Plasma concentrations of adiponectin, a novel adipose-specific protein with putative antiatherogenic and antiinflammatory effects, were found to be decreased in Japanese individuals with obesity, type 2 diabetes, and cardiovascular disease, conditions commonly associated with insulin resistance and hyperinsulinemia. To further characterize the relationship between adiponectinemia and adiposity, insulin sensitivity, insulinemia, and glucose tolerance, we measured plasma adiponectin concentrations, body composition (dual-energy x-ray absorptiometry), insulin sensitivity (M, hyperinsulinemic clamp), and glucose tolerance (75-g oral glucose tolerance test) in 23 Caucasians and 121 Pima Indians, a population with a high propensity for obesity and type 2 diabetes. Plasma adiponectin concentration was negatively correlated with percent body fat (r = -0.43), waist-to-thigh ratio (r = -0.46), fasting plasma insulin concentration (r = -0.63), and 2-h glucose concentration (r = -0.38), and positively correlated with M (r = 0.59) (all P < 0.001); all relations were evident in both ethnic groups. In a multivariate analysis, fasting plasma insulin concentration, M, and waist-to-thigh ratio, but not percent body fat or 2-h glucose concentration, were significant independent determinates of adiponectinemia, explaining 47% of the variance (r(2) = 0.47). Differences in adiponectinemia between Pima Indians and Caucasians (7.2 +/- 2.6 vs. 10.2 +/- 4.3 microg/ml, P < 0.0001) and between Pima Indians with normal, impaired, and diabetic glucose tolerance (7.5 +/- 2.7, 6.1 +/- 2.0, 5.5 +/- 1.6 microg/ml, P < 0.0001) remained significant after adjustment for adiposity, but not after additional adjustment for M or fasting insulin concentration. These results confirm that obesity and type 2 diabetes are associated with low plasma adiponectin concentrations in different ethnic groups and indicate that the degree of hypoadiponectinemia is more closely related to the degree of insulin resistance and hyperinsulinemia than to the degree of adiposity and glucose intolerance.

Ghrelin is a novel endogenous natural ligand for the growth hormone (GH) secretagogue receptor that has recently been isolated from the rat stomach. Ghrelin administration stimulates GH secretion but also causes weight gain by increasing food intake and reducing fat utilization in rodents. To investigate the possible involvement of ghrelin in the pathogenesis of human obesity, we measured body composition (by dual X-ray absorption) as well as fasting plasma ghrelin concentrations (radioimmunoassay) in 15 Caucasians (8 men and 7 women, 31 ؎ 9 years of age, 92 ؎ 24 kg body wt, and 29؎10% body fat, mean ؎ SD) and 15 Pima Indians (8 men and 7 women, 33 ؎ 5 years of age, 97 ؎ 29 kg body wt, and 30 ؎ 8% body fat). Fasting plasma ghrelin was negatively correlated with percent body fat (r ‫؍‬ -0.45; P ‫؍‬ 0.01), fasting insulin (r ‫؍‬ -0.45; P ‫؍‬ 0.01) and leptin (r ‫؍‬ -0.38; P ‫؍‬ 0.03) concentrations. Plasma ghrelin concentration was decreased in obese Caucasians as compared with lean Caucasians (P < 0.01). Also, fasting plasma ghrelin was lower in Pima Indians, a population with a very high prevalence of obesity, compared with Caucasians (87 ؎ 28 vs. 129 ؎ 34 fmol/ml; P < 0.01). This result did not change after adjustment for fasting plasma insulin concentration. There was no correlation between fasting plasma ghrelin and height. Prospective clinical studies are now needed to establish the role of ghrelin in the pathogenesis of human obesity. Diabetes 50: [707][708][709] 2001 W e recently reported (1) that the gastric hormone ghrelin (2) provides a peripheral signal to the brain that induces adiposity in rodents. To investigate a possible involvement of ghrelin in the pathogenesis of human obesity, we measured endogenous ghrelin concentrations in lean and obese Caucasian and Pima Indian individuals. We hypothesized that 1) obese individuals would present with elevated ghrelin levels that could contribute to the pathogenesis of obesity and 2) Pima Indians, a population with one of the highest reported prevalence rates of obesity and type 2 diabetes in the world, would present with elevated ghrelin levels when compared with Caucasians. RESEARCH DESIGN AND METHODSA total of 15 Caucasian and 15 Pima Indian subjects matched for age, sex, and body weight were divided into lean (n ϭ 7) and obese (n ϭ 8) subgroups (Table 1). Obesity was defined as BMI Ͼ30 kg/m 2 , according to the criteria of both the World Health Organization and the International Obesity Task Force. All participants were between 20 and 50 years of age, nondiabetic according to an oral glucose tolerance test, and healthy according to a physical examination and routine laboratory tests. Subjects were admitted to the research ward of the Clinical Diabetes and Nutrition Section of the National Institutes of Health in Phoenix, Arizona, where they received a weightmaintaining diet (50% carbohydrate, 30% fat, and 20% protein) and abstained from exercise for at least 2 days before the study. The protocol was approved by the Tribal Council of the Gila River In...

Type 2 diabetes mellitus is characterized by 4 major metabolic abnormalities: obesity, impaired insulin action, insulin secretory dysfunction, and increased endogenous glucose output (EGO) (1-3). Although there is substantial evidence that the first 3 of these abnormalities are present in most individuals before the onset of diabetes, the sequence with which they develop and their relative contributions to the progression from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT), and ultimately to type 2 diabetes (4-6), remain unknown in the absence of a detailed longitudinal study (7)(8)(9)(10)(11)(12). Current understanding of the pathogenesis of type 2 diabetes is based on a large number of cross-sectional (13-25) and prospective (26-40) studies.In cross-sectional studies, subjects with IGT were on average more obese and more insulin-resistant than those with NGT. Basal EGO, largely reflecting hepatic glucose production, was not increased (3,7,8,(13)(14)(15). Whether insulin secretion is impaired in individuals with IGT is controversial. Some studies have found a lower early insulin secretory response (occurring within minutes of an intravenous or oral glucose load) in individuals with IGT compared with those with . Lower early insulin responses have also been demonstrated in first-degree relatives of individuals with type 2 diabetes, a population at high risk for developing diabetes (20)(21)(22). However, others have reported normal or increased early insulin secretion in both groups of individuals (13,14,23,24). Similarly, both lower (18) and higher (25) late insulin responses (2 hours after an oral glucose load) have been reported in subjects with IGT compared with those with NGT. With respect to the pathogenesis of diabetes, such cross-sectional findings must be interpreted with caution, because many individuals with IGT will never develop diabetes, and their metabolic characteristics may well differ from those who do.In recent years, several prospective studies, in which nondiabetic individuals are metabolically characterized on a single occasion and then followed for several years to determine who develops diabetes, have helped to identify metabolic abnormalities that predispose to diabetes. These studies have shown that obesity (27-29, 33-35, 39) and insulin resistance (30-35) predict the development of diabetes in many populations, whereas basal EGO was not predictive in the only study in which it was measured (30). A low early insulin response predicted diabetes in most (30,(35)(36)(37)(38)(39) but not all (31, 32) studies. Together, these results indicate that defects in both insulin action and insulin secretion predispose some individuals with NGT to diabetes, but they give little information about the time course with which these abnormalities change as glucose tolerance worsens.To determine the natural history of insulin secretory dysfunction and insulin resistance during the development of diabetes, and to understand how these factors interact with one another during the developm...