Obesity is associated with insulin resistance, particularly when body fat has a central distribution. However, insulin resistance also frequently occurs in apparently lean individuals. It has been proposed that these lean insulin-resistant individuals have greater amounts of body fat than lean insulin-sensitive subjects. Alternatively, their body fat distribution may be different. Obesity is associated with elevated plasma leptin levels, but some studies have suggested that insulin sensitivity is an additional determinant of circulating leptin concentrations. To examine how body fat distribution contributes to insulin sensitivity and how these variables are related to leptin levels, we studied 174 individuals (73 men, 101 women), a priori classified as lean insulinsensitive (LIS, n ‫؍‬ 56), lean insulin-resistant (LIR, n ‫؍‬ 61), and obese insulin-resistant (OIR, n ‫؍‬ 57) based on their BMI and insulin sensitivity index (S I ). Whereas the BMI of the two lean groups did not differ, the S I of the LIR subjects was less than half that of the LIS group. The subcutaneous and intra-abdominal fat areas, determined by computed tomography, were 45 and 70% greater in the LIR subjects (P < 0.001) and 2.5-and 3-fold greater in the OIR group, as compared with the LIS group. Fasting plasma leptin levels were moderately increased in LIR subjects (10.8 ؎ 7.1 vs. 8.1 ؎ 6.4 ng/ml in LIS subjects; P < 0.001) and doubled in OIR subjects (21.9 ؎ 15.5 ng/ml; P < 0.001). Because of the confounding effect of body fat, we examined the relationships between adiposity, insulin sensitivity, and leptin concentrations by multiple regression analysis. Intraabdominal fat was the best variable predicting insulin sensitivity in both genders and explained 54% of the variance in S I . This inverse relationship was nonlinear (r ‫؍‬ ؊0.688). On the other hand, in both genders, fasting leptin levels were strongly associated with subcutaneous fat area (r ‫؍‬ 0.760) but not with intraabdominal fat. In line with these analyses, when LIS and LIR subjects were matched for subcutaneous fat area, age, and gender, they had similar leptin levels, whereas their intra-abdominal fat and insulin sensitivity remained different. Thus, accumulation of intra-abdominal fat correlates with insulin resistance, whereas subcutaneous fat deposition correlates with circulating leptin levels. We conclude that the concurrent increase in these two metabolically distinct fat compartments is a major explanation for the association between insulin resistance and elevated circulating leptin concentrations in lean and obese subjects. Diabetes 51: 1005-1015, 2002

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Transgenic mice expressing the amyloidogenic human islet amyloid polypeptide (hIAPP) in their islet ␤-cells are a model of islet amyloid formation as it occurs in type 2 diabetes. Our hIAPP transgenic mice developed islet amyloid when fed a breeder chow but not regular chow. Because the breeder chow contained increased amounts of fat, we hypothesized that increased dietary fat enhances islet amyloid formation. To test this hypothesis, we fed male hIAPP transgenic and nontransgenic control mice diets containing 15% (low fat), 30% (medium fat), or 45% (high fat) of calories derived from fat for 12 months, and we measured islet amyloid, islet endocrine cell composition, and ␤-cell function. Increased dietary fat in hIAPP transgenic mice was associated with a dose-dependent increase in both the prevalence (percentage of islets containing amyloid deposits; 34 ؎ 8, 45 ؎ 8, and 58 ؎ 10%, P < 0.05) and severity (percentage of islet area occupied by amyloid; 0.8 ؎ 0.5, 1.0 ؎ 0.5, and 4.6 ؎ 2.5%, P ‫؍‬ 0.05) of islet amyloid. In addition, in these hIAPP transgenic mice, there was a dose-dependent decrease in the proportion of islet area comprising ␤-cells, with no significant change in islet size. In contrast, nontransgenic mice adapted to diet-induced obesity by increasing their islet size more than twofold. Increased dietary fat was associated with impaired insulin secretion in hIAPP transgenic (P ‫؍‬ 0.05) but not nontransgenic mice. In summary, dietary fat enhances both the prevalence and severity of islet amyloid and leads to ␤-cell loss and impaired insulin secretion. Because both morphologic and functional defects are present in hIAPP transgenic mice, this would suggest that the effect of dietary fat to enhance islet amyloid formation might play a role in the pathogenesis of the islet lesion of type 2 diabetes in humans. Diabetes 52:372-379, 2003 T ype 2 diabetes is characterized by ␤-cell dysfunction and insulin resistance. An underlying defect in the islet ␤-cell is thought to contribute to the inability of the ␤-cell to compensate for the increased demand for insulin, leading to decreased glucose tolerance and eventually type 2 diabetes. The cause(s) of this ␤-cell dysfunction is unknown and is likely associated with both genetic and environmental factors. One of these environmental factors appears to be increased dietary fat, which has been associated with obesity, insulin resistance, and type 2 diabetes in humans (1-3), and in animal studies it leads to the development of insulin resistance (4,5). In addition to the ␤-cell secretory defect, islet amyloid deposition occurs in the pancreatic islets of the vast majority of subjects with type 2 diabetes (6,7). Islet amyloid has been shown to lead to a progressive loss of ␤-cell mass and function (8 -11), and thus it has been proposed as a factor contributing toward the ␤-cell secretory defect in type 2 diabetes. The unique protein component of islet amyloid is the 37-amino acid peptide islet amyloid polypeptide (IAPP, also known as amylin) (12,13), a normal secret...