The nutrient-sensitive kinase mammalian target of rapamycin (mTOR) and its downstream target S6 kinase (S6K) are involved in amino acid-induced insulin resistance. Whether the mTOR/S6K pathway directly modulates glucose metabolism in humans is unknown. We studied 11 healthy men (29 years old, BMI 23 kg/m 2 ) twice in random order after oral administration of 6 mg rapamycin, a specific mTOR inhibitor, or placebo. An amino acid mixture was infused to activate mTOR, and somatostatin-insulin-glucose clamps created conditions of low peripheral hyperinsulinemia (ϳ100 pmol/l, 0 -180 min) and prandial-like peripheral hyperinsulinemia (ϳ450 pmol/l, 180 -360 min). Glucose turnover was assessed using D-[6,6-2 H 2 ]glucose infusion (n ‫؍‬ 8). Skeletal muscle biopsies were performed at baseline and during prandial-like peripheral hyperinsulinemia (n ‫؍‬ 3). At low peripheral hyperinsulinemia, whole-body glucose uptake was not affected by rapamycin. During prandial-like peripheral hyperinsulinemia, rapamycin increased glucose uptake compared with placebo by 17% (R dԽ300 -360 min , 75 ؎ 5 vs. 64 ؎ 5 mol ⅐ kg ؊1 ⅐ min ؊1 , P ‫؍‬ 0.0008). Rapamycin affected endogenous glucose production neither at baseline nor during low or prandial-like peripheral hyperinsulinemia. Combined hyperaminoacidemia and prandial-like hyperinsulinemia increased S6K phosphorylation and inhibitory insulin receptor substrate-1 (IRS-1) phosphorylation at Ser312 and Ser636 in the placebo group. Rapamycin partially inhibited this increase in mTOR-mediated S6K phosphorylation and IRS-1 Ser312 and Ser636 phosphorylation. In conclusion, rapamycin stimulates insulin-mediated glucose uptake in man under conditions known to activate the mTOR/S6K pathway. Diabetes 56:1600-1607, 2007 T ype 2 diabetes is closely linked to obesity and insulin resistance (1-3). In addition to polygenic predisposition, environmental factors including quality and quantity of food supply, dietary behavior, and physical activity are of major importance for the development of type 2 diabetes (4,5). The availability of nutrients plays a pivotal role in the modulation of insulin action (6,7). In industrialized countries, nutrient excess comprises high intake of not only fat but also proteins (8). A chronic excess in protein intake is associated with insulin resistance, glucose intolerance, and type 2 diabetes (9 -12). We have shown that a short-term rise in plasma free fatty acids (FFAs) (13-15) or amino acids (16 -18) leads to decreased insulin-stimulated whole-body glucose disposal, which is preceded by an impaired rise in intramuscular glucose-6-phosphate concentrations and followed by reduction in rates of glycogen synthesis. These findings indicate that both FFAs and amino acids directly inhibit skeletal muscle glucose transport/phosphorylation (17).The mammalian target of rapamycin (mTOR) pathway (19) could be involved in sensing of nutrient availability and modulation of insulin action in vivo. Recent reports indicate that the activity of the mTOR pathway is increased in rodent models ...

Our data demonstrate that healthy, insulin-resistant humans do not show altered plasma retinol binding factors, such as RBP and PCI. Both do not significantly correlate with insulin sensitivity. Thus, our findings do not support the hypothesis of insulin sensitivity modulation by proteins involved in retinol transport.

OBJECTIVE -Insulin resistance, the underlying pathophysiological mechanism of the metabolic syndrome, can not only predict type 2 diabetes development but also cardiovascular disease. Thus, precise insulin resistance measurement in individuals at risk for metabolic diseases would support clinical risk stratification. However, the gold standard for measuring insulin resistance, the hyperinsulinemic clamp test, is too labor intensive to be performed in large clinical studies/settings.RESEARCH DESIGN AND METHODS -Using plasma glucose and C-peptide concentrations from oral glucose tolerance tests (OGTTs), we developed the novel "clamp-like index" (CLIX) for insulin sensitivity calculation and compared CLIX to clamp glucose infusion rates (GIR) (100 -120 min). We evaluated CLIX in 89 nondiabetic subjects (58 female and 31 male, aged 45 Ϯ 1 years, BMI 27.5 Ϯ 0.8 kg/m 2 ) who underwent frequently sampled 3-h 75-g OGTTs and 2-h hyperinsulinemic-isoglycemic clamp (40 mU/min per m 2 ) tests.RESULTS -CLIX, calculated as serum creatinine (ϫ0.85 if male)/(mean AUC glucose ϫ mean AUC C-peptide ) ϫ 6,600, was highly correlated (r ϭ 0.670, P Ͻ 10 Ϫ12 ) with and comparable to clamp GIRs 100 -120 min . In subgroup analyses, GIRs 100 -120 min were lower (P Ͻ 0.005) in type 2 diabetic offspring (6.2 Ϯ 0.7 mg ⅐ min Ϫ1 ⅐ kg Ϫ1 ) than in sex-, age-, and BMI-matched subjects without a family history of type 2 diabetes (8.6 Ϯ 0.5 mg ⅐ min Ϫ1 ⅐ kg Ϫ1 ), which was also reflected by CLIX (insulin-resistant offspring 6.4 Ϯ 0.6 vs. those without a family history of type 2 diabetes 9.0 Ϯ 0.5; P Ͻ 0.002). When compared with normal-weight subjects (GIR 8.8 Ϯ 0.4 mg ⅐ min Ϫ1 ⅐ kg Ϫ1 ; CLIX 9.0 Ϯ 0.5), both GIRs 100 -120 min and CLIX of obese (5.2 Ϯ 0.9 mg ⅐ min Ϫ1 ⅐ kg Ϫ1 ; 5.7 Ϯ 0.9) and morbidly obese (2.4 Ϯ 0.4 mg ⅐ min Ϫ1 ⅐ kg Ϫ1 ; 3.3 Ϯ 0.5) humans were lower (each P Ͻ 0.02).CONCLUSIONS -CLIX, a novel index obtained from plasma OGTT glucose and Cpeptide levels and serum creatinine, without inclusion of anthropometrical measures to calculate insulin sensitivity in nondiabetic humans, highly correlates with clamp GIRs and reveals even slight insulin sensitivity alterations over a broad BMI range and is as sensitive as the hyperinsulinemic clamp test. Diabetes Care 30:2374-2380, 2007I nsulin resistance, the underlying pathophysiological mechanism of the metabolic syndrome, is closely associated with common metabolic and inflammatory diseases, such as type 2 diabetes, obesity, nonalcoholic fatty liver disease, and cardiovascular disease (1-3). The degree of insulin resistance in the insulinresistant offspring of parents with type 2 diabetes, but not in humans without a family history of type 2 diabetes, serves as a predictor for later onset of the disease (4 -6). Overweight or obesity also results in a tremendous fall in insulin sensitivity, combined with a markedly increased risk for type 2 diabetes and other disturbances (such as hyperlipidemia or arterial hypertension) (1,7).Insulin sensitivity can best be measured with the labor-intensive h...

Obestatin, a recently discovered 23-amino acid peptide, is involved in the regulation of appetite and body weight in antagonistic fashion to ghrelin, both deriving from a common precursor peptide. Ghrelin was shown to be associated with insulin resistance, which may also affect obestatin. We investigated the association between insulin resistance and plasma concentrations of obestatin and ghrelin in nondiabetic individuals with high (IS; n ϭ 18, 13 females and 5 males, age 47 Ϯ 2 yr, BMI ϭ 25.5 Ϯ 0.9 kg/m 2 ) and low (IR; n ϭ 18, 12 females and 6 males, age 45 Ϯ 2 yr, P ϭ 0.49, BMI ϭ 27.5 Ϯ 1.1 kg/m 2 , P ϭ 0.17) insulin-stimulated glucose disposal (M), measured by 2-h hyperinsulinemic (40 mU ⅐ min Ϫ1 ⅐ m Ϫ2 ) isoglycemic clamp tests. M100-120 min was higher in IS (10.7 Ϯ 0.7) than in IR (4.4 Ϯ 0.2 mg ⅐ min Ϫ1 ⅐ kg Ϫ1 , P Ͻ 10 Ϫ9 ), whereas insulin-dependent suppression of free fatty acids (FFA) in plasma was reduced in IR (71 Ϯ 6% vs. IS: 82 Ϯ 5%, P Ͻ 0.02). In both groups, plasma ghrelin concentrations were comparable at fasting and similarly reduced by 24 -28% during insulin infusion. IR had lower fasting plasma obestatin levels (383 Ϯ 26 pg/ml vs. IS: 469 Ϯ 23 pg/ml, P Ͻ 0.02). Clamp insulin infusion reduced plasma obestatin to ϳ81% of basal values in IS (P Ͻ 0.00002), but not in IR. Fasting plasma obestatin was correlated positively with M (r ϭ 0.34, P ϭ 0.04), HDL cholesterol (r ϭ 0.45, P ϭ 0.01), and plasma ghrelin concentrations (r ϭ 0.80, P Ͻ 0.000001) and negatively with measures of adiposity, plasma FFA during clamp (r ϭ Ϫ0.42, P Ͻ 0.01), and systolic blood pressure (r ϭ Ϫ0.33, P Ͻ 0.05). In conclusion, fasting plasma concentrations of obestatin, but not of ghrelin, are reduced in insulin resistance and are positively associated with whole body insulin sensitivity in nondiabetic humans. Furthermore, plasma obestatin is reduced by insulin in insulin-sensitive but not in insulinresistant persons.ghrelin; hyperinsulinemic clamp test; free fatty acids; appetite regulation OBESTATIN, A RECENTLY DISCOVERED 23-amino acid peptide hormone, is derived by posttranslational cleavage of the same peptide precursor (preproghrelin) as ghrelin, which is a 28-amino acid peptide released from the stomach (34, 38). Obestatin appears to have actions opposite to ghrelin in the regulation of food intake, emptying of the stomach, and body weight in rodents and could be part of a dual system connecting the gut and the brain to regulate energy homeostasis (38). However, other recent studies (25, 32, 36) did not provide evidence for a crucial role of obestatin in regulating food intake. Intracerebroventricular and intravenous administration of obestatin in rats did not affect food intake and could not antagonize the ghrelin-stimulated increase in food intake.The administration of ghrelin increased the food intake and body weight in rodents and humans (23,34, 35) and accelerated gastric emptying (10). In the presence of a negative energy balance, such as starvation, cachexia, or anorexia nervosa, the secretion of ghrelin increa...

Dietary proteins and amino acids are potent modulators of glucose metabolism and might also affect satiety and energy intake. However, due to the lack of well-controlled long-term studies the optimal macronutrient composition for treatment and prevention of obesity and type 2 diabetes is not known.