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Integrated Physiology/Obesity INTEGRATED PHYSIOLOGY—INSULINCATEGORY SECRETION IN VIVO 1770-P & 1772-P DNA Repair Enzyme OGG1 Regulates Obesity and Insulin Sensitiv- Association of a Type 1 Diabetes Genetic Risk Score with C-Peptide ity with Age and Age of Diagnosis in Type 1 Diabetes LARYSA YUZEFOVYCH, MYKHAILO RUCHKO, MICHELE SCHULER, LYUDMILA DELNAZ ROSHANDEL, RICHARD A. ORAM, ANDREW T. HATTERSLEY, MICHAEL RACHEK, Mobile, AL N. WEEDON, ROSE GUBITOSI-KLUG, SHELLEY B. BULL, ANDREW D. PATERSON, Oxidative stress and mitochondrial dysfunction in skeletal muscle are DCCT/EDIC RESEARCH GROUP, Toronto, ON, Canada, Exeter, United Kingdom, important factors leading to insulin resistance (IR) during the aging process Cleveland, OH but the underlying mechanisms are still unknown. Among the potential tar- A proportion of people with type 1 diabetes (T1D) have detectable C-pep- gets is mitochondrial DNA (mtDNA), since mtDNA is highly specialized and tide years after diagnosis: they maintain better glycemic control and experi- encodes for proteins essential for energy metabolism and, also, damage to ence lower risk for diabetic complications. Multiple loci have been identifi ed mtDNA heightens mitochondrial ROS (mtROS) production that is very criti- for risk of T1D, but it is unknown whether they or a T1D genetic risk score cal for IR. Despite extensive age-related studies on mtDNA mutations, until (GRS) are associated with C-peptide. recently, the integrity of mtDNA and repair mechanisms have received little The study population included 1303 Caucasian subjects from the Diabetes attention in diabetes research. We hypothesized that progressive oxidative Control and Complications Trial (DCCT), recruited in 2 cohorts: primary and mtDNA damage triggers development of age-associated oxidative stress in secondary with 1-5, and 1-15 yrs of diabetes, respectively. We calculated skeletal muscle, and thus, potentiates development of IR with age. To vali- a weighted T1D GRS of 30 SNPs of which 5 were in HLA. T1D GRS, a DR3/ date this hypothesis, we performed studies in vivo using DNA repair enzyme, DR4 GRS (2 SNPs) and individual SNPs (coded additively) were tested for 8-oxoguanine (8-OxoG) DNA glycosylase (Ogg1) knockout and overexpressing association with stimulated C-peptide after a standard meal measured at models: 1) Ogg1 -/- (KO); 2) Tg MTS-hOGG1 (Tg, mice overexpressing human DCCT baseline. Separate analyses of primary cohort (N = 651), secondary OGG1 (hOGG1, subunit 1-α) in mitochondria; 3) wild type (WT, ogg1 +/+). We cohort with duration 1-5 yrs (N = 135), and secondary cohort with duration evaluated obesity and IR phenotypes, oxidative mtDNA damage, oxidative 5-15 yrs (N = 517) were combined through meta-analysis using Tobit models stress and expression of several mitochondrial proteins in skeletal muscle for c-peptide adjusting for sex, age at diagnosis and duration. Similarly, T1D from young (~5 month old) and aging (~15 month old) males from all three OGG1 GRS, DR3/DR4 GRS and individual SNPs were tested for association with groups. Our results showed that mitochondrial hOGG1 overexpression amelio- age of diagnosis using linear regression. rated age-associated obesity and IR phenotypes and protected against oxi- T1D GRS and DR3/DR4 GRS were not associated with stimulated C-pep- dative mtDNA damage and oxidative stress. Additionally, protein content for tide. The risk alleles (T) of SNPs in HLA-A24 region (rs1264813, β (SE) = -0.3 transcriptional coactivator peroxisome proliferator activated receptor alpha (0.1), p = 3E-5) and Insulin gene (rs689, β (SE) = -0.2 (0.1), p = 0.01) were (PGC-1α) and mitochondrial protein porin was signifi cantly increased in skel- associated with lower stimulated C-peptide. T1D GRS (β (SE) = -0.8 (0.1), p = etal muscle from aging Tg mice. Collectively, these proof-of-concept results 3E-8), DR3/DR4 GRS (β (SE) = -0.5 (0.2), p = 6E-4) and the risk allele (T) of provide fi rst direct evidence that oxidative mtDNA damage triggers oxidative the non-HLA SNP rs5753037 (HORMAD2, β (SE) = -1.0 (0.3), p = 4E-4) were stress and development of age-associated IR in mice, thus making mtDNA all negatively associated with age of diagnosis, and exceeded Bonferroni damage and repair a novel target for treatment of IR and type 2 diabetes. correction (< 0.002). At all loci, there was no signifi cant heterogeneity of the effect among the 3 subgroups. We identifi ed risk alleles of 2 T1D susceptibility loci, HLA-A24 and INS, INTEGRATED PHYSIOLOGY—INSULIN SECRETION associated with lower C-peptide levels. T1D GRS, DR3/DR4 GRS and IN VIVO rs5753037 were associated with age of diagnosis. Supported By: National Institutes of Health (U01 DK094157, U01 DK094176, DP3 DK104438) Moderated Poster Discussion: Insulin Secretion in Animals and Humans (Posters: 1771-P to 1777-P), see page 14. & 1773-P Racial Differences in Early GIP Contribute to Postprandial Hyperin- & 1771-P sulinemia in Black Women: The Federal Women Study Insulin Receptor Knockout Using Two Beta-Cell-Specifi c Cre Mouse PAOLA C. ALDANA, AMBER COURVILLE, MARY WALTER, MICHELLE T. DUONG, Lines Transiently Improves Glucose Homeostasis BRIANNA A. BINGHAM, LILIAN S. MABUNDO, MADIA RICKS, JOON HA, ARTHUR SØS SKOVSØ, LYNDA ELGHAZI, DEREK A. DIONNE, MELISSA M. PAGE, HONG S. SHERMAN, ANNE E. SUMNER, STEPHANIE T. CHUNG, Bethesda, MD LI, DARIA HUTCHINSON, XIAOKE HU, FARNAZ TAGHIZADEH, ERNESTO BERNAL- Black women are more hyperinsulinemic than whites after exposure to MIZRACHI, JAMES D. JOHNSON, Vancouver, BC, Canada, Miami, FL intravenous glucose but the post-meal insulin response by race is unclear. Insulin signaling is important for glucose homeostasis and is disrupted in Since incretins mediate 50% of postprandial insulin secretion, we hypothe- type 2 diabetes. The insulin receptor is highly expressed in beta cells, where sized that black women would have higher insulin, active glucagon-like pep- its function remains to be fully established. Previous studies on mice gener- tide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) compared ated to delete insulin receptors (InsR f/f) from beta-cells reported impaired glu- to whites during a 2 h mixed meal test (MMT). To quantify insulin and incretin cose tolerance, reduced insulin secretion, and reduced beta-cell mass. How- response, early (0-30 min) and total (0-120 min) area under the curves were ever, the so-called BIRKO model employed Cre recombinase under the control calculated for the MMT (52% carbohydrate, 15% protein, 33% fat) in 36 fed- of a short fragment of the RIP, which led to deletion of the insulin receptor in erally employed women without diabetes (17 African-American, 6 African both beta-cells and the brain. We generated two new mouse models to re- immigrants, 13 whites; age 43±9 (mean±SD), range 25- 62 y; BMI 30.8±5.8, address the function of insulin receptors specifi cally in beta-cells. First, we range 20.5-45.3 kg/m2). Glucose tolerance status was previously determined crossed InsR f/f mice with a mouse line expressing Cre within the endogenous by OGTT and percent (%) body fat by DXA. Analyses of covariance were Ins1 gene locus (Ins1 Cre), as our group and others have shown little or no Ins1 used to examine insulin and incretin response by race accounting for glucose gene expression in the brain. At 25 weeks of age, female InsR f/f:Ins1 Cre mice and % fat. Glucose tolerance status did not differ by race. During the MMT, exhibited improved glucose tolerance relative to InsR wt/wt:Ins1 Cre littermate glucose concentrations did not differ by race (P≥0.50). After adjusting for % f/f Cre Obesity controls. Interestingly, InsR :Ins1 mice were also signifi cantly heavier fat, early insulin response was 50% higher in black vs. whites (insulin0-30min POSTERS from 7-16 weeks of age. Second, we employed the tamoxifen-inducible Ins1- 1100±770 vs. 719±371, P=0.01) and total insulin response was 20% higher ERT Cre transgenic mouse model, which has been shown to have virtually no (insulin0-120min 8012±5645 vs. 6598±3305 µU·min/mL, P=0.10) but this did not f/f ERT Integrated Physiology/ recombination in the brain. Similarly, InsR :Ins1-Cre mice had signifi cantly reach signifi cance. Postprandial early and total GIP was higher in blacks vs. improved glucose tolerance 4 weeks after tamoxifen injection relative to both whites (GIP0-30min: 3468±3053 vs.1778±1003, GIP0-120min: 54159±22792 vs. InsR wt/wt:Ins1-CreERT and InsR f/f littermate controls, although this reversed to 39849±15582 pg·min/mL, both P<0.03). There were no differences by race impaired glucose homeostasis later in life. There were no signifi cant dif- in GLP-1 or C-peptide concentrations. Early GIP (P<0.001) and % fat (P<0.001) ferences in body weight in the tamoxifen-inducible model, suggesting that mediated 46% of the racial differences in early insulin response. Greater effects of beta-cell InsR deletion were restricted to developing and/or young early GIP was related to black race (P=0.03), % fat (P=0.04), and glucose0-30min mice. Collectively, these data are consistent with the concept that insulin (P<0.01). Overall, racial differences in postprandial insulin response were inhibits its own secretion, at least initially. Together, these data provide new identifi ed during a meal and may be partially explained by higher early GIP, information about the function of beta-cell insulin receptors and will provide not GLP-1, in black women relative to whites. more insight into the pathogenesis of type 2 diabetes. Supported By: National Institute of Diabetes and Digestive and Kidney Diseases Supported By: Canadian Institutes of Health Research For author disclosure information, see page A696. & Moderated Poster Discussion ADA-Supported Research A458 INTEGRATED PHYSIOLOGY—INSULINCATEGORY SECRETION IN VIVO & 1774-P & 1776-P Greater Increase in Insulin Clearance after Gastric Bypass vs.
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