and acute insulin response (AIR) (25-g intravenous glucose challenge). Sixty-three subjects developed diabetes over an average follow-up of 6.9 ؎ 4.9 years. In 224 subjects, who remained nondiabetic, follow-up measurements of M and AIR were available. At baseline, ALT, AST, and GGT were related to percent body fat (r ‫؍‬ 0.16, 0.17, and 0.11, respectively), M (r ‫؍‬ ؊0.32, ؊0.28, and ؊0.24), and HGO (r ‫؍‬ 0.27, 0.12, and 0.14; all P < 0.01). In a proportional hazard analysis with adjustment for age, sex, body fat, M, and AIR, higher ALT [relative hazard 90th vs. 10th centiles (95% CI): 1.9 (1.1-3.3), P ‫؍‬ 0.02], but not AST or GGT, predicted diabetes. Elevated ALT at baseline was associated prospectively with an increase in HGO (r ‫؍‬ 0.21, P ‫؍‬ 0.001) but not with changes in M or AIR (both P ‫؍‬ 0.1). Higher ALT concentrations were cross-sectionally associated with obesity and whole-body and hepatic insulin resistance and prospectively associated with a decline in hepatic insulin sensitivity and the development of type 2 diabetes. Our findings indicate that high ALT is a marker of risk for type 2 diabetes and suggest a potential role of the liver in the pathogenesis of type 2 diabetes.

Chronic low-grade inflammation may be involved in the pathogenesis of insulin resistance and type 2 diabetes. We examined whether a high white blood cell count (WBC), a marker of inflammation, predicts a worsening of insulin action, insulin secretory function, and the development of type 2 diabetes in Pima Indians. We

VOZAROVA, BARBORA, CHRISTIAN WEYER, KRISTIN HANSON, P. ANTONIO TATARANNI, CLIFTON BOGARDUS, AND RICHARD E. PRATLEY. Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion. Obes Res. 2001;9:414 -417. Objective: Plasma concentrations of interleukin-6 (IL-6), a proinflammatory cytokine produced and released in part by adipose tissue, are elevated in people with obesity and type 2 diabetes. Because recent studies suggest that markers of inflammation predict the development of type 2 diabetes, we examined whether circulating plasma IL-6 concentrations were related to direct measures of insulin resistance and insulin secretory dysfunction in Pima Indians, a population with high rates of obesity and type 2 diabetes. Research Methods and Procedures: Fasting plasma IL-6 concentrations (enzyme-linked immunosorbent assay), body composition (DXA), insulin action (M; hyperinsulinemic euglycemic clamp), and acute insulin secretory responses to glucose (25 g intravenous glucose tolerance test) were measured in 58 Pima Indians without diabetes (24 women, 34 men). Results: Fasting plasma IL-6 concentrations were positively correlated with percentage of body fat (r ϭ 0.26, p ϭ 0.049) and negatively correlated with M (r ϭ Ϫ0.28, p ϭ 0.031), but were not related to acute insulin response (r ϭ 0.13, p ϭ 0.339). After adjusting for percentage of body fat, plasma IL-6 was not related to M (partial r ϭ Ϫ0.23, p ϭ 0.089). Discussion: Fasting plasma IL-6 concentrations are positively related to adiposity and negatively related to insulin action in Pima Indians. The relationship between IL-6 and insulin action seems to be mediated through adiposity.

Adiponectin, the most abundant adipose-specific protein, has been found to be negatively associated with degree of adiposity and positively associated with insulin sensitivity in Pima Indians and other populations. Moreover, adiponectin administration to rodents has been shown to increase insulin-induced tyrosine phosphorylation of the insulin receptor (IR) and also increase whole-body insulin sensitivity. To further characterize the relationship between plasma adiponectin concentration and insulin sensitivity in humans, we examined 1) the cross-sectional association between plasma adiponectin concentration and skeletal muscle IR tyrosine phosphorylation and 2) the prospective effect of plasma adiponectin concentration at baseline on change in insulin sensitivity. Fasting plasma adiponectin concentration, body composition (hydrodensitometry or dual energy X-ray absorptiometry), insulin sensitivity (insulinstimulated glucose disposal, hyperinsulinemic clamp), and glucose tolerance (75-g oral glucose tolerance test) were measured in 55 Pima Indians (47 men and 8 women, aged 31 ؎ 8 years, body fat 29 ؎ 8% [mean ؎ SD]; 50 with normal glucose tolerance, 3 with impaired glucose tolerance, and 2 with diabetes). Group 1 (19 subjects) underwent skeletal muscle biopsies for the measurement of basal and insulin-stimulated tyrosine phosphorylation of the IR (stimulated by 100 nmol/l insulin). The fold increase after insulin stimulation was calculated as the ratio between maximal and basal phosphorylation.Group 2 (38 subjects) had follow-up measurements of insulin-stimulated glucose disposal. Cross-sectionally, plasma adiponectin concentration was positively associated with insulin-stimulated glucose disposal (r ‫؍‬ 0.58, P < 0.0001) and negatively associated with percent body fat (r ‫؍‬ ؊0.62, P < 0.0001) in the whole group. In group 1 plasma adiponectin was negatively associated with the basal (r ‫؍‬ ؊0.65, P ‫؍‬ 0.003) and positively associated with the fold increase in IR tyrosine phosphorylation (r ‫؍‬ 0.69, P ‫؍‬ 0.001) before and after the adjustment for percent body fat (r ‫؍‬ ؊0.58, P ‫؍‬ 0.01 and r ‫؍‬ 0.54, P ‫؍‬ 0.02, respectively). Longitudinally, after adjustment for age, sex, and percent body fat, low plasma adiponectin concentration at baseline was associated with a decrease in insulin sensitivity (P ‫؍‬ 0.04). In conclusion, our cross-sectional data suggest a role of physiological concentration of fasting plasma adiponectin in the regulation of skeletal muscle IR tyrosine phosphorylation. Prospectively, low plasma adiponectin concentration at baseline precedes a decrease in insulin sensitivity. Our data indicate that adiponectin plays an important role in regulation of insulin sensitivity in humans. Diabetes 50:1884 -1888, 2002 A dipose tissue serves not only as an energy storage organ, but also secretes hormones and metabolites that are thought to regulate insulin sensitivity and energy metabolism (1,2). Adiponectin, the most abundant adipose-specific protein, is exclusively expressed in and secreted from a...

Prader-Willi syndrome (PWS) is a genetic disorder occurring in 1 of 10,000-16,000 live births and is characterized by excessive appetite with progressive massive obesity as well as short stature and mental retardation. Most patients have GH deficiency and hypogonadotropic hypogonadism. The causes of the hyperphagia and abnormal GH secretion are unknown. To determine whether ghrelin, a novel GH secretagogue with orexigenic properties, is elevated in PWS, we measured fasting plasma ghrelin concentration; body composition (dual-energy x-ray absorptiometry); and subjective ratings of hunger (visual analog scale) in seven subjects (6 males and 1 female; age, 26 +/- 7 yr; body fat, 39 +/- 11%, mean +/- SD) with PWS (diagnosis confirmed by genetic test) and 30 healthy subjects (reference population, 15 males and 15 females; age, 32 +/- 7 yr; body fat, 36 +/- 11%) fasted overnight. All subjects were weight stable for at least 6 months before admission to the study. The mean plasma ghrelin concentration was higher in PWS than in the reference population (307 +/- 164 vs. 109 +/- 24 fmol/ml; P < 0.001), and this difference remained significant after adjustment for percentage body fat (P < 0.001). Plasma ghrelin was also higher (P = 0.0004) in PWS than in five healthy subjects fasted for 36 h. A positive correlation was found between plasma ghrelin and subjective ratings of hunger (r = 0.71; P = 0.008). Furthermore, in subjects with PWS, the concentration of the hormone was not different before and after ingestion of 2 ml and a satiating amount of the same liquid meal (ghrelin concentrations: 307 +/- 164 vs. 306 +/- 205 vs. 260 +/- 134 fmol/ml, respectively; ANOVA for repeated measures, P = 0.56). This is the first evidence that ghrelin, a novel orexigenic hormone, is elevated in subjects with PWS. Our finding suggests that ghrelin may be responsible, at least in part, for the hyperphagia observed in PWS.

BACKGROUND:Obesity results from a chronic imbalance between energy intake and energy expenditure. However, experimental evidence of the relative contribution of interindividual differences in energy intake and expenditure (resting or due to physical activity) to weight gain is limited. OBJECTIVE: To assess prospectively the association between baseline measurements of daily energy metabolism and weight changes by studying free-living adult Pima Indians, one of the most obese populations in the world. DESIGN: A study of the pathogenesis of obesity in the Pima Indians living in Southwestern Arizona. The participants were 92 nondiabetic Pima Indians (64M/28F, 35712 y, 3579% body fat; mean7s.d.). At baseline, free-living daily energy metabolism was assessed by doubly labeled water and resting metabolic rate (RMR) by indirect calorimetry. Data on changes in body weight (5.876.5 kg) over a follow-up period of 473 y were available in 74 (49M/25F) of the 92 subjects. RESULTS: The baseline calculated total energy intake (r ¼ 0.25, P ¼ 0.028) and RMR (r ¼ À0.28, P ¼ 0.016) were significantly associated with changes in body weight. The baseline energy expenditure due to physical activity was not associated with changes in body weight. CONCLUSION: Using state-of-the-art methods to assess energy intake and expenditure in free-living conditions, we show for the first time that the baseline calculated total energy intake is a determinant of changes in body weight in Pima Indians. These data also confirm that a low RMR is a risk factor for weight gain in this population.

In many organisms, normoglycemia is achieved by a tight coupling of nutrient-stimulated insulin secretion in the pancreatic ␤-cell (acute insulin response [AIR]) and the metabolic action of insulin to stimulate glucose disposal (insulin action [M]). It is widely accepted that in healthy individuals with normal glucose tolerance, normoglycemia can always be maintained by compensatorily increasing AIR in response to decreasing M (and vice versa). This has been mathematically described by the hyperbolic relationship between AIR and M and referred to as glucose homeostasis, with glucose concentration assumed to remain constant along the hyperbola. Conceivably, glucose is one of the signals stimulating AIR in response to decreasing M. Hypothetically, as with any normally functioning feed-forward system, AIR should not fully compensate for worsening M, since this would remove the stimulus for the compensation. We provide evidence from cross-sectional, longitudinal, and prospective data from Pima Indians (n ‫؍‬ 413) and Caucasians (n ‫؍‬ 60) that fasting and postprandial glucose concentrations increase with decreasing M despite normal compensation of AIR. For this physiologic adaptation to chronic stress (insulin resistance), we propose to use the term "glucose allostasis." Allostasis (stability through change) ensures the continued homeostatic response (stability through staying the same) to acute stress at some cumulative costs to the system. With increasing severity and over time, the allostatic load (increase in glycemia) may have pathological consequences, such as the development of type 2 diabetes. Diabetes 52:903-909, 2003 I nsulin action and secretion are the principal determinants of glycemia. In people with normal glucose tolerance (NGT), a decrease in insulin action (M) is accompanied by upregulation of insulin secretion (and vice versa). This is interpreted as compensation of insulin secretion for insulin resistance to maintain normoglycemia (1,2). Insulin resistance is a common consequence of obesity, for example, and represents a key factor in the pathogenesis of type 2 diabetes (3). Mathematically, the relationship between insulin secretion and insulin sensitivity is thought to be best expressed twodimensionally by a hyperbola with the product of the two variables equalling a constant (4), named the "disposition index" (DI). The DI is considered to measure the ability of the ␤-cells to compensate for insulin resistance. It decreases when glucose tolerance becomes impaired (5).While the insulin secretion/M hyperbola elegantly conceptualizes many cross-sectional and longitudinal observations (reviewed in 5), the physiologic signal that stimulates the compensatory increase in ␤-cell function in response to decreasing M remains unexplained. Insulin secretion is primarily substrate controlled, and glucose, the preeminent secretagogue among nutrient molecules, would be a good candidate for such a signal. Glucosestimulated insulin secretion is primarily controlled by the enzyme glucokinase, which governs the ge...

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