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Objective: Forkhead box O (FoxO) transcription factors represent evolutionarily conserved targets of insulin signaling, regulating metabolism and cellular differentiation in response to changes in nutrient availability. Although the FoxO1 isoform is known to play a key role in adipogenesis, its physiological role in differentiated adipose tissue remains unclear.Research Design and Methods: In this study, we analyzed the phenotype of FoxO1 haploinsufficient mice to investigate the role of FoxO1 in high-fat diet-induced obesity and adipose tissue metabolism.Results: We showed that reduced FoxO1 expression protects mice against obesity-related insulin resistance with marked improvement not only in hepatic insulin sensitivity but also in skeletal muscle insulin action. FoxO1 haploinsufficiency also resulted in increased peroxisome proliferator-activated receptor (PPAR)gamma gene expression in adipose tissue, with enhanced expression of PPARgamma target genes known to influence metabolism. Moreover, treatment of mice with the PPARgamma agonist rosiglitazone caused a greater improvement in in vivo insulin sensitivity in FoxO1 haploinsufficient animals, including reductions in circulating proinflammatory cytokines.Conclusions: These findings indicate that FoxO1 proteins negatively regulate insulin action and that their effect may be explained, at least in part, by inhibition of PPARgamma function. [ABSTRACT FROM AUTHOR]

Objective: Many prevalent diseases of advanced societies, such as obesity-induced type 2 diabetes, are linked to indolent mononuclear cell-dependent inflammation. We previously proposed that blockade of alpha4 integrin signaling can inhibit inflammation while limiting mechanism-based toxicities of loss of alpha4 function. Thus, we hypothesized that mice bearing an alpha4(Y991A) mutation, which blocks signaling, would be protected from development of high-fat diet-induced insulin resistance.Research Design and Methods: Six- to eight-week-old wild-type and alpha4(Y991A) C57Bl/6 male mice were placed on either a high-fat diet that derived 60% calories from lipids or a chow diet. Metabolic testing was performed after 16-22 weeks of diet.Results: Alpha4(Y991A) mice were protected from development of high-fat diet-induced insulin resistance. This protection was conferred on wild-type mice by alpha4(Y991A) bone marrow transplantation. In the reverse experiment, wild-type bone marrow renders high-fat diet-fed alpha4(Y991A) acceptor animals insulin resistant. Furthermore, fat-fed alpha4(Y991A) mice showed a dramatic reduction of monocyte/macrophages in adipose tissue. This reduction was due to reduced monocyte/macrophage migration rather than reduced monocyte chemoattractant protein-1 production.Conclusions: Alpha4 integrins contribute to the development of HFD-induced insulin resistance by mediating the trafficking of monocytes into adipose tissue; hence, blockade of alpha4 integrin signaling can prevent the development of obesity-induced insulin resistance. [ABSTRACT FROM AUTHOR]

Troglitazone and metformin lower glucose levels in diabetic patients without increasing plasma insulin levels. We compared the insulin sparing actions of these two agents and their effects on insulin sensitivity and insulin secretion in 20 type 2 diabetic patients. To avoid the confounding effect of improved glycemic control on insulin action and secretion, patients were first rendered euglycemic with 4 weeks of continuous subcutaneous insulin infusion (CSII) before randomization to CSII plus troglitazone (n = 10) or CSII plus metformin (n = 10); euglycemia was maintained for another 6-7 weeks. Insulin sensitivity was assessed by a hyperinsulinemic-euglycemic clamp 1) at baseline, 2) after 4 weeks of CSII, and 3) after CSII plus either troglitazone or metformin. The 24-h glucose, insulin, and C-peptide profiles were performed on the day before the second and third glucose clamps. Good glycemic control was achieved with CSII alone and was maintained with CSII plus an oral agent (mean 24-h glucose: troglitazone, 6.2+/-0.6 mmol/l; metformin, 6.2 +/-0.3 mmol/l). Insulin requirements decreased 53% with troglitazone compared with CSII alone (48+/-4 vs. 102+/-13 U/day, P < 0.001), but only 31% with metformin (76+/-13 vs. 110+/-18 U/day, P < 0.005). The 24-h C-peptide profiles were similar. Normal fasting hepatic glucose output was maintained with both agents despite lower insulin levels than on CSII alone. Insulin sensitivity did not change significantly with CSII alone or with CSII plus metformin, but improved 29% with CSII plus troglitazone (P < 0.005 vs. CSII alone) and was then 45% higher than in the CSII plus metformin patients (P < 0.005). In conclusion, metformin has no effect on insulin-stimulated glucose disposal independent of glycemic control in type 2 diabetes. Troglitazone (600 mg/day) has greater insulin-sparing effects than metformin (1,700 mg/day) in CSII-treated euglycemic patients. This is probably explained by the peripheral tissue insulin-sensitizing effects of troglitazone. [ABSTRACT FROM AUTHOR]

Background: Troglitazone is a new insulin-sensitizing agent used to treat type 2 diabetes mellitus. The mechanism by which troglitazone exerts its effect on systemic glucose metabolism is unknown.Objective: To determine the effects of 6 months of troglitazone monotherapy on glucose metabolism in patients with type 2 diabetes mellitus.Design: Randomized, double-blind, placebo-controlled trial.Setting: Six general clinical research centers at university hospitals.Patients: 93 patients (mean age, 52 years) with type 2 diabetes mellitus (mean fasting plasma glucose level, 11.2 mmol/L) who were being treated with diet alone or who had discontinued oral antidiabetic medication therapy.Intervention: Patients were randomly assigned to one of five treatment groups (100, 200, 400, or 600 mg of troglitazone daily or placebo) and had metabolic assessment before and after 6 months of treatment.Measurements: Plasma glucose and insulin profiles during a meal tolerance test; basal hepatic glucose production and insulin-stimulated glucose disposal rate during a hyperinsulinemic-euglycemic clamp procedure.Results: Troglitazone at 400 and 600 mg/d decreased both fasting (P < 0.001) and postprandial (P = 0.016) plasma glucose levels by approximately 20%. All four troglitazone dosages also decreased fasting (P = 0.012) and postprandial (P < 0.001) triglyceride levels; 600 mg of the drug per day decreased fasting free fatty acid levels (P = 0.018). Plasma insulin levels decreased in the 200-, 400-, and 600-mg/d groups (P < 0.001), and C-peptide levels decreased in all five study groups (P < 0.001). Basal hepatic glucose production was suppressed in the 600-mg/d group compared with the placebo group (P = 0.02). Troglitazone at 400 and 600 mg/d increased glucose disposal rate by approximately 45% above pretreatment levels (P = 0.003). Stepwise regression analysis showed that troglitazone therapy was the strongest predictor of a decrease in fasting (P < 0.001) or postprandial (P = 0.01) glucose levels. Fasting C-peptide level was the next strongest predictor (higher C-peptide level equaled greater glucose-lowering effect).Conclusion: Troglitazone monotherapy decreased fasting and postprandial glucose levels in patients with type 2 diabetes, primarily by augmenting insulin-mediated glucose disposal. [ABSTRACT FROM AUTHOR]