At doses between 1 and 2 g/day, resveratrol improves insulin sensitivity and postmeal plasma glucose in subjects with IGT. These preliminary findings support the conduct of larger studies to further investigate the effects of resveratrol on metabolism and vascular function.

Whereas thiazolidinediones (TZDs) are known to rapidly improve insulin action in animals, short durations of TZD therapy have never been studied in humans. Among the many known actions of TZDs, increased circulating levels of the high molecular weight (HMW) multimer of adiponectin may be an important insulinsensitizing mechanism. We examined the effects of only 21 days of 45 mg of pioglitazone (P؉) versus placebo (P؊) in nine subjects with type 2 diabetes (HbA 1c , 10.9 ؎ 0.6%; BMI, 31.9 ؎ 1.5 kg/m 2 ). Total adiponectin levels increased by approximately twofold in P؉ in association with increased adipose tissue gene expression. However, plasma free fatty acid and glucose levels were unchanged, and there were only minimal changes in other "adipokines." Glucose fluxes ([3-3 H]glucose infusion) were measured during 6-h euglycemic (5 mmol/l) "pancreatic clamp" studies (somatostatin/glucagon/growth hormone) with stepped insulin levels. Pioglitazone induced marked decreases in endogenous glucose production (P؉ ‫؍‬ 0.9 ؎ 0.1 vs. P؊ ‫؍‬ 1.7 ؎ 0.3 mg ⅐ kg ؊1 ⅐ min ؊1 ; P < 0.05) at physiologic hyperinsulinemia (ϳ50 U/ml), which was highly correlated with an increased ratio of HMW adiponectin/total levels (r 2 ‫؍‬ 0.90). Maximal insulin stimulation (ϳ400 U/ml) revealed pioglitazone-associated increases in glucose uptake (P؉ ‫؍‬ 10.5 ؎ 0.9 vs. P؊ ‫؍‬ 8.9 ؎ 0.8 mg ⅐ kg ؊1 ⅐ min ؊1 ; P < 0.05), which did not correlate with HMW or total adiponectin levels. Thus, only 21 days of pioglitazone therapy improved insulin action in humans with type 2 diabetes. Increased abundance of the HMW adiponectin multimer may contribute to the hepatic insulin-sensitizing effects of these agents.

Recent studies have indicated that the mass/content of intramyocellular lipid (IMCL), intrahepatic triglyceride (IHTG), visceral fat (VF), and even deep abdominal subcutaneous fat (SF) may all be correlated with insulin resistance. Since simultaneous measurements of these parameters have not been reported, the relative strength of their associations with insulin action is not known. Therefore, the goals of this study were 1) to simultaneously measure IMCL, IHTG, VF, and abdominal SF in the same nondiabetic individuals using noninvasive (1)H-magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) and 2) to examine how these fat stores are correlated with systemic insulin sensitivity as measured by whole body glucose disposal (R(d)) during euglycemic-hyperinsulinemic clamp studies. Positive correlations were observed among IMCL, IHTG, and VF. There were significant inverse correlations between whole body R(d) and both IMCL and VF. Notably, there was a particularly tight inverse correlation between IHTG and whole body R(d) (r = -0.86, P < 0.001), consistent with an association between liver fat and peripheral insulin sensitivity. This novel finding suggests that hepatic triglyceride accumulation has important systemic consequences that may adversely affect insulin sensitivity in other tissues.

Increased endogenous glucose production (EGP) is a hallmark of type 2 diabetes mellitus. While there is evidence for central regulation of EGP by activation of hypothalamic ATP-sensitive potassium (K ATP ) channels in rodents, whether these central pathways contribute to regulation of EGP in humans remains to be determined. Here we present evidence for central nervous system regulation of EGP in humans that is consistent with complementary rodent studies. Oral administration of the K ATP channel activator diazoxide under fixed hormonal conditions substantially decreased EGP in nondiabetic humans and Sprague Dawley rats. In rats, comparable doses of oral diazoxide attained appreciable concentrations in the cerebrospinal fluid, and the effects of oral diazoxide were abolished by i.c.v. administration of the K ATP channel blocker glibenclamide. These results suggest that activation of hypothalamic K ATP channels may be an important regulator of EGP in humans and that this pathway could be a target for treatment of hyperglycemia in type 2 diabetes mellitus.

Increased circulating free fatty acids (FFAs) inhibit both hepatic and peripheral insulin action. Because the loss of effectiveness of glucose to suppress endogenous glucose production and stimulate glucose uptake contributes importantly to fasting hyperglycemia in type 2 diabetes, we examined whether the approximate twofold elevations in FFA characteristic of poorly controlled type 2 diabetes contribute to this defect. Glucose levels were raised from 5 to 10 mmol/l while maintaining fixed hormonal conditions by infusing somatostatin with basal insulin, glucagon, and growth hormone. Each individual was studied at two FFA levels: with (NA؉) and without (NA؊) infusion of nicotinic acid in nine individuals with poorly controlled type 2 diabetes (HbA 1c ‫؍‬ 10.1 ؎ 0.7%) and with (LIP؉) and without (LIP؊) infusion of lipid emulsion in nine nondiabetic individuals. Elevating FFA to ϳ500 mol/l blunted the ability of glucose to suppress endogenous glucose production (LIP؊ ‫؍‬ ؊48% vs. LIP؉ ‫؍‬ ؊28%; P < 0.01) and increased glucose uptake (LIP؊ ‫؍‬ 97% vs. LIP؉ ‫؍‬ 51%; P < 0.01) in nondiabetic individuals. Raising FFA also blunted the endogenous glucose production response in 10 individuals with type 2 diabetes in good control (HbA 1c ‫؍‬ 6.3 ؎ 0.3%). Conversely, normalizing FFA nearly restored the endogenous glucose production (NA؊ ‫؍‬ ؊7% vs. NA؉ ‫؍‬ ؊41%; P < 0.001) and glucose uptake (NA؊ ‫؍‬ 26% vs. NA؉ ‫؍‬ 64%; P < 0.001) responses to hyperglycemia in individuals with poorly controlled type 2 diabetes. Thus, increased FFA levels contribute substantially to the loss of glucose effectiveness in poorly controlled type 2 diabetes. Diabetes 52:2748 -2758, 2003 T ype 2 diabetes is a multifaceted disorder characterized by hyperglycemia with insulin resistance and impaired insulin secretion, resulting in decreased peripheral glucose uptake and increased endogenous glucose production (1,2). The progression toward worsening glycemic control in type 2 diabetes is accompanied by moderate elevations in plasma free fatty acid (FFA) levels (3,4). These chronically elevated FFA levels result from resistance to the effects of both insulin and glucose on adipose tissue lipolysis and triglyceride storage (5). Important consequences of increased circulating FFAs include hepatic and peripheral insulin resistance (6,7), hepatic steatosis (8), diminished hepatic insulin clearance (9,10), and impaired pancreatic ␤-cell function (11,12).Increased endogenous glucose production is believed to be the major cause of postabsorptive hyperglycemia in type 2 diabetes (1,2). Hepatic insulin resistance probably contributes to these inappropriate elevations in endogenous glucose production, given the known suppressive effects of insulin on endogenous glucose production (13,14). In addition, the effectiveness of glucose per se to inhibit endogenous glucose production seems to be markedly blunted in individuals with less optimally controlled type 2 diabetes (4,15,16). Indeed, there are prominent inhibitory effects of hyperglycemia, independent of othe...