LETTERS

1 liferative or proliferative diabetic retinop- ATSUSHI MINAMOTO, PHD 3 OBSERVATIONS athy. Data are presented as means Ϯ SD. HIDEHARU FUNATSU, PHD 4 The Mann-Whitney U test was used to HIDETOSHI YAMASHITA, PHD ␣ 5 compare IL-6 and TNF- levels. To deter- SHIGEO NAKAMURA, PHD 4 mine the relationship between the sever- KEN KIRIYAMA, PHD 5 Relationship ity of periodontal disease and ETDRS, HIDEMI KURIHARA, PHD 1 retinopathy severity, or angiogenic fac- HIROMU K. MISHIMA, PHD Between Periodontal tors, as well as between X and Y parame- Disease and Diabetic ters, Spearman’s rank-order correlation Retinopathy coefficient and logistic regression model From the 1Department of Ophthalmology and Vi- were applied. sual Science, Hiroshima University Graduate School The severity of periodontal disease of Biomedical Sciences, Hiroshima, Japan; the 2De- was significantly correlated with the se- partment of Ophthalmology, Hiroshima Prefectural ecently, various studies have re- verity of (P ϭ Hospital, Hiroshima, Japan; the 3Department of ported that periodontal disease ad- 0.0012), and the risk of proliferative dia- Ophthalmology, Center, Tokyo Women’s Medical University, Tokyo, Japan; the 4Department versely affects diabetes (1). The betic retinopathy was significantly higher R of Ophthalmology and Visual Science, Yamagata control of periodontal disease in elderly in the presence of periodontal disease ϭ ϭ University School of Medicine, Yamagata, Japan; individuals has been reported to improve (odds ratio 2.80, P 0.036). There and the 5Department of Periodontal Medicine, Hi- the control of blood glucose (2). Severe was no significant relationship between roshima University Graduate School of Biomedical periodontal disease is associated with el- the severity of periodontal disease and Sciences, Hiroshima, Japan. ϭ Address correspondence to Hiromu K. Mishima, evated blood lipopolysaccharide levels as HbA1c or duration of diabetes (P 0.098 and 0.295, respectively). There was a sig- PhD, Hiroshima University Graduate School of Bio- a result of periodontogenic bacteria, medical Sciences, Department of Ophthalmology which induce higher levels of interleu- nificant relationship between the severity and Visual Science, 1-2-3 Kasumi, Minami-ku, Hi- kin-6 (IL-6) and tumor necrosis factor-␣ of diabetic retinopathy and duration of roshima 734-8551, Japan. E-mail: hkmishi@ (TNF-␣) (3,4). Control of periodontal diabetes (P ϭ 0.002). The vitreous fluid hiroshima-u.ac.jp. disease is now considered not only a den- level of IL-6 (mean 154.2 Ϯ 164.6 pg/ml © 2004 by the American Diabetes Association. tal problem but also an issue affecting the [range 0.993–597.0]) was significantly el- patient’s overall quality of life. Proinflam- evated in patients with diabetic retinopa- matory cytokines such as IL-6 have been thy compared with that in nondiabetic shown to be involved in the pathogenesis patients (mean 1.34 Ϯ 0.91 pg/ml [0.6– of diabetic retinopathy (DR) (5), while the 3.68]) (P Ͻ 0.0001). Furthermore, the ●●●●●●●●●●●●●●●●●●●●●●● relationship between diabetic retinopathy vitreous fluid level of IL-6 was signifi- References and periodontal disease remains unclear. cantly correlated with the severity of peri- ϭ 1. Loe H: Periodontal disease: the sixth com- We investigated whether periodontal dis- odontal disease (P 0.012). There was plication of diabetes mellitus. Diabetes ease is correlated with diabetic retinopathy. no significant relationship between the Care 16:329–334, 1993 The study was based on a prospective vitreous fluid level of IL-6 and HbA1c or 2. Grossi SG, Skrepcinski FB, DeCaro T, review of 73 eyes in 73 consecutive dia- duration of diabetes (P ϭ 0.293 and Robertson DC, Ho AW, Dunford RG, betic patients. The mean duration of dia- 0.705, respectively). In contrast, the vit- Genco RJ: Treatment of periodontal dis- betes was 14.3 Ϯ 7.1 years (range 2–33), reous fluid level of TNF-␣ was not signif- ease in diabetics reduces glycated hemo- Ϯ and the mean HbA1c was 7.5 1.6% icantly correlated with the severity of globin. J Periodontol 68:713–719, 1997 (5.2–13.7). IL-6 and TNF-␣ levels in the periodontal disease. The IL-6 concentra- 3. Grossi SG, Genco RJ: Periodontal disease vitreous fluid samples from 32 eyes ob- tion in vitreous fluid (mean 154.2 Ϯ and diabetes mellitus: a two-way relation- tained during vitrectomy and in paired 164.6 pg/ml [0.993–597.0]) was signifi- ship. Ann Periodontol 3:51–61, 1998 plasma samples were measured by en- cantly higher than that in plasma (mean 4. Soolari AS, Champagne C, Punzi JS, Amar zyme-linked immunosorbent assay. Non- 1.89 Ϯ 3.47 pg/ml [0.156–18.8]) (P Ͻ S, Van Dyke TE: Serum modulation of diabetic patients included 10 with 0.0001). neutrophil response to Porphyromonas macular hole and 2 with epiretinal mem- There was a significant relationship gingivalis LPS in periodontal disease. J Int brane. Institutional ethics committee ap- between periodontal disease and severity Acad Periodontol 1:101–109, 1999 proval was obtained, and all participants of diabetic retinopathy, but it was unclear 5. Funatsu H, Yamashita H, Shimizu E, Kojima R, Hori S: Relationship between gave informed consent. The severity of di- whether periodontal disease directly af- fects the progression of diabetic retinopa- vascular endothelial growth factor and in- abetic retinopathy was quantified accord- terleukin-6 in diabetic retinopathy. Retina thy because this was a cross-sectional ing to the modified Early Treatment 21:469–477, 2001 Diabetic Retinopathy Study (ETDRS) ret- study. Further prospective studies, in- 6. The Early Treatment Diabetic Retinopa- inopathy severity scale (6). The severity of cluding evaluation of systemic factors, are thy Study Research Group: Fundus pho- periodontal disease was quantified ac- necessary. tographic risk factors for progression of cording to bone loss and then graded and diabetic retinopathy: ETDRS report num- 1 evaluated (7). Patients with periodontal HIDETAKA NOMA, MD ber 12. Ophthalmology 98:823–833, 1991 1 disease were classified as positive or neg- IKUO SAKAMOTO, PHD 7. Jeffcoat MK, Wang IC, Reddy MS: Radio- 1 ative based on median values. Diabetic HIDEKI MOCHIZUKI, MD graphic diagnosis in periodontics. Peri- 2 patients were classified as having nonpro- HIDETOSHI TSUKAMOTO, PHD odontol 2000 7:54–68, 1995

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Effect of Diabetes a car (1.5 h/week), and sitting at home OW: A culturally sensitive tool for Mexi- (1.38 h/week). can people with diabetes: “La Manzana de Intervention This study shows that the majority of la Salud”. Rev Biomed 14:51–59, 2003 Programs on Mexicans with diabetes who are willing to 4. Clark DO: Physical activity efficacy and participate in diabetes education groups effectiveness among older adults and mi- Physical Activity norities. Diabetes Care 20:1176–1182 at the primary health care clinics engage Among Migrant Ͼ 5. Aguilar-Salinas CA, Velazquez-Monroy in 20 min of daily physical activity, O, Gomez-Perez FJ, Gonzalez-Chavez A, Mexican Women which therefore reinforces the need for Esqueda AL, Molina-Cuevas V, Rull- With Type 2 promoting culturally based interventions Rodrigo JA, Tapia Conyer R, the Encuesta (3,4). These results are better than the na- Nacional de Salud 2000 Group: Charac- Diabetes tional data for adults with teristics of patients with type 2 diabetes in in Mexico and the U.S. (5,6); however, Mexico: results from a large population- the groups we studied were especially based nationwide survey. Diabetes Care he 2000 Dietary Guidelines for motivated subjects interested in obtaining 26:2021–2026, 2003 Americans and the dietary guide- better metabolic control through diabetes 6. Nelson KM, Reiber G, Boyko EJ: Diet and T lines for the control of diabetes in education groups. On the other hand, the exercise among adults with type 2 diabe- tes. Diabetes Care 25:1722–1728, 2002 Mexico include recommendations that population from this study, which has a adults participate in at least 30 min of low socioeconomic status, usually con- moderate physical activity, preferably fronts major environmental or economic daily (1,2). However, to our knowledge, barriers that prevent access to safe recre- there have been no studies that explore ational areas or fitness facilities. Thus, the effect of diabetes intervention pro- even with economic constraints and inad- Alternative Site grams on physical activity among migrant equate environmental access to physical Testing at the Mexican women with type 2 diabetes. activity, promoting physical activity in a Earlobe Tip All women from seven diabetes edu- culturally based intervention is a worth- cation groups from three different Mexi- while strategy that should be supported. can institutions located in Tijuana were Although further studies in large popula- Reliability of glucose measurements invited to answer a previously validated tions are still required to evaluate the ef- and pain perception questionnaire on physical activity. Of 111 fectiveness at a larger scale, at the primary questionnaires, 100 were adequately an- care level of Mexican institutions, stron- Ϯ swered. The mean age was 53 12 years. ger emphasis should be placed on pro- here is growing interest in alterna- The majority of the sample was migrants moting physical activity. tive less painful sites for capillary from other Mexican states, and 40% were T blood glucose (CBG) monitoring. classified as overweight and 31% as MONTSERRAT BACARDı´-GASCO´ N, MD The earlobe tip is a potential site (1) that obese. Of the women, 62, 45, and 15% PERLA ROSALES-GARAY, MD has been occasionally used by nurses Ͼ Ͼ Ͼ reported 20, 30, and 60 min of ARTURO JIME´ NEZ-CRUZ, MD, PHD when fingertip testing is refused or diffi- physical activity per day, respectively. cult. We investigated the clinical value Seventy-three percent reported Ͼ80 min From the Nutrition Program, Medical School, Uni- and accuracy of earlobe CBG measure- of weekly physical activity. Daily outdoor versidad Autonoma de Baja California, Tijuana, ments as an alternative to fingertip and Ϯ Mexico. activity of participants was 39 4.2 min Address correspondence to Montserrat Bacardı´- forearm testing. (mean Ϯ SE), and daily indoor activity Gasco´n, MD, Universidad Autonoma de Baja Cali- A total of 50 patients with type 2 di- was 5.72 Ϯ 0.27 h. Total light activity fornia, Medical School, Nutrition, Av. Tecnologico abetes (aged 42–82 years, 28% with neu- (Ͻ3.0 metabolic equivalents [METs]) was 14418, Mesa de Otay, Baja California, Tijuana ropathy) were enrolled in the study. The Ϯ 22390, Mexico. E-mail: [email protected]. Ϯ 5.28 0.24 h/day, total moderate activity © 2004 by the American Diabetes Association. duration of diabetes was 9.5 8.3 years (3–6 METs) was 55 Ϯ 14 min/day, and (means Ϯ SD). Testing sites (lateral aspect total vigorous activity (Ͼ6.0 METs) was ●●●●●●●●●●●●●●●●●●●●●●● of the fingertip, earlobe tip, and flexor 4.2 Ϯ 0.6 min/day. The average physical surface of the forearm) were rubbed and Ϯ References activity level was 1.54 0.03. The main 1. US Department of Agriculture/Depart- cleaned before lancing was performed by indoor activities were cooking (11 ment of Health and Human Services: a physician using Lifescan Unistick-2 lan- h/week), dishwashing and clothes wash- Home and garden bulletin no. 232. In cets (Lifescan, Milpitas, CA). The forearm ing (3.2 h/week), cleaning (3.1 h/week), 2000 Dietary Guidelines for Americans. 5th was lanced using the Microlet-Vaculance and shopping (1.9 h/week), and the main ed. Washington, DC, U.S. Department of device (Bayer, Tarrytown, NY). The order outdoor physical activities were walking Agriculture, 2000 of site testing was randomized. Pain was (3.1 h/week), semiactive exercise and 2. Secretaria de Salud: Norma Oficial Mexi- immediately assessed after the first at- stretching (1.26 h/week), running (0.23 cana Para la Prevencio´n, Tratamiento y tempt using a 100-mm graphic visual Control de la Diabetes Mellitus en la Aten- h/week), and bicycle riding (0.18 cio´n Primaria a la Salud.Me´xico, DF, Mex- scale (2). CBG was measured with an h/week). The main resting activity was ico, Secretaria de Salud, 2000 (NOM- Accu-Check Advantage glucose meter sleeping (49.16 h/week), followed by 015-SSA2-1994) (Roche, Indianapolis, IN). watching television (11.3 h/week), rest- 3. Jimenez-Cruz A, Bacardı´-Gasco´nM,Ro- First-attempt sampling success rates ing in bed (2 h/week), driving or sitting in sales-Garay P, Herrera-Espinoza J, Willis were 88% (fingertip), 74% (earlobe), and

616 DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 Letters

62% (forearm). After earlobe pricking, From the 1Department of Medicine, Division of En- stopper. Light micrographs and scanning bleeding lasted for Ͻ60 s in all subjects docrinology and Metabolism, University of Pitts- electron micrographs supported the con- (Ͻ30 s in 90%). Earlobe pain (median burgh Medical Center, Pittsburgh, Pennsylvania; clusion that little or no damage to needle 2 score 5.5 mm) was less uncomfortable and the Department of Internal Medicine, Division tips occurred as a result of multiple inser- Ͻ of Endocrinology and Metabolism, University of Mi- than fingertip pain (17 mm, P 0.01, ami School of Medicine and Miami VA Medical Cen- tions. We observed no hooks, bending, or Wilcoxon test) but not statistically differ- ter, Miami, Florida. other needle tip damage, although there ent from forearm (8.0 mm). Although ear- Address correspondence to Frederico G.S. To- was some evidence for deterioration of the lobe pain was more tolerable, a limitation ledo, MD, University of Pittsburgh Medical Center, silicon lubricant coating of needles. Department of Medicine, Division of Endocrinology At the same time, our examination of in this study is that it did not evaluate pain and Metabolism, E1140 Biomedical Science Tower, perception after repeated testing on mul- 200 Lothrop St., Pittsburgh, PA 15261. E-mail: new, unused needles revealed imperfec- tiple days, when skin soreness might be- [email protected]. tions when observed at high magnifica- come relevant. © 2004 by the American Diabetes Association. tion. Our observations make it clear that CBG measurements from the earlobe damage attributed to reuse must be dis- deviated from the fingertip by 9.5 Ϯ 1.0% ●●●●●●●●●●●●●●●●●●●●●●● tinguished from inherent imperfections (mean Ϯ SE). The correlation coefficient References associated with the manufacturing between these two sites was 0.97 (P Ͻ 1. Carley SD, Libetta C, Flavin B, Butler J, process. 0.01). Of earlobe measurements, 97.8% Tong N, Sammy I: An open trial to reduce Clinical and manufacturer recom- were within clinically acceptable zones the pain of blood glucose testing: ear ver- mendations that discourage reuse of nee- ϩ sus thumb. BMJ 321:20, 2000 dles because of assumed dulling, A B by error grid analysis (3). When ear- 2. Huskisson EC: Measurement of pain. Lan- lobe was compared with forearm, CBG bending, and/or fragmenting of needle Ϯ cet 9:1127–1131, 1974 deviation was 10 1.4%, correlation co- 3. Clarke WL, Cox D, Gonder-Frederick LA, tips are at variance with our findings, in efficient 0.96 (P Ͻ 0.01), and 95.3% of Carter W, Pohl SL: Evaluating clinical ac- which repeated penetration of vial measurements were within zones AϩBby curacy of systems for self-monitoring of stoppers did not damage needle tips (2). error grid analysis. blood glucose. Diabetes Care 10:622–628, Although we found no evidence of needle In contrast to other sites that require 1987 damage when penetrating the rubber vacuum-assisted lancing devices or so- stopper on insulin vials, there is need to phisticated glucose meters, our observa- ascertain the effect of cutaneous tissue tions demonstrate that CBG monitoring at penetration on needle tips. The reuse of the earlobes is attainable with regular needles by a significant number of pa- standard lancets and that earlobe CBG Needle Reuse and tients with diabetes as a matter of conve- concentrations correlate well and deviate Tip Damage nience, or out of concern for cost and/or minimally from either fingertip or fore- the creation of nonbiodegradable waste, arm values. Earlobe testing was also clin- indicates that further examination of nee- ically accurate by the error grid analysis uestions about needle reuse are dle reuse in vial stoppers and cutaneous method, which takes into account the ef- raised in recommendations by the tissue is warranted. fects on the clinical decision that would Q American Diabetes Association (1) 1 have been made if the CBG had been mea- and by practitioners and manufacturing DOUGLAS KLINE, PHD 2 sured in the reference site. These data companies (2). As an initial approach to TERRY KUHN, PHD support the notion that earlobe CBG con- examining these questions, we investi- gated whether multiple insertions of nee- 1 centrations can be used in substitution of From the Department of Biological Sciences, Kent fingertip values. However, one limitation dles through the rubber stoppers on State University, Kent, Ohio; and the 2Division of in our data series is that glucose values insulin vials would cause damage to nee- Undergraduate Studies, Kent State University, Kent, Ohio. Ͻ70 mg/dl were not observed. Therefore, dle tips (3). New needles were selected, attached to a precision manipulator, and Address correspondence to Terry Kuhn, Kent earlobe testing should be avoided if hypo- State University, Division of Undergraduate Studies, glycemia is suspected. inserted into insulin vials attached to a P.O. Box 5190, Kent, OH 44242-0001. E-mail: For many patients, the earlobe prick- transducer that measured the force neces- [email protected]. ing technique may be less convenient be- sary to insert and remove a needle © 2004 by the American Diabetes Association. cause it requires a second person to lance through the stopper. If needles were dam- aged by multiple insertions, an increase in the skin and collect the blood. This cer- force required to penetrate the rubber ●●●●●●●●●●●●●●●●●●●●●●● tainly limits the applicability of the tech- stopper would be expected. References nique in the outpatient setting. In five experiments, we found that 1. American Diabetes Association: American Nevertheless, earlobe testing seems to be there was no significant difference in the Diabetes Association Complete Guide to Di- a useful alternative that could minimize mean force required to penetrate the rub- abetes. 3rd ed. American Diabetes Associ- costs and discomfort in patients assisted ber stopper of an insulin vial between 17 ation, Alexandria, VA, 2002, p. 106, 480 by a relative or nurse in hospitals and 2. Effect of multiple insulin vial insertions on initial (41.5 g) and 17 subsequent (42.0 g) nursing homes. needle tips [article online], 2003. Available insertions. This suggests that needle tips from http://www.diabetesneedlereuse.org. are not dulled or damaged by multiple Accessed 8 December 2003 1,2 FREDERICO G.S. TOLEDO, MD insertions to a degree that more force 3. The Editors: Questions and answers (Let- 2 ANDREW TAYLOR, MD would be required to penetrate a vial ter). Diabetes Self Manag 17:94–95, 2000

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The Diabetes 0.54, P Ͻ 0.01), and better health (r ϭ ●●●●●●●●●●●●●●●●●●●●●●● Treatment 0.50, P Ͻ 0.01). Language, sex, age, and References employment status were not related to 1. Bradley C: Diabetes treatment satisfaction questionnaire. In Handbook of Psychology Satisfaction treatment satisfaction or general well- Ͼ and Diabetes: A Guide to Psychological Mea- Questionnaire being (P 0.05), confirming the con- surement in Diabetes Research and Practice. struct validity of the measures. HbA1c Bradley C, Ed. Chur, Switzerland, Har- A cross-cultural South African results were not significantly related to wood Academic, 1994, p. 111–132 treatment satisfaction, subjective meta- 2. Stewart AL, Hays RD, Ware JE: The MOS perspective bolic control, general well-being, or gen- Short-Form General Health Survey: reli- eral health for either group (P Ͼ 0.05). ability and validity in a patient popula- For Bantu-speaking patients, fewer tion. Med Care 26:724–735, 1988 eliable and valid multicultural in- 3. Bradley C: The well-being questionnaire. struments are important in multi- incidents of significantly In Handbook of Psychology and Diabetes: A Ͻ R cultural societies that are typical of predicted 33% of the variance (P Guide to Psychological Measurement in Dia- modern cities, and clinicians, using psy- 0.001) in treatment satisfaction; an addi- betes Research and Practice. Bradley C, Ed. chosocial assessments, need to ensure tional 11% of the variance (P Ͻ 0.001) Chur, Switzerland, Harwood Academic, that their diagnostic and screening tools was explained by general well-being. For 1994, p. 89–109 are appropriate. This study was con- Afrikaans-speaking patients, general 4. Child D: The Essentials of Factor Analysis. London, Holt, Rinehart & Winston, ducted with 176 diabetic outpatients well-being predicted 29% of the variance Ͻ 1970, p. 33–34 from two culturally distinct groups (95 (P 0.001) in treatment satisfaction; an 5. Arias E, de Vos S: Using housing items to Bantu-speaking and 81 Afrikaans- additional 7% of the variance (P ϭ 0.001) indicate socio-economic status: Latin speaking subjects) to 1) ascertain the un- was explained by general health. America. Soc Indic Res 38:53–80, 1996 derlying dimensions of treatment In conclusion, the study demon- 6. Petterson T, Young B, Lee P, Newton P, satisfaction as measured by the Diabetes strated that the underlying dimensions of Hollis S, Dornan T: Well-being and treat- Treatment Satisfaction Questionnaire the DTSQ for both groups were treatment ment satisfaction in older people with di- (DTSQ status) (1), 2) determine the reli- satisfaction and hyper- and hypoglyce- abetes. Diabetes Care 21:930–935, 1998 ability (internal consistency) of the mea- 7. Wredling R, Sta¨lhammar J, Adamson U, mia, all measures had excellent reliability Berne C, Larsson Y, O¨ stman J: Well-being sures, and 3) investigate the effects of (5), and well-being is an important pre- and treatment satisfaction in adults with objective (HbA1c results) and subjective dictor of treatment satisfaction for both diabetes: a Swedish population-based metabolic control, health (2), and well- groups of patients. These findings were study. QualLife Res 4:515–522, 1995 being (3) on satisfaction with diabetes consistent with those reported in the U.K. treatment. and Sweden (6–7) and support the idea Principal components analysis was that the DTSQ can be used in multicul- conducted on the 8-item DTSQ (1). All tural settings. communality estimates exceeded the cri- Depression, terion of 0.30 (4) for both Bantu-speaking and Afrikaans-speaking patients (range Diabetes, and 0.62–0.79 and 0.55–0.76, respectively). Acknowledgments— We thank Novo Nor- Glycemic Control in Two factors explained 71% of the vari- disk (South Africa) for funding the interview- ers’ salaries. We also thank Professor Clare Pima Indians ance for Bantu-speaking patients and Bradley for permission to use her measures 68% of the variance for Afrikaans- and Rosalind Plowright for constructive com- speaking patients. The first factor con- ments on the application of the DTSQ in mul- ew studies have addressed the rela- sisted of the six treatment satisfaction ticultural settings. tionship of depression and diabetes items, and the second factor consisted of F in ethnic minority groups, especially the two subjective metabolic control 1,2 Native Americans (1). We examined the MARGARET SANDRA WESTAWAY, PHD items. Reliability (internal consistency) 1,3 relationship between depression and dia- coefficients were excellent (5) and very JOHN R. SEAGER, PHD betes in a community-based sample of similar for both groups (Ͼ0.80 on all 541 Pima Indians aged Ն18 years (192 measures). From the 1South Africa Medical Research Council, with and 349 without diabetes) examined Treatment satisfaction was associated Health and Development Research Group, Pretoria, 2 from September 2002 through February with fewer incidents of hyperglycemia Gauteng, South Africa; the School of Health Sys- 2003. ϭϪ Ͻ tems and Public Health, University of Pretoria, Pre- (r 0.58, P 0.01) and 3 Depression was defined by five or ϭϪ Ͻ toria, Gauteng, South Africa, and the Faculty of (r 0.32, P 0.01), higher general Community and Health Sciences, University of the more depressive symptoms lasting Ն2 well-being (r ϭ 0.56, P Ͻ 0.01), and bet- Western Cape, Cape Town, Western Cape, South weeks, as assessed with PRIME-MD ter health (r ϭ 0.44, P Ͻ 0.01) for Bantu- Africa. (Mood Module in the Primary Care Eval- speaking patients. For Afrikaans- Address correspondence to Prof. Margaret San- uation of Mental Disorders) (2). Diabetes speaking patients, greater treatment dra Westaway, SA Medical Research Council, Health was defined by a and Development Department, Private Bag X385, Ն satisfaction was associated with fewer in- Pretoria, Gauteng, 0001 South Africa. E-mail: (fasting plasma glucose 7.0 mmol/l or cidents of hyperglycemia (r ϭϪ0.29, P Ͻ [email protected]. 2-h plasma glucose Ն11.1 mmol/l) or 0.01), higher general well-being (r ϭ © 2004 by the American Diabetes Association. previous clinical diagnosis.

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The prevalence of depression was From the National Institute of Diabetes and Diges- Improper Insulin 16.3% (18.7% in women and 12.6% in tive and Kidney Diseases, National Institutes of ϭ Health, Phoenix, Arizona. Compliance May men, P 0.06). In both sexes, the prev- Address correspondence to Helen C. Looker, Na- alence of depression was higher in dia- tional Institutes of Health, 1550 E. Indian School Lead to betic individuals (men 17.2 vs. 10.9%, Rd., Phoenix, AZ 85014. E-mail: hlooker@ Hepatomegaly and women 20.2 vs. 17.6%), although these mail.nih.gov. differences were not statistically signifi- © 2004 by the American Diabetes Association. Elevated Hepatic cant (for total sample: age- and sex- Enzymes in Type 1 adjusted odds ratio 1.3 [95% CI 0.7– Acknowledgments— We thank Dr. Richard Diabetic Patients 2.1]). In diabetic individuals, HbA1c was Rubin, Dr. Patrick Lustman, and Dr. Mary higher by 1.2% in those with depression de Groot for advice; Dr. Diane Montella and Ͻ (9.3 vs. 8.1%, P 0.01), although de- Priscilla Foote, MSW, of Gila River Health e have encountered hepatomeg- pression was not related to HbA1c in non- Care; and the members of the Gila River Indian aly and pronounced elevation of ϭ diabetic individuals (5.2 vs. 5.3%, P Community for their participation. W liver enzymes AST and ALT in 0.2). This association remained signifi- four patients with . These cant in a multivariate linear regression ●●●●●●●●●●●●●●●●●●●●●●● patients shared similar clinical features. model that included age, sex, duration of References They were all female (aged 11–14 years) diabetes, and BMI (HbA1c higher by 1.1% 1. Anderson RJ, Freedland KE, Clouse RE, ϭ with poor glycemic control. All had fre- in depressed persons, P 0.01). Fasting Lustman PJ: The prevalence of comorbid quent hyperglycemia and intermittent plasma glucose was also higher, but not depression in adults with diabetes: a hypoglycemia related to their history of significantly so, in depressed diabetic in- meta-analysis. Diabetes Care 24:1069– ϭ 1078, 2001 poor compliance. Most of them had mul- dividuals (10.2 vs. 9.5 mmol/l, P 0.3). tiple hospital admissions for severe hy- Although studies of depression in Na- 2. Spitzer RL, Williams JB, Kroenke K, Lin- perglycemia and/or . tive-American communities are limited, zer M, deGruy FV III, Hahn SR, Brody D, Johnson JG: Utility of a new procedure for In addition to their high daily doses of our findings are consistent with previous Ϫ Ϫ diagnosing mental disorders in primary insulin (1.3–2.2 units kg 1 day 1), suggestions that depression is several care: the PRIME-MD 1000 study. JAMA most were receiving extra doses of insulin times more prevalent among Native 272:1749–1756, 1994 to correct their frequent hyperglycemia. Americans than in the general U.S. popu- 3. US Department of Health and Human A1C levels were all higher than normal lation (3). Our finding that the prevalence Services: Mental health. A supplement to (ranging from 9.2 to 14.5%). Their initial of depression was somewhat higher in di- Mental Health: A Report of the Surgeon Gen- abetic individuals is also consistent with eral: Culture, Race, and Ethnicity. Rock- AST and ALT levels were at least 30- and previous studies (1,4–6). Our study lacks ville, MD, U.S. Department of Health and 14-fold higher than the normal limits, re- precision to estimate the association of Human Services, 2001 spectively, but the other liver function depression with diabetes because of the 4. Egede LE, Zheng D, Simpson K: Comor- tests, such as alkaline phosphatase, pro- relatively small sample size (541, as com- bid depression is associated with in- thrombin/partial prothrombintime, and creased health care use and expenditures total bilirubin, were normal except for pared with 21,513 to 1.3 million in other in individuals with diabetes. Diabetes Care recent reports [4–6]). The high preva- one patient who had a minimal increase in 25:464–470, 2002 alkaline phosphatase and total billirubin. lence of depression in our study suggests 5. Nichols GA, Brown JB: Unadjusted and that certain social, cultural, or economic adjusted prevalence of diagnosed depres- The degree of hepatomegaly did not cor- factors may overshadow the influence of sion in type 2 diabetes. Diabetes Care 26: relate with the liver enzyme levels, nor did diabetes on depression in this population. 744–749, 2003 it correlate with glycemic control or 6. Finkelstein EA, Bray JW, Chen H, Larson HbA levels. The higher HbA1c in depressed dia- 1c betic individuals is consistent with previ- MJ, Miller K, Tompkins C, Keme A, Upon admission to the hospital, ous findings in other populations (7). Manderscheid R: Prevalence and costs of proper insulin dosing was established. Treatment of depression reportedly im- major depression among elderly claim- Three of the four patients were able to ants with diabetes. Diabetes Care 26:415– lower their insulin dose to 0.9–1.2 units proves glycemic control in diabetic pa- Ϫ Ϫ 420, 2003 kg 1 day 1 and achieve normal glyce- tients, although the long-term effects are 7. Lustman PJ, Anderson RJ, Freedland KE, not known (8,9). This study adds to the de Groot M, Carney RM, Clouse RE: De- mic control. The AST and ALT levels were sparse literature on depression and diabe- pression and poor glycemic control: a quickly decreased in just a few days after tes in ethnic minority groups. Identifica- meta-analytic review of the literature. Di- the patients obtained better glycemic con- tion and treatment of depression may be abetes Care 23:934–942, 2000 trol during hospitalization. Except for one an important aspect of treating diabetes in 8. Lustman PJ, Freedland KE, Griffith LS, patient, who was admitted for diabetic ke- Native Americans. Clouse RE: Fluoxetine for depression toacidosis, the patients had no apparent in diabetes: a randomized double-blind symptoms of liver disease before the admis- placebo-controlled trial. Diabetes Care 23: PUNEET K. SINGH, BA sion. Their hepatomegaly was an inciden- 618–623, 2000 HELEN C. LOOKER, MBBS 9. Lustman PJ, Griffith LS, Freedland KE, tal finding. Other than poorly controlled ROBERT L. HANSON, MD, MPH Kissel SS, Clouse RE: Cognitive behavior diabetes, the investigations did not reveal JONATHAN KRAKOFF, MD therapy for depression in type 2 diabetes any other causes for hepatomegaly and PETER H. BENNETT, MB, FRCP mellitus: a randomized, controlled trial. increased liver enzymes. The normal cre- WILLIAM C. KNOWLER, MD, DRPH Ann Intern Med 129:613–621, 1998 atine phosphokinase level and negative

DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 619 Letters myoglobinuria from one patient ruled out hepatic enzymes have been reported emia secondary to renal artery vasocon- the possibility of rhabdomyolysis. The in children and adolescents who were striction (3). Historically, diabetic liver biopsy obtained in one patient re- chronically over-treated with insulin patients have been identified as a high- vealed abundant glycogen deposits in (4,5). risk group for the development of con- hepatocytes that were consistent with the We therefore advocate the high vigi- trast-induced nephropathy following abdominal computed tomography find- lance in promoting patient compliance to cardiac catheterization; however, the ing of “fatty” appearance of those enlarged insulin dosing rather than simply increas- mechanism for this increased risk is un- livers in all four patients. There were also ing insulin dosage in response to hyper- clear (4). The purpose of this study was to some features that these patients did not glycemia. The swift reduction of hepatic determine whether acute hyperglycemia share. One patient with the most pro- enzymes in our cases after achieving rea- is an independent risk factor for the de- found hepatomegaly had significant delay sonable glycemic control suggests that velopment of contrast-induced nephrop- in growth and puberty consistent with liver biopsy and other extensive work-up athy after cardiac catheterization Mauriac syndrome as previously de- may be unnecessary in managing similar procedures. scribed (1), whereas the other three pa- patients. A prospective, observational study tients had normal growth and puberty. was performed on all patients with diabe- One patient, who was found to have hep- Y. MILES YU, MD tes (insulin dependent and independent) atomegaly and elevated hepatic enzymes CAMPBELL P. HOWARD, MD or any patient with a baseline serum cre- during one of her admissions to the hos- atinine Ն1.2 mg/dl receiving a cardiac pital for diabetic ketoacidosis, had some From the Section of Endocrinology, Children’s catheterization procedures in a universi- Mercy Hospital, University of Missouri at Kansas nonspecific gastrointestinal symptoms City School of Medicine, Kansas City, Missouri. ty-affiliated cardiac catheterization facil- that might have been related to her dia- Address correspondence to Miles Yu, Section of ity between June 2001 and January 2002. betic ketoacidosis rather than the hepatic Endocrinology, Children’s Mercy Hospital, 2401 Patients with a diagnosis of acute renal disorder. Although all of our cases were Gillham Rd., Kansas City, MO 64108. E-mail: failure or patients on dialysis were ex- girls, similar cases have been identified in [email protected]. cluded. Patients were divided into two © 2004 by the American Diabetes Association. boys (2). groups, hyperglycemic (AHG) (serum Ն Hepatomegaly and elevated hepatic ●●●●●●●●●●●●●●●●●●●●●●● glucose 150 mg/dl) and nonhypergly- enzymes, reported in both adult and pe- cemic (NHG) (serum glucose Ͻ150 mg/ References diatric patients with type 1 diabetes (2,3), 1. Lee RGG, Bode HH: Stunted growth and dl), at the time of cardiac catheterization could be relatively common but may be hepatomegaly in diabetes mellitus. J Peds procedures. Contrast-induced nephropa- under-recognized or misidentified as the 91:82–84, 1977 thy was defined as an increase in serum more common nonalcoholic steatohepa- 2. Chatila R, West AB: Hepatomagely and creatinine Ն0.3 mg/dl or Ͼ25% above titis (NASH) because of similar clinical abnormal liver tests due to glycogenesis in the patient’s baseline, determined 3–5 features. NASH is commonly seen in adults with diabetes. Medicine 75:327– days following cardiac catheterization obese type 2 diabetic patients with insulin 333, 1996 procedures. resistance. The hepatic enzyme elevation 3. Olssen R, Wesslau C, William-Olsen T, The mean age, baseline creatinine, is slow to resolve. Our patients, however, Zettergren L: Elevated aminotransferases presence or absence of diabetes, hydra- were all nonobese type 1 diabetic pa- and alkaline phosphatases in unstable di- tion status, type and dose of contrast abetes mellitus without ketoacidosis or tients. Their pronounced elevation of he- hypoglycemia. J Clin Gastroenterol 11: agent received, and use of specific medi- patic enzymes was resolved in just a few 541–545, 1989 cations, including acetylcysteine, were days once they achieved reasonable glyce- 4. Asherov J, Mimouni M, Varsano I, Lubin not different between groups. The per- mic control at insulin dosages that were E, Laron Z: Hepatomegaly due to self-in- centage of inpatients was greater in the lower than what they were prescribed at duced hyperinsulinism. Arch Dis Child 54: AHG group (74%) than in the NHG home. Though the mild hepatomegaly 148–149, 1979 (26%), P ϭ 0.049. Ventricular function, and abnormal liver enzymes were be- 5. Rosenbloom AL, Giordano BP: Chronic as measured by left ventricular end- lieved to be associated with liver steatic overtreatment with insulin in children diastolic pressure, was the same between change in NASH, whether the pro- and adolescents. Am J Dis Child 131:881– groups (AHG ϭ 17 Ϯ 10 mmHg vs. nounced elevation of the liver enzymes 885, 1977 NHG ϭ 13 Ϯ 3 mmHg, P ϭ 0.21), and was directly caused by liver glycogen de- left ventricular ejection fraction was sig- posit is not known. The pathogenesis for Acute Hyperglycemia nificantly lower in the AHG group these problems has not been well studied. (AHG ϭ 45 Ϯ 13% vs. NHG ϭ 59 Ϯ Nevertheless, both the increased hepatic 14%, P ϭ 0.023). A total of 38 patients enzymes and glycogen deposits may be Implications for contrast-induced were studied, including 33 diabetic sub- related to poor glycemic control. Most of nephropathy during cardiac jects (87%). One-half of the study group our patients received relatively high doses catheterization (19 patients) was found to have hypergly- of insulin at home. We question the pos- cemia at the time of their cardiac catheter- sible role of insulin over-treatment that ization procedure. Mean serum glucose might contribute to the pathogenesis of cute hyperglycemia exacerbates was 217 Ϯ 78 mg/dl for the AHG group hepatomegaly because insulin is clearly a ischemic injury of the brain and vs. 124 Ϯ 15 mg/dl for the NHG group, promoting agent for glycogenesis. Similar A heart (1,2). Renal contrast agents P Ͻ 0.001. The incidence of contrast- cases of hepatomegaly and elevated are nephrotoxic, largely due to acute isch- induced nephropathy for the entire study

620 DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 Letters population was 24% (9 of 38). The inci- EMS/Trauma, 80 Seymour St., P.O. Box 5037, Hart- studied for association with obesity and dence of contrast-induced nephropathy ford, CT 06102-5037. E-mail: gperdri@ type 2 diabetes (2,3). harthosp.org. in the AHG group was 42% (8 of 19) and © 2004 by the American Diabetes Association. The Parkataje Indians, from the Bra- was significantly greater than that for the zilian Amazon region, remained largely ϭ NHG group, 5.3% (1 of 19), P 0.01. ●●●●●●●●●●●●●●●●●●●●●●● isolated. Recently, they underwent a Acute hyperglycemia is a potential in- rapid and intensive process of accultura- References dependent risk factor for the develop- 1. Malmberg K, for the DIGAMI (Diabetes tion, with important changes in their life- ment of contrast-induced nephropathy in Mellitus, Insulin Glucose Infusion in style. Accompanying these changes, an diabetic patients undergoing cardiac Acute Myocardial Infarction) Study increasing prevalence of obesity and other catheterization procedures. The glucose Group: Prospective randomized study of features of the metabolic syndrome have molecule has been shown to be a potential intensive insulin treatment on long-term been observed. This study examines the cytotoxin in the context of hyperglycemia survival after acute myocardial infarction relevance of the Trp64Arg mutation in the (5). Acute hyperglycemia in patients with in patients with diabetes mellitus. BMJ ␤3-adrenergic receptor gene and the or without diabetes can detract from clin- 314:1512–1515, 1997 Pro12Ala mutation in the PPAR␥2 gene as ical outcomes in cardiovascular disease 2. Weir CJ, Murray GD, Dyker AG, Lees KR: a susceptibility factor to features of the (1). The mechanism by which acute hy- Is hyperglycemia a predictor of poor out- metabolic syndrome in this population. come after acute stroke? BMJ 314:1303– perglycemia worsens ischemic myocar- Participants were individuals aged 1306, 1997 Ն dial injury is currently under study. 3. Brezis M, Rosen S: Hypoxia of the renal 20 years; those with admixture and Conceivably, hyperglycemia may exacer- medulla: its implication for disease. pregnant women were excluded. The bate acute renal ischemia associated with N Engl J Med 332:647–655, 1995 study population comprised 85 (52 men administration of radiographic contrast 4. Parfrey PS, Griffiths SM, Barrett BJ, Paul and 33 women) individuals (mean age agents. The observational design of this MD, Genge M, Withers J, Farid N, Mc- 41 Ϯ 14.9 years). The degree of related- study limits the relationship between Manamon PJ: Contrast material-induced ness among the individuals was deter- acute hyperglycemia and contrast- renal failure in patients with diabetes mel- mined, and 37 nuclear families from six induced nephropathy to that of a tempo- litus, renal insufficiency, or both: a pro- pedigrees were verified. Polygamy, in- ral association and does not address spective controlled study. N Engl J Med cluding polyandry, occurs in this popula- 320:143–149, 1989 causality. Confounding variables, such as 5. Porte D Jr, Schwartz MW: Diabetes com- tion. BMI, waist-to-hip ratio, systolic and the slightly worse left ventricular ejection plications: why is glucose potentially diastolic blood pressures, and serum li- fraction in the AHG group, may have con- toxic? Science 272:699–700, 1996 poproteins were studied. Fasting and 2-h tributed to the development of contrast- blood samples were drawn for glucose induced nephropathy; however, the and insulin measurements. Changes in hyperglycemia in the AHG group may Influence of the body weight were analyzed in 80 individ- have contributed to poorer ventricular uals for a 3-year period. Genotypes were function. The relationship between acute Polymorphisms determined by PCR/restriction fragment– hyperglycemia and contrast-induced ne- Tpr64Arg in the ␤3- length polymorphism, as previously de- phropathy reported here will require a Adrenergic Receptor scribed (1,2). randomized controlled clinical trial for A principal component analyses from definitive characterization. This report Gene and Pro12Ala the correlation matrix of the variables suggests that a temporal association exists in the PPAR␥2 Gene measured was performed. Statistical anal- between acute hyperglycemia and con- on Metabolic yses (ANOVA and family-based associa- trast-induced nephropathy at the time of tion test) were done with the first two cardiac catheterization procedures in dia- Syndrome–Related principal components because the mea- betic patients with mild renal dysfunc- Phenotypes in an sured variables are all related to the met- tion, and this topic bears further study. Indigenous abolic syndrome. The principal component, therefore, reflects the vari- 1 DIANE B. TURCOT, MD Population of the ance common to these variables and 1 FRANCIS J. KIERNAN, MD, FACC avoids corrections for multiple indepen- 1 Brazilian Amazon RAYMOND G. MCKAY, MD, FACC dent tests. 2 NEIL J. GREY, MD, FACP Obesity rates were higher in women 1 WILLIAM BODEN, MD, FACC etabolic syndrome is a cluster of than in men (27.2 vs. 3.8% at baseline, 3 GEORGE A. PERDRIZET, MD, PHD, FACS risk factors for type 2 diabetes and P ϭ 0.006 and 45.2 vs. 16.3% at 3-year cardiovascular disease. Multiple follow-up, P ϭ 0.01), and for both sexes, From the 1Division of Cardiology, Hartford Hospi- M mechanisms, including genetic factors, there was an increase in these rates during tal, University of Connecticut School of Medicine, Hartford, Connecticut; the 2Division of Endocrinol- may contribute to this condition. The the follow-up period (12.94 vs. 27.5%, ogy, Hartford Hospital, University of Connecticut Trp64Arg variant in the ␤3-adrenergic re- P ϭ 0.03). Diabetes was diagnosed in one School of Medicine, Hartford, Connecticut; and the ceptor has been associated with features individual, impaired glucose tolerance in 3 Division of Trauma, Hartford Hospital, University of the metabolic syndrome (1). A rela- another, and the remaining were classi- of Connecticut School of Medicine, Hartford, Con- necticut. tively common gene variant, Pro12Ala of fied as normal glucose tolerant according Address correspondence to George A. Perdrizet, the peroxisome proliferator–activated re- to World Health Organization criteria. MD, PhD, FACS, Hartford Hospital, Division of ceptor-␥2 (PPAR␥2) has been previously Frequencies of the ␤3-adrenergic re-

DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 621 Letters ceptor Arg and the PPAR␥2 Ala variants peroxisome proliferation-activated recep- degree relatives in type 2 diabetic pedi- were 0.33 and 0.31, respectively. These tor-␥2 (PPAR-␥2): divergent modulating grees, and 85 healthy control subjects. All frequencies are in the Hardy-Weinberg effects on body mass index in obese and patients underwent an oral glucose toler- equilibrium. The ␤3-adrenergic receptor lean Caucasian men. Diabetologia 42:892– ance test (OGTT) and insulin release tests Arg allele frequency (0.33) is much higher 895, 1999 after8hoffasting, and blood levels of 3. Altshuler D, Hirschhorn JN, Klannermark than those reported in other populations, M, Lindgren CM, Vohl MC, Nemesh J, ferritin, HbA1c, glucose, insulin, C- except for Pima Indians (4). Similarly, the peptide, and lipids were measured. Se- ␥ Lane CR, Schaffner SF, Bolk S, Brewer C, PPAR 2 Ala allele was more prevalent in Tuomi T, Gaudet D, Hudson TJ, Daly M, rum ferritin levels were measured with the Parkateje Indians than in the other Groop L, Lander ES: The common PPAR the radioimmunoassay kit (Beijing North populations, whose frequency ranges gamma Pro12Ala polymorphism is asso- Institute of Biological Technology). Nor- from 0.12 among Caucasians to 0.01 in ciated with decreased risk of type 2 dia- mal ranges for ferritin concentration are Chinese (5). ANOVA (with Welch’s cor- betes. Nat Genet 26:76–80, 2000 ϳ12–245 ng/ml for adult men and ϳ5– rection) showed that the first principal 4. Walston J, Silver K, Bogardus C, Knowler 130 ng/ml for women. We defined ele- component was heterogeneous among WC, Celli FS, Austin S, Manning B, Stros- vated concentrations of ferritin as Ն295 the genotypic classes of the PPAR␥2 lo- berg AD, Stern MP, Raben N, Sorkin JD, ng/ml for men and Ն155 ng/ml for Roth J, Shuldiner AR: Time of onset of cus; the AlaAla genotype was different non-insulin-dependent diabetes mellitus women. from the others (F ϭ 3.51, P ϭ 0.035). Levels of fasting and postprandial ␤ and genetic variation in the B3-adrener- The 3-adrenergic receptor locus showed gic-receptor gene. N Engl J Med 333:347– plasma glucose in the NGT group were no differences among the genotypes. The 347, 1995 remarkably higher than in the healthy FBAT analyses showed that the PPAR␥2 5. Yen CJ, Beamer BA, Negri C, Silver K, control subjects. Fasting insulin concen- locus presented a significant segregation Brown KA, Yamall DP, Burns DK, Roth J, trations in the NGT group were also distortion with the recessive model (P ϭ Shuldiner AR: Molecular scanning of the higher than those of the other groups, 0.032) but not with the additive or dom- human peroxisome proliferator activated while postprandial insulin concentrations inant models. receptor gamma gene in diabetic Cauca- increased significantly when compared Among the Parkateje Indians, the sians: identification of a Pro12Ala PPAR with healthy control subjects. Ferritin Pro12Ala variant in the PPAR␥2 gene, but gamma 2 missense mutation. Biochem Bio- concentrations were the highest in type 2 phys Res Commun 241:270–274, 1997 not the Trp64Arg variant in the ␤3- diabetic subjects, followed by the IGT adrenergic receptor, was associated with group, the NGT group, and the healthy features of the metabolic syndrome. control group (412.88 Ϯ 155.58, Elevated Serum 354.19 Ϯ 173.03, 231.31 Ϯ 130.32 [P Ͻ 1 JOA˜ O PAULO B. VIEIRA-FILHO, MD, PHD Ferritin 0.05 compared with healthy control sub- 1 ANDRE´ F. REIS, MD, PHD jects], and 164.69 Ϯ 110.54 ng/ml, re- 1 Concentrations in a TERESA S. KASAMATSU, BSC spectively). In the type 2 diabetic group, 1 EDELWEISS F. TAVARES, MD, PHD Glucose-Impaired the newly diagnosed patients had higher 2 LAE´ RCIO J. FRANCO, MD, PHD ferritin concentrations than previously di- 3 Population and in SERGIO R. MATIOLI, PHD agnosed (461.72 Ϯ 132.41 vs. 354.19 Ϯ 1 REGINA S. MOISE´ S, MD, PHD Normal Glucose 173.03 ng/ml, P Ͻ 0.05). Tolerant First- We also compared concentrations of From the 1Division of Endocrinology, Department Degree Relatives in serum ferritin in men and women for each of Medicine, Federal University of Sa˜o Paulo, Sa˜o group. In general, concentrations of fer- Paulo, Brazil; the 2Department of Social Medicine, Familial Type 2 Faculty of Medicine of Ribeira˜o Preto-University of ritin in men were higher than in women Sa˜o Paulo, Sa˜o Paulo, Brazil; and the 3Department of Diabetic Pedigrees (P Ͻ 0.05) except for in the healthy con- Biology, University of Sa˜o Paulo, Sa˜o Paulo, Brazil. trol group. In male subjects, ferritin con- Address correspondence to Regina S. Moise´s, centrations of both newly and previously MD, PhD, Universidade Federal de Sa˜o Paulo, Es- cola Paulista de Medicina, Disciplina de Endocrino- wo large epidemiological studies diagnosed type 2 diabetic, IGT, NGT, and logia, Rua Botucatu, 740-2o,° andar, 04034-970 Sa˜o have recently reported a strong as- healthy control groups showed the same Paulo, SP, Brazil. E-mail: rmoises@ T sociation between elevated serum trend as the whole group (494.30 Ϯ endocrino.epm.br. ferritin concentration and increased risk 142.6, 425.01 Ϯ 136.77, 390.07 Ϯ © 2004 by the American Diabetes Association. for diabetes (1,2). Moreover, other stud- 125.09, 284.74 Ϯ 112.04 [P Ͻ 0.001 ies have revealed the relationship among compared with the healthy control sub- ●●●●●●●●●●●●●●●●●●●●●●● excess ferritin, coronary heart disease, jects], and 197.93 Ϯ 110.41 ng/ml, re- References and and have therefore spectively). However, in female subjects, 1. Wide´n E, Lehto M, Kanninen T, Walston renewed interest in ferritin as a risk factor ferritin concentrations in newly J, Shuldiner AR, Groop LC: Association of for diabetes. (425.65 Ϯ 137.5 ng/ml) and previously a polymorphism in the B3-adrenergic-re- This study further investigates the as- (295.37 Ϯ 150.98 ng/ml) diagnosed type ceptor gene with features of the insulin sociation between ferritin metabolism 2 diabetes and IGT (330.72 Ϯ 131.03 ng/ resistance syndrome in Finns. N Engl Ϯ J Med 333:348–351, 1995 and different status of glucose tolerance, ml) were higher than the NGT (174.06 2. Ek J, Urhammer SA, Sorensen TIA, including 121 type 2 diabetic subjects, 86 123.45 ng/ml) and healthy contol Andersen T, Auwerx J, Pedersen O: Ho- impaired glucose tolerant (IGT) subjects, (137.28 Ϯ 89.63 ng/ml) groups (P Ͻ mozygosity of the Pro12Ala variant of the 58 normal glucose tolerant (NGT) first- 0.001). No significant difference was

622 DIABETES CARE, VOLUME 26, NUMBER 2, FEBRUARY 2004 Letters found between female NGT and female sity, 37 Guoxue Lane, Chengdu, Sichuan China agnosis of bilateral peripheral facial paral- healthy control subjects. Moreover, in 610041. E-mail: [email protected]. ysis. Five weeks after his admission to our newly diagnosed type 2 diabetes, the con- © 2004 by the American Diabetes Association. hospital, he made a full recovery. We have centrations of ferritin were significantly to note that glucocorticoids were not ad- higher than in the previously diagnosed ●●●●●●●●●●●●●●●●●●●●●●● ministered to him. type 2 diabetic and IGT patients. References His full blood count, erythrocyte sed- Using multiple regression analysis, 1. Tuomainen TP, Nyyssonen K, Salonen R, imentation rate, liver function tests, tu- we found an association between ferritin Tervahauta A, Korpela H, Lakka T, mor markers, thyroid hormones, serum concentration and BMI, waist-to-hip ra- Kaplan GA, Salonen JT: Body iron stores protein immunoelectrophoresis, serum tio, systolic blood pressure, diastolic are associated with serum insulin and ACE levels, C-reactive protein, and rapid blood pressure. HbA , FPG, 2-h plasma blood glucose concentration: population protein reagent (RPR) were all within nor- 1c study in 1,013 eastern Finnish men. Dia- postprandial glucose, triglycerides, and betes Care 20:426–428, 1997 mal limits. HbA1c was 7.0%, and the au- total cholesterol were positively related to 2. Ford ES, Cogswell ME: Diabetes and serum toantibody screen was negative. Purified ferritin concentrations, while HDL cho- ferritin concentration among U.S. adults. protein derivative was 5 mm. Serological lesterol levels were inversely related to Diabetes Care 22:1978–1983, 1999 tests for varied infectious agents, includ- ferritin concentrations. 3. Salonen JT, Tuomainen TP, Nyyssonen K, ing herpes simplex virus (HSV)-I and -II, In recent years, the issue of the poten- Lakka HM, Punnonen K: Relation be- Varicella-Zoster virus (VZV), Epstein- tial pathology of serum ferritin in type 2 tween iron stores and non-insulin depen- Barr, Coxsackie, HIV-I and -II, cytomeg- diabetes has gained remarkable interest dent diabetes in men: case-control study alovirus (CMV), and hepatitis B viruses, (3). In this study, we found that serum (Abstract). BMJ 317:727, 1998 as well as Mycoplasma and Borrelia Burg- ferritin concentrations were remarkably 4. Moczulski DK, Grzeszczak W, Gawlik B: dorferi, were all negative. Role of hemochromatosis C282Y and H63D increased in type 2 diabetes, especially in mutations in HFE gene in development of Lumbar puncture revealed a normal newly diagnosed patients. Subjects with type 2 diabetes and . pressure. Glucose, protein, and white higher concentrations of ferritin conse- Diabetes Care 24:1187–1191, 2001 blood count of the cerebrospinal fluid quently had higher HbA1c, glucose, and 5. Van Lerberghe S, Hermans MP, Dahan K, (CSF) were all within normal limits. Fur- insulin concentrations. These results fur- Buysschaert M: Clinical expression and thermore, stains and cultures for micro- ther proved a positive association be- insulin sensitivity in type 2 diabetic pa- organisms were negative, as were tests for tween type 2 diabetes and high plasma tients with heterozygous for haemochro- viruses (HSV and HSV-II, VZV, amd ferritin concentrations. matosis. Diabetes Metab 28:33–38, 2002 CMV), Borrelia Burgdorferi, and syphilis The exact mechanism through which 6. Salonen JT, Tuomainen TP, Kontula K: (venereal disease reaction level [VDRL] elevated ferritin promotes the develop- Role of C282Y mutation of in haemochro- test). matosis gene in development of type 2 ment of type 2 diabetes is unknown. diabetes in healthy men: prospective co- Magnetic resonance imaging (MRI) of Some investigations argued that abnor- hort study. BMJ 24:1706–1707, 2000 the brain and computed tomography malities in ferritin metabolism might be a (CT) scans of the head, thorax, and abdo- primary cause of type 2 diabetes (4–6). In Simultaneous men were all normal. our study, ferritin concentration in IGT Facial diplegia may have diverse eti- subjects, the high-risk population for type Bilateral Facial Palsy ologies and may prove to be a diagnostic 2 diabetes, already significantly increased in a Diabetic Patient dilemma. The most common causes are when compared with normal control sub- bilateral Bell’s palsy, Lyme disease, Guil- jects, implying that hyperferritinemia oc- lain-Barre syndrome, sarcoidosis, Moebi- curs before elevation of plasma glucose nilateral facial paralysis is a rela- ous syndrome, leukemia, viral infections, concentrations. This observation was fur- tively common condition with an syphilis, basilar skull fractures, and pon- ther substantiated by evidence that NGT U incidence of 20–25 per 100,000 tine gliomas. first-degree relatives in the type 2 diabetic population. However, simultaneous bilat- The most common infectious cause of pedigrees had higher ferritin concentra- eral facial palsy (facial diplegia) is an ex- facial diplegia is Lyme disease, caused by tions than normal control subjects. tremely rare clinical entity and occurs in Borrelia Burgdorferi (3). Regarding the 0.3–2% of facial paralysis patients (1). case presented, the IgG antibodies against 1 YAN REN, MD, PHD The annual incidence is approximately 1 this agent in serum, as well as in CSF, were 1 HAOMING TIAN, MD per 5 million (2). negative. Other rare infectious causes in- 1 XIUJUN LI, MD A 78-year-old diabetic patient pre- clude syphilis and Mycoplasma (4). How- 1 JINZHONG LIANG, MD sented to the emergency room of our hos- ever, VDRL tests in CSF and RPR in serum 2 GUIZHI ZHAO, pital with dysarthry and bilateral were negative, while antibody titer against symmetrical facial weakness. He was un- Mycoplasma was negative. From the 1Division of Endocrinology, Department able to show his teeth, close his eyelids, or Guillan-Barre syndrome is thought to of Internal Medicine, West China Hospital, Sichuan dilate his cheeks. From the neurologic ex- be a postinfectious inflammatory polyra- University; and the 2Laboratory of Endocrinology amination, there were no other important diculoneuritis. Up to 50% of the fatal and Metabolism, West China Hospital, Sichuan Uni- findings, except for a minor instability cases have bilateral facial paralysis (5). versity, Chengdu, China. Address correspondence to Haoming Tian, MD, during walking. The patient did not refer The diagnosis is made on lumbar punc- Division of Endocrinology, Department of Internal head injury or febrile viral infection in the ture (with a typically elevated protein in Medicine, West China Hospital of Sichuan Univer- recent past. We made the presumptive di- the absence of a raised number of cells)

DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 623 Letters and peripheral areflexia. Our patient had ●●●●●●●●●●●●●●●●●●●●●●● transplantation on self-reported health- neither peripheral muscle weakness nor References related quality of life (HRQL) outcomes, areflexia, and the CSF examination was 1. Stahl N, Ferit T: Recurrent bilateral pe- we compared islet-transplanted patients normal. ripheral facial palsy. J Laryngol Otol 103: with pretransplant patients on measures Basilar skull fractures and pontine gli- 117–119, 1989 of fear of hypoglycemia and anxiety. 2. George MK, Pahor AL: A cause for bilat- omas were excluded by means of both eral facial palsy. Ear Nose Throat J 70: Patients were asked to self-complete a brain CT and MRI. Because there was no 492–3, 1991 battery of measures, including the Hypo- hilar adenopathy on chest CT and be- 3. Clark JR, Carlson RD, Pachner AR: Facial glycemia Fear Survey (HFS) (4,5) and the cause serum ACE levels were normal, sar- paralysis in Lyme disease. Laryngoscope Health Utilities Index Mark two (HUI2) coidosis was rejected. 95:1341–1345, 1985 (6). The HFS contains 23 questions that Bilateral Bell’s palsy does not seem to 4. Keane JR: Bilateral seventh nerve palsy: assess patients’ concerns and worries be a plausible diagnosis because our pa- analysis of 43 cases and review of the lit- about hypoglycemia and the behaviors in tient had neither a preceding viral infec- erature. Neurology 44:1198–1202, 1994 which patients may engage to avoid low tion nor the characteristic symptoms of 5. Arias G, Nogues J, Manos M, Amilibia E, blood glucose. The emotion attribute of this condition (facial numbness or pain, Dicenta M: Bilateral facial nerve palsy: the HUI2 can be used as an index of anx- four case reports. ORL J Otorhinolaryngol change in taste, numbness of the tongue, Relat Spec 60:227–229, 1998 iety (6). Our standard protocol for admin- hyperacusis, etc.). 6. Hattori T, Schlagenhauff RE: Bilateral fa- istration of HRQL questionnaires occurs Diabetes has previously been associ- cial palsy: occurrence with diabetes mel- at baseline (pretransplant); midtransplant ated with facial diplegia (4,6,7). Accord- litus. N Y State J Med 77:1492–1494, 1977 (i.e., between the first and second); 1, 3, ing to Adour, Wingerd, and Doty (7), 7. Adour K, Wingerd J, Doty HE: Prevalence 6, and 12 months posttransplant; and an- diabetes was present in 28.4% of 67 pa- of concurrent diabetes mellitus and idio- nually thereafter. Because islet-transplanted tients with recurrent or bilateral facial pathic facial paralysis (Bell’s palsy). Dia- patients may have completed multiple palsy. A plausible explanation could be betes 24:449–451, 1975 surveys during follow-up, we initially that diabetic patients are more prone to used only the last available HRQL assess- nerve degeneration. In another series of ment. Surveys were completed by 81 (46 43 patients with bilateral seventh nerve Reduced Fear of pretransplant and 35 islet-transplanted) palsy, there was one case associated with Hypoglycemia in patients. Among the islet-transplanted diabetes (4). Thus, having excluded all patients, questionnaires were completed the other possible causes of this disorder Successful Islet a median of 11.9 months (range 1–36) after extensive evaluation, we could as- Transplantation after transplant. Scores between the two sume that the most likely cause of facial groups of patients were compared using diplegia in the case presented is diabetes. nonparametric statistical tests. In conclusion, bilateral facial paraly- he recent dramatic improvement in Fear of hypoglycemia was signifi- sis may be due to a life-threatening condi- clinical outcomes in islet transplan- cantly lower in islet-transplanted (median tion and, therefore, the practitioner should T tation in type 1 diabetes with the Ed- 5.0) compared with pretransplant (me- be aware of the diagnostic possibilities monton Protocol has led to considerable dian 47.0) patients for the HFS total score that cause this extremely rare condition. A excitement in the field of diabetes (1,2). (P Ͻ 0.001). The magnitude of the differ- review of the literature reveals that diabe- The unprecedented 1-year success rates ence in HUI2 emotion scores between tes is associated with facial diplegia and provide considerable evidence of the clin- pretransplant and islet-transplanted pa- should always be included in the differ- ical effectiveness of the procedure (2,3). tients would be considered clinically im- ential diagnosis of this condition. However, the benefits of freeing or reduc- portant (6) (1.00 vs. 0.86, respectively), ing insulin requirements for these pa- although the difference was not statically 1 ALEXANDER KAMARATOS, MD, PHD tients must be weighed against the risks of significant (P ϭ 0.96). Among all islet- 1 STELIOS KOKKORIS, MD the procedure itself, as well as the life- transplanted patients, the small number 1 JOHN PROTOPSALTIS, MD, PHD long immunosuppression. Before making (n ϭ 3) without C-peptide secretion and 2 DIMITRIOS AGORGIANITIS, MD this treatment available to a larger num- requiring exogenous insulin had substan- 2 HARIS KOUMPOULIS, MD ber of people with type 1 diabetes, mea- tially more fear about hypoglycemia (P ϭ 1 JOHN LENTZAS, MD sures of quality of care and of clinical 0.041) and reported more anxiety on the 3 ANDREAS MELIDONIS, MD, PHD effectiveness must be incorporated to HUI2 emotion attribute (P ϭ 0.023) than 1 GREGORY GIANNOULIS, MD, PHD fully evaluate the benefit of this treatment. islet-transplanted patients with successful Episodes of severe hypoglycemia, a transplants. From the 1Second Department of Internal Medicine, 2 common occurrence in patients with la- Because anxiety pre- and posttrans- Tzanio Hospital, Piraeus, Greece; the Neurology bile type 1 diabetes and hypoglycemia un- plant could be related to the procedure Department, Tzanio Hospital, Piraeus, Greece; and the 3Diabetologic Center, Tzanio Hospital, Piraeus, awareness, result in considerable fear and itself, we also compared HFS and HUI2 Greece. anxiety (4,5). When these concerns be- emotion scores between pretransplant Address correspondence to Alexander Kamara- come an overwhelming burden for pa- and islet-transplanted patients in the im- tos, MD, PhD, Tzanio General Hospital of Piraeus, tients with type 1 diabetes, islet mediate posttransplant period; for these Second Department of Internal Medicine,Tzani and Afentouli 1, Piraeus 185 36, Greece. E-mail: transplantation with the Edmonton Pro- comparisons, we used all available HRQL [email protected]. tocol is a potential solution (1–3). To de- assessments at 1 and 3 months posttrans- © 2004 by the American Diabetes Association. termine the potential impact of islet plant. We found that fear of hypoglyce-

624 DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 Letters mia was lower, with a median HFS total 230–238, 2000 Lispro insulin administered in a multiple of 30.0 for islet-transplanted patients 2. Ryan EA, Lakey JR, Rajotte RV, Korbutt dose regimen that disregards the role of (n ϭ 20) at 1 month and 6.5 (n ϭ 18) at 3 GS, Kin T, Imes S, Rabinovitch A, Elliott CSII as a necessary factor for its genesis. months, both of which were significantly JF, Bigam D, Kneteman NM, Warnock Our patient is a 35-year-old woman lower (P Ͻ 0.01) than pretransplant. GL, Larsen I, Shapiro AM: Clinical out- diagnosed in January of 1992 at 22 years comes and insulin secretion after islet Conversely, the HUI2 emotion score transplantation with the Edmonton Pro- of age. From the start, she was treated was not significantly different from tocol. Diabetes 50:710–719, 2001 with recombinant DNA human insulin pretransplant at either 1 or 3 months 3. Ryan EA, Lakey JRT, Paty BW, Imes S, (Humulin Regular and Humulin NPH; posttransplant. Korbutt GS, Kneteman NM, Bigam D, Ra- Lilly) in a regimen of three daily doses. These initial evaluations of self- jotte EV, Shapiro AMJ: Successful islet She always exhibited a good degree of reported HRQL outcomes of in islet trans- transplantation: continued insulin reserve metabolic control, with HbA1c between 6 plant recipients demonstrate that clinical provides long-term glycemic control. Di- and 7%. Seven years after diagnosis, she success is associated with substantial re- abetes 51:2148–2157, 2002 began to exhibit episodes of hypoglyce- duction in emotional burden through re- 4. Cox D, Irvine A, Gonder-Frederick L, mia not perceived with accompanying duced fear of hypoglycemia. General Nowacek G, Butterfield J: Fear of hypo- neuroglycopenia, which persisted in spite glycemia: quantification, validation, and anxiety in islet-transplanted patients is re- utilization. Diabetes Care 10:617–621, of several changes of her prior insulin reg- duced overall, which seems to be related 1987 imen. For that reason, in November of to the freedom from requirement of exog- 5. Irvine A, Cox D, Gonder-Frederick L: 2000 it was decided that she would enous insulin rather than to recovering Thefear of hypoglycemia scale. In Hand- change to LisPro insulin administered be- from the transplant procedure itself. Al- book of Psychology and Diabetes. Bradley C, fore breakfast, lunch, snack, and dinner, though the interpretation of our initial Ed. Amsterdam, Hardwood Academic, and NPH insulin administered before data is interesting and informative, sev- 1994, p. 133–155 breakfast and dinner. With the new regi- eral limitations and questions remain. 6. Feeny DH, Torrance GW, Furlong WJ: men, metabolic control remained similar These initial data were collected cross- Health utilities index. In Quality of Life and to the previous control and the episodes sectionally and on a relatively small but Pharmacoeconomics in Clinical Trials. 2nd of neuroglycopenia persisted. Anti- growing sample of islet-transplanted pa- ed. Spilker B, Ed. Philadelphia, Lippin- insulin antibody (IAA) levels were mea- cott-Raven, 1996, p. 239–251 tients; even with the small sample sizes, sured and were high (49.6%, reference the observed differences were statistically value Ͻ8.5%). In October of 2002, 23 significant. Longitudinal assessments to months after beginning with LisPro, the measure within-person change over time patient consulted the physician because are required to fully assess the impact on she had a circumscribed localized lipoat- HRQL. A Case of rophy area of ϳ3 cm in diameter on the Lipoatrophy With anterior aspect of the right thigh, one of 1,2 JEFFREY A. JOHNSON, PHD her normal injection areas. Six months 2 Lispro Insulin MARIA KOTOVYCH, MA later, a period in which injection in said 3,4 EDMOND A. RYAN, MD, FRCPC Without Insulin area was avoided, the lesion remained un- A.M. JAMES SHAPIRO, MBBS, BMEDSCI, Pump Therapy changed, but an incipient localized lipoat- 4,5 PHD, FRCSC rophy area could be observed in the same area of the contralateral thigh. For this From the 1Department of Public Health Sciences, ocalized lipoatrophy occurring in reason, it was decided to change from University of Alberta, Edmonton, Alberta, Canada; the subcutaneous insulin injection Lispro to Aspart insulin. the 2Institute of Health Economics, Edmonton, Al- 3 area in diabetic patients was a phe- berta, Canada; the Division of Endocrinology and L Six months after said change of insu- Metabolism, Department of Medicine, University of nomenon practically forgotten after the lin, which was when this letter was sent, Alberta, Edmonton, Alberta, Canada; the 4Clinical introduction of human insulin in medical neither progression nor improvement of Islet Transplant Program, University of Alberta, Ed- 5 practice. In recent years, there have been the localized lipoatrophy lesions had been monton, Alberta, Canada; and the Department of very few publications in relation to this Surgery, University of Alberta, Edmonton, Alberta, observed. IAA levels were 30.5%, slightly Canada. matter. lower than the previous levels. Address correspondence to Jeffrey A. Johnson, Three cases of patients with type 1 The development of localized lipoat- PhD, Institute of Health Economics, 1200-10405 diabetes who presented with subcutane- rophy in the insulin injection area is a Jasper Ave., Edmonton, Alberta, Canada T5J 3N4. ous localized lipoatrophy areas and who practically exclusive complication of type E-mail: [email protected]. © 2004 by the American Diabetes Association. were in treatment with Lispro insulin 1 diabetic patients, although cases have were recently reported (1,2). The three been reported in patients with type 2 di- ●●●●●●●●●●●●●●●●●●●●●●● patients used a continuous subcutaneous abetes (3). From the etiopathogenic point insulin infusion (CSII) system; therefore, of view, it is considered an immunological References the authors posed the doubt of whether phenomenon. Although this has not been 1. Shapiro AMJ, Lakey JRT, Ryan EA, Kor- butt GS, Toth E, Warnock GL, Kneteman such an administration system locally sufficiently clarified, a strong association NM, Rajotte RV: Islet transplantation in played a determinant role in the occurrence between the lesions and high IAA plasma seven patients with type 1 diabetes melli- of subcutaneous localized lipoatrophy. levels and the presence of insulin and im- tus using a glucocorticoid-free immuno- We present a case of localized lipoat- munoglobulin G deposits in subcutane- suppressive regimen. N Engl J Med 343: rophy associated with treatment with ous tissue of the affected areas (4) have

DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 625 Letters been reported. The consequences of this insulin in insulin pump therapy (Letter). scribed an adolescent female with neona- immunological activation are the local in- Diabetes Care 26:953–954, 2003 tal nesidioblastosis who developed hibition of adipocyte differentiation, 3. Mu L, Goldman JM: Human recombinant diabetes after medical treatment with dia- probably mediated by the local hyperpro- DNA insulin-induced lipoatrophy in pa- zoxide/octreotide. To our knowledge, this duction of tumor necrosis factor-␣ (5). tient with type 2 diabetes mellitus. Endocr is the first nesidioblasosis case subject Pract 6:151–152, 2000 In affected patients, the pharmacoki- 4. Reeves WG, Allen BR, Tattersall RB: Insu- who developed diabetes following medi- netic variations of insulin due to high IAA lin induced lipoatrophy evidence for an cal therapy. levels and the erratic absorption of the immune pathogenesis. BMJ 1:1500– A 14-year-old Saudi female presented drug when it is injected in the areas af- 1506, 1980 with severe persistent hypoglycemia fected with localized lipoatrophy imply a 5. Atlan-Gepner C, Bondgrand P, Farnarier during the first few days of life. She was glycemic variability making it very diffi- C, Xerri L, Choux R, Gauthier JF, Brue T, diagnosed with hyperinsulinemic hypo- cult to achieve suitable metabolic control. Vague P, Grob JJ, Vialettes B: Insulin-in- glycemia of infancy based on her intrave- Although the immunogenic profile of duced lipoatrophy in type 1 diabetes: a nous glucose requirement of Ͼ14 mg Ϫ Ϫ the patients treated with Lispro insulin possible tumor necrosis factor-␣–medi- kg 1 min 1, an insulin-to-glucose ratio and recombinant human insulin are com- ated dedifferentiation of adipocytes. Dia- of Ͼ0.3 (her insulin level was 98 ␮U/ml at parable (6), the recent occurrence of de- betes Care 19:1283–1285, 1996 a serum glucose of 32 mg/dl), negative 6. Fineberg SE, Huang J, Brunelle R, Gulliya scriptions of localized lipoatrophy urinary ketones, a 30-min glucose incre- KS, Anderson JH: Effect of long-term ex- Ն associated to this analogue can decrease posure to insulin Lispro on the induction ment of 30 mg/dl in response to intra- the therapeutic alternatives of this com- of antibody response in patients with type muscular 0.5 mg glucagon, and normal plication when, especially in recent years, 1 or type 2 diabetes. Diabetes Care 26:89– blood spot acylcarnitine profile deter- in the few published cases of human in- 96, 2003 mined by tandem mass spectrometry. She sulin–induced localized lipoatrophy the 7. Chantelau E, Reuter M, Schotes S, Starke also had a normal growth hormone level attempted solution to the problem was to AA: Severe lipoatrophy with human insu- of Ͼ20 mU/l and a normal cortisol level of change to Lispro. It is possible that the use lin: successfully treated by CSII (Letter). Ͼ500 nmol/l during hypoglycemia. She of CSII may favor the occurrence of local- Diabet Med 10:580–581, 1993 was treated initially with frequent feeding ized lipoatrophy but, as can be seen in the supplemented with complex carbohy- case we present, it is not a factor sine qua drates (polycose/corn starch) and then Ϫ Ϫ non for its development. Curiously, severe started on diazoxide 15 mg kg 1 day 1 cases of human insulin–induced localized divided three times a day, which kept her lipoatrophy have been previously re- Diabetes In A euglycemic with occasional hypoglyce- ported that responded satisfactorily after Nonpancreatectomized mic episodes. In 1992, octreotide was first the introduction of CSII (7). introduced in our hospital as an adjunc- The association of localized lipoatro- Child With tive therapy to diazoxide. She was started Ϫ Ϫ phy and Lispro insulin without the con- Nesidioblastosis on 25 ␮g kg 1 day 1 of subcutaneous course of CSII has not been reported octreotide divided four times a day. She previously. We therefore believe it is in- responded to medical treatment with no teresting to disclose our case and to ersistent hyperinsulinemic hypogly- hypoglycemic episodes. She was contin- encourage publishing for other diabetolo- cemia of infancy (PHHI) (Online ued on diazoxide and octreatide until the gists who have observed similar cases for P Mendelian Inheritance in Man age of 10 years, when she became eugly- the purpose of clarifying its pathogenesis [OMIM] 256450), formerly known as ne- cemic and these two medications were and therapeutic approach. sidioblastosis, is a glucose metabolism stopped. At the age of 14, she developed disorder characterized by profound hy- hyperglycemia associated with weight ALFONSO ARRANZ, MD poglycemia and inappropriate secretion gain. Her blood glucose ranged from 200 VICTOR ANDIA, MD of insulin (1). Affected children run the to 300 mg/dl, and her weight was 75 kg ANTONIO LO´ PEZ-GUZMA´N, MD risk of severe neurological damage unless (Ͼ95%). She had an insulin level of 10 immediate and adequate steps are taken ␮U/ml and C-peptide level of 0.16 nmol/l From the Endocrinology Unit, Hospital Nuestra Se- (2). Treatment with diazoxide and/or so- at a serum glucose level of 350 mg/dl. An- n˜ ora de Sonsoles, Avila, Spain. Address correspondence to Dr. Alfonso Arranz, matostatin analogue is the first line of tiglutamic acid decarboxylase, insulin, Endocrinology Unit, Ntra. Sra. De Sonsoles, Car- therapy. However, it not always effective, and islet cell antibodies were negative. retera de Madrid, km 109, Avila, Spain 05071. E- especially in familial cases, which may ne- She responded to metformin 250 mg mail: [email protected]. cessitate an alternative intervention such twice a day with a serum mean glucose © 2004 by the American Diabetes Association. as pancreatectomy (3). level of 109 mg/dl and HbA1c of 7.5%. ●●●●●●●●●●●●●●●●●●●●●●● Several studies have suggested that The long-term outcome of PHHI is partial pancreatectomy endangers future not well documented. Previous reports References islet cell function (4,5). The incidence of suggested that subtotal or near total pan- 1. Griffin ME, Feder A, Tamborlane WV: Li- poatrophy associated with lispro insulin diabetes increases with age and correlates createctomy in infants will endanger the in insulin pump therapy (Letter). Diabetes with the extent of surgical resection (6,7). future islet function (4–8). Long-term Care 24:174, 2001 However, there was no report of occur- follow-up studies in medically treated pa- 2. Ampudia-Blasco FJ, Hasbum B, Carmena rence of overt diabetes in medically tients with diazoxide or octreotide R: A new case of lipoatrophy with lispro treated patients (8). In this report, we de- showed that some of these patients re-

626 DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 Letters sponded to medical therapy and became mouse model. We recommend, based on Fekete C, Czernichow P, Saudubray JM: euglycemic (9–11). Some patients were this human clinical evidence, weight con- Long-term treatment of persistent hyper- weaned off medical therapy and contin- trol in aged PHHI patients to decease the insulinemic hypoglycemia of infancy with ued to be euglycemic; however, none of incidence of diabetes. diazoxide: a retrospective review of 77 them became hyperglycemic or diabetic. cases and analysis of efficacy-predicting criteria. Eur J Pediatr 157:628–633, 1998 Leibowitz et al. (8) followed six conserva- BASSAM S. BIN-ABBAS, MD 10. Glaser B, Landaw H: Long-term treatment tively treated patients with PHHI. Intra- ABDULLAH A. AL-ASHWAL, MD with somatostatin analogue SMS 201– venous glucose tolerance was performed 995: alternative to pancreatectomy in per- in all patients and showed a blunted in- From the Department of Pediatrics, King Faisal Spe- cialist Hospital and Research Center, Riyadh, Saudi sistent hyperinsulinemic hypoglycemia of sulin response in two with no overt hy- Arabia. infancy. Digestion 45:27–35, 1990 perglycemia. Histologically, Kassem et al. Address correspondence to Bassam Saleh Bin- 11. Darendeliler F, Bundak R, Bas F, Saka N, (12) showed that ␤-cell proliferation and Abbas, MD Consultant, Section of Pediatric Endo- Gunoz H: Long term diazoxide treatment apoptosis, which normally occurrs in the crinology Department of Pediatrics, MBC 58 King in persistent hyperinsulinemic hypogly- Faisal Specialist Hospital and Research Center, P.O. cemia of infancy: a patient report. J Pediatr normal developing human pancreas, also Box 3354 Riyadh 11211 Saudi Arabia. E-mail: occurs in the PHHI pancreas with a higher Endocrinolo Metabol 10:79–81, 1997 [email protected]. 12. Kassem SA, Ariel I, Thornton PS, Scheim- frequency of apoptosis. They suggested © 2004 by the American Diabetes Association. berg I, Glaser B: ␤-Cell proliferation and that this phenomenon will result in a apoptosis in the developing normal hu- slow, progressive, and complete loss of ●●●●●●●●●●●●●●●●●●●●●●● man pancreas and in the hyperinsulin- ␤-cell mass. This histological report and References ism of infancy. Diabetes 49:1325–1333, the development of diabetes in our non- 1. Aynsley-Green A: Nesidioblastosis of the 2000 pancreatectomized PHHI patient may pancreas in infancy. Dev Med Child Neurol 13. Miki T, Tashiro F, Iwanaga T, Nagashima suggest that patients with PHHI will nat- 23:372–379, 1981 K, Yoshitomi H, Aihara H, Nitta Y, Gonoi urally develop diabetes whether they 2. Schwitzgebel VM, Gitelman SE: Neonatal T, Inagaki N, Miyazaki JI, Seino S: Abnor- were treated medically or surgically or hyperinsulinism. Clin Perinatol 25:1015– malities of pancreatic islets by targeted ex- even if they are left untreated. This hy- 1038, 1998 pression of a dominant-negative KATP 3. Shilyansky J, Fisher S, Cutz E, Perlman K, pothesis was further raised when the nat- channel. Proc Natl Acad Sci U S A Filler RM: Is 95% pancreatectomy the 94:11969–11973, 1997 ural history of this disease was discussed procedure of choice for the treatment of 14. Miki T, Nagashima K, Tashiro F, Kotake in knockout mouse models. Transgenic persistent hyperinsulinemic hypoglyce- K, Yoshitomi H, Tamamoto A, Gonoi T, mice engineered to express a dominant- mia of the neonate? J Pediatr Surg 32:342– Iwanaga T, Miyazaki JI, Seino S: Defect in negative form of Kir6.2 or mice with ATP- 346, 1997 insulin secretion and enhanced insulin ϩ sensitive K channel deficiency devel- 4. Dunger DB, Burns C, Ghale GK, Muller action in KATP deficient mice. Proc Natl oped hyperinsulinemic hypoglycemia DP, Spitz L, Grant DB: Pancreatic exo- Acad SciUSA95:10402–10406, 1998 followed by hypoinsulinemic hyperglyce- crine and endocrine function after subto- 15. Seino S, Iwanaga T, Nagashima K, Miki T: tal pancreatectomy for nesidioblastosis. mia. Diabetes in these transgenic mice Diverse roles of KATP channels learned was thought to be due to sustained unreg- J Pediatr Surg 23:112–115, 1988 from Kir6.2 genetically engineered mice. 5. Mahachoklertwattana P, Suprasongsin C, ulated Ca influx and premature ␤-cell ap- Diabetes 49:311–318, 2000 Teeraratkul S, Preeyasombat C: Persistent 16. Winarto A, Miki T, Seino S, Iwanaga T: optosis (burn-out phenomenon) (13,14). hyperinsulinemic hypoglycemia of infan- Morphological changes in pancreatic is- Seino et al. (15,16) reported another pos- cy: long-term outcome following subtotal lets of KATP channel-deficient mice: the sible predisposing factor to hyperglyce- pancreatectomy. J Pediatr Endocrinol involvement of KATP channels in the sur- mia in PHHI patients. They showed that Metabol 13:37–44, 2000 vival of insulin cells and the maintenance hyperglycemia in Kir6.2 knockout mice 6. De Lonlay- Debeney P, Poggi-Travert F, of islet architecture. Arch Histol Cytol 64: was more evident with age and increasing Fournet JC, Sempoux C, Vici CD, 59–67, 2001 weight. They suggested that the Kir6.2 Brunelle F, Touati G, Rahier J, Junien C, knockout mouse provides a model of type Nihoul-Fekete C, Robert JJ, Saudubray 2 diabetes, and that both the genetic de- JM: Clinical features of 52 neonates with hyperinsulism. N Engl J Med 340:1169– Oral Glucose fect in glucose-induced insulin secretion 1175, 1999 Tolerance Test and the acquired insulin resistance due to 7. Dacou-Voutetakis C, Psychou F, Maniati- environmental factors are necessary to de- Christidis M: Persistent hyperinsulinemic Evaluation With velop diabetes in the Kir6.2 knockout hypoglycemia of infancy: long term re- Forearm and mouse. sults. J Pediatr Endocrinol Metabol 11:131– We hypothesized that diabetes was 141, 1998 Fingertip Glucose induced by weight gain and obesity in our 8. Leibowitz G, Glaser B, Higazi AA, Measurements in patient. She responded to metformin, Salameh M, Cerasi E, Landau H: Hyper- which may suggest that her diabetes is insulinemic hypoglycemia of infancy (ne- Pregnant Women due to insulin resistance induced by both sidioblastosis) in clinical remission: high incidence of diabetes mellitus and persis- weight gain and insulin insufficiency. tent beta-cell dysfunction at long term fol- t is known that glucose levels in capil- Simple type 2 diabetes is still a possibility, low-up. J Endocrinol Metabol 80:386–392, lary blood in the fingertip after a liquid although there was no 1995 I glucose load are constantly higher in the family. This patient could be the 9. Tuoati G, Poggi-Travert F, Ogier de when compared with venous blood mea- human example of the Kir6.2 knockout Baulny H, Rahier J, Brunelle F, Nihoul- surements (1). Recently alternative sites

DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 627 Letters for capillary blood drawing (e.g., fore- cose levels are constantly higher (15– and Koschinsky: glucose monitoring at arm) have been proposed (2) that are less 26%) than venous glucose levels. On the the arm (Letter). Diabetes Care 24:1304– painful compared with fingertip. Data contrary, forearm glucose levels were 1306, 2001 have shown that there was no significant closer to venous plasma glucose levels: difference between the capillary blood There was no significant difference be- drawn from forearm and fingertip in dia- tween them after 1 h, whereas a signifi- betic patients with glucose values in a cant increase of 16% appeared at 2 and wide range (3). Nevertheless, some data 3 h. These findings are in accordance with Silent Hypoglycemia have shown that glucose results from al- the concept of slower glucose kinetics at Presenting As ternative sites and fingertip were not the forearm than the fingertip due to identical. This difference was more pro- lesser arteriovenous anastomoses (4). To Dysesthesias nounced when there was a rapid increase be sure, this physiological difference or decrease of blood glucose values (4). It needs to be taken into consideration in seemed that significant differences ap- the detection of hypoglycemia in diabetic ypoglycemia is not often in the dif- peared when glucose values declined at a patients. However, it is precisely this ferential diagnosis for dysesthesias Ϫ Ϫ mean rate Ͼ2mg dl 1 min 1 (5), but physiological difference that supports the H but should be considered when in- not at a lower rate (6). All the above- suggestion that capillary forearm glucose volved in the care of diabetic patients. mentioned reports compared capillary measurements using a portable glucose Such symptoms may herald silent hypo- blood drawn from either the forearm or meter may be useful for the 50-g chal- glycemia and resultant nerve injury, as il- fingertip, but so far, it appears that no lenge test for screen- lustrated in the following case. direct comparison has been made be- ing in an outpatient environment. A 26-year-old female with type 1 di- tween venous plasma blood and capillary abetes presented with a 2-month history forearm blood. CHARALAMPOS STAVRIANOS, MD of numbness and tingling in her hands Thus, the purpose of this investiga- ELENI ANASTASIOU, MD and feet upon waking in the morning. tion is to study the pattern of capillary Symptoms began when her treatment was forearm blood and that of capillary finger- From the First Endocrine Section, Diabetes Center, altered from NPH 50 units q A.M. to NPH Alexandra Hospital, Athens, Greece. 35 and Regular 3 q A.M. and NPH 8 and tip blood glucose using the same glucom- Address correspondence to Eleni Anastasiou, eter (FreeStyle; Therasense) and to MD, Alexandra Hospital, First Endocrine Section, Regular 5 at dinner. The patient moni- compare both with venous blood labora- Diabetes Center, 80 V. Sofias Ave., Athens 11528, tored her glucose more than four times tory measurements during a 100-g oral Greece. E-mail: [email protected]. each day and reported three to four glu- glucose tolerance test (OGTT) in preg- © 2004 by the American Diabetes Association. cose values a week that were Ͻ60 mg/dl without symptoms. Her morning glucose nant women. A total of 47 pregnant ●●●●●●●●●●●●●●●●●●●●●●● women (age 31 Ϯ 3 years, BMI 24 Ϯ 3 levels averaged 60 mg/dl. The symptoms kg/m2, and gestational age 24–28 weeks) References were more pronounced in her hands than underwent a 100-g OGTT. Half of these 1. Kuwa K, Nakayama T, Hoshino T, Tomi- feet and resolved within minutes. On ϭ naga M: Relationships of glucose concen- exam, she showed no objective sensory women (n 23) had simultaneous glu- trations in capillary whole blood, venous cose samples drawn from the forearm af- loss, possessed good muscle tone, bulk, whole blood and venous plasma. Clin ϩ ter rubbing (7) using FreeStyle in 0Ј,60Ј, Chim Acta 307:187–192, 2001 and strength, had intact reflexes (2 ) bi- 120Ј, and 180Ј, whereas the other half 2. Ellison JM, Stegmann JM, Colner SL, Mi- laterally, and had no focal neurological (n ϭ 24) underwent the same procedure chael RH, Sharma MK, Ervin KR, Horwitz signs. HbA1c was 6.8%. with blood drawn from the fingertip. The DL: Rapid changes in postprandial blood Symptoms were attributed to periph- two groups were matched for age, BMI, glucose produce concentration differ- eral neuropathy secondary to hypoglyce- and gestational age. Glucose difference in ences at finger, forearm, and thigh sam- mia. Her insulin regimen was adjusted to percentage (GDP) was calculated for both pling sites. Diabetes Care 25:961–964, NPH 35 and Regular 3 q A.M., NPH 4 q groups separately. Mean GDP between 2002 HS, and Regular 5 before dinner for glu- 3. Lock JP, Szuts EZ, Malomo KJ, Anagnos- finger glucose and venous glucose sam- cose Ͼ200 mg/dl. One month later, she Ј topoulos A: Whole-blood glucose testing ples was significantly higher at 60 at alternate sites: glucose values and he- reported the disappearance of the symp- (14.6 Ϯ 20.4%), 120Ј (25.2 Ϯ 34.7%), matocrit of capillary blood drawn from toms and a reduction in the frequency of and 180Ј (26.4 Ϯ 26.7%) than at 0Ј fingertip and forearm. Diabetes Care 25: values Ͻ60 mg/dl to once a week. (Ϫ3.1 Ϯ 14.1%) (P Ͻ 0.01). Mean GDP 337–341, 2002 Hypoglycemia has been proposed to between forearm glucose and venous glu- 4. Jungheim K, Koschinsky T: Glucose mon- induce nerve injury by several mecha- cose samples was significantly higher at itoring at the arm: risky delays of hypo- nisms. Lack of substrate leads to a reduc- 120Ј (16.3 Ϯ 21.5%) and 180Ј (16.3 Ϯ glycemia and hyperglycemia detection. tion in axonal transport, causing an 21.5%) than at 0Ј (Ϫ2.5 Ϯ 16.3%) (P Ͻ Diabetes Care 25:956–960, 2002 accumulation of intraneural metabolites 0.01). On the contrary, mean GDP at 60Ј 5. Jungheim K, Koschinsky T: Response to and neuronal injury (1). Hypoglycemia Ϯ the letter by Pfu¨ tzner and Forst (Letter). (6.7 20.9%) was not found signifi- Diabetes Care 25:639–640, 2002 can induce a reduction in blood flow, cantly different. 6. Pfu¨ tzner A, Forst T: Response to Jung- leading to neural hypoxia (2–4). These These findings confirmed the already heim and Koschinsky (Letter). Diabetes mechanisms may all play a role in nerve reported observation that up to 3 h after a Care 25:638–639, 2002 injury; disturbance in neural blood flow liquid glucose load, capillary finger glu- 7. McGarraugh G: Response to Jungheim may be the initial manifestation of hypo-

628 DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 Letters glycemia, while prolonged hypoglycemia Exercise Increases The subjects’ mean age was 37.1 Ϯ may induce axonal damage (2). 1.3 years, and before exercise mean BMI Adiponectin Levels 2 Peripheral neural injury has been re- was 30.7 Ϯ 0.7 kg/m and VO was 2max Ϫ ported in patients with hypoglycemia and Insulin 48.4 Ϯ 0.8 ml kg fat-free mass (FFM) 1 Ϫ due to insulinomas (5). These patients Sensitivity in min 1. Correlations between glucose in- displayed paresthesias and/or muscle fusion rate (GIR), a measure of insulin wasting and weakness. After tumor resec- Humans sensitivity, and indexes of adiposity in the tion, patients showed resolution of sen- sedentary males were highly significant sory symptoms, while muscle wasting (all P Ͻ 0.0001). Fasting plasma adi- diponectin is an abundant circulat- persisted. ponectin levels were strongly inversely re- ing adipocytokine with anti- We propose that practitioners con- lated to insulin resistance in these inflammatory properties (1) linked sider undetected hypoglycemia as a pos- A subjects (r ϭϪ0.52, P ϭ 0.0007) and to to cardiovascular disease, type 2 diabetes, sible cause of paresthesias in diabetic total fat (r ϭϪ0.39, P ϭ 0.015), central subjects. Frequent episodes of hypoglyce- and obesity (2–5). Numerous reports (3– subcutaneous fat (r ϭϪ0.37, P ϭ 0.02), mia can hinder patients’ efforts to achieve 5), including the present one, confirm and visceral fat mass (r ϭϪ0.32, P ϭ normoglycemia. Early measures taken plasma adiponectin levels to be inversely 0.05). Two to three bouts of moderately to reduce such episodes will promote related to insulin resistance. Longer term, intense aerobic exercise performed within normoglycemia. a rise in adiponectin has been shown to ϳ1 week of baseline assessments resulted occur in response to weight loss and gli- in a mean 23% increase in GIR (35.0 Ϯ Ϫ tazone therapy, but not after chronic ex- 2.7 vs. 43.0 Ϯ 2.8 ␮mol min 1 kg NOLAWIT TESFAYE, BS Ϫ ercise training. However, understanding FFM 1, P Ͻ 0.0001) and a mean 37% ELIZABETH R. SEAQUIST, MD of the shorter-term regulation of adi- increase in basal fat oxidation rate Ϫ ponectin in particular remains unclear. As (1.05 Ϯ 0.14 vs. 1.44 Ϯ 0.08 g day 1 Ϫ From the Division of Endocrinology and Diabetes, an extension to a previously reported ex- kg FFM 1). These effects were main- Department of Medicine, University of Minnesota ercise intervention in sedentary males by Medical School, Minneapolis, Minnesota. tained after 10 weeks of exercise training Ϫ1 Ϫ1 Address correspondence to Elizabeth R. Seaquist, our group (6), we have now examined the (42.4 Ϯ 3.1 ␮mol min kg FFM and Ϫ Ϫ MD, MMC 101, 420 Delaware St. SE, University of effects of this training intervention on adi- 1.35 Ϯ 0.07 g day 1 kg FFM 1, respec- Minnesota, Minneapolis, MN 55455. E-mail: ponectin levels in overweight males. We tively). Body weight was unchanged after [email protected]. demonstrate that the short-term exercise Ϯ © 2004 by the American Diabetes Association. two to three bouts of exercise (93.5 1.9 training increased circulating adiponectin vs. baseline 93.4 Ϯ 1.8 kg) and was not levels with accompanied improved insu- significantly reduced at 10 weeks (92.6 Ϯ lin sensitivity. 1.9 kg, P ϭ 0.08) in this cohort. Twenty-six overweight males partici- Adiponectin levels rose by 260% after pated in an exercise program, as previ- ϳ ●●●●●●●●●●●●●●●●●●●●●●● two to three bouts of exercise ( 1 week) ously described (6). Full data were (7.0 Ϯ 0.7 vs. 18.2 Ϯ 1.9 ␮g/ml, P Ͻ References available on 19 subjects who completed 0.0001) despite unchanged body weight 1. Sidenius P, Jakobsen J: Anterograde fast the entire program. At baseline and pos- Ϯ ␮ component of axonal transport during in- and remained elevated (16.4 1.9 g/ sulin-induced hypoglycemia in nondia- texercise intervention, all subjects were ml, P Ͻ 0.0001) after 10 weeks. However, betic and diabetic rats. Diabetes 36:853– assessed for anthropometric measures individual changes in adiponectin levels 858, 1987 (dual-energy X-ray absorptiometry, mag- after two to three bouts (ϳ1 week) and 2. Ohshima J, Nukada H: Hypoglycaemic netic resonance imaging, and BMI), insu- after 10 weeks of exercise were not corre- neuropathy: microvascular changes due lin sensitivity (insulin clamp), and lated with the respective changes in insu- to recurrent hypoglycaemic episodes in indirect calorimetry (for fat oxidation lin sensitivity or fat oxidation rate. Our rat sciatic nerve. Brain Res 947:84–89, rates), and overnight fasting plasma sam- results contrast with Hulver et al. (7) 2002 ples were collected for adiponectin levels. where adiponectin is unaltered with exer- 3. Kihara M, Zollman PJ, Smithson IL, La- Briefly, exercise consisted of aerobic exer- gerlund TD, Low PA: Hypoxic effect of cise training despite enhanced insulin ac- exogenous insulin on normal and diabetic cise (brisk walking mixed with light jog- tion. However, we assessed the acute peripheral nerve. Am J Physiol 266:E980– ging) 4–5 days per week for 40 min per effect of exercise after two to three bouts ϳ E985, 1994 session ( 55–70% VO2max) over 10 of exercise (6), whereas they took their 4. Hilsted J, Bonde-Petersen F, Norgaard weeks (6). Plasma adiponectin was deter- “basal” samples 6 weeks after a ramping MB, Greniman M, Christensen NJ, Parv- mined using a radioimmunoassay kit exercise period before the 6-month en- ing HH, Suzuki M: Haemodynamic (Linco Research, St. Charles, MO). Two- durance exercise training program (7). changes in insulin-induced hypoglycae- tailed paired Student’s t tests were used Our data indicate that elevated adiponec- mia in normal man. Diabetologia 26:328– for comparisons between time points be- tin levels are first apparent after 1 week 332, 1984 fore and after exercise, and associations (two to three bouts) of moderately intense 5. Jaspan JB, Wollman RL, Bernstein L, Rubenstein AH: Hypoglycemic peripheral between continuous variables were inves- exercise. We suggest that it is likely that neuropathy in association with insuli- tigated using simple regression analyses. this short-term moderate exercise train- noma: implication of glucopenia rather Analyses were performed using StatView ing can modify regulation of adiponectin, than hyperinsulinism. Medicine 61:33– software (version 4.5; Abacus Concepts, and this could be postulated to provide 44, 1982 Berkeley, CA). another mechanism by which exercise re-

DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 629 Letters duces atherogenic risk, at least in over- 1126–1133, 2001 factor controlling LDL oxidation. Coen- weight males. 5. Weyer C, Funahashi T, Tanaka S, Hotta K, zyme Q10 is an electron carrier–proton Matsuzawa Y, Pratley RE: Hypoadi- translocator in the respiratory chain and ponectinemia in obesity and type 2 diabe- is an antioxidant factor by directly scav- Acknowledgments— We acknowledge the tes: close association with insulin enging radicals or indirectly by regenerat- resistance and hyperinsulinemia. J Endo- assistance of the nursing staff of the Clinical ing vitamin E. ROMs were assayed using Research Facility, laboratory technicians of the crinol Metab 86:1930–1935, 2001 Diabetes Research Group, Dr. Judith Freund 6. Gan SK, Kriketos AD, Ellis BA, Thompson the kit d-ROMs test (Diacron), which is and technicians of the Nuclear Medicine De- CH, Kraegen EW, Chisholm DJ: Changes based on the Fenton reaction (8). Vitamin partment, St Vincent’s Hospital Sydney, and in aerobic capacity and visceral fat but not E was determined by reversed-phase volunteers who participated in this study. myocyte lipid levels predict increased in- high-performance liquid chromatogra- sulin action after exercise in overweight phy. Coenzyme Q10 was also determined ADAMANDIA D. KRIKETOS, PHD and obese men. Diabetes Care 26:1706– by reversed-phase high-performance liq- SENG KHEE GAN, MBBS, FRACP 1713, 2003 uid chromatography, according to the 7. Hulver MW, Zheng D, Tanner CJ, ANN M. POYNTEN, MBBS, FRACP method of Grossi et al. (9). Statistical sig- Houmard JA, Kraus WE, Slentz CA, TUART URLER PHD nificance was assessed using Student’s t S M. F , Sinha MK, Pories WJ, MacDonald KG, DONALD J. CHISHOLM, MBBS, FRACP Dohm GL: Adiponectin is not altered test and Pearson correlation index for LESLEY V. CAMPBELL, MBBS, FRACP with exercise training despite enhanced normally distributed data and using insulin action. Am J Physiol 283:E861– Mann-Whitney and Spearman rank cor- From the Diabetes and Obesity Research Program, E865, 2002 relation for nonnormally distributed data. Garvan Institute of Medical Research, Sydney, Aus- tralia. All results that were nominally significant Address correspondence to Dr. Adamandia D. at P Ͻ 0.05 are indicated. Diabetic pa- Kriketos, Diabetes and Obesity Research Program, tients did not have different ROMs, vita- Garvan Institute of Medical Research, 384 Victoria min E, and coenzyme Q10 levels from St., Sydney, NSW 2010, Australia. E-mail: age-matched control subjects. Significant [email protected]. © 2004 by the American Diabetes Association. positive correlations were found between High Glucose Levels the following parameters: vitamin E and ●●●●●●●●●●●●●●●●●●●●●●● Induce an Increase in coenzyme Q10, coenzyme Q10 and References HbA1c, and vitamin E and HbA1c. No cor- 1. Okamoto Y, Arita Y, Nishida M, Muraga- Membrane relation was observed between ROM lev- chi M, Ouchi N, Takahashi M, Igura T, Antioxidants, in els and coenzyme Q10, vitamin E, or Inui Y, Kihara S, Nakamura T, Yamashita HbA1c values. Vitamin E and coenzyme S, Miyagawa J, Funahashi T, Matsuzawaw Terms of Vitamin E Q10 values were higher in patients (n ϭ Y: An adipocyte-derived protein, adi- Ͼ and Coenzyme Q10, 37) with poor control (HbA1c 8%) than ponectin, adheres to injured vascular in Children and in those (n ϭ 38) with good control walls. Horm Metab Res 32:47–50, 2001 (HbA Ͻ8%) (vitamin E, 25.2 Ϯ 9.5 vs. 2. Arita Y, Kihara S, Ouchi N, Takahashi M, 1c Adolescents With 20.9 Ϯ 4.6, P ϭ 0.044; coenzyme Q10, Maeda K, Miyagawa J, Hotta K, Shimo- Ϯ Ϯ ϭ mura I, Nakamura T, Miyaoka K, Type 1 Diabetes 1.12 0.56 vs. 0.82 0.33, P 0.012, Kuriyama H, Nishida M, Yamashita S, respectively). The patients with retinal or Okubo K, Matsubara K, Muraguchi M, renal complications (n ϭ 19) compared Ohmoto Y, Funahashi T, Matsuzawa Y: xidative stress is defined as an im- with those without had higher values of Paradoxical decrease of an adipose-spe- balance between prooxidants and vitamin E (25.8 Ϯ 7.1 vs. 20.9 Ϯ 4.8, P ϭ cific protein, adiponectin, in obesity. Bio- O antioxidants in favor of the former 0.009). chem Biophys Res Commun 257:79–83, (1), and diabetic patients are considered a Therefore, in our patients vitamin E 1999 risk group for increased oxidative stress levels increased in all of the situations 3. Hotta K, Funahashi T, Arita Y, Takahashi (2,3). Studies regarding oxidant/ where an increase of oxidative stress was M, Motsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida antioxidant balance in type 1 diabetic putative, i.e., in the presence of poor met- M, Kihara S, Sakai N, Nakajima T, Hase- children and adolescents have given con- abolic control and complications. This re- gawa K, Muraguchi M, Ohmoto Y, Naka- flicting results (4–7). The aim of this sult is in disagreement with most of the mura T, Yamashita S, Hanafusa T, study was to determine whether serum data of the literature (5,7,10,11), but in Matsuzawa Y: Plasma concentrations of hydroperoxides (reactive oxygen metabo- agreement with a few studies (12,13). a novel, adipose-specific protein, adipo- lites [ROMs]) as oxidative markers and However, a further confirmation of this nectin, in type 2 diabetic patients. Arte- plasma ␣-tocopherol (vitamin E) and co- result is indirectly provided by our find- rioscler Thromb Vasc Biol 20:1595–1599, enzyme Q10 as indexes of antioxidant ca- ings regarding coenzyme Q10. In fact, co- 2000 pacity could be related to metabolic enzyme Q10 levels, like vitamin E levels, 4. Hotta K, Funahashi T, Bodkin NL, Ort- control in 75 unselected children, adoles- are also higher in poorly controlled than meyer HK, Arita Y, Hansen BC, Matsu- zawa Y: Circulating concentrations of the cents, and young adults with type 1 dia- in well-controlled patients and are posi- adipocyte protein adiponectin are de- betes. ROMs are the first markers of tively correlated with HbA1c values. This creased in parallel with reduced insulin oxidation and one of the most reliable in- finding is not surprising because these sensitivity during the progression to type dicators of oxidative stress. Vitamin E is two antioxidants have strict physiological 2 diabetes in rhesus monkeys. Diabetes 50: an important chain-breaking antioxidant interrelationships and are positively inter-

630 DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 Letters correlated in both the patients and control J, Trefil L, Pomahacova R: Parameters of ox- Increased Oxidative subjects. On the other hand, it has already idative stress in children with type 1 diabe- been demonstrated that high-glucose tes mellitus and their relatives. J Diabetes Stress Is Associated conditions produce an overexpression of Complications 17:7–10, 2003 With Serum Levels of intracellular antioxidant enzymes in hu- 7. Willems D, Dorchy H, Dufrasne D: Serum Triglyceride, Insulin man endothelial cells in culture (14) or in antioxidant status and oxidized LDL in skin fibroblasts from diabetic patients well-controlled young type 1 diabetic pa- Resistance, and (15) and that the decreased susceptibility tients with and without subclinical com- Hyperinsulinemia in to oxidative stress in diabetic rats is asso- plications. Atherosclerosis 137 (Suppl.): S61–S64, 1998 Japanese ciated with an increase in mitochondrial 8. Alberti A, Bolognini L, Macciantelli D, Metabolically Obese, glutathione and coenzyme Q contents Caratelli M: The radical cation of N, N- (16). This effect seems to represent an Diethyl-para-phenylediamine: a possible Normal-Weight Men adaptive response to increased oxidative indicator of oxidative stress in biological stress. In very young patients, this re- samples. Res Chem Intermed 26:253–267, sponse is high enough to neutralize the 2000 etabolically obese, normal-weight Ͻ increase in reactive oxygen species. In 9. Grossi G, Bargossi AM, Fiorella PL, Piazzi (MONW) subjects (BMI 25 kg/ 2 fact, we found this unchanged in the S, Battino M, Bianchi GP: Improved high- m ) are characterized by an excess M 2 blood of our patients. performance liquid chromatographic (Ն100 cm by abdominal computed to- method for the determination of coen- mography scanning) visceral fat area 1 SILVANA SALARDI, MD zyme Q10 in plasma. J Chromatogr 593: (VFA), insulin resistance, and hyperinsu- 1 STEFANO ZUCCHINI, MD 217–226, 1992 linemia (1,2). The criteria for MONW 1 DANIELA ELLERI, MD 10. Krempf M, Ranganathan S, Ritz P, Morin M, subjects and the insulin resistance syn- 2 GABRIELE GROSSI, MC Charbonnel B: Plasma vitamin A and E in drome are very similar, and the patho- 2 ALBERTO M. BARGOSSI, AM, MD type 1 (insulin-dependent) and type 2 (non physiological events occurring in MONW 1 insulin-dependent) adult diabetic patients. STEFANO GUALANDI, PHD subjects have recently been the focus of 1 Int J Vitam Nutr Res 61:38–42, 1991 ROBERTA SANTONI, MD many investigators (1–4). 1 11. Cinaz P, Hasanoglu A, Bideci A, Biberoglu ALESSANDRO CICOGNANI, MD Several studies have reported the as- 1 G: Plasma and erythrocyte vitamin E lev- EMANUELE CACCIARI, MD sociation of oxidative stress with insulin els in children with insulin dependent di- resistance and hyperinsulinemia in obese abetes mellitus. J Pediatr Endocrinol Metab From the 1Department of Pediatrics, University of subjects (5,6). However, the degree of ox- 2 12:193–196, 1999 Bologna, Bologna, Italy; and the Central Laboratory idative stress and its correlation with in- 12. Hozumi M, Murata T, Morinobu T, of “S.Orsola-Malpighi” Hospital, Bologna, Italy. sulin resistance and insulin secretion have Address correspondence to Prof. Silvana Salardi, Manago M, Kuno T, Tokuda M, Konishi Department of Pediatrics, Via Massarenti 11, 40138 K, Mingci Z, Tamai H: Plasma beta-caro- not yet been evaluated in MONW Bologna, Italy. E-mail: [email protected]. tene, retinol, and alpha-tocopherol levels subjects. © 2004 by the American Diabetes Association. in relation to glycemic control of children The present study comprised 18 Jap- Ϯ with insulin-dependent diabetes mellitus. anese MONW (aged 34.7 1.7 years, 2 J Nutr Sci Vitaminol 44:1–9, 1998 BMI 23.9 Ϯ 0.3 kg/m , and VFA 146.3 Ϯ 2 13. Campoy C, Baena RM, Blanca E, Lopez- 5.8 cm [means Ϯ SE]) and 18 age- ●●●●●●●●●●●●●●●●●●●●●●● Sabater C, Fernandez-Garcia JM, Miranda matched normal (BMI Ͻ25 kg/m2 and References MT, Molina-Font JA, Bayes R: Effects of VFA Ͻ100 cm2) men (aged 33.8 Ϯ 1.4 1. Betteridge DJ: What is oxidative stress? metabolic control on vitamin E nutri- years, BMI 21.9 Ϯ 0.5 kg/m2, and VFA Metabolism 49:3–8, 2000 tional status in children with type 1 dia- 59.3 Ϯ 5.3 cm2). 2. Baynes JW: Role of oxidative stress in de- betes mellitus. Clin Nutr 22:81–86, 2003 According to the American Diabetes velopment of complications in diabetes. 14. Ceriello A, dello Russo P, Amstad P, Association’s diagnostic criteria, all sub- Diabetes 40:405–412, 1991 Cerutti P: High glucose induces antioxi- jects had normal glucose tolerance based 3. Hartnett ME, Stratton RD, Browne RW, dant enzymes in human endothelial cells on the 75-g oral glucose tolerance test Rosner BA, Lanham RJ, Armstrong D: Se- in culture: evidence linking hyperglyce- rum markers of oxidative stress and sever- (OGTT) (7). mia and oxidative stress. Diabetes 45: The plasma levels of free 8-epi- ity of diabetic retinopathy. Diabetes Care 471–477, 1996 23:234–240, 2000 prostaglandin F2␣ (8-epi-PGF2␣) were 15. Ceriello A, Morocutti A, Mercuri F, Qua- 4. Asayama K, Uchida N, Nakane T, Hayash- measured as marker of oxidative stress us- gliaro L, Moro M, Damante G, Viberti GC: ibe H, Dobashi K, Amemiya S, Kato K, ing a commercially available enzyme im- Nakazawa S: Antioxidants in the serum of Defective intracellular antioxidant en- zyme production in type 1 diabetic pa- munoassay kit (Cayman Chemical, Ann children with insulin-dependent diabetes Arbor, MI). mellitus. Free Radic Biol Med 15:597–602, tients with nephropathy. Diabetes ␣ 49:2170–2177, 2000 8-epi-PGF2 plasma levels in 1993 MONW men (40.4 Ϯ 6.2 pg/ml; P Ͻ 5. Dominguez C, Ruiz E, Gussinye M, 16. Palmeira CM, Santos DL, Seic¸a R, Moreno AJ, Santos MS: Enhanced mitochondrial 0.01) were significantly increased com- Carrascosa A: Oxidative stress at onset Ϯ and in early stages of type 1 diabetes in testicular antioxidant capacity in Goto- pared with normal subjects (8.5 1.5 children and adolescents. Diabetes Care Kakizaki diabetic rats: role of coenzyme Q pg/ml). The glucose infusion rates (index 21:1736–1742, 1998 Am J Physiol Cell Physiol 281:C1023– of insulin resistance during the euglyce- 6. Varvarovska J, Racek J, Stozicky F, Soucek C1028, 2001 mic-hyperinsulinemic clamp study) in

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Ϫ1 1 MONW subjects (53.9 Ϯ 3.2 ␮mol kg ESTEBAN C. GABAZZA, MD sis 148:17–21, 2000 Ϫ1 2 ␤ min ; P Ͻ 0.02) were significantly de- SHUICHI MURASHIMA, MD 9. Prentki M, Corkey BE: Are the -cell sig- 3 creased compared with normal subjects KANAME NAKATANI, MD naling molecules malonyl-CoA and cyto- Ϫ1 Ϫ1 1 solic long-chain acyl-CoA implicated in (65.0 Ϯ 2.5 ␮mol kg min ). Fasting YUTAKA YANO, MD 1 multiple tissue defects of obesity and serum levels of insulin (49.1 Ϯ 4.1 YUKIHIKO ADACHI, MD Ͻ NIDDM. Diabetes 45:273–283, 1996 pmol/l; P 0.01), insulin area under the 10. Milburn JL Jr, Hirose H, Lee YH, Naga- From the 1Third Department of Internal Medicine, curve (AUC) during the 75-g OGTT sawa Y, Ogawa A, Ohneda M, Beltrandel- Ϯ Ͻ Mie University School of Medicine, Mie, Japan; the (44721.7 3811.3 pmol/l; P 0.02), 2 Rio H, Newgard CB, Johnson JH, Unger Ϯ Department of Radiology, Mie University School of ␤ and serum levels of triglycerides (1.6 Medicine, Mie, Japan; and the 3Department of Lab- RH: Pancreatic -cell in obesity: evidence 0.1 mmol/l; P Ͻ 0.01) were significantly oratory Medicine, Mie University School of Medi- for induction of functional, morphologic, increased in MONW subjects compared cine, Mie, Japan. and metabolic abnormalities by increased with normal subjects (fasting insulin lev- Address correspondence to Y. Sumida, MD, long chain fatty acids. J Biol Chem 270: Ϯ Third Department of Internal Medicine, Mie Univer- 1295–1299, 1995 els 29.9 2.9 pmol/l, insulin AUC sity School of Medicine, 2-174 Edobashi, Tsu, Mie 31341.7 Ϯ 3388.9 pmol/l, and serum lev- 11. Dandona P, Aljada A, Mohanty P, Ghanim 514-8507, Japan. E-mail: [email protected]. H, Hamouda W, Assian E, Ahmad S: In- els of triglyceride 0.9 Ϯ 0.1 mmol/l). mie-u.ac.jp. ␣ © 2004 by the American Diabetes Association. sulin inhibits intranuclear nuclear factor The 8-epi-PGF2 plasma levels were ␬B and stimulates I␬B in mononuclear significantly correlated with the glucose cells in obese subjects: evidence for an an- infusion rate (r ϭϪ0.513, P Ͻ 0.05), ●●●●●●●●●●●●●●●●●●●●●●● ti-inflammatory effect? J Clin Endocrinol VFA (r ϭ 0.868, P Ͻ 0.01), serum levels References Metab 86:3257–3265, 2001 of triglyceride (r ϭ 0.658, P Ͻ 0.02), fast- 1. Ruderman N, Chisholm D, Pi-Sunyer X, 12. Kyselova P, Zourek M, Rusavy Z, TrefilL, ing serum levels of insulin (r ϭ 0.502, Schneider S: The metabolically obese, Racek J: Hyperinsulinemia and oxidative P Ͻ 0.05), and the insulin AUC (r ϭ normal-weight individual revisited. Dia- stress. Physiol Res 51:591–595, 2002 0.655, P Ͻ 0.01) only in MONW betes 47:699–713, 1998 subjects. 2. Katsuki A, Sumida Y, Urakawa H, Gaba- Bakker et al. (8) have previously re- zza EC, Murashima S, Maruyama N, Mo- rioka K, Nakatani K, Yano Y, Adachi Y: ported that elevated concentration of cy- Increased visceral fat and serum levels of Efficacy of tosolic long-chain acyl-CoA, which is triglyceride are associated with insulin re- Conversion From associated with increased cytosolic tri- sistance in Japanese metabolically obese, glyceride stores, induces mitochondrial normal-weight subjects with normal glu- Bedtime NPH Insulin oxygen free radical production due to in- cose tolerance. Diabetes Care 26:2341– Injection to Once- or tramitochondrial ADP deficiency. There- 2344, 2003 Twice-Daily fore, increased trigylceride content in 3. Davidson MB: Is treatment of insulin re- nonadipose tissue together with increased sistance beneficial independent of glyce- Injections of Insulin serum levels of trigylcerides may play an mia? Diabetes Care 26:3184–3186, 2003 Glargine in Type 1 important role in the production of oxi- 4. Lorenzo C, Okoloise M, Williams K, Stern MP, Haffner SM: The metabolic syndrome Diabetic Patients dative stress in Japanese MONW subjects. ␣ as predictor of type 2 diabetes: the San 8-epi-PGF2 plasma levels were sig- Antonio Heart Study. Diabetes Care 26: Using Basal/Bolus nificantly correlated with insulin resis- 3153–3159, 2003 Therapy tance in MONW men. This relationship 5. Davi G, Guagnano MT, Ciabattoni G, Basili was also observed in obese men (6). Al- S, Falco A, Marinopiccoli M, Nutini M, though correlation does not prove causa- Sensi S, Patrono C: Platelet activation in he efficacy of glycemic control in tion, these findings suggest that oxidative obese women: role of inflammation and ox- type 1 diabetic patients with either stress may contribute to the development idant stress. JAMA 288:2008–2014, 2002 once- or twice-daily glargine insulin 6. Urakawa H, Katsuki A, Sumida Y, Gaba- T of insulin resistance in obese and MONW injection was evaluated in this long-term, men. zza EC, Murashima S, Morioka K, Ma- prospective, nonrandomized study. ruyama N, Kitagawa N, Tanaka T, Hori Y, The results of the present study are in Nakatani K, Yano Y, Adachi Y: Oxidative Eighty-two type 1 diabetic patients were agreement with a previous study (9,10) stress is associated with adiposity and in- followed over 12–15 months after con- that showed increased cytosolic long- sulin resistance in men. J Clin Endocrinol version from a single bedtime NPH insu- chain acyl-CoA and oxidative stress lower Metab 88:4673–4676, 2003 lin injection to a single bedtime insulin glucose-induced insulin secretion from 7. The Expert Committee on the Diagnosis glargine injection. These patients were pancreatic ␤-cells. On the other hand, it and Classification of Diabetes Mellitus: Re- switched with the availability of glargine has been reported that hyperinsulinemia port of the Expert Committee on the Diag- insulin to reduce frequency and severity reduces oxidative stress production nosis and Classification of Diabetes of nocturnal hypoglycemia and to im- (11,12). Hyperinsulinemia may also have Mellitus. Diabetes Care 20:1183–1197, prove fasting glucose levels. This group of a protective role against increased oxida- 1997 type 1 diabetic patients was switched to 8. Bakker SJL, IJzermen RG, Teerlink T, tive stress in MONW men. Westerhoff HV, Gans ROB, Heine RJ: Cy- glargine insulin in place of twice-daily NPH. These patients continued their 1 tosolic triglycerides and oxidative stress in AKIRA KATSUKI, MD central obesity: the missing link between same bolus therapy with either insulin lis- 1 YASUHIRO SUMIDA, MD excessive atherosclerosis, endothelial dys- pro or aspart and underwent frequent 1 HIDEKI URAKAWA, MD function, and ␤-cell failure? Atherosclero- (three to five times daily) home glucose

632 DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 Letters

monitoring. This study showed the ex- nificant drop in the HbA1c from the time glargine (HOE 901) versus NPH insulin in pected fewer nocturnal hypoglycemic of spilt to the end of the study (8.1 to patients with type 1 diabetes on multiple events, but the primary outcome was an 7.4%) did reach statistical significance daily insulin regimens. Diabetes Care 23: improvement in glycemic control based (P ϭ 0.001). To achieve this improved 1137–1142, 2000 on the HbA values. Patients HbA val- glycemic control in these patients, 70% 3. Pieber TR, Eugene-Jolchine I, Derobert E, 1c 1c the European Study Group of HOE 901 in ues were determined every 8 weeks, and more glargine was required (44 Ϯ 26 vs. Ϯ Ͼ Type 1 Diabetes: Efficacy and safety of insulin doses were titrated, with glargine 26 13 units, P 0.008). HOE 901 versus NPH insulin in patients adjusted based on morning fasting glu- In conclusion, in this prospective, with type 1 diabetes. Diabetes Care 23: cose values. If the HbA1c remained above nonblinded, nonrandomized, prospec- 157–162, 2000 goal, the intensity of home glucose mon- tive study, one-quarter of type 1 diabetic itoring was increased and bolus therapy patients required twice-daily glargine in- was adjusted accordingly. In one-quarter sulin injections to achieve acceptable gly- of patients, the lunch bolus titration re- cemic control. The reason for this was that COMMENTS AND sulted in mid-afternoon hypoglycemia, more glargine insulin could be safely and when reduced, the patients had ele- and/or effectively used when split in this RESPONSES vated presupper glucose values. Patients population. Regardless, type 1 diabetic who had an increase in their HbA1c patients on glargine insulin improved and/or persistent elevation of presupper their glycemic control, as measured by the Memory glucose despite titration of both bolus in- HbA1c values. Patients who do not Impairments sulin and glargine insulin were then achieve control after a titration period placed on twice-daily glargine injections. should receive split daily doses to achieve Associated With A spilt dose of glargine was given only glycemic control. Postprandial after titration of glargine insulin resulted This is the first study to demonstrate Hyperglycemia and in morning hypoglycemia and/or persis- an improvement in HbA1c in type 1 dia- tent elevation of the afternoon blood glu- betic subjects using basal-bolus therapy Glycemic Control coses that could not be corrected with after conversion from basal NPH insulin bolus titration. to basal glargine insulin. Previous studies Comment on Greenwood et al. Sixty-two subjects were using were not continued beyond 6 months, glargine insulin once daily, and the re- and the protocols restricted glargine to maining 20 (24.2%) subjects required once-daily dosing (1–3). Using our study t was with interest that we read the twice-daily therapy. The 24.2% of pa- data to project the outcome, if all patients study by Greenwood et al. (1), which tients on split glargine were converted remained on single daily dosing, then the I investigated the impact of postprandial from once-daily glargine injections after average HbA1c reduction would have hyperglycemia on memory function in an average of 289 Ϯ 203 days (median been 0.3%, which is similar to other stud- type 2 diabetic patients and demonstrated 259). At that time, their HbA1c had dete- ies, and would not have been statistically impaired memory function after carbohy- riorated from an initial value of 7.9 Ϯ 1.5 significant. drate ingestion. As they thoroughly dis- to 8.1 Ϯ 1.4% (P ϭ 0.16) and titration cussed, the impact of glycemic control was limited by the symptoms outlined ERIC S. ALBRIGHT, MD and transient hyperglycemia has been un- above. Subjects on split glargine did not RENEE DESMOND, DVM, PHD der investigation since the mid-1980s differ from those subjects using once- DAVID S.H. BELL, MB (2,3), with study results that are hetero- daily glargine injections in regard to their geneous and not very conclusive. In fact, age (P ϭ 0.21), duration of diabetes (P ϭ From the Department of Medicine, University of Al- data from a study at our diabetes center ϭ abama at Birmingham, Birmingham, Alabama. 0.21), baseline HbA1c (P 0.91), pres- (4) comprising 53 type 2 diabetic patients ϭ Address correspondence to David S.H. Bell, MD, ence of detectable C-peptide (P 0.78), University of Alabama at Birmingham, Department suggest that glycemic control has no in- or the presence of microvascular compli- of Medicine, 1808 Seventh Ave. S., BDB 802, Bir- fluence on cognitive functioning, includ- cations: retinopathy (P ϭ 0.37), nephrop- mingham, AL 35294. E-mail: [email protected]. ing memory (Auditory Verbal Learning athy (P ϭ 0.44), neuropathy (P ϭ 0.30), uab.edu. Test), whereas patients with diabetic or macrovascular complications (P ϭ © 2004 by the American Diabetes Association. complications show lower performance. 0.88). One reason for the heterogeneity of In the single-daily injection patients, ●●●●●●●●●●●●●●●●●●●●●●● results probably stems from the lack of the HbA1c improved significantly (from References consensus on which instruments to use 7.8 to 7.3%, P ϭ 0.01) after 476 Ϯ 178 1. Raskin P, Klaff L, Bergenstal R, Halle JP, for cognitive function assessment (5) and days on glargine insulin. The split Donley D, Mecca T: A 16-week compari- the usually small sample sizes. In this re- glargine injection subjects also had an im- son of the novel insulin analog insulin spect, unfortunately, Greenwood et al. glargine (HOE 901) and NPH human in- provement in the HbA1c from 7.9 to 7.4% did not use the standard versions of the ϭ sulin used with insulin lispro in patients (P 0.03) over a 3- to 6-month period. with type 1 diabetes. Diabetes Care 23: tests for memory assessment but instead The ending HbA1c between groups was 1666–1671, 2000 used instruments that were constructed of not significant (P ϭ 0.80). The decrease 2. Rosenstock J, Park G, Zimmerman J, the parallel forms and had obviously under- from the mean starting HbA1c was identi- US Insulin Glargine (HOE 901) Type 1 gone profound changes, like omitting cal between groups; however, a more sig- Diabetes Investigator Group: Basal insulin items. The precise nature of the test that

DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 633 Letters was applied is not described in their pre- Wolever TMS: Cognitive performance is blood glucose resulted in memory en- vious study either (6). Although they associated with glucose regulation in hancement and more extreme increases in thoroughly addressed parallels of the ver- healthy elderly persons and can be en- blood glucose were associated with defi- sions used, the possible interference ef- hanced with glucose and dietary carbohy- cits (what is often referred to as an invert- fects of several verbal memory tests used drates. Am J Clin Nutr 72:825–836, 2000 ed-U dose-response relationship) (8). in a row are not discussed. Based on this argument, we concluded Taken together with the small sample that adults with type 2 diabetes likely re- size, the large interindividual variability of Memory sponded to a glucose challenge in a man- performance within the groups, and hence Impairments ner comparable with that of older adults, the fact that the adequacy of regression with the caveat that they were more likely analysis is disputable, in our point of view Associated With to attain levels of hyperglycemia associ- the conclusions of Greenwood et al. are Postprandial ated with cognitive impairment given daring. Surely, neuropsychological ef- Hyperglycemia and their underlying disease. Clearly, this is a fects of transient hyperglycemic excur- conclusion requiring further verification. sions are worth being studied further, but Glycemic Control One issue of concern raised by Ku- concluding that ingestion of one-half ba- biak et al. is that we include alternate ver- gel and grape juice leads to acute memory Response to Kubiak et al. sions, developed by us and others (9), of impairment seems, in our opinion, too standardized neuropsychologic tests, al- far-reaching. though we apply these versions using e thank Kubiak et al. (1) for their standardized methodology. Our within- 1 THOMAS KUBIAK, PHD thoughtful appraisal of our study individual design, i.e., requiring multiple 1 NORBERT HERMANNS, PHD W relating to memory response in testing of subjects, necessitates their use. 2 MICHAEL PREIER, MA adults with type 2 diabetes following car- While we do not provide the precise de- 3 BERNHARD KULZER, MA bohydrate ingestion (2). We agree en- tails used to develop these alternate ver- 1,3 THOMAS HAAK, MD tirely with their comment that the sions, we previously directed readers to underlying origins of memory impair- those publications that we relied on to do From the 1Research Institute of the Diabetes Acad- ment in this population is poorly under- so. Importantly, we have never stated or emy, Diabetes Center Mergentheim, Bad Mergen- 2 stood and that lack of consensus on implied that these alternate versions theim, Germany; the Department of Neuropsy- standardized neuropsychologic testing chology, Rehabilitation Clinic Staffelstein, Bad should be used clinically from a diagnos- Staffelstein, Germany; the 3Diabetes Clinic, Diabetes procedures may, in part, be contributing tic perspective; rather they are only used Center Mergentheim, Mergentheim, Germany. to this confusion (3). Clearly, as Kubiak et as experimental research tools. We agree Address correspondence to Dr. Thomas Kubiak, al. point out, a major contributor to the that the use of these alternate versions po- PhD, Forschungsinstitut der Diabetes Akademie variance in cognitive performance ob- tentially adds unwanted variance to our Mergentheim (FIDAM), Diabetes Zentrum Mergen- theim, Th.-Klotzbuecher-Str. 12, D-97980 Bad Mer- served in this population is the high prev- measures, but disagree that this detracts gentheim, Germany. E-mail: kubiak@diabetes- alence of other risk factors for cognitive from the results obtained. Rather, the ad- zentrum.de. decline, including cardiovascular disease, ditional variance contributed by the use of © 2004 by the American Diabetes Association. hypertension, and depression (4,5), mak- alternate test versions makes it more, not ing it challenging to isolate the potential less, difficult to observe change following ●●●●●●●●●●●●●●●●●●●●●●● contribution of diabetes per se. glucose ingestion or associations between References We sought to explore cognitive func- subject characteristics and performance 1. Greenwood CE, Kaplan RJ, Hebbleth- tion in adults with type 2 diabetes by levels. We address test version variability waite S, Jenkins DJA: Carbohydrate-in- perturbing the system through the ad- through the random allocation of differ- duced memory impairment in adults with ministration of glucose, which is a treat- ent test versions both between and within type 2 diabetes. Diabetes Care 26:1961– ment commonly used in studies of subjects to uniformly distribute this addi- 1966, 2003 cognitive aging to explore the system’s tional variance (as much as possible) 2. Holmes CS: Metabolic control and audi- tory information processing at altered glu- plasticity in the face of underlying age- throughout the data, thereby minimizing cose levels in insulin-dependent diabetes. related deficits (6,7). A major advantage potential bias associated with their use. Brain Cogn 6:161–174, 1987 of applying this approach to the type 2 Another concern expressed was the 3. Holmes CS: Neuropsychological and Behav- diabetic population is that changes ob- limited number (n ϭ 19) of subjects in ioral Aspects of Diabetes. New York, served in response to the challenge were our study, which is in essence an exten- Springer, 1990 unlikely to be directly attributable to vas- sion of those concerns related to test ver- 4. Hewer W, Mussell M, Rist F, Kulzer B, cular complications. Our data provided sion variability. While not commented on Bergis K: Short-term effects of improved evidence for cognitive deficits, primarily in the original publication, this sample glycemic control on cognitive function in related to declarative memory function, size was based on power analyses drawing patients with type 2 diabetes. Gerontology following the ingestion of 50 g of glucose on our results in healthy senior adults re- 49:86–92, 2003 5. Strachan MW, Frier BM, Deary IJ: Cogni- in the form of rapidly absorbed carbohy- ceiving glucose in the form of carbohy- tive assessment in diabetes: the need for drate foods (bagel and juice). We then ar- drate foods and including the same consensus (Editorial). Diabet Med 14: gued that this impairment was consistent alternate versions of the neuropsycho- 421–422, 1997 with observations in healthy senior logic tests (9). Thus we believe our study 6. Kaplan RJ, Greenwood CE, Winocur G, adults, in whom moderate elevations in to be statistically sound. Nevertheless, as

634 DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 Letters with all studies, the extension of the re- whereas others will see this as reason to critical review of published studies. Dia- sults to the broader population is compli- discount “explained” variance in func- betes Care 20:438–445, 1997 cated by the fact that subjects willing to tion. 5. Stewart R, Liolitsa D: Type 2 diabetes mel- participate in experimental procedures Certainly, it is essential that as we litus, cognitive impairment and dementia. are somewhat unique and, in this sense, wade through conflicting data regarding Diabet Med 16:93–112, 1999 6. Gold P: Glucose modulation of memory differ from the more heterogeneous pop- the origins of cognitive deficits in adults storage processing. Behav Neural Biol 45: ulation typically observed in clinical prac- with type 2 diabetes, be they primarily or 342–349, 1986 tice—a factor of importance in all studies secondarily associated with the high prev- 7. Messier C, Tsiakas M, Gagnon M, Desro- drawing on human volunteers. alence of other risk factors in this popu- chers A, Awad N: Effect of age and glu- Finally, Kubiak et al. comment on lation, that we not lose sight of the shared coregulation on cognitive performance. concerns related to interference when and common interest, which is helping Neurobiol Aging 24:985–1003, 2003 multiple tests probing declarative mem- those with type 2 diabetes prevent or min- 8. Parsons MW, Gold PE: Glucose enhance- ory are used. This factor is not discussed imize their risk of cognitive dysfunction. ment of memory in elderly humans: an in this work but is addressed by us previ- Kubiak et al. state that we were daring to inverted-U dose-response curve. Neuro- ously (9) in studies conducted on healthy conclude that transitory food-induced biol Aging 13:401–404, 1992 9. Kaplan RJ, Greenwood CE, Winocur G, senior adults. This comment raises multi- hyperglycemic episodes could be associ- Wolever TMS: Cognitive performance is ple issues of interest. The first is that the ated with acute cognitive deficits in this associated with glucose regulation in exact nature of the declarative memory population. We continue to stand by our healthy elderly persons and can be en- deficits observed in adults with type 2 di- conclusions but recognize that further hanced with glucose and dietary carbohy- abetes remains largely unexplored. studies will either support or refute our drates. Am J Clin Nutr 72:825–836, 2000 Clearly, multiple components of cogni- conclusions. 10. Li KZ, Hasher L, Jonas D, Rahhal TA, May tive function are recruited and contribute CP: Distractibility, circadian arousal, and 1,2,3 to performance on end measures of de- CAROL E. GREENWOOD, PHD aging: a boundary condition? Psychol Ag- 1,2 ing 13:574–583, 1998 layed verbal recall; yet the precise deficit, RANDALL J. KAPLAN, PHD 1 potentially including interference and in- STACEY HEBBLETHWAITE, BSC 1,4,5 hibitory control, remains largely unex- DAVID J.A. JENKINS, MD, PHD Off-Loading in Trials plored. Admittedly, we observed deficits From the 1Department of Nutritional Sciences, Fac- in Neuropathic in our study on the second, not the first, ulty of Medicine, University of Toronto, Toronto, verbal recall test used, thus raising the Ontario, Canada; the 2Department of Food and Nu- possibility that interference is an impor- trition Services, Baycrest Centre for Geriatric Care, Ulceration tant contributor and one requiring further Toronto, Ontario, Canada; the 3Kunin-Lunenfeld exploration. Yet this does not detract from Applied Research Unit, Baycrest Centre for Geriatric Care, Toronto, Ontario, Canada; the 4Clinical Nu- No, it’s not time for a paradigm the fact that performance on this second trition and Risk Modification Centre, St. Michael’s shift test was poorer when subjects were tested Hospital, Toronto, Ontario, Canada; and the 5Divi- following carbohydrate ingestion com- sion of Endocrinology and Metabolism, St. Michael’s pared with when they were tested follow- Hospital, Toronto, Ontario, Canada. rofessor Boulton and Dr. Armstrong Address correspondence to Carol Greenwood, ing placebo (water) ingestion. The second Department of Nutritional Sciences, Faculty of (1) argued recently that “all future issue relating to the comment by Kubiak Medicine, University of Toronto, Toronto, Ontario, P trials of therapy should use a nonre- et al. is the degree to which one controls Canada M5S 3E2. E-mail: carol.greenwood@ movable off-loading device.” In doing so, for external factors influencing cognitive utoronto.ca. they betray a failure to understand how performance. Clearly, our data suggest © 2004 by the American Diabetes Association. the structure of trials must be determined that the fed/fasted state of the individual ●●●●●●●●●●●●●●●●●●●●●●● by their purpose: those designed to deter- may be an important contributor to ob- mine the efficacy (“Can it work in ideal served variance. Similarly, time of day of References circumstances?”) may differ from those testing is another recognized contributor 1. Kubiak T, Hermanns N, Preier M, Kulzer designed to determine effectiveness B, Haak T: Memory impairments associ- to within-individual variance in cognitive ated with postprandial hyperglycemia (“Does it work in practice?”). Two factors function and shifts in peak performance and glycemic control: comment on that underlie the capacity of a controlled times occur in states, such as aging, Greenwood et al. (Letter). Diabetes Care trial to demonstrate efficacy are 1) the ef- wherein disruptions to circadian sleep 27:633–634, 2004 fect, or lack of it, of the intervention and rhythms are apparent (10). This is clearly 2. Greenwood CE, Kaplan RJ, Hebbleth- 2) the effect of the control. Boulton and a pattern disruption to which adults with waite S, Jenkins DJA: Carbohydrate-in- Armstrong concluded (with no evidence) type 2 diabetes may be especially vulner- duced memory impairment in adults with that the failure of Veves et al. (2) to dem- able. Yet rarely do authors address when type 2 diabetes. Diabetes Care 26:1961– onstrate any benefit of Promogran was during the day testing occurred and 1966, 2003 “likely” to be the result of a failure to stan- whether a fixed time of day was used, as 3. Strachan MW, Frier BM, Deary IJ: Cogni- dardize off-loading techniques. Another tive assessment in diabetes: the need for we did in our studies. All of these factors consensus (Editorial). Diabet Med 14: interpretation is that the product is com- are likely important and contribute to the 421–422, 1997 paratively ineffective in routine practice. “unexplained” variance in regression 4. Strachan MW, Deary IJ, Ewing FM, Frier The classical total contact cast (TCC) models. Some will view this as exciting BM: Is type II diabetes associated with an does not have a dressing window, and so opportunities for new exploration, increased risk of cognitive dysfunction? A how can it be used in trials of dressings

DIABETES CARE, VOLUME 27, NUMBER 2, FEBRUARY 2004 635 Letters and applications designed to be changed for a paradigm shift? (Editorial). Diabetes than stating that many patients cannot more often than the off-loading device? A Care 26:2689–2690, 2003 tolerate nonremovable devices, surely re- TCC, but not their modified walker, can 2. Veves A, Sheehan P, Pham HT: A random- search should be directed at improving be modified by incorporating a dressing ized controlled trial of promogran vs stan- the design of such casts to make them window, but dressing windows have their dard treatment in the management in the more safe and acceptable. We suggest that management of diabetic foot ulcers. Arch problems. If too small, they limit the abil- Surg 137:822–827, 2002 the failure to develop satisfactory off- ity to clean and dress the wound properly. 3. Spencer S: Pressure relieving interven- loading in recent years is responsible for If too large, they limit the effectiveness of tions for preventing and treating diabetic the poor results of trials of potential new off-loading by allowing the ulcerated area foot ulcers. Cochrane Database Syst Rev therapies for plantar ulcers. to prolapse. 3:CD002302, 2000 Jeffcoate and Game then assert that Crucially, however, Boulton and TCCs do not have dressing windows. Co- Armstrong fail to satisfactorily address the Off-Loading in Trials incidentally, in the very next issue of Di- questions of acceptability and safety. of Neuropathic abetes Care, Ha Van et al. (6) describe a They acknowledge that TCCs have ad- TCC incorporating just such a window. verse effects and suggest that these may be Diabetic Foot Further support for our position ap- overcome with their modified walker, but Ulceration pears in several articles published in the admit that relevant trials have not been months since the appearance of our edi- completed. In truth, many people find Further evidence of the need for a torial. In addition to describing the incor- nonremovable devices unacceptable, poration of a dressing window into a with reasons that include secondary ul- paradigm shift nonremovable cast, Ha Van et al. reported ceration of the index foot, abrasions on that only 10% of patients complied with the contralateral foot, unsteadiness (espe- e are happy that our recent edi- the removable off-loading device in their cially in the elderly, those with postural torial (1) stimulated interest studies, suggesting that the 28% reported hypotension or impaired propriocep- W from other experts in the dia- in our study (3) was likely realistic, if not tion), and falls from tripping, not to men- betic foot. However, we find ourselves in optimistic. Secondly, Caravaggi et al. (7) tion the ease—or lack of it—with which disagreement with the letter by Jeffcoate demonstrated that trials of new dressings patients can shower or take a bath. Trials and Game in this issue of Diabetes Care (2) could be successfully executed using a of nonremovable off-loading devices may in several respects. They suggest that our nonremovable cast. Finally, Piaggesi et al. be critically biased by population selection. editorial betrays “a failure to understand (8) provide pivotal histological evidence In conclusion, we emphasize our how the structure of trials must be deter- strongly demonstrating the importance of enormous respect for the work under- mined.” Surely, this cannot be the case. adequate off-loading. It is now clear why taken by Boulton and Armstrong but Any trial assessing dressings, drugs, or so many trials have failed to demonstrate think that their arguments are simply not constructs should be designed to provide efficacy in recent years. Hence, we reiter- justified. The recent Cochrane review of the maximum opportunity for the prod- ate the need for a paradigm shift in the off-loading (3) concluded that “there is uct to demonstrate efficacy by removing design of future clinical trials of putative very limited evidence of the effectiveness all possible confounding variables. As we therapies for plantar neuropathic ulcers. of total contact casts” and highlighted the have recently demonstrated (3), those pa- 1 fact that there has been no comparison tients provided with removable cast walk- ANDREW J.M. BOULTON, MD, FRCP 2 undertaken between TCC and Scotchcast ers only wear their device for 28% of DAVID G. ARMSTRONG, MSC, DPM (or equivalent) removable boots, which activity daily, so we proposed that future From the 1Diabetes Research Unit, University of Mi- are widely used in many countries. The trials should therefore standardize off- ami, Miami, Florida; and the 2Department of Sur- TCC is an option, but not sine qua non in loading, preferably using a nonremovable gery, Tucson Veterans Affairs Medical Center, either clinical practice or future trials. device. As off-loading in the trial of pro- Tucson, Arizona. mogram (4) was “left to the individual Address correspondence to Andrew J.M. Boul- 1 ton, MD, FRCP, Diabetes Research Unit, University WILLIAM J. JEFFCOATE, MRCP center,” we stand by our assessment that a 1 of Miami, P.O. Box 016960 (D110), Miami, FL FRANCES L. GAME, MRCP, MRCPATH likely explanation of the failure to dem- 33101. E-mail: [email protected]. 2 PATRICIA E. PRICE, PHD onstrate efficacy was related to a failure to © 2004 by the American Diabetes Association. From the 1Department of Diabetes and Endocrinol- standardize off-loading. ●●●●●●●●●●●●●●●●●●●●●●● ogy, Foot Ulcer Trials Unit, City Hospital, Notting- Having demonstrated the efficacy of ham, U.K.; and the 2Wound Healing Research Unit, any new product, it then behooves us to References Cardiff Medicenter, Heath Park, Cardiff, U.K. translate the results into clinical practice. 1. Boulton AJM, Armstrong DG: Trials in Address correspondence to Dr. W.J. Jeffcoate, Here we agree with Jeffcoate and Game neuropathic diabetic foot ulcers: time for Foot Ulcer Trials Unit, Department of Diabetes and that not all patients can tolerate casts; a paradigm shift? (Editorial). Diabetes Endocrinology, City Hospital, Nottingham NG5 Care 26:2689–2690, 2003 1PB, U.K. E-mail: [email protected]. however, our experience to date suggests 2. Jeffcoate WJ, Game FL: Off-loading in tri- © 2004 by the American Diabetes Association. that the instant total contact cast (TCC) is als in neuropathic - better tolerated by patients than the TCC ation: no, it’s not time for a paradigm shift ●●●●●●●●●●●●●●●●●●●●●●● (5). (The instant TCC is a removable cast (Letter). Diabetes Care 27:635–636, 2004 References walker rendered nonremovable by wrap- 3. Armstrong DG, Lavery LA, Kimbriel HR, 1. Boulton AJM, Armstrong DG: Trials in ping it with cast material.) Further studies Nixon BP, Boulton AJ: Activity patterns of neuropathic diabetic foot ulceration: time on this will be published in 2004. Rather patients with diabetic foot ulceration: pa-

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tients with active ulceration may not ad- lin and found no association (r ϭ 0.0748, From the Department of Medicine, University of Al- here to a standard pressure off-loading ϭ abama Medical School, Birmingham, Alabama. P 0.28) between HbA1c levels and regimen. Diabetes Care 26:2595–2597, Address correspondence to David S.H. Bell, MD, hsCRP. With this negative association, we University of Alabama at Birmingham, Department 2003 investigated 108 C-peptide–positive type 4. Veves A, Sheehan P, Pham HT: A random- of Medicine, 1808 Seventh Ave. S., BDB 802, Bir- 2 diabetic patients, all of whom were on a mingham, AL 35294. E-mail: [email protected]. ized controlled trial of promogran vs stan- statin, an aspirin, and a TZD, to see uab.edu. dard treatment in the management of © 2004 by the American Diabetes Association. diabetic foot ulcers. Arch Surg 137:822– whether there was an association between 827, 2002 hsCRP and HbA1c in this homogenous 5. Armstrong DG, Short B, Espensen EH, group on maximal hsCRP-lowering ther- ●●●●●●●●●●●●●●●●●●●●●●● Abu-Rumman PL, Nixon BP, Boulton AJ: apy. The association was again negative, References Technique for fabrication of an “instant with an r value of 0.0424 and a P value of 1. King DE, Mainous AG, Buchanan TA, total-contact cast” for treatment of neuro- 0.78. Pearson WS: C-reactive protein and gly- pathic diabetic foot ulcers. J Am Podiatr Why then did King et al. find an as- cemic control in adults with diabetes. Di- Med Assoc 92:405–408, 2002 sociation of HbA with hsCRP and we abetes Care 26:1535–1539, 2003 1c 2. Ford ES: Body mass index, diabetes, and 6. Ha Van G, Siney H, Hartmann-Heurtier did not? We believe that King et al.’s as- A, Jacqueminet S, Greau F, Grimaldi A: C-reactive protein among U.S. adults. Di- Nonremovable, windowed, fiberglass cast sociation was with insulin resistance and abetes Care 22:1971–1977, 1999 boot in the treatment of diabetic plantar not hyperglycemia. An association of in- ulcers: efficacy, safety, and compliance. sulin resistance and hsCRP has been well Diabetes Care 26:2848–2852, 2003 documented, and theoretically at least, 7. Caravaggi C, DeGiglio R, Pritelli C, Som- the greater the insulin resistance the maria M, Dalla Noce S, Faglia E, Mantero worse the glycemic control and, con- M, Clerici G, Fratino P, Morabito A: versely, the higher the glucose the greater C-Reactive Protein HYAFF 11–based autologous dermal and the insulin resistance (glucotoxicity). In and Glycemic Control epidermal grafts in the treatment of non- our group of type 2 diabetic patients who in Adults With infected diabetic plantar and dorsal foot were all on a TZD, insulin resistance ulcers: a prospective, multicenter, con- Diabetes trolled, randomized clinical trial. Diabetes should be maximally treated so that if hy- Care 26:2853–2859, 2003 perglycemia did affect the hsCRP, its ef- 8. Piaggesi A, Viacava P, Rizzo L, Naccarato fects would not be confounded by the Response to Bell, Hardy, and G, Baccetti F, Romanelli M, Zampa V, Del- effects of insulin resistance. Desmond Prato S: Semiquantitative analysis of the That insulin resistance was not a fac- histopathological features of the neuro- tor in the King et al. study could be con- pathic foot ulcer: effect of pressure relief. cluded from the inclusion of fasting e thank Bell, Hardy, and Des- Diabetes Care 26:3123–3128, 2003 insulin levels in the regression model. mond (1) for their comments re- When diabetic subjects are treated with W garding our recent article (2), insulin, insulin secretagogues, or insulin and we appreciate the opportunity to re- sensitizers, the effectiveness of a fasting spond to the issues they have raised. C-Reactive Protein serum insulin level as a marker for insulin Based on their analysis of two groups of and Glycemic Control resistance is negated and the conclusion patients in their practice, Bell, Hardy, and in Adults With that insulin resistance was eliminated as a Desmond question whether there is an as- factor nullified. sociation between CRP and glycemic con- Diabetes To resolve this problem of differing trol. Several possible explanations exist conclusions from an epidemiological for the difference in our findings. First, we Response to King et al. cross-sectional study and a retrospective used a nationally representative popula- cross-sectional clinical study, a prospec- tion-derived database that may be more tive longitudinal study should be per- diverse than the one used by them. Sec- ing et al. (1) recently suggested an formed. An ideal study would be of type 1 ond, we specifically excluded people on association between glycemic con- diabetic patients at onset who are clini- anti-inflammatory and cholesterol- K trol and systemic inflammation, i.e., cally free of infection, with measurements lowering medications, precisely because between HbA1c levels and highly sensitive of hsCRP being performed before insulin the use of such individuals is likely to con- C-reactive protein (hsCRP) levels, based therapy and 2 months later when they are found the relationship between C-reac- on data from 1,018 participants in the well controlled in the honeymoon period. tive protein (CRP) and HbA1c (insulin- Third National Health and Nutrition Ex- This is of clinical importance because if sensitizing drugs were not widely amination Survey. This report prompted hsCRP levels are elevated due to hyper- available at the time of the study [1988– us to search for a similar association in our glycemia, then hsCRP levels should only 1994]). Another reason for the difference clinical practice. be measured when glycemia is controlled in our findings could be our ability to ac- Since hsCRP levels can be lowered by to avoid unnecessary prescribing. count for several other factors that might statins, thiazolidinediones (TZDs), and confound or mask the relationship, in- anti-inflammatory drugs, we first looked DAVID S.H. BELL, MB, FACE cluding age, race, sex, BMI, smoking, at 64 C-peptide–negative type 1 diabetic ROBERT W. HARDY, PHD length of time with diabetes, and fasting patients whose only medication was insu- RENEE DESMOND, PHD insulin levels. Further supporting our

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findings, other researchers have found a prospective and interventional studies are © 2004 by the American Diabetes Association. similar association between CRP and needed to investigate the association be- ●●●●●●●●●●●●●●●●●●●●●●● HbA1c in nondiabetic individuals (3). tween CRP and glycemia, as we urged in References Bell, Hardy, and Desmond correctly our article. 1. Bell DSH, Hardy RW, Desmond R: C-re- note the limitation of fasting insulin level 1 active protein and glycemic control in DANA E. KING, MD as a measure of insulin resistance. How- 1 adults with diabetes (Letter). Diabetes ARCH G. MAINOUS, III, PHD ever, their conclusion that CRP is related 2 Care 27:637, 2004 THOMAS A. BUCHANAN, MD 2. King DE, Mainous AG, Buchanan TA, to insulin resistance rather than glycemia 1 may also be premature, since the term in- WILLIAM S. PEARSON, MHA Pearson WS: C-reactive protein and gly- sulin resistance is a very general one that cemic control in adults with diabetes. Di- From the 1Department of Family Medicine, Medical includes several possible underlying abetes Care 26:1535–1539, 2003 University of South Carolina, Charleston, South 3. Wu T, Dorn JP, Donahue RP, Sempos CT, mechanisms. Our report did not address 2 Carolina; and the General Clinical Research Center, Trevisan M: Associations of serum C-re- University of Southern California School of Medi- specific mechanisms for the association active protein with fasting insulin, glu- we found, but instead called for more re- cine, Los Angeles, California. Address correspondence to Dana E. King, MD, cose, and glycosylated hemoglobin: the search to further delineate the nature of Medical University of South Carolina, Department Third National Health and Nutrition Ex- the association. We agree with Bell, of Family Medicine, 295 Calhoun St., Charleston, amination Survey, 1988–1994. Am J Epi- Hardy, and Desmond that more definitive SC 29425. E-mail: [email protected]. demiol 155:65–71, 2002

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