Reggio Calabria, Italy We recruited a family with clustered diabetes in Japan. The family Type 2 diabetes (T2D) and cardiovascular (CV) disease are major factors contained 10 members and 9 of them had been diagnosed with diabetes. increasing all-cause mortality. Both clinical entities recognize a common soil Five affected members had been diagnosed before the age of 45 and their represented by insulin resistance (IR), which by itself also predicts all-cause body mass index was lower than 25. We performed whole exome sequencing mortality. IR is, at least partly, genetically determined. Thus, it is concievable in the 5 young-onset members and a family member aged over 80 without that genetic factors, which modulate IR, play also a role in modulating T2D, diabetes using the Agilent SureSelect Human All Exon V4 kit and an Illumina CV desease and all-cause mortality. Hiseq sequencer. In fact, we have previously reported the combined effect of single We predicted the familial clustering of diabetes was caused by a rare nucleotide polymorphisms (SNPs) perturbing insulin signaling (ENPP1 K121Q, non-synonymous variant, and therefore we focused our analysis on non- rs1044498; IRS1 G972R, rs1801278; TRIB3 Q84R, rs2295490) on IR and, as a synonymous variants present in the affected family members and not likely consequence, T2D and major CV events. Based on these encouraging present in unaffected members. Whole exome sequencing identifi ed 370 results, we investigated whether a combined effect of these 3 SNPs affects non-synonymous variants present in all 5 young-onset members and not also all-cause mortality. present in the unaffected member. After excluding common variants with We fi rst studied a sample comprising 742 patients (i.e. discovery sample; minor allele frequency of >1% in the 1000 genomes project, we selected 238 deaths/3,520 person-years; py). Replication was assessed in a second 14 candidate variants. Three of the candidate variants (p.T314M in GPR128, sample of 725 diabetic patients (i.e. replication sample; 129 deaths/5,495 py). p.P146S in CD200R1L, and p.P215S on AGBL2) were predicted to be damaging In the discovery sample, weighted genetic risk score (GRS), based on each by PolyPhen-2 and they were all confi rmed in all young-onset members by SNP’s effect size, was associated with all-cause mortality (HR=1.12, 95% Sanger sequencing. Then we genotyped 105 normal Japanese subjects CI=1.03-1.23). After stratifi cation according to low or high genetic load (GL) for the 3 variants. As a result, the only variant that was rare (minor allele (i.e. 0-1 or > 2 risk alleles), patients with high GL (n=123) were at increased frequency <1%) in normal population was the T314M mutation in the GPR128 risk of all-cause mortality (HR=1.36, 95% CI=1.00-1.86), as compared to gene (minor allele frequency=0.00, 0/210). those with low GL (n=619). In the replication sample, HR (95% CI) for all- Accordingly, the T314M mutation in the GPR128 gene might be a cause mortality was 1.06 (0.94-1.19) for GRS and 1.58 (1.06-2.35) for GL. susceptibility mutation in Japanese population. Family-based comprehensive In a pooled analysis (1,467 individuals; 367 deaths) both GRS and GL were exome sequencing may be a promising strategy to elucidate the complex associated with all-cause mortality HRs (95% CI)=1.11 (1.01-1.22) and 1.41 genetic background of type 2 diabetes. (1.10-1.80), respectively. Our fi nding indicates that functional non-synonymous variants affecting insulin signaling exert a joint effect on all-cause mortality and is consistent with a pathogenic role of IR on life expectancy.

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A417 GENETICS—TYPECATEGORY 2 DIABETES

1602-P 1604-P sRAGE Genetics and Clinical Outcomes in a Community-based ABCC10 (ATP-Binding Cassette Transporter Subfamily C) Is a Population Physiological Regulator of Glucose Transport NISA M. MARUTHUR, MAN LI, MARC H. HALUSHKA, BRAD C. ASTOR, JAMES ELIZABETH A. HOPPER-BORGE, JOELY JACOBS, EKATERINA MALOFEEVA, RYAN PANKOW, ERIC BOERWINKLE, JOSEF CORESH, ELIZABETH SELVIN, WEN HONG DAVIS, Philadelphia, PA L. KAO, Baltimore, MD, Madison, WI, Minneapolis, MN, Houston, TX ABCC10 (ATP-Binding Cassette protein, family C, member 10) is a broad Lower levels of plasma soluble Receptor for Advanced Glycation End- specifi city transporter of xenobiotics, including drugs important for cancer products (sRAGE) may be associated with increased risk of death, coronary therapy such as taxanes, vinca alkaloids and epothilone B, and modulators heart disease (CHD) and diabetes mellitus (DM), and sRAGE is lower in of the estrogen pathway. We recently established that Abcc10-/- mice blacks vs. whites. Using data from the Atherosclerosis Risk in Communities exhibit increased tissue sensitivity and lethality resulting from paclitaxel Study, we conducted a genome-wide analysis of sRAGE in whites and exposure compared to wild-type counterparts, indicating ABCC10 functions blacks and evaluated the association between genetic determinants of as a major determinant of in vivo taxane sensitivity in mice. However to sRAGE and clinical outcomes to understand the black-white difference in date, no physiological substrate for this protein has been identifi ed in vivo. sRAGE and the causal contribution of sRAGE levels to clinical outcomes. Interestingly, we have observed that the mice have a novel phenotype; Median sRAGE levels were 727.9 and 1066.5 pg/ml in blacks and whites, specifi cally the Abcc10 -/- mice have a tendency to be hyperglycemic and are respectively (P<0.0001). In whites (N=1737), we identifi ed rs2070600, a heavier in weight than their wild-type counterparts. These initial results have missense mutation in AGER, the gene encoding RAGE, as most signifi cantly been verifi ed on two different mouse strains. To gain further insight into the associated with sRAGE (P=7.26x10-16; MAF=0.04). The T allele of rs2070600 causes of the hyperglycemia we have performed a series of analyses. As was associated with ~50% lower sRAGE levels in both whites and blacks a fi rst step we measured the weights of the organs in the mice and found (P=0.02; MAF=0.01). In blacks, rs2071288, intronic to AGER, was associated that the Abcc10-/- mice have altered fat storage compared to the wild-type with 43% lower sRAGE in blacks (N=581; P=2.22x10-8; MAF=0.10) and was animals. We also found that the null mice are insulin resistant as indicated nearly absent and not associated with sRAGE in whites. While these AGER by a statistically signifi cant reduction in response to insulin stimulation. In SNPs explained a signifi cant proportion of variation in sRAGE within each addition, using glucose challenge experiments we observed that the Abcc10- population (blacks, 5.1%; whites, 3.5%), they did not explain a signifi cant /- animals require a longer time to moderate glucose levels compared to their portion of the black-white difference in sRAGE nor were they associated wild-type counterparts. To further extend our observations and to determine with risk of incident death, CHD, or DM in whites (N up to 9017) or blacks (N the potential for translational relevance, here we show that human ABCC10 up to 2871) after median follow up >20 years, suggesting that the observed directly transports glucose using well established accumulation assays in associations between sRAGE and clinical outcomes are due to unknown vitro. Lastly, we found that glucose modestly stimulates ABCC10 ATPase factors, possibly environmental or epigenetic. While sRAGE appears to activity. From these studies we conclude that ABCC10 is a glucose modulator. mark important clinical outcomes, future studies must identify the specifi c We are currently undertaking studies to determine if ABCC10 also affects mechanisms by which this occurs. Given the substantial racial differences in glucose levels indirectly via a signaling cascade. sRAGE levels, a further understanding of sRAGE could help to address racial disparities in DM and cardiovascular disease. 1605-P Supported By: R01DK076770 The TCF7L2 Gene Variants Affect Postprandial Glucose and Fat Genetics

POSTERS Oxidation in Non-Diabetic Subjects Epidemiology/ 1603-P ADAM KRETOWSKI, EDYTA ADAMSKA, JOANNA GOSCIK, MAGDALENA Genome-Wide Association Study Identifi es Two Novel Loci with WASZCZENIUK, NATALIA WAWRUSIEWICZ-KURYLONEK, ANNA CITKO, MICHAL Sex-specifi c Effects for Type 2 Diabetes and Glycemic Traits in the CIBOROWSKI, KATARZYNA MALISZEWSKA, MARIA GORSKA, Białystok, Poland Korean Population Although it is generally accepted that TCF7L2 gene has the strongest effect MIN JIN GO, JOO-YEON HWANG, TAE-JOON PARK, BOK-GHEE HAN, BONG-JO on the individual risk of type 2 diabetes, the mechanism for this is not fully KIM, Chung-buk, Republic of Korea understood. It has been shown that HapB haplotype (incl. rs7901695 C and Background: Until recently, genome-wide association study (GWAS)-based rs7903146 T) is related to pancreatic B-cell dysfunction but not to obesity. fi ndings have provided a substantial genetic contribution to type 2 diabetes On the other hand, HapA haplotype (represented by rs7903146 C variant) (T2D) or related glycemic traits. However, identifying allelic heterogeneity shows a signifi cant correlation with BMI and level of appetite regulating and population-specifi c genetic variants under consideration of potential hormones. The aim of the study was to analyze whether TCF7L2 variants confounding factors will be very valuable for clinical applicability. To identify may infl uence body fat composition and postprandial energy metabolism in novel susceptibility loci for T2D and glycemic traits, we performed a two- non-diabetic subjects. stage genetic association study in the Korean population. We genotyped previously identifi ed TCF7L2 SNPs: rs7901695, rs7903146 Methods: In a logistic analysis for T2D, the fi rst discovery GWAS was and rs4506565 in 944 subjects (329 normal-weight, 337 overweight, 278 analyzed for 1,042 cases and 2,943 controls recruited from a population- obese) who underwent anthropometric measurements, body composition based cohort (KARE, n = 8,842). The second stage de novo replication analysis and OGTT. In randomly selected 59 healthy subjects standardized analysis was conducted in 1,216 cases and 1,352 controls selected from meal tests were performed and postprandial carbohydrate and fat oxidation an independent population-based cohort (Health2, n = 8,500). A multiple by indirect calorimetry were evaluated. Kruskal-Wallis non-parametric linear regression analysis for glycemic traits was further performed in a analysis to evaluate difference between the studied parameters was total of 14,232 non-diabetic individuals comprising 7,696 GWAS and 6,536 performed. replication study participants. A meta-analysis was performed on the In the studied group the TCF7L2 rs7903146 genotypes were signifi cantly combined results using effect size and standard errors estimated for stage associated with visceral fat tissue accumulation (respectively for CC vs. 1 and 2, respectively. CT vs.TT: 82.0 vs. 144.6 vs. 176.4 cm3, p=0.03), but not with BMI or body Results: A combined meta-analysis for T2D identifi ed two new (rs11065756 fat content. Subjects with CC genotype (rs7901695) presented lower and rs2074356) loci reaching genome-wide signifi cance in CCDC63 and carbohydrate oxidation from 60 min after meal intake and signifi cantly lower C12orf51 on 12q24 region. In addition, these variants were signifi cantly area under the curve (AUC) for glucose oxidation (p=0.005) in postprandial associated with fasting plasma glucose and HOMA-B. Interestingly, state in comparison to those with other genotypes. Moreover signifi cantly two independent SNPs were found to be associated with sex-specifi c higher postprandial fat oxidation were found for TT (rs7903146) vs. CC and stratifi cation in this study. CT genotypes (p=0.0013). Conclusion: Our study showed the strong association with T2D and Our study suggests that the TCF7L2 variants may be associated with the glycemic traits. We further observed that two novel loci with multiple regulation of postprandial energy metabolism. If our results are confi rmed, diverse effects are highly specifi c to men. These fi ndings could bring TCF7L2 gene-related personalized nutrition, such as diet with lower additional insights into clinical assessment or sub-classifi cation of disease carbohydrate content can be considered for T2DM prevention. risk in the Korean population. Supported By: MNiSzW 4774/B/P01/2009/37 Supported By: KNIH

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A418 GENETICS—TYPECATEGORY 2 DIABETES

1606-P 1608-P Variants in PPARG Interact with High-Fat Diet to Infl uence Longi- Analysis of Established Type 2 Diabetes Variants in Soutwestern tudinal Decline in β-Cell Function in Mexican Americans at Risk for American Indians Type 2 Diabetes (T2D) ROBERT L. HANSON, SAYUKO KOBES, JEFFREY M. CURTIS, E. JENNIFER. WEIL, MARY HELEN BLACK, JUN WU, KENT D. TAYLOR, TALIN HARITUNIANS, EN- ROBERT G. NELSON, LESLIE J. BAIER, Phoenix, AZ RIQUE TRIGO, JEAN M. LAWRENCE, RICHARD M. WATANABE, THOMAS A. Several single nucleotide polymorphisms (SNPs) are reproducibly associated BUCHANAN, ANNY H. XIANG, Pasadena, CA, Los Angeles, CA with type 2 diabetes mellitus (T2DM) in European and Asian populations. PPARG is a known susceptibility locus for T2D. Four SNPs (C-681G, There are only a few studies, however, on these variants in American Indian Pro12Ala, C-689T, C1431T) have been reported to infl uence obesity, metabolic populations, many of which have a high prevalence of T2DM. syndrome and/or diet-induced weight loss observed in intervention trials. We genotyped a “sentinel” SNP at 41 established T2DM loci in 3106 We hypothesized that these SNPs may interact with dietary intake to American Indians (1563 women, 1543 men, mean age=36.6 years) from infl uence longitudinal changes in anthropometric and metabolic traits in urban Phoenix who were not part of our previous studies in Pima Indians; individuals at risk for T2D. We tested these hypotheses in a subset of 346 individuals came from several southwestern American Indian tribes, and 868 BetaGene participants (mean age: 35±8 years; 75% female) with follow- (27.9%) had diabetes. Logistic regression was used to analyze association of up phenotyping (mean length of follow-up: 4.6 ± 1.5 years). Body fat was T2DM with the established risk allele at each locus, and to calculate the odds assessed by DXA, and insulin sensitivity (SI), acute insulin response (AIR) ratio (OR) under an additive model. Linear regression was used to analyze and β-cell function (disposition index; DI) were estimated from FSIGTs quantitative traits. A multiallelic risk score, constructed by summing the with Minimal Model analysis. We tested whether the interaction between number of risk alleles over all loci, was also analyzed. The genomic control each SNP (or its proxy: r2>0.8) and a high-fat dietary pattern (35% fat, 44% procedure, using 42 markers, was used to correct for potential population carbohydrate, 21% protein) previously reported in BetaGene participants, stratifi cation. was associated with rates of change in anthropometric and metabolic traits Nominally statistically signifi cant (P<0.05) associations were seen with after adjustment for age, sex and baseline body fat percentage. An additive T2DM in a direction consistent with other populations for SNPs in WFS1 genetic model was assumed for SNPs with MAF >20% and a dominant (OR=1.23), KLF14 (OR=1.17), CDC123 (OR=1.27), KCNQ1 (OR=1.20), HMG20A model otherwise. P-values were Bonferroni-corrected for four interaction (OR=1.31) and FTO (OR=1.28). The multiallelic score was also strongly tests. rs11828598 (tags C-681G), rs13064760 (tags Pro12Ala) and rs17036328 associated with T2DM (OR=1.07 per copy of a risk allele, (P=2.2×10-7), and, (tags C-689T) each interacted with high-fat diet to alter the rate of change among 949 nondiabetic individuals with measurements of fasting serum in DI (corrected p=0.05, 0.009 and 0.005, respectively). Interactions with insulin concentration, with a lower HOMA-B estimate of insulin secretion rs13064760 and rs17036328 were also marginally associated with the rate (effect= 1.8% per allele, P=0.002). When the six nominally signifi cant of change in AIR (corrected p: 0.09 and 0.11, respectively). Among individuals variants were excluded from the multiallelic score, results were attenuated carrying one or more risk alleles for each SNP, declines in DI and AIR were but still signifi cant (OR=1.04, P=0.005; effect=1.6%, P=0.011). only observed among those with a high-fat diet. Further adjustment for This study suggests that genetic variants associated with T2DM in other changes in adiposity over time did not alter these results. These data suggest populations also generally infl uence diabetes risk in American Indians, and that variation in PPARG interacts with high-fat diet to infl uence β-cell decline that the effects may be mediated by decreased insulin secretion. in Mexican Americans at risk for T2D. Genetics

1609-P POSTERS 1607-P Exome Array Analysis in >30,000 Europeans Identifi es Novel Coding Epidemiology/ Whole-Exome Sequencing in Koreans Identifi es PAX4 R192H Variant Variants Associated with Glycemic Traits as Susceptibility Locus for Type 2 Diabetes ANUBHA MAHAJAN, HUI JIN NG, ADAM LOCKE, XUELING SIM, ALISA SOO HEON KWAK, SEUNGBOK LEE, HYUN-JIN KIM, CHANG HO AHN, MIN MANNING, NIELS GRARUP, HEATHER M. HIGHLAND, HAE K. IM, MANUEL KYEONG KIM, EUN ROH, EU JEONG KU, KYONGYEUN JUNG, DONG HWA LEE, RIVAS, ANDREW P. MORRIS, CECILIA M. LINDGREN, ANNA L. GLOYN, JAMES BOKYUNG KOO, HYE SEUNG JUNG, MIN KYONG MOON, YOUNG MIN CHO, B. MEIGS, ON BEHALF OF T2D-GENES AND GOT2D CONSORTIA, Oxford, United SOO LIM, KYUNGA KIM, JONG-IL KIM, HAK C. JANG, KYONG SOO PARK, Seoul, Kingdom, Ann Arbor, MI, Cambridge, MA, Copenhagen, Denmark, Houston, TX, Republic of Korea, Seongnam, Republic of Korea Chicago, IL, Headington, United Kingdom, Boston, MA Type 2 diabetes is a common complex disorder with strong genetic To identify coding variants associated with fasting plasma glucose (FG) predisposition. Although more than 75 common genetic variants of diabetes and fasting insulin (FI), we studied up to 33,407 and 30,992 non-diabetic have been identifi ed through genome-wide association studies, their effect Europeans, respectively. Samples were genotyped using the Illumina exome sizes are small and they only explain a limited proportion of the heritability. array, which collectively represents >80% protein altering variation with In this study we used whole exome sequencing to identify low frequency, >0.5% minor allele frequency (MAF) in Europeans. We tested single variants functional variants of type 2 diabetes. This was a case-control analysis using for association with FG and FI using a linear mixed model to account for 320 type 2 diabetes patients and 100 carefully selected controls subjects. relatedness. We also carried out gene-based analyses using the sequence Whole exome capture was prepared using Agilent SureSelect version 4+UTR kernel association test (SKAT). We then combined association summary and sequencing was performed by Illumina HiSeq 2000. Sequence alignment statistics by meta-analysis across studies at up to 135,904 high-quality was done using BWA and Picard software and variant identifi cation was done autosomal variants and 13,356 genes. using GATK software. EPACTS software was used for association testing. In G6PC2, which resides in an established genome wide association study The average throughput depth of target regions was 170.1X and mean read (GWAS) locus, multiple low-frequency (LF; MAF 0.5-5%) or rare (MAF<0.5%) -10 depth of target regions was 96.2X. In average, one individual had 65,233 missense variants were associated with FG in aggregate (PSKAT=8.0x10 ). single nucleotide polymorphisms (SNPs) with 7,254 nonsynonymous SNPs. Conditional single-variant analysis established the presence of two A nonsynonymous SNP in PAX4 (rs2233580, R192H) was associated with independent association signals at exome-wide signifi cance (P<5x10-7) in -9 risk of diabetes with minor allele frequency (MAF) in diabetes subjects 0.122 this gene, one common (PCOND =3.7x10 , 48.1% MAF, V219L) and one rare -11 and controls 0.030 (Odds ratio [OR]=4.64, P=1.4x10-4). We then compared (PCOND =2.0x10 , 0.8% MAF, H177Y), neither of which weakened association -58 diabetes subjects having the rs2233580T variant of PAX4 gene (N=77) and of the GWAS SNP at this locus (rs560887; PCOND on V219L=7.4x10 and PCOND on -54 diabetes subjects not having this variant (N=243). Those with the variant H177Y=6.8x10 , 30.1% MAF). had lower body mass index (23.3±2.5 vs. 24.0±2.5, P=0.037) and lower waist We also identifi ed three genes not mapping to previously reported GWAS circumference (83.0±7.3 vs. 84.7±6.7, P=0.047) with nominal signifi cance. loci in which coding variants were associated with FG (GLP1R: P=4.4x10-7, We further genotyped this variant in additional 1,066 case-control subjects 1.6% MAF, A316T) or FI (URB2: P=3.8x10-7, 0.1% MAF, E594V; and NLRP14: -7 and found that it was associated with type 2 diabetes (OR=1.61, P=0.0018). PSKAT=1.5x10 , 17 variants with MAF<5%). An intergenic, common variant Overall the OR was 1.81 and P value was 4.18x10-5. Currently we have rs6905288 near VEGFA was also associated with FI (P=2.4x10-7, MAF=44.0%). fi nished sequencing 500 additional type 2 diabetes cases and controls and Of these, GLP1R encoding glucagon-like peptide 1 receptor transduces the results are being analyzed. In conclusion, we have identifi ed a common incretin signaling in pancreatic islets. We demonstrate that coding variants nonsynonymous variant in PAX4 to be associated with risk of diabetes in infl uence glycemic trait levels, but did not fi nd evidence that LF and/or rare Koreans. coding variants could account for existing common-variant GWAS signals.

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A419 GENETICS—TYPECATEGORY 2 DIABETES

1610-P 1612-P Resistin SNP-358, SNP-420, and rs1423096 Were Identifi ed as Decreased MicroRNA-15a Levels in Peripheral Blood of Bahraini Major Quantitative Trait Loci for Serum Resistin by a Genome-Wide Patients with Type 2 Diabetes Mellitus and Prediabetes Association Study in Japanese GHADA AL-KAFAJI, GHAZI AL-MAHROOS, NASREEN A. ALSAYED, ZUHEIR A.K. RYOICHI KAWAMURA, YASUHARU TABARA, MICHIYA IGASE, YASUNORI HASAN, Manama, Bahrain TAKATA, RYUICHI KAWAMOTO, ISAO SAITO, TAKESHI TANIGAWA, HIROSHI MicroRNAs (miRNAs), a class of small non-coding RNAs, are crucial ONUMA, KATSUHIKO KOHARA, NORIHIRO KATO, TETSURO MIKI, HARUHIKO regulators of gene expression and have been implicated to play important OSAWA, Toon, Japan, Kyoto, Japan, Tokyo, Japan role in insulin secretion. Dysregulation of several circulating miRNAs has Resistin is a cytokine inducing insulin resistance. We reported that single been described in type 2 diabetes (T2D) and may contribute to related nucleotide polymorphism (SNP) -420 (rs1862513) in the human resistin gene pathologic process. In this study, we focused on examining the levels of (RETN) was associated with type 2 diabetes susceptibility (Am J Hum Genet miRNA-15a (miR-15a) expression, an important regulator of insulin synthesis, 75: 678, 2004). SNP-358 (rs3219175) as well as SNP-420, both located in in the blood from Bahraini patients with T2D and pre-diabetes. the promoter region of RETN, was tightly correlated with circulating resistin Circulating miR-15a was extracted from peripheral blood of 21 patients via a cis-acting effect (PLoS ONE 5: e9718, 2010). We recently showed that with T2D, 20 subjects with pre-diabetes, and 21 non-diabetic controls. circulating resistin was also affected by tag SNPs around the human decorin Levels of miR-15a were determined by real time PCR using TaqMan assay gene, identifi ed as a possible resistin receptor of mice, via a trans-acting and were compared among the three groups. effect (Diabetes 62: 649, 2013). Peripheral blood miR-15a levels were signifi cantly decreased in T2D To identify quantitative trait loci for circulation resistin, we conducted a patients and pre-diabetic subjects compared to control subjects (P<0.05). genome-wide association study (GWAS). We analyzed 463 general Japanese In multivariate logistic regression analysis, miR-15a levels were signifi cantly subjects who underwent medical checkup using HumanOmni 2.5. Serum associated with T2D and pre-diabetes (odds ratio [OR] = 0.75; confi dence resistin was measured by ELISA. interval [CI] = 0.74 to 1.25; P < 0.005) and odds ratio [OR] = 0.74; confi dence The peak of -log P was found on the chromosome 19 where RETN was interval [CI] = 0.72 to 1.48; P < 0.005) respectively. Furthermore, lower miR- located. Precisely, serum resistin was most strongly associated with SNP- 15a levels were signifi cantly correlated with higher glycated hemoglobin 358, followed by rs1423096 located at 5 kb downstream from the transcription (HbA1C; > 5.7 percent) (β coeffi cient = 0.6; P < 0.005) and higher fasting initiation site of RETN, and SNP-420 (P<10-40, <10-20, and <10-10, respectively). blood glucose [(FBS; > 5.6 millimoles per liter (100 milligram per deciliter)] The association between serum resistin and these 3 SNPs was replicated (β coeffi cient = 0.5; P < 0.005), and showed no correlation with BMI, blood in other 2 general Japanese populations (both n=~2,000; SNP-358, P<10-200; pressure, total cholesterol, triglyceride as well as other factors such as age SNP-420, P<10-100; rs1423096, P<10-50). It was reported that SNP-420 was and sex (P > 0.05). not associated with circulating resistin in Caucasians (Hivert et al, Diabetes Our preliminary results demonstrated that levels of peripheral blood miR- 58: 750, 2009). The association between these 3 SNPs and serum resistin 15a are decreased in Bahraini patients with T2D and pre-diabetes. Studies appear to be stronger in Japanese than Caucasians, which could account for are underway to further investigate the prognostic signifi cance of miR-15a this ethnic difference. for risk estimation in larger Bahraini population. In summary, the GWAS identifi ed RETN SNP-358, SNP-420, and rs1423096 Supported By: Arabian Gulf University were major 3 quantitative trait loci for serum resistin in Japanese. These Genetics SNPs merit further investigation to clarify ethnic differences in the POSTERS 1613-P Epidemiology/ association of circulating resistin. Variants in the Promoter of STAM2 Are Associated with Type 2 Diabetes in Pima Indians 1611-P ANUP K. NAIR, ROBERT L. HANSON, PAOLO PIAGGI, NELLIE MCLEAN, YUNHUA The DNA Methylation at Single Nucleotide Polymorphism (SNP)-420 MULLER, KE HUANG, SAYUKO KOBES, WILLIAM C. KNOWLER, CLIFTON in the Promoter of the Human Resistin Gene Is Inversely Associated BOGARDUS, LESLIE J. BAIER, Phoenix, AZ with Plasma Resistin in the General Japanese Population A recent GWAS report identifi ed rs10930939 in STAM2 as being nominally HIROSHI ONUMA, YASUHARU TABARA, RYOICHI KAWAMURA, RYUICHI associated with Type 2 Diabetes (T2D) in full heritage Pima Indians. In the KAWAMOTO, WATARU NISHIDA NISHIDA, YASUNORI TAKATA, HIDEICHI current study we further investigated the region containing this signal. MAKINO, KATSUHIKO KOHARA, TETSURO MIKI, HARUHIKO OSAWA, Toon, Whole genome sequence data from 234 Pima Indians were used to identify Japan, Kyoto, Japan, Imabari, Japan the linkage disequilibrium (LD) pattern across this region which found We reported that SNP at -420 (rs1862513) was associated with type 2 rs10930939 in high LD (r2=1) with a promoter SNP (rs4368329) in STAM2. diabetes (T2D). The G/G genotype at -420 increased T2D susceptibility by This SNP and 3 additional variants (rs72864765, rs6740224 and rs60252671 enhancing its promoter activity (Am J Hum Genet 2004). Plasma resistin [insertion/deletion]) in the promoter region of STAM2 were predicted to was highest in G/G genotype, followed by C/G, and C/C (Diabetes Care be located in ENCODE transcription factor binding sites (TFBS). Based on 2007). A cytosine-phosphate-guanine (CpG) dinucleotide “CpG” is a possible the LD pattern, tag SNPs (r2>0.8) in STAM2 and the 4 ENCODE TFBS SNPs methylation site of DNA. Since increased methylation in the promoter is were genotyped in 3604 full heritage Pima Indians which identifi ed nominal associated with decreased transcription, promoter SNPs affecting CpG associations for rs6740224, rs4368329, rs60252671 and an intronic variant, sequences, could affect gene expression. When SNP-420 (C>G) is C, this rs7603232, with T2D (P=0.06 - 1.4×10-3, OR=1.13-1.2). We further replicated element can read “CpG”, which could be methylated. The aim of this study the association of these 4 SNPs with T2D by genotyping a non-overlapping is to examine whether methylation at -420 affects resistin gene expression sample of 3950 mixed heritage American Indians (P=0.052 - 3.9×10-4, OR=1.13- and plasma level. 1.29). The strongest evidence for T2D association came from the combined We fi rst analyzed plasma resistin and methylation at -420 in the analysis of both data sets for SNPs rs7603232 and rs6740224 (P=1.2×10-5, human resistin gene in 2,078 Japanese. Methylation was quantitated by OR=1.23[1.12-1.35] and P=1.3×10-4, OR=1.19[1.09-1.29] respectively). We also pyrosequencing (QIAGEN). Plasma resistin was measured using ELISA analyzed the mRNA expression data available from skeletal muscle (N=207) (Millipore). Methylation at -420 was inversely correlated with plasma and percutaneous abdominal adipose (N=197) tissue from Pima Indians. This resistin when genotypes were not considered (r= -0.490, P<0.0001). When identifi ed signifi cant association of the 4 T2D associated variants with the analyzed in each SNP genotype, methylation at -420 showed the inverse expression of STAM2 in skeletal muscle (P=2.5×10-3 - 6.3×10-4, β= 0.29-0.34 correlation with plasma resistin in CC genotype (r=-0.193, P<0.0001) and CG SD unit per copy of the risk allele) with the T2D risk alleles increasing the genotype (r= -0.175, P<0.0001). No association was found in G/G genotype. expression of STAM2 mRNA. STAM2 has been identifi ed to play a role in We next examined the relation between methylation at -420 and resistin downstream signaling of cytokine and growth factor receptors. It forms mRNA in THP-1 human monocytes. A demethylating reagent, 5-Aza- a part of the ESCRT-0 complex involved in the sorting of ubiquitinated dC, decreased methylation at -420, and increased resistin mRNA. The receptors for downstream processes. Recent studies also identifi ed STAM2 resistin mRNA was inversely correlated with methylation at -420 (r=-0.81, as a downstream substrate for PTP1B. P<0.0001). In summary, methylation at -420 was inversely associated with plasma resistin in the general Japanese population. In THP-1cells, resistin mRNA was inversely correlated with methylation at -420. Therefore, in addition to SNP-420 itself, methylation at -420 could regulate the human resistin gene expression and plasma resistin.

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A420 GENETICS—TYPECATEGORY 2 DIABETES

1614-P bioinformatics in ascribing pathogenicity, and seems to be most helpful for The IRS1 G972R Polymorphism Is Associated with Failure to Oral variants in class 3. Hypoglycemic Agents in Patients with Type 2 Diabetes Supported By: Kristian Gerhard Jebsen Foundation; University of Bergen; Western SABRINA PRUDENTE, ELEONORA MORINI, DANIELA LUCCHESI, OLGA LA- Norway Regional Health Authority MACCHIA, DIEGO BAILETTI, LUANA MERCURI, FEDERICA ALBERICO, MASSI- MILIANO COPETTI, LAURA PUCCI, STEFANIA FARIELLO, LAURA GIUSTI, MAURO 1616-P CIGNARELLI, GIUSEPPE PENNO, SALVATORE DE COSMO, VINCENZO TRISCHITTA, MicroRNA in Insulin Resistance and Response to Glitazones San Giovanni Rotondo, Italy, Rome, Italy, Pisa, Italy, Foggia, Italy ELENA FLOWERS, BRADLEY AOUIZERAT, FAHIM ABBASI, CYNTHIA LAMENDOLA, Oral hypoglycemic agents (OHA), especially in combination, are widely GERALD REAVEN, San Francisco, CA, Stanford, CA used for treating hyperglycemia in patients with in type 2 diabetes (T2D). MicroRNAs (miR) are an epigenetic mechanism that regulates gene When no good glycemic control is achieved, the addition of insulin therapy expression. Given that miRs provide an aggregate measure of individual either on or instead of OHA is the most effective choice. Thus, the initiation response to genetic and environmental exposures, they may provide a novel of insulin therapy in patients who are already treated with OHA may be biomarker to evaluate an individual’s risk for type-2 diabetes (T2D) and considered a consequence, and therefore a proxy, of secondary failure to treatment response. The aims of this study were to compare miR expression these agents. between individuals with and without insulin resistance and to determine Among the few genetic markers able to predict the need of adding insulin whether miR levels predict response to glitazone treatment. In a sample in patients treated with OHA, is the IRS1 G972R missense polymorphism of 93 generally healthy adults, insulin sensitivity was measured using a (rs1801278). Such fi nding has been reported in a relatively small sample and modifi cation of the hyperinsulinemic euyglycemic clamp. Insulin resistance has not been replicated in independent studies. We tried to replicate this was defi ned as steady state plasma glucose ≥180mg/dL and insulin sensitive previously reported association in a large sample of White patients with was defi ned as <120mg/dL. Response to glitazone therapy was defi ned as at T2D living in a geographically and culturally homogenous area (i.e. Central least one standard deviation improvement in steady state plasma glucose and Southern Italy). (≤140mg/dL) after 12 weeks. Thirty-one plasma miRs were measured using A total of 2,409 patients from 4 independent studies were investigated. hydrogel particle hybridization and fl ow cytometry. Relative fold change Cases (n=1,193) were patients in whom, because of uncontrolled diabetes was calculated and Student’s t-test was used to compare normalized miR (i.e. HbA1c>8%), insulin therapy had been added either on, or instead of, expression between groups. At baseline, 81% (n=75) of participants were maximal or near maximal doses of OHA; controls (n=1,216) were patients insulin resistant. Three miRs exhibited ≥1.5-fold differential expression with HbA1c<8% in the absence of insulin therapy. The G972R polymorphism between the insulin resistant and sensitive groups: miR-126-3p (1.5, p<0.005), was typed by TaqMan allele discrimination. miR-34a-5p (-2.1, p=0.05), and miR-320a (13.2, p<0.001). In the subset who In all study samples, individuals carrying the IRS1 R972 risk variant were insulin resistant at enrollment (n=75) and received glitazones, 23% tended to be more frequent among cases than controls, though reaching (n=17) became insulin sensitive. MiR-27a-3p (4.3, p<0.005) and miR 34a- statistical signifi cance only in one case. Since no IRS1 G972R-by-study 5p (-2.5, p<0.05) were differentially expressed between responders and sample interaction was observed, data from the 4 samples were pooled and non-responders. The miRs that were differentially expressed between the analyzed together; a signifi cant association was observed (allelic OR=1.30, insulin resistant and sensitive groups were found to be associated with T2D 95% CI=1.03-1.63). When data from the 4 study samples were meta-analyzed and related conditions. To our knowledge, this study is the fi rst to report with those from the previous study, an overall R972 allelic OR of 1.37 (1.12- Genetics miRs associated with response to a pharmacologic intervention for insulin POSTERS 1.69) was observed. resistance. Additional studies are needed to determine whether miRs can Epidemiology/ This study confi rms in a large and ethnically homogeneous sample that predict treatment response and guide pharmacologic therapy. IRS1 G972R polymorphism is associated with failure to OHA among patients with T2D. 1617-P Supported By: Italian Ministry of Health Transcription Factor 7-like 2 Contributes to the Regulation of Hepatic Gluconeogenesis 1615-P RENUKA T. MENON, SUSAN L. SAMSON, Houston, TX Transactivation Analysis Can Supplement Bioinformatics in Genome wide association studies have established that human single Assessing Effect of Rare HNF1A Variants in the General Population nucleotide polymorphisms of transcription factor 7-like 2 (TCF7L2) convey LAEYA A. NAJMI, INGVILD AUKRUST, JANNE MOLNES, JASON A. FLANNICK, risk for the development of type 2 diabetes in multiple ethnic backgrounds. NOËL BURTT, ANDERS NOLVEN, LEIF GROOP, DAVID ALTSHULER, STEFAN Studies examining the role of TCF7L2 in liver glucose metabolism have JOHANSSON, LISE BJØRKHAUG, PÅL NJØLSTAD, Bergen, Norway, Cambridge, shown disparate results, with TCF7L2 appearing to promote or repress MA, Malmö, Sweden hepatic gluconeogenesis dependingon the approach used. We have Around 2% of 4003 randomly selected individuals from Framingham employed a fl oxed TCF7L2 mouse model to study the role of this factor in the and Jackson Heart, and Swedish/Finnish T2D cohorts (814 diabetes, 3189 liver. TCF7L2fl ox/fl ox mice were injected intravenously with helper-dependent normoglycemia) carry 108 rare (MAF <1%), nonsynonymous variants in 1 adenovirus (1.5 x10 11vp/mouse) expressing Cre recombinase under the of 7 MODY genes (Flannick et al, Nat Genet, 2013). Of these, 27 were in regulation of the Apolipoprotein A1 promoter (HDAd-Cre) to knockout hepatic HNF1A. Since most variant carriers remain normoglycemic through middle expression of TCF7L2. Control mice received empty HDAd (HDAd-0). Pyruvate age, improved criteria in ascribing pathogenicity to rare variants are needed. tolerance testing (PTT) at 6 weeks revealed signifi cantly increased glucose We questioned whether in cellulo functional testing of HNF1A variants could excursion at 30 and 60 minutes consistent with increased gluconeogenesis supplement the bioinformatics assessment. in the HDAd-Cre mice. Using primary hepatocytes from TCF7L2fl ox/fl ox mice We classifi ed variants in 5 classes: 1, not pathogenic; 2, likely not treated with HDAd-Cre or HDAD-0 in vivo (6 weeks) or in vitro (72 hours), pathogenic; 3, uncertain; 4, likely pathogenic; 5, defi nitely pathogenic (Plon there was increased glucose producton from the Cre treated hepatocytes et al, Hum Mutat, 2008). The effect of variants with score of ≥2 was further in culture, supporting that depletion of TCF7L2 increased gluconeogenesis. investigated. HeLa cells were transiently transfected with WT or mutant There are several putative TCF7L2 binding sites in the promoter regions of HNF1A plasmids and Luciferase reporter plasmids pGL3-RA (rat albumin gluconeogenic enzymes, phosphoenolpyruvate carboxykinase and glucose- promoter) and pRL-SV40 (internal control). Variant transcriptional activity 6-phosphatase and transfection of TCF7L2 in Hek293 cells activates promoter was calculated relative to WT activity. activity but only when transfected in concert with its cofactor, activated Of 27 HNF1A variants, 24 were class 2-4 (none class 5). One was excluded beta-catenin. This suggests that these potential transcription regulatory due to technical problems and 23 were investigated. Transcriptional activity sites have a role in regulating gluconeogenic gene expression but whether was mean 41.0% for variants found only in diabetic subjects and 63.4% for the TCF7L2 acts as a transcription activator or repressor of gluconeogenic genes others. Four variants had transcriptional activity of 0-40%. These were class depends on the state of activation of the Wnt pathway. 2, 3 or 4, and were identifi ed in 4 subjects who had diabetes. Three variants Supported By: ADA (1-11-JF-46) had transcriptional activity of 73-100%. These variants were class 3, and were identifi ed in 3 normoglycemic subjects. The remaining 16 variants had transcriptional activity of 41-72%. These variants were class 2 or 3, and were identifi ed in 27 subjects of whom 6 had diabetes and 21 were normoglycemic. Functional characterization by measurement of transcriptional activity for 23 rare HNF1A variants identifi ed in the general population can supplement

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1618-P 1620-P Characterization of Glucose Tolerance of Two Beta Cell-specifi c Dietary Intervention-induced Midlife MicroRNA Expression Asso- and Inducible Cre Recombinase Mouse Lines in Response to High ciated with Longevity and Metabolic Function Fat/High Sucrose Diet CHRISTOPHER D. GREEN, YI HUANG, LIU YANG, YONG LIU, JING-DONG J. HAN, RENUKA T. MENON, ERICA V. GONZALEZ, LAYLA ABU-SHAMAT, SUSAN L. Shanghai, China SAMSON, Houston, TX Dietary interventions, such as modulating lipid, carbohydrate, or total Transgenic mouse models which enable beta-cell specifi c expression of caloric intake, dramatically affect obesity and type II diabetes susceptibility Cre recombinase are indispensable for the study of fl oxed gene contributions but also modify lifespan in various aging models. Recently, using different to glucose homeostasis and development of diabetes. The Rat insulin dietary interventions, we demonstrated the close relationship between promoter 2 (RIP) driven Cre expression has been shown to have an infl uence midlife metabolic function and lifespan, and we further showed midlife liver on glucose homeostasis compared to wild type mice but characterization of gene expression could predict novel lifespan regulators. To gain insight into beta cell specifi c tamoxifen (Tam) inducible Cre (Cre-ER) models has not been the epigenetic role of microRNA (miRNA) regulation, we performed mRNA- reported. High fat-high sucrose (HFHS) diet is used in mouse studies to cause and miRNA-sequencing of livers obtained from 62 week old mice (midlife) metabolic stress and to unmask gene contributions which may not be obvious chronically treated with low fat diet (LF), high fat diet (HF), LF or HF diet under chow fed conditions. We have examined RIP-Cre-ER and the newer plus voluntary exercise, or LF or HF diet with calorie restriction to 70% of mouse insulin promoter (MIP)-Cre-ER models in this context. Male mice (6-8 normal food intake. Dietary intervention-induced changes in overall miRNA weeks) were treated Tam or vehicle by gavage and glucose tolerance testing expression profi les refl ected the differences in average lifespan and liver was performed intermittently over the next 24 weeks on diet to determine physiology. Specifi cally, we identifi ed 87 miRNAs exhibiting signifi cant any effects on glucose homeostasis. Sibling C57BL/6J mice also were lifespan and metabolism-related expression profi les with a predominately treated with Tam or vehicle in parallel. Tam treated RIP-Cre-ER+ mice on negative correlation (72) rather than positive (15). Characterization of miRNAs HFHS diet displayed glucose intolerance compared to vehicle RIP-Cre-ER+ signifi cantly regulated by specifi c interventions found the effects of exercise mice beginning at 10 weeks on diet and worsening to the end of the study. or calorie restriction are highly dependent on dietary fat content. Based on There was no difference in weight but insulin levels were lower during GTT our RNA-seq data, TargetScan predicted miRNA-mRNA target gene pairs for the Tam mice signifying compromised insulin secretion. In comparison, are more likely to be negatively correlated, compared to background and neither MIP-Cre-ER or sibling C57BL/6J Tam and vehicle groups displayed permutation, and similarly, miRNA-mRNA pairs with negative correlations differences in glucose tolerance when exposed HFHS diet. Our present study are more likely to be included in TargetScan. A network based approach suggests that careful consideration of control groups is essential when further identifi ed overlaps between clusters of miRNA-mRNA target gene performing experiments using RIP-Cre-ER mice, Tam treatment, and special pairs associated with lifespan. Together, our fi ndings demonstrate that diet. Moreover, the newer transgenic line, MIP-Cre-ER does not appear to dietary interventions signifi cantly regulate miRNA expression profi les and be susceptible to such effects in comparing Tam and vehicle treatment and their predicted downstream targets, providing a basis for future studies when stressed with HFHS diet. The mechanism by which transient treatment characterizing miRNAs that mediate the gene expression and metabolic with Tam can cause such delayed differences in glucose tolerance of RIP- changes associated with altered lifespan. Cre-ER mice on HFHS diet remains to be elucidated. Supported By: Chinese Academy of Sciences; NNSF Supported By: ADA (1-11-JF-46) Genetics

POSTERS 1621-P Epidemiology/ 1619-P Proteomic Analysis of Livers from Protein Kinase C-defi cient Mice Mutations in KCNJ11 Are Associated with the Development of Fed a High-Fat Diet Autosomal Dominant, Early-Onset Type 2 Diabetes BING QING (MANA) LIAO, KATY RADDATZ, CARSTEN SCHMITZ-PEIFFER, Sydney, LIMEI LIU, KAZUAKI NAGASHIMA, TAKAO YASUDA, YANJUN LIU, HAI-RONG Australia, Greifswald, Germany HU, GUANG HE, BO FENG, MINGMING ZHAO, LANGEN ZHUANG, TAISHAN The two isoforms of protein kinase C (PKC), PKCδ and PKCε, have been ZHENG, HONG CHEN, RONG ZHANG, THEODORE C. FRIEDMAN, KUNSAN XIANG, associated with insulin resistance in the liver, which is a characteristic of Shanghai, China, Kyoto, Japan, Kobe, Japan, Los Angeles, CA Type 2 diabetes. Our previous comparison between PKCδ knockout (KO) mice Aims/Hypothesis: More than 90% of Chinese familial early-onset type and PKCε KO mice revealed roles for both of the kinases in the generation of 2 diabetes mellitus is genetically unexplained. To investigate molecular insulin resistance, yet opposing roles in hepatic triglyceride accumulation. etiology of these patients, we identifi ed and characterized whether muta- In order to gain mechanistic insights into the roles of PKCs in the modulation tions in KCNJ11 gene are responsible for these families. of insulin action and lipid metabolism, we conducted an unbiased in vivo Methods: KCNJ11 mutations were screened for 96 familial early-onset spike-in SILAC proteomic profi ling of livers from these animals. A total of type 2 diabetic probands and their families. Functional signifi cance of the 3359 proteins and 3488 proteins were identifi ed from the PKCδ KO and PKCε identifi ed mutations was confi rmed by physiological analysis, molecular KO study groups respectively, and we showed that several enzymes of lipid modeling and population survey. metabolism were affected by the fat diet. Results: Three novel KCNJ11 mutations R27H, R192H and S116F117del In fat-fed mice, 23 proteins showed signifi cant changes upon PKCδ were identifi ed in three families with early-onset type 2 diabetes mellitus. deletion while 19 proteins were affected by PKCε deletion. Notably, retinol Mutated KCNJ11 with R27H or R192H markedly reduced ATP sensitivity pathway was signifi cantly upregulated in fat-fed mice with either deletion. (E23K> R27H > C42R> R192H> R201H), but no ATP-sensitive potassium The majority of the proteins affected in this pathway belonged to the Cyp450 channel (KATP) currents were detected in the loss-of-function S116F117del family which is involved in the metabolism of all-trans retinoic acid (atRA). channel in vitro. Molecular modeling indicated R192H had a larger effect Thus it is possible that alterations in atRA or its derivatives protect PKC KO on the channel ATP binding pocket than R27H, which may qualitatively mice from fat diet-induced insulin resistance. interpret why the ATP sensitivity of the R192H is seven times lower than Furthermore, gene ontology (GO) analysis showed proteins involved in R27H. The shape of the S116F117del channel may be compressed, which biological processes such as lipid biosynthesis and oxidation-reduction were could explain why the mutated channel had no currents. Discontinuation of enriched in the absence of either PKC isoform. However certain GO terms insulin and implementation of sulfonylureas for R27H or R192H carriers, and such as monosaccharide metabolism were enriched solely in PKCδ KO and continuation/switch to insulin therapy for S116F117del carriers resulted in isoprenoid biosynthesis only in PKCε KO. good glycemic control. Taken together, these further suggest that PKCδ and PKCε exert partly Conclusion/Interpretation: Our results suggest that genetic diagnosis for overlapping and differential effects on liver metabolism in response to fat the KCNJ11 mutations in the familial early-onset type 2 diabetes mellitus, oversupply. may be quite helpful for understanding molecular etiology and providing These studies therefore provide a detailed comparison of the effects of more personalized treatment to these specifi c form of diabetes in Chinese fat feeding and deletion of PKC isoforms at the protein level, which will aid individuals and other Asian patients. further understanding of the function of these PKCs, given their association Supported By: NSFC with defective glucose homeostasis.

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A422 GENETICS—TYPECATEGORY 2 DIABETES

1622-P 1624-P Genetic Variants (SNP´s) of Phosphatase and Tensin Homolog A Novel, Inverse Relationship between LASY Expression and Stage (PTEN) Gene Is Associated with Hepatic and Peripheral Insulin of Glucose Intolerance in Type 2 Diabetes Sensitivity in Twins EZHILARASI KRISHNAMOORTHY, INDIRA PADMALAYAM, DHAMODHARAN LAURA GRINDER-HANSEN, LOUISE G. GRUNNET, JØRGEN WOJTASZEWSKI, UMAPATHY, RAMA RAJARAM, SATYAVANI KUMPATLA, VIJAY VISWANATHAN, PERNILLE POULSEN, TORBEN HANSEN, OLUF PEDERSEN, RASMUS RIBEL- Chennai, India, Birmingham, AL MADSEN, ALLAN A. VAAG, Copenhagen, Denmark, Bagsværd, Denmark Lipoic acid Synthase (LASY) is the enzyme that is involved in the PTEN reduces insulin sensitivity in vitro by inhibiting the PI3K/Akt endogenous synthesis of lipoic acid, a potent mitochondrial antioxidant. We pathway. We aimed to investigate whether 5 selected single nucleotide have previously reported that LASY expression is signifi cantly decreased in polymorphisms (rs2142136, rs10788569, rs11202589, rs11202614, rs7076964) type 2 diabetes (T2DM). The purpose of this study was to determine if there close to the PTEN gene may infl uence in vivo hepatic or peripheral insulin is a relationship between stage of glucose intolerance and expression of sensitivity and/or insulin signalling parameters in skeletal muscle biopsies. LASY. In a parallel study, we investigated the existence of polymorphisms In total 196 young (mean age 27,9 years) and elderly (mean age 61,8 years) within the putative promoter region of the LASY gene, to determine possible twins were studied. All subjects were studied at baseline and during a 2-hours association with T2DM. hyperinsulinemic euglycemic clamp combined with a primed continuous Peripheral blood samples were collected from 463 subjects who were infusion of 3-tritiated glucose to determine hepatic and peripheral insulin grouped based on the results of their oral glucose tolerance test as follows: sensitivity. Muscle biopsies were excised for the purpose of measuring Group 1: Normal Glucose Tolerant (NGT, n=116); Group II: Prediabetic (PDM, expression and activities of relevant insulin signalling molecules using n=108); Group III: Newly Diagnosed Diabetic (NDM, n=137); and Group IV: Western blots. Five SNP´s located close to the PTEN gene were selected Known diabetic (KDM, n=102). Gene expression analysis was performed by from the Hap Map-database and the subjects were genotyped. quantitative real time PCR (qRT-PCR) in 10 NGT, 5 PDM, 10 NDM, and 10 KDM The rare allele in all of the 5 SNP´s was signifi cantly correlated to an subjects. Polymorphisms within the putative LASY promoter were analyzed increased fasting plasma insulin level as well as to the Hepatic-Insulin in all of the 463 subjects by PCR-RFLP, and confi rmed by sequencing. resistance-index (p< 0,06). Two out of the 5 SNP´s (rs2142136, rs11202614) LASY gene expression was upregulated in PDM, NDM and KDM by 25, 5 were associated borderline signifi cantly with peripheral insulin action and 1.5 fold respectively, compared to NGT subjects. This fi nding suggests (p≤0,08). there is an initial “surge” in LASY expression in pre-diabetics, which is The rare allele of the SNP rs11202589 was signifi cantly associated with followed by a progressive decline in expression, with increased glucose decreased activity of IRS1-PI3K signalling (p=0,02). In addition, the rare intolerance and disease advancement. A single nucleotide polymorphism allele of the SNP rs10788569 and rs11202589 was signifi cantly associated (C/G or G/G) was identifi ed within the putative promoter region of the LASY with decreased activity of AKT2 (p<0.04).The rare alleles of genetic variants gene. Strikingly, the C/G polymorphism is strongly associated with diabetes, near the PTEN gene are consistently associated with in vivo hepatic insulin since it is present in all three of the diabetic groups (PDM, NDM and KDM) resistance, and to some extent also with peripheral insulin sensitivity, but not in normal glucose tolerant subjects (C/C). the latter being partly explained by an impaired skeletal muscle PI3K/Akt The inverse relationship between LASY mRNA levels and glucose signalling. intolerance is a novel fi nding, suggesting that LASY expression is Supported By: Rigshospitalet compromised with advancement of T2DM. The effects of this decrease in plasma lipoic acid levels and redox status is under investigation. Genetics POSTERS 1623-P Epidemiology/ Identifi cation of Genetic Variation Infl uencing DNA Methylation in 1625-P a Genome-Wide mQTL Analysis in Human Adipose Tissue Shows Genome-Wide Association Study of CRP Response to Statin Therapy Impact on Gene Expression and Obesity Related Traits in Diabetes in the CARDS Trial ANDERS H. OLSSON, PETR VOLKOV, LINN GILLBERG, SINE W. JØRGENSEN, HELEN M. COLHOUN, HARSHAL A. DESHMUKH, GRAHAM HITMAN, SHONA CHARLOTTE BRØNS, KARL-FREDRIK ERIKSSON, LEIF GROOP, PER-ANDERS J. LIVINGSTONE, PAUL N. DURRINGTON, SABITA S. SOEDAMAH-MUTHU, JANSSON, EMMA A. NILSSON, TINA RÖNN, ALLAN A. VAAG, CHARLOTTE A. Dundee, United Kingdom, London, United Kingdom, Manchester, United Kingdom, LING, Malmö, Sweden, Copenhagen, Denmark, Gothenburg, Sweden Wageningen, Netherlands Both genetic and epigenetic variation contributes to susceptibility of Reduction of C reactive protein (CRP) may underlie part of the benefi ts human disease. However, to date, it remains unclear if interactions between of statins in people with Type 2 diabetes (T2D), but whether this is through genetics and epigenetics affect the risk of complex diseases such as obesity different pathways than low-density lipoprotein cholesterol (LDL-C) reduction and type 2 diabetes. To study interactions between genetic and epigenetic is unclear. Our aim was to examine the variability in statin induced change in variation, we performed a genome-wide DNA methylation quantitative trait CRP in diabetes and to seek genetic determinants of this change. locus (mQTL) analysis in human adipose tissue of 119 Scandinavian men. CRP was measured at baseline and one year in T2D patients in the CARDS Here, we pairwise associated 592,794 single nucleotide polymorphisms trial. ~2.5 million SNPs typed on Perlegen platform and imputed with HAPMAP (SNPs) with DNA methylation of 477,891 CpG sites throughout the genome 2 were used. Multivariate linear regression was used to model change from using a linear regression model. SNPs in signifi cant mQTLs were further baseline to 1 year in CRP in 1005 patients allocated to Atorvastatin. Post- related to gene expression in adipose tissue and obesity related traits. We treatment (log)CRP level was used as the dependent variable with baseline found 101,911 SNP-CpG pairs corresponding to 15,208 unique CpG sites CRP, age, sex, BMI, smoking, duration of diabetes and HbA1c as covariates. (mQTLs) in cis, and, 5,342 SNP-CpG pairs corresponding to 596 unique CpG Genome-Complex Trait Analysis (GCTA) was used to identify narrow sense sites in trans showing signifi cant associations between genotype and DNA heritability of CRP response. methylation after correction for multiple testing. These include reported The median (interquartile range) of change in CRP on statin was -0.12(-1.03, obesity and metabolic syndrome loci. CpGs of signifi cant mQTLs were found 0.69) mg/L with 45.3% of those on statin having no fall in CRP. In contrast to be overrepresented in intergenic regions and outside of CpG islands. LDL-C fell in 96.5% of people on statin. Narrow-sense heritability h2(±SE) for We further identifi ed that several SNPs in signifi cant mQTLs affecting CRP response was 0.19(±0.24) compared to 0.05(±0.12) for LDL-C response. gene expression in adipose tissue. SNPs in signifi cant mQTLs did also Previously identifi ed variants for LDL-C -response to statin (in genes APOε2, affect numerous obesity and diabetes related traits including BMI, WHR, APOε4 and LPA) were not associated with CRP response (p>0.05) but three HOMA-IR, HbA1c, total cholesterol, triglycerides, HDL and LDL in our study borderline GWAS signifi cant loci (p<1.00E-05) were identifi ed at 1p13.1, 4q12, cohort and these results could be replicated in public available consortia 6p22.3 regions. data from GIANT, MAGIC and GLGC. Together, our study demonstrates how There is much higher variability in CRP response than the LDL-C response genome-wide interactions between genetic and epigenetic variation in both to statins in diabetes. Known LDL-C response variants were not associated cis and trans may contribute to altered gene expression in adipose tissue with CRP response, consistent with statin induced change in CRP having and impaired metabolism in humans. Our study provides novel molecular a mechanism distinct from LDL-C change. Although no GWAS signifi cant mechanisms that affect obesity and diabetes related traits in humans. genetic determinants of CRP response were found the heritability estimate suggests that further pursuit of such genetic determinants including replication of borderline associations in this trial is warranted. Supported By: Pfi zer Ltd.; Diabetes UK; NHS Research & Development

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A423 GENETICS—TYPECATEGORY 2 DIABETES

1626-P 1628-P The Genetics of Metabolic Syndrome in Arabs: “Oman Family Study” The PEA15 Gene Related to Insulin Resistance Is Overexpressed in NAJMA N. AL KHARUSI, SAID A. AL YAHYAEE, SULAYMA A. ALBARWANI, Renal Transplant Recipients MOHAMMED O. HASSAN, MARIE-CLAUDE GINGRAS, DONNA M. MUZNY, AGNIESZKA WITKOWSKA, KATARZYNA NABRDALIK, ALEKSANDER OWCZAR- ERIC BOERWINKLE, RICHARD GIBBS, JENNIFER E. BELOW, RIAD A. BAYOUMI, EK, BARBARA STRZALKA-MROZIK, JOANNA GOLA, BOZ˙ENA KAMIN’SKA-TRUS’, Muscat, Oman, Houston, TX URSZULA MAZUREK, WLADYSLAW GRZESZCZAK, JANUSZ GUMPRECHT, Kato- Metabolic Syndrome (MS) is a polygenic condition that combines a wice, Poland cluster of related disorders: elevated obesity, diabetes, dyslipemia and Diabetes, a metabolic disorder, is one of serious side effects of immuno- hypertension. Prior investigations of MS and its sub-phenotypes have suppressive therapy after organ transplantation. This study aimed to assess explained only a small proportion of its heritability. Special populations the expression of genes associated with glucose metabolism or onset having large extended families enriched for a phenotype are a valuable diabetes development in renal transplant recipients. In the fi rst stage of the resource for identifying novel genes infl uencing a complex trait. study expression profi les of 1341 transcripts, (837 genes) were assessed in 227 individuals from a single extended family enriched for MS in peripheral mononuclear blood cells (PBMCs) with oligonucleotide microarray the Nizwa village in Oman underwent GWAS array genotyping and 24 method (Affymetrix) in 7 euglycemic transplant recipients (5M and 2F; aged informative individuals had whole exome sequencing using VChrome2.1 46.5±8.6 years) on a three drug immunosuppressive regimen including: capture and Illumina HiSeq. We consider all variation in regions identifi ed in cyclosporine, prednisone and mycophenolate mofetil or sodium and 4 a previously published linkage analysis of microsatellite data in this village, healthy controls (2M and 2F; aged 59±4.5 years). Among 91 transcripts with and rare variants shared within the family in genes identifi ed based on prior signifi cantly different expression the most relevant ones: BLK and PEA15 GWAS of MS and its constituent traits. 45 genes contain rare or novel (novel were selected to the second stage of the study, both were assessed in to dbSNP and <1% in ESP) functional variation and are shared across ≥ 2 PBMCs with using quantitative RT-PCR assay for 51 euglycemic transplant affected, and ≤2 unaffected, individuals. In GCK, whose protein product is recipients (35M, 16F, aged 48.7 +/-13.6 years, average 9.6 years after important in fasting glucose regulation and beta-cell function, we observed transplantation) and 54 healthy controls. Results are presented in Table1. Our a novel missense variant (chr 7, ex 4, VAL>ILE) shared across 4/1 case/ results revealed up-regulation in PEA15 gene expression level in euglycemic control (PolyPhen =0.929, GERP = 5.23). Another novel missense variant in kidney transplant recipients. The outcomes may not only contribute to the the HS3ST3A1 gene (chr 17, ex 1, ARG>PRO), was shared across 8/2 case/ knowledge of post-transplant diabetes pathogenesis, but infl uence the control (PolyPhen =0.972, GERP = 5.32), which is expressed in liver and has strategy of immunosuppressive therapy in the future, as well. been associated with multiple MS-related traits. Table 1. Exome sequence analysis of affected and unaffected family members, combined with a family-specifi c linkage analysis will help to narrow this I study stage II study stage candidate gene list, identify new genes contributing to the MS, and identify Method Microarray assay qRT-PCR assay putatively causal variants for functional analyses. statistical Agilent GeneSpring GX t-Student test, normalized with analysis 11.0 (unpaired t -test with asymptotic logarithmic transformation, Statistica 9.0, p-value corrected with Benjamini-Hochberg results presented as mean ± standard devia- 1627-P multiple test) Fold Change >2.0, p-value <0.001 tion, copy count(log)/ul RNA, p-value <0.05 Translational Research into Human Gut Microbiota in Non-Diabetes, Genetics

POSTERS Prediabetes (Pre-DM), and Type 2 Diabetes (T2DM) Gene symbol Association p-value expression Study group: Control group: p-value expression Epidemiology/ THIRUVARANGAN RAMARAJ, CALLUM BELL, JONATHAN LEFF, STACEY with glucose regulation 51 transplant 54 healthy regulation metabolism recipients objects LAMBETH, TRECHELLE CARSON, JANAE LOWE, VALLABH SHAH, Santa Fe, NM, Boulder, CO, Albuquerque, NM BLK insulin synthesis 0.0003 down 3.60 ± 1.11 3.33 ± 1.15 0.572 T2DM currently affects over 27 million. Several studies showed and secretion compositional changes in the gut microbiota associated with T2DM, but PEA15 insulin resistance 0.0004 up 4.48 ± 1.17 4.65 ± 1.09 0.006 up there has not been a study characterizing the microbiota composition in Pre- DM. The prevalence of Pre-DM is estimated to be over 80 million Americans. We hypothesize that there will be a difference within the microbiota among 1629-P these groups and that early exposure in PreDM will be sustained in T2DM. Multiple Metabolic-related Genetic Risk Scores and Type 2 Diabetes Fifty participants were recruited, 16 T2DM, 19 Pre-DM, and 15 Non-DM. Risk in Three Ethnic/Racial Groups DNA was extracted from the fecal samples. Bacterial composition was YANN C. KLIMENTIDIS, NATHAN WINEINGER, ANA VAZQUEZ, GUSTAVO DE LOS investigated using Illumina sequencing of the V4 region within the 16S CAMPOS, Tucson, AZ, La Jolla, CA, Birmingham, AL rRNA gene. Analyses were performed to investigate potential relationships Metabolic syndrome is a cluster of traits that are thought to lead to type-2 between the relative abundance of gut bacterial taxa and diabetes diabetes (T2D) and cardiovascular disease. Prospective studies suggest that diagnosis. this cluster of traits is predictive of T2D incidence. Meta-analyses of genome- Non-parametric Kruskal-Wallis (K-W) tests were performed to evaluate wide association studies (GWAS) over the past several years have identifi ed the differences in the relative abundance of specifi c taxa among Non- single nucleotide polymorphisms (SNPs) associated with T2D as well as with DM, Pre-DM and T2DM patients. There were differences in the relative each of the traits that comprise the metabolic syndrome as well as other abundances of the phyla Firmicutes & Bacteroidetes between T2DM and implicated phenotypes. Here, in four datasets of Whites, three datasets of Non-DM patients that agreed with prior studies, but the differences were African-Americans, and two datasets of Hispanic-Americans, we calculate not statistically signifi cant (P > 0.1). Similar patterns were also found at seventeen genetic risk scores (GRS) based on SNPs identifi ed through meta- the genus level. Potential differences in alpha diversity among diabetes analysis of GWAS for glycemic, anthropometric, lipid, hemodynamic, and diagnosis were also investigated and results indicate that Pre-DM patients other traits, and examine their association with T2D risk. We then determine tend to have lower Shannon diversity than others, but this trend was not the extent to which the use of these GRSs can increase the accuracy of statistically signifi cant when tested with K-W test (P > 0.2). T2D risk prediction in the three ethnic-racial groups. In general, we fi nd that Based on our results it is evident that Pre-DM patients exhibited largest glycemic and anthropometric GRSs exhibit the strongest associations with differences in community composition compared to Non-DM and T2DM T2D risk. Interestingly, our fi ndings in Whites suggest that genetic risk for patients suggesting that earlier treatment/medications in Pre-DM could high LDL and total cholesterol are associated with decreased T2D risk. Finally, possibly have an impact on the gut microfl ora transitioning to T2DM. we fi nd that prediction of T2D risk is slightly, but not signifi cantly, improved Supported By: NIH by the use of these additional risk scores in all three ethnic/racial groups. Further work is needed to understand the negative association of genetic risk for non-HDL lipids and T2D risk, and to develop more comprehensive GRSs that could be applied to diverse ethnic groups or to specifi c ethnic groups.

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A424 IMMUNOLOGYCATEGORY

1629A-P Stretch Enhancers and Their Target Genes in Type 2 Diabetes & 1631-P STEPHEN PARKER, LELAND TAYLOR, MICHAEL STITZEL, BROOKE WOLFORD, Maturation Defects in NOD Macrophages Impacts Beta-Cell Re- MIKE ERDOS, PETER CHINES, NARISU NARISU, FRANCIS COLLINS, Bethesda, generation MD, Farmington, CT GINA M. COUDRIET, ANGELA CRISCIMANNA, FARZAD ESNI, JON D. PIGANELLI, The majority (91%) of the >100 Genome Wide Association Study (GWAS)- Pittsburgh, PA + identifi ed type 2 diabetes (T2D) and related quantitative trait loci are located In Type 1 Diabetes (T1D), self-reactive CD4 T cells drive the autoimmune in non-coding regions, suggesting that disease susceptibility is infl uenced destruction of pancreatic β cells by activating macrophages to a cytotoxic by regulatory variants. Functional genomic analyses implicate enhancers as phenotype (M1) hindering β cell repair potential. It has been shown that critical regulatory elements infl uencing gene expression. The high-resolution endogenous β cell growth can occur if the infl ammation is tempered. In and integrative enhancer landscape of T2D relevant tissues is unknown. fact, a more controlled infl ammatory response appears to be necessary In previous work, we performed systematic chromatin and transcriptome to induce the regenerative process, characterized by a transition of profi ling in a T2D-relevant tissue: pancreatic islets. Integrated analysis macrophage phenotypes from infl ammatory (M1) to anti-infl ammatory across ten cell types revealed an abundance of large (>3 kb) enhancers. (M2). Macrophages from the autoimmune NOD mouse are known to We showed that (i) these “stretch enhancers” are signifi cantly enriched have a number of maturation defects. Therefore, we hypothesize that in for genetic variants associated with traits relevant to the respective cell autoimmunity, defective macrophages fail to transition from the M1 to M2 type, including T2D and related traits in islets; (ii) known locus control phenotype upon β cell destruction, which is necessary to initiate the repair regions overlap stretch enhancers; (iii) tissue specifi city of enhancers and program. We adoptively transferred NOD.scid mice with BDC-2.5-TCR-Tg + levels of nearby gene expression increase with enhancer size; and (iv) splenocytes to cause T1D. Mice receiving a CD4 T cell-depleting antibody stretch enhancer-containing neighborhoods are enriched for important cell (GK 1.5) had a restricted infl ammatory response and delayed T1D onset. Ten type-specifi c genes. Here, we extend analyses to 33 cell types, including days after CD4 depletion, we observed low levels of M1 macrophage genes T2D-relevant adipose, liver, and skeletal muscle, and identify additional (inos, ccl2, il6, and tnf) in pancreatic tissue, while M2-macrophage gene stretch enhancers implicated in cell type-specifi c programs and disease expression (arg1) was maintained. However, control mice demonstrated a + + susceptibility. Human islet stretch enhancers are largely preserved in human persistent M1 phenotype (IL-6 and TNF macrophages) overwhelming the + and mouse beta cell culture models, supporting their importance in governing IL-10 M2 macrophage lineage. β cell maintenance is also achieved through beta cell identity and prioritizing T2D GWAS functional genomics follow- β cell expressed growth factors, which is facilitated through the help of up. To identify enhancer target genes, we constructed a computational alternatively activated M2 macrophages. Indeed, in pancreatic injury we algorithm that utilizes functional signal variation across cell types to predict observed that autoimmune mice have decreased growth factor expression, enhancer-gene links. This analysis elucidated target genes for T2D stretch including hepatocyte growth factor (HGF), which was reduced compared enhancers. Our results indicate that stretch enhancers are critical chromatin to non-autoimmune mice. These macrophage defects may render β cells features for cell-specifi c regulatory programs and that sequence variation in unable to initiate replicative programs. Therefore, we propose that addition stretch enhancers affects T2D risk and related quantitative traits. of exogenous growth factors, such as HGF, to the islet will provide the Supported By: ADA Pathway (1-14-INI-07); K99DK099240, K99DK092251, ZIAHG necessary cues from macrophages for β cell growth and function. 000024 Supported By: ADA (1-12-BS-161); JDRF & 1632-P IMMUNOLOGY Zinc-Finger Nuclease Mediated Gene Targeting in NOD Mouse Embryos Reveals a Role of CD137 in the Diabetogenic Activity of T Cells Guided Audio Tour: Immunologic Aspects of Development and Prevention MATTHEW H. FORSBERG, SHAMIM KHAJA, ASHLEY E. CIECKO, YI-GUANG CHEN, of Type 1 Diabetes (Posters: 1630-P to 1637-P), see page 17. Milwaukee, WI Over the past few decades, the NOD mouse has provided important & 1630-P information on both the genetics and pathogenesis of type 1 diabetes (T1D). More than 30 T1D susceptibility loci (Idd) have been identifi ed, of POSTERS

Superoxide Defi ciency Hinders the Response of Nonobese Diabetic Immunology/ Macrophages During Diabetogenic Coxsackie B4 Virus Infection which Tnfrsf9 (encoding CD137) is a candidate gene for Idd9.3 on the distal Transplantation ASHLEY R. BURG, LINDSEY E. PADGETT, HUBERT M. TSE, Birmingham, AL end of Chromosome 4. Using the zinc-fi nger nuclease (ZFN) technique, we Type 1 diabetes (T1D) is defi ned by the autoimmune destruction of generated CD137-defi cient NOD mice to test the role of this molecule in T1D. Our previous studies demonstrated that when compared to the wild- pancreatic β-cells. While the events that initiate the autoimmune attack remain elusive, studies have suggested that pancreatic viral infections may type NOD mouse, progression to T1D in the CD137-defi cient stock was trigger this destructive process. The innate immune anti-viral response can signifi cantly delayed. T-cell transfer experiments from either wild-type or create an infl amed environment, producing reactive oxygen species (ROS) CD137-defi cient NOD donors to NOD.Rag1-/- recipients revealed that T-cells and pro-infl ammatory cytokines. We recently demonstrated a critical role lacking this co-stimulatory molecule were less diabetogenic than the wild- for NADPH oxidase (NOX)-derived ROS production in T1D pathogenesis, type counterpart. In the current study, we further compared the activation as superoxide-defi cient Non-Obese Diabetic (NOD.Ncf1m1J ) mice are highly status of CD4 and CD8 T-cells in wild-type and CD137-defi cient NOD mice. Flow cytometry analyses showed that 10-week-old NOD mice harbored T1D-resistant. Interestingly, bone marrow-derived macrophages (BMMΦ) from these mice have reduced viral RNA sensing capacity against the signifi cantly more activated/memory (CD44high) CD8 T-cells in the bone viral dsRNA-mimic, poly(I:C). Therefore, we hypothesize that the absence marrow when compared to the age matched CD137-defi cient mice, although of NOX-derived ROS will reduce the diabetogenicity of viral infections by no difference was observed in the spleen and pancreatic lymph nodes. dampening innate immune anti-viral responses that contribute to T1D and Additional transfer experiments indicated that CD137 expressing CD4 T-cells were not more diabetogenic than those lacking this molecule. MHC class I pancreatic β-cell destruction. We performed both in vivo and in vitro viral infection studies with Coxsackie B4 virus (CB4), a hypothesized viral trigger tetramer staining showed that the frequency of IGRP206-214 specifi c beta- of T1D in both humans and rodents. Following a 6-hour infection with CB4 cell autoreactive CD8 T-cells was reduced in CD137-defi cient NOD mice. In summary, our research has shown that CD137 plays a role in the progression in vitro, NOD.Ncf1m1J BMMΦ displayed signifi cant 1.4- and 2-fold decreases in protein expression of the viral RNA sensors, TLR3 and RIG-I, respectively, of T1D in NOD mice likely through its diabetogenic function in CD8 T-cells. compared to NOD BMMΦ. By 24 hours this resulted in a 2-fold decrease (p<0.0005) in TNFα production, and a dramatic 11-fold decrease (p<0.0001) & 1633-P in IFNβ release by NOD.Ncf1m1J BMMΦ. This defective response by NOD. Prevention of Autoimmune Diabetes in NOD Mice by Dimethyl Fu- Ncf1m1J BMMΦ was recapitulated in vivo, as CB4-infected NOD.Ncf1m1J marate mice had a 2.5-fold decrease in the percentages of both TNFα- and IL-1β- SHIRI LI, LOURDES ROBLES, CHIE TAKASU, KELLY VO, MIZUKI TAKASU, producing macrophages infi ltrating the pancreas. These results suggest CLARENCE E. FOSTER, NOSRATOLA D. VAZIRI, MICHAEL J. STAMOS, HIROHITO that depletion of ROS may curtail the viral-induced initiating events in T1D. ICHII, Orange, CA Future studies will defi ne the role of ROS in potentiating the innate immune Oxidative stress and its constant companion infl ammation play critical response to diabetogenic viral infections that trigger T1D onset. roles in the pathogenesis of diabetes. Nuclear factor erythroid-derived Supported By: ADA (7-12-CD-11) 2-related factor (Nrf2) is a transcription factor that mediates a broad-based

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