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Plasma Adiponectin Levels in High Risk African-Americans with Normal Glucose Tolerance, Impaired Glucose Tolerance, and Type 2 Diabetes Kwame Osei, Trudy Gaillard, and Dara Schuster

Abstract OSEI, KWAME, TRUDY GAILLARD, AND DARA SCHUSTER. Plasma adiponectin levels in high risk African-Americans with normal glucose tolerance, impaired glucose tolerance, and type 2 diabetes. Obes Res. 2005;13: 179 –185. Objective: We studied plasma adiponectin, insulin sensitivity, and insulin secretion before and after oral glucose challenge in normal glucose tolerant, impaired glucose tolerant, and type 2 diabetic first degree relatives of AfricanAmerican patients with type 2 diabetes. Research Methods and Procedures: We studied 19 subjects with normal glucose tolerance (NGT), 8 with impaired glucose tolerance (IGT), and 14 with type 2 diabetes. Serum glucose, insulin, C-peptide, and plasma adiponectin levels were measured before and 2 hours after oral glucose tolerance test. Homeostasis model assessment-insulin resistance index (HOMA-IR) and HOMA-␤ cell function were calculated in each subject using HOMA. We empirically defined insulin sensitivity as HOMA-IR ⬍ 2.68 and insulin resistance as HOMA-IR ⬎ 2.68. Results: Subjects with IGT and type 2 diabetes were more insulin resistant (as assessed by HOMA-IR) when compared with NGT subjects. Mean plasma fasting adiponectin levels

Received for review November 18, 2003. Accepted in final form November 8, 2004. The costs of publication of this article were defrayed, in part, by the payment of page charges. This article must, therefore, be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, The Ohio State University College of Medicine and Public Health, Columbus, Ohio. Address correspondence to Kwame Osei, Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, 491 McCampbell Hall, The Ohio State University College of Medicine and Public Health, Columbus OH 43210. E-mail: [email protected] Copyright © 2005 NAASO

were significantly lower in the type 2 diabetes group when compared with NGT and IGT groups. Plasma adiponectin levels were 2-fold greater (11.09 ⫾ 4.98 vs. 6.42 ⫾ 3.3811 ␮g/mL) in insulin-sensitive (HOMA-IR, 1.74 ⫾ 0.65) than in insulin-resistant (HOMA-IR, 5.12 ⫾ 2.14) NGT subjects. Mean plasma adiponectin levels were significantly lower in the glucose tolerant, insulin-resistant subjects than in the insulin sensitive NGT subjects and were comparable with those of the patients with newly diagnosed type 2 diabetes. We found significant inverse relationships of adiponectin with HOMA-IR (r ⫽ ⫺0.502, p ⫽ 0.046) and with HOMA-␤ cell function (r ⫽ ⫺0.498, p ⫽ 0.042) but not with the percentage body fat (r ⫽ ⫺0.368, p ⫽ 0.063), serum glucose, BMI, age, and glycosylated hemoglobin A1C (%A1C). Discussion: In summary, we found that plasma adiponectin levels were significantly lower in insulin-resistant, nondiabetic first degree relatives of African-American patients with type 2 diabetes and in those with newly diagnosed type 2 diabetes. We conclude that a decreased plasma adiponectin and insulin resistance coexist in a genetically prone subset of first degree African-American relatives before development of IGT and type 2 diabetes. Key words: adiponectin, insulin sensitivity, type 2 diabetes, first degree relatives, African Americans

Introduction Adiponectin, a 244-amino acid peptide produced and secreted solely by adipose tissues, has been reported to improve insulin sensitivity and, indeed, could potentially prevent type 2 diabetes and atherosclerosis (1–17). Paradoxically, adiponectin levels are decreased in obese individuals with insulin resistance (5–7,12–14). Thus, the lower adiponectin levels in obese individuals with larger adiposity OBESITY RESEARCH Vol. 13 No. 1 January 2005

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Adiponectin in High-Risk African Americans, Osei, Gaillard, and Schuster

when compared with that of lean subjects suggest that the adiponectin gene may be down-regulated. Furthermore, English et al. (20) found greater plasma adiponectin increases after glucose challenge in obese subjects but not in lean subjects when compared with the fasting values. The authors postulated that postprandial increases in plasma adiponectin responses may compensate for insulin resistance in obese subjects and suggested a potentially larger role of adiponectin in acute glucose tolerance in humans. Furthermore, adiponectin is unlike other adipose tissuederived peptides, e.g., tumor necrosis factor ␣, resistin, interleukin-6, etc., which are elevated in obesity in humans and have been associated with insulin resistance (6,23–25). Non-diabetic first degree relatives of patients with type 2 diabetes tend to manifest insulin resistance and are more prone to type 2 diabetes and cardiovascular diseases. The etiology of the insulin resistance is attributed partly to genetic inheritance and environmental factors (23). Most of these subjects are overweight or obese. Thus, it is unclear whether obesity per se or the concomitant genetic insulin resistance with hyperinsulinemia is the major determinant of the decreased adiponectin levels in humans (14). In this regard, Pelme et al. (9) and Lihn et al. (10) recently showed that non-diabetic first degree relatives of white patients with type 2 diabetes manifested lower adiponectin levels and/or its gene expression than healthy subjects without family history of diabetes, independent of obesity. This suggested a potential role of genetic inheritance in adiponectin levels and its regulation in humans. Recently, racial and ethnic differences have been reported in plasma adiponectin levels in whites and Pima Native Americans (2). Hulver et al. (19) showed that fasting plasma adiponectin levels were lower in African Americans when compared with white Americans. Although African-American adults and adolescents are more insulin resistant than their white counterparts (24 –29), we are not aware of any studies in first degree relatives of African-American patients with type 2 diabetes that have investigated adiponectin levels. Thus, the role of plasma adiponectin in glucose tolerance and insulin sensitivity in African Americans who are genetically prone to type 2 diabetes remains uncertain. Therefore, we asked the question whether the wellknown relationship between adiponectin and obesity also pertains to African Americans who are genetically prone to type 2 diabetes but who, themselves, have varying degrees of glucose tolerance. Hence, in the present study, we sought to investigate the plasma adiponectin levels in first degree relatives of African-American patients with type 2 diabetes with varying degrees of glucose tolerance, insulin sensitivity indices, and obesity indices and examined the acute postprandial plasma adiponectin responses to the overall glycemic control and glucose tolerance in African Ameri180

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cans with normal glucose tolerance (NGT),1 impaired glucose tolerance (IGT), and type 2 diabetes.

Research Methods and Procedures Populations We studied 41 first degree relatives (offspring and siblings) of African-American patients with type 2 diabetes. Informed written consent approved by the institutional review board for human biomedical research at The Ohio State University (Columbus, OH) was obtained from each subject after the risks entailed in the study were thoroughly explained. There were 19 first degree relatives with NGT test, 8 with IGT test, and 14 with newly diagnosed type 2 diabetes who were residing in Franklin County, Central Ohio, U.S. After at least 10 minutes of bed rest, two blood pressure readings were taken at 10-minute intervals by trained nurses using a zero-centered sphygmomanometer. Body composition was measured using DXA (Lunar, Madison, WI). Each subject was weighed to the nearest gram, and the height was measured to the nearest centimeter. The clinical characteristics of our cohort of African Americans with varying degrees of glucose tolerance are shown in Table 1. We excluded those taking medications known to influence glucose and insulin metabolism; those individuals with liver, heart, lung, and kidney diseases; those with established diabetes on antidiabetic medications; those who participated in endurance exercise or indulged in regular competitive sport; and those who participated in a weight reduction program within the past 6 months. Metabolic Studies All of the subjects were admitted to the Endocrine/Diabetes Clinical Research Unit of The Ohio State University after a 10- to 12-hour overnight fast. With the subject in the sitting position, an intravenous needle was inserted into a forearm vein. Blood samples were drawn for serum glucose, insulin, C-peptide, adiponectin, and hemoglobin A1c (HbA1c) levels and routine kidney and liver function tests. Based on the fasting serum glucose, categories of glucose tolerance status of the subjects were defined by the new American Diabetes Association recommendation (30). Oral Glucose Tolerance Test (OGTT) After 10 to 12 hours of overnight fasting, the subjects ingested 75 grams of oral glucose load (Glucola) over a 2-minute period. Blood samples were obtained at baseline and 2 hours after oral glucose load for serum glucose, insulin, C-peptide, and plasma adiponectin levels.

1 Nonstandard abbreviations: NGT, normal glucose tolerance; IGT, impaired glucose tolerance; HbA1c, hemoglobin A1c; OGTT, oral glucose tolerance test; CV, coefficient(s) of variation; HOMA-IR, homeostasis model assessment-insulin resistance index; HOMA-%B, HOMA-␤ cell function; PP, postprandial.


Table 1. Baseline clinical and biochemical characteristics of African Americans with NGT, IGT, and type 2 diabetes Parameters n Age (years) Sex (F/M) Height (cm) Body weight (kg) BMI (kg/m2) Body fat mass (%) Blood pressure (mm Hg) Systolic Diastolic Metabolic parameters Glucose (mg/dL) Fasting (mg/dL) 2-Hour PP Insulin (␮U/mL) Fasting 2-Hour PP C-peptide (ng/mL) Fasting 2-Hour PP HOMA-IR HOMA-%B HbA1c (%) Adiponectin (␮g/mL) Fasting 2-Hour

NGT

IGT

Type 2 diabetes

19 49.10 ⫾ 7.86 17/2 162.5 ⫾ 8.8 87.1 ⫾ 16.0 32.45 ⫾ 6.69 42.2 ⫾ 12.4

8 51.0 ⫾ 9.3 6/2 161.5 ⫾ 8.3 109.7 ⫾ 31.7‡ 40.16 ⫾ 9.36‡ 48.6 ⫾ 12.8‡

14 49.0 ⫾ 8.44 12/2 164.0 ⫾ 8.1 109.9 ⫾ 15.8* 35.78 ⫾ 4.41* 48.0. ⫾ 5.12*

129.1 ⫾ 14.7 76.9 ⫾ 9.6

139.1 ⫾ 17.9 81.1 ⫾ 8.8

136.0 ⫾ 17.7 82.9 ⫾ 11.7

85.2 ⫾ 12.2 85.6 ⫾ 20.1

113.6 ⫾ 9.5 162.1 ⫾ 22.5

164.0 ⫾ 71.8† 289.2 ⫾ 102.3†

13.01 ⫾ 9.32 72.75 ⫾ 87.76

16.75 ⫾ 10.63 114.15 ⫾ 66.70

19.60 ⫾ 12.30 89.72 ⫾ 50.18

3.68 ⫾ 1.44 10.10 ⫾ 4.12 2.81 ⫾ 2.06 252 ⫾ 87 5.77 ⫾ 0.50

3.56 ⫾ 1.16 10.66 ⫾ 3.46 4.81 ⫾ 3.49‡ 132 ⫾ 62 5.92 ⫾ 0.56

4.88 ⫾ 2.26 9.48 ⫾ 3.53 6.33 ⫾ 2.46† 110 ⫾ 84* 7.77 ⫾ 2.10*

9.61 ⫾ 5.09 10.56 ⫾ 5.32

10.42 ⫾ 6.89 10.04 ⫾ 6.56

6.74 ⫾ 1.95†§ 6.56 ⫾ 1.89†§

Values are mean ⫾ SD. PP, postprandial. * p ⬍ 0.05. † p ⬍ 0.01, type 2 diabetes vs. NGT. ‡ p ⬍ 0.05 IGT vs. NGT. § p ⬍ 0.05 vs. IGT and NGT.

Analytical Methods Serum glucose concentrations were measured by the glucose oxidase method using a glucose autoanalyzer (Yellow Springs Instruments, Yellow Springs, OH). The serum insulin and C-peptide levels were determined by a standard double-antibody radioimmunoassay technique at The Core Laboratories of The Ohio State University Hospitals. The sensitivity of the insulin assay was 2.5 ␮U/mL. The intraand interassay coefficients of variation (CV) were 6% and 10%, respectively. The lower limit of the C-peptide assay was 0.47 ng/mL, and the intra - and interassay CV were 7% and 13%, respectively. Adiponectin levels were measured by an enzyme-linked immunosorbent assay method (B-

Bridge International, Inc., Sunnyvale, CA). The lower limit of adiponectin sensitivity was 0.77 ␮g/mL. The inter- and intra-assay CV were 5.76% and 3.65%, respectively. The HbA1c level was measured by the immuno-based method (DCA 2000, Bayer Corporation, Indianapolis, IN). The normal reference range was 3.6% to 6.1%. Calculations and Statistical Analyses Results are expressed as mean ⫾ SD, unless stated otherwise. The BMI was calculated as weight (kilograms) divided by height squared (meters). Obesity was defined as BMI ⱖ 30 kg/m2 for both women and men, and not obese OBESITY RESEARCH Vol. 13 No. 1 January 2005

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Table 2. Baseline clinical and biochemical characteristics of obese and non-obese African Americans with NGT Parameters

Overall

Non-Obese (30 kg/m2)

p

n Age (years) BMI (kg/m2) Fasting glucose (mg/dL) 2 hour PP glucose (mg/dL) Fasting insulin (␮U/mL) 2 hour PP insulin (␮U/mL) Fasting C-peptide (ng/mL) 2 hour PP C-peptide (ng/mL) HOMA-IR HOMA-%B HbA1c (%) Fasting adiponectin (␮g/mL) 2 hour PP adiponectin (␮g/mL)

19 49.10 ⫾ 7.86 32.45 ⫾ 6.69 85.2 ⫾ 12.2 85.6 ⫾ 20.1 13.01 ⫾ 9.32 72.75 ⫾ 87.7 3.68 ⫾ 1.44 10.10 ⫾ 4.12 2.81 ⫾ 2.06 252 ⫾ 187 5.77 ⫾ 0.50 9.61 ⫾ 5.09 10.56 ⫾ 5.34

8 46.00 ⫾ 4.58 27.03 ⫾ 4.11 82.38 ⫾ 10.60 83.00 ⫾ 13.00 8.22 ⫾ 3.92 50.13 ⫾ 49.79 2.64 ⫾ 1.07 7.57 ⫾ 3.46 1.72 ⫾ 0.97 102 ⫾ 48 5.51 ⫾ 0.40 10.75 ⫾ 5.82 13.01 ⫾ 5.55

11 51.36 ⫾ 9.66 36.38 ⫾ 5.34 87.36 ⫾ 13.40 87.00 ⫾ 24.62 16.49 ⫾ 10.68 89.18 ⫾ 96.81 4.52 ⫾ 1.14 12.14 ⫾ 4.58 3.61 ⫾ 2.32 185 ⫾ 13 5.91 ⫾ 0.51 8.79 ⫾ 4.61 8.71 ⫾ 4.59

0.117 0.001 0.396 0.749 0.053 0.353 0.001 0.024 0.046 0.086 0.01 0.424 0.082

Values are mean ⫾ SD.

was defined as BMI ⬍ 30 kg/m2. Insulin resistance and ␤ cell function were also calculated using HOMA (31). Statistical analyses were performed using Student’s t test (paired) and unpaired t test between the groups and ANOVA with repeated measures, where appropriate. Bonferroni method was used for post hoc testing. The nonparametric data were analyzed using ␹2. The relationships of adiponectin with homeostasis model assessment-insulin resistance index (HOMA-IR) and HOMA-␤ cell function (HOMA-%B), fasting insulin, and body composition variables were calculated using least square method and stepwise linear regression. For comparison of the mean data with unequal variance, Neuman-Keuls Multiple t test was used. p ⬍ 0.05 was considered statistically significant.

Results Clinical and Biochemical Characteristics of African Americans with NGT, IGT, and Type 2 Diabetes As shown in Table 1, the mean age was not significantly different in the IGT and type 2 diabetes groups when compared with the NGT group. The IGT and type 2 diabetes groups were significantly heavier than the NGT group. Also, we found that the IGT and type 2 diabetes groups had higher percentage body fat when compared with the NGT group. As shown in Table 1 and as predicted by the classification of diabetes, the mean fasting and 2-hour serum glucose levels during OGTT were significantly higher in the IGT (p ⬍ 0.05) and type 2 diabetes (p ⬍ 0.01) groups than 182


in the healthy NGT group. Both fasting serum insulin and C-peptide trended upward with increasing fasting glucose levels (Table 1). However, after oral glucose load, the 2-hour serum insulin and C-peptide levels were not significantly different despite the higher corresponding serum glucose levels in the IGT and type 2 diabetes groups (Table 1). HOMA-%B was slightly lower in the type 2 diabetes group when compared with the NGT and IGT groups. HOMA-IR was significantly greater in the IGT and type 2 diabetes groups when compared with the NGT group. Indeed, HOMA-IR was also significantly (⬍0.05) greater in the type 2 diabetes group when compared with IGT group. As shown in Table 1, the mean adiponectin levels were significantly lower in African Americans with type 2 diabetes when compared with those with NGT and IGT. The mean plasma adiponectin levels were similar in African Americans with NGT and IGT. As shown in Table 1, we found that during the OGTT, acute glucose load did not change the levels of plasma adiponectin despite varying insulin, C-peptide, and glycemic responses in the NGT, IGT, and type 2 diabetes groups. Effects of Obesity on Glucose Homeostasis and Plasma Adiponectin Levels in African Americans with NGT Test We examined plasma adiponectin levels in obese and non-obese glucose-tolerant African Americans to examine the effects of obesity per se on adiponectin (Table 2 and Figure 1). The mean plasma adiponectin levels were only slightly but not significantly different in the obese.


Figure 2: HOMA-IR (top) and plasma adiponectin levels (bottom) in insulin-sensitive (INS SEN) and insulin-resistant (INS RES) African Americans with NGT. (*) p ⬍ 0.01; insulin sensitive vs. insulin resistant. Figure 1: HOMA-IR (top), HOMA-%B (middle), and adiponectin (bottom) in obese and non-obese African Americans with parental history of type 2 diabetes. (*) p ⬍ 0.05; obese vs. non-obese for HOMA-IR and HOMA-%B.

Effects of Insulin Sensitivity Indices on Adiponectin Levels in African Americans with NGT We examined the effects of insulin sensitivity per se on plasma adiponectin levels, independent of glucose level or hyperglycemia, in insulin-sensitive (HOMA-IR ⬍ 2.68) and insulin-resistant (HOMA-IR ⬎ 2.68) subjects in the NGT group. As shown in Figure 2, the mean HOMA-IR was 1.74 ⫾ 0.65 for the insulin-sensitive group and 5.12 ⫾ 2.14 (p ⬍ 0.01) for the insulin-resistant group. Mean plasma adiponectin level was significantly (p ⬍ 0.05) higher in the insulin-sensitive than in the insulin-resistant group (11.09 ⫾ 4.99 vs. 6.42 ⫾ 3.98 ␮g/mL) Relationships of Adiponectin Levels with Metabolic and Obesity Parameters in African Americans Plasma adiponectin correlated with HOMA-IR (r ⫽ ⫺0.502, p ⫽ 0.048) and HOMA-%B (r ⫽ ⫺0.498, p ⫽

0.042). We also found that adiponectin did not significantly correlate with percentage body fat (r ⫽ ⫺0.368, p ⬍ 0.068), BMI (r ⫽ ⫺0.068, p ⫽ 0.79), HbA1c, and age.

Discussion The most important findings of our present study were that adiponectin levels were significantly lower in the type 2 diabetes group when compared with IGT and NGT groups and in a subset of insulin-resistant but glucose-tolerant first degree relatives of African Americans with family history of type 2 diabetes; obesity per se and glucose tolerance status did not determine plasma adiponectin levels. Previous studies have found decreased adiponectin levels in obese subjects, especially those with truncal (visceral) obesity (5,13). We found that adiponectin levels were not significantly different in the obese and non-obese subjects. Nevertheless, plasma adiponectin did not correlate with percentage body fat nor with body weight and BMI in our first degree relatives of African-American patients with type 2 diabetes. Thus, obesity per se as defined by BMI or OBESITY RESEARCH Vol. 13 No. 1 January 2005

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percentage body fat per se did not seem to influence plasma adiponectin levels in the first degree relatives of AfricanAmerican patients with type 2 diabetes. We found that adiponectin levels were significantly lower (by 2-fold) in the insulin-resistant than in the insulin-sensitive subjects (Figure 2). This was independent of the glucose tolerance status of the subjects. Indeed, we found that adiponectin inversely correlated with HOMA-IR, but not with acute glucose responses nor HbA1c, in our subjects. Our results are consistent with those of some other races and ethnic groups (16 –18) but differ from those in some others (1–7). First, we studied first degree relatives of AfricanAmerican patients with and without IGT and type 2 diabetes who presumably have genetically inherited insulin resistance. We found that having a parental history of type 2 diabetes alone was a major determinant of lower adiponectin levels in our African-American population. Indeed, obese insulin-resistant subjects with NGT had adiponectin levels similar to those of obese patients with clinical type 2 diabetes. This study suggests that African Americans who are prone to developing type 2 diabetes manifest lower plasma adiponectin levels that seem to antecede the disease. Whether adiponectin is a predictor of type 2 diabetes in African Americans (similar to other racial and ethnic populations) remains to be determined in long-term prospective studies. Nevertheless, we speculate that lower adiponectin levels could be responsible for the insulin resistance found in the first degree relatives of African Americans. The other possibility is that adiponectin and insulin resistance are coinherited in African-American individuals who are genetically prone to type 2 diabetes and cardiovascular diseases. In this regard, Lihn et al. (10) and Pelme et al. (9) have reported that non-diabetic first degree relatives demonstrate lower plasma adiponectin levels or gene expression before the development of IGT and type 2 diabetes in whites. Finally, there is the possibility that African Americans, as a group, may have lower adiponectin levels due to intrinsic insulin resistance, independent of obesity, when compared with white Americans (19). This will be consistent with the greater insulin-resistant state that we and others have previously reported in African Americans when compared with white Americans (24 –29). This view is supported by the report by Hulver et al. (19), who have shown that fasting plasma adiponectin is lower in non-diabetic, non-obese African Americans than in white Americans. Glucose tolerance is maintained as a balance between mediators of stimulated insulin secretion and those that promote insulin sensitivity and, hence, total glucose disposal. Thus, adiponectin, a potent insulin sensitizer, could contribute to the overall postprandial glucose tolerance in humans if we can demonstrate that adiponectin levels are stimulated during oral nutrient meal ingestion. Indeed, English et al. (20) have shown that plasma adiponectin levels are increased in non-diabetic, obese whites but not in non184


diabetic, non-obese whites after ingestion of a physiological, standard mixed meal. The authors suggest that adiponectin could play a significant role in the postprandial glucose tolerance in obese subjects. Therefore, we examined the acute adiponectin responses to the oral glucose challenge in the NGT, IGT, and type 2 diabetes groups. Despite varying degrees of serum glucose, insulin, and C-peptide responses to oral glucose challenge, we found no acute changes in plasma adiponectin levels from the baseline after a standard glucose tolerance challenge in obese and non-obese African-American subjects. Furthermore, we found no relationships between adiponectin levels and serum glucose, insulin, and C-peptide responses or HbA1c levels in the NGT, IGT, and type 2 diabetes groups (data not shown). Because the half-life of plasma adiponectin levels is unknown (because it exists in different molecular species with varying potencies) in African Americans, it is unknown whether circulating plasma molecular species are different among individuals with NGT, IGT, or type 2 diabetes before or after oral glucose challenge. To the best of our knowledge, we are not aware of any data on adiponectin polymorphism and mutants or kinetics in African Americans. In summary, our study demonstrated that adiponectin levels are lower in insulin-resistant first degree relatives of African Americans with NGT and those with newly diagnosed type 2 diabetes. We found that insulin sensitivity, rather than obesity or percentage body fat per se, appears to be a major determinant of plasma adiponectin levels in African Americans. The lower plasma adiponectin levels in high-risk African Americans seem to antecede the development of IGT and type 2 diabetes. We conclude that plasma adiponectin levels are genetically determined and cosegregate with insulin resistance but not obesity, percent body fat, or glucose tolerance in African-American individuals who are genetically likely to develop type 2 diabetes.

Acknowledgments We thank the volunteers for the study, the registered nurses and dietitians in The General Clinical Research Center (GCRC), the Core Laboratory, and NIH Grant GCRCRR0034. The study was supported by Grants NIH NIDDK DK48127 (to K.O.) and KO8 and R03 (to D.A.) and by an unrestricted research grant from GlaxoSmithKline Pharmaceutical, Inc. (Philadelphia, PA). References 1. Krakoff J, Funahaser T, Stenhouwer CDA, et al. Inflammatory markers, adiponectin and the risk of type 2 diabetes in the Pima Indians. Diabetes Care. 2003;26:1745–51. 2. Weyer C, Funahashi T, Tanaka S, et al. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab. 2001;86:1930 –5.


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