Both rosiglitazone and metformin increase hepatic insulin sensitivity, but their mechanism of action has not been compared in humans. The objective of this study was to compare the effects of rosiglitazone and metformin treatment on liver fat content, hepatic insulin sensitivity, insulin clearance, and gene expression in adipose tissue and serum adiponectin concentrations in type 2 diabetes. A total of 20 drug-naive patients with type 2 diabetes (age 48 ؎ 3 years, fasting plasma glucose 152 ؎ 9 mg/dl, BMI 30.6 ؎ 0.8 kg/m 2 ) were treated in a double-blind randomized fashion with either 8 mg rosiglitazone or 2 g metformin for 16 weeks. Both drugs similarly decreased HbA 1c , insulin, and free fatty acid concentrations. Body weight decreased in the metformin (84 ؎ 4 vs. 82 ؎ 4 kg, P < 0.05) but not the rosiglitazone group. Liver fat (proton spectroscopy) was decreased with rosiglitazone by 51% (15 ؎ 3 vs. 7 ؎ 1%, 0 vs. 16 weeks, P ‫؍‬ 0.003) but not by metformin (13 ؎ 3 to 14 ؎ 3%, NS). Rosiglitazone (16 ؎ 2 vs. 20 ؎ 1 ml ⅐ kg ؊1 ⅐ min ؊1, P ‫؍‬ 0.02) but not metformin increased insulin clearance by 20%. Hepatic insulin sensitivity in the basal state increased similarly in both groups. Insulin-stimulated glucose uptake increased significantly with rosiglitazone but not with metformin. Serum adiponectin concentrations increased by 123% with rosiglitazone but remained unchanged during metformin treatment. The decrease of serum adiponectin concentrations correlated with the decrease in liver fat (r ‫؍‬ ؊0.74, P < 0.001). Rosiglitazone but not metformin significantly increased expression of peroxisome proliferator-activated receptor-␥, adiponectin, and lipoprotein lipase in adipose tissue. In conclusion, rosiglitazone but not metformin decreases liver fat and increases insulin clearance. The decrease in liver fat by rosiglitazone is associated with an increase in serum adiponectin concentrations. Both agents increase hepatic insulin sensitivity, but only rosiglitazone increases peripheral glucose uptake.

To examine whether and how intramyocellular lipid (IMCL) content contributes to interindividual variation in insulin action, we studied 20 healthy men with no family history of type 2 diabetes. IMCL was measured as the resonance of intramyocellular CH 2 protons in lipids/ resonance of CH 3 protons of total creatine (IMCL/Cr T ), using proton magnetic resonance spectroscopy in vastus lateralis muscle. Whole-body insulin sensitivity was measured using a 120-min euglycemic-hyperinsulinemic (insulin infusion rate 40 mU/m 2 ⅐ min) clamp. Muscle biopsies of the vastus lateralis muscle were taken before and 30 min after initiation of the insulin infusion to assess insulin signaling. The subjects were divided into groups with high IMCL (HiIMCL; 9.5 ؎ 0.9 IMCL/Cr T , n ‫؍‬ 10) and low IMCL (LoIMCL; 3.0 ؎ 0.5 IMCL/Cr T , n ‫؍‬ 10), the cut point being median IMCL (6.1 IMCL/Cr T ). The groups were comparable with respect to age (43 ؎ 3 vs. 40 ؎ 3 years, NS, HiIMCL versus LoIMCL), BMI (26 ؎ 1 vs. 26 ؎ 1 kg/m 2 , NS), and maximal oxygen consumption (33 ؎ 2 vs. 36 ؎ 3 ml ⅐ kg ؊1 ⅐ min ؊1 , NS). Whole-body insulin-stimulated glucose uptake was lower in the HiIMCL group (3.0 ؎ 0.4 mg ⅐ kg ؊1 ⅐ min ؊1 ) than the LoIMCL group (5.1 ؎ 0.5 mg ⅐ kg ؊1 ⅐ min ؊1 , P < 0.05). Serum free fatty acid concentrations were comparable basally, but during hyperinsulinemia, they were 35% higher in the HiIMCL group than the LoIMCL group (P < 0.01). Study of insulin signaling indicated that insulin-induced tyrosine phosphorylation of the insulin receptor (IR) was blunted in HiIMCL compared with LoIMCL (57 vs. 142% above basal, P < 0.05), while protein expression of the IR was unaltered. IR substrate-1-associated phosphatidylinositol (PI) 3-kinase activation by insulin was also lower in the HiIMCL group than in the LoIMCL group (49 ؎ 23 vs. 84 ؎ 27% above basal, A bnormal lipid metabolism is a feature of the insulin resistance syndrome (1). In addition to an increase in the total amount of fat, the lipid disturbances include elevated circulating concentrations of triglycerides and free fatty acids (FFAs) (2) and an increase in visceral fat (3). Recently, several studies have shown an association between lipid accumulation in skeletal muscle and insulin resistance (4 -10). In four of these studies, this relation was shown to be caused by intramyocellular rather than extramyocellular lipids, as measured by proton spectroscopy (5-7,11).The causes for intramyocellular lipid (IMCL) accumulation are poorly understood. The first possibility is that IMCL is an innocent bystander and simply reflects overall adiposity. This is not supported by recent experiments in mice lacking subcutaneous fat, the A-ZIP/F-1 mice (12,13). These mice deposit fat intramyocellularly and exhibit severe insulin resistance, which is reversible by fat transplantation and rechanneling of IMCL back to subcutaneous depots. In humans, however, it is less clear whether IMCL is associated with insulin resistance independent of obesity. In 20 Europeans, Forouhi et al. (6) found the rela...

Multiple alterations characterize gene expression in the subcutaneous adipose tissue of patients with HAART-associated lipodystrophy compared with HIV-positive, HAART-treated patients without lipodystrophy. The low expression of transcription factors inhibits adipocyte differentiation. The low expression of PGC-1 may contribute to mitochondrial defects. In addition, IL-6 and CD45 expressions are increased, the latter implying an excessive number of cells of leukocyte origin in lipodystrophic adipose tissue. Mitochondrial injury and an excess of proinflammatory cytokines may lead to increased apoptosis. All these changes may contribute to the loss of subcutaneous fat in HAART-associated lipodystrophy.

Highly active antiretroviral therapy (HAART) has dramatically reduced HIV-related mortality, but is associated with severe metabolic adverse events, such as lipodystrophy and insulin resistance, the mechanisms of which are unknown. Adiponectin is a adipocytokine that is decreased in insulin resistant conditions. In mice, adiponectin decreases liver and muscle fat content and enhances insulin sensitivity. We determined serum adiponenctin and adiponectin mRNA concentrations in subcutaneous adipose tissue in HIV-positive HAART-treated patients with (HAART+LD+, n = 30) and without lipodystrophy (HAART+LD-, n = 13). The HAART+ LD+ group had significantly less subcutaneous and more intra-abdominal fat than the HAART+LD- group. Liver fat content (spectroscopy), serum insulin, C-peptide and triglyceride concentrations were significantly higher, and HDL cholesterol concentration lower in the HAART+LD+ than the HAART+LD- group. Serum adiponectin (3.4 +/- 0.4 vs 8.5 +/- 1.0 micro g/mL, p < 0.001) and adiponectin mRNA concentration in subcutaneous adipose tissue (7 +/- 1 x 10(-4) vs 24 +/- 6 x 10(-4), p < 0.001) were significantly lower in the HAART+LD+ than the HAART+LD- group. Both serum adiponectin and mRNA concentrations correlated closely with features of insulin resistance, including liver fat content. These data suggest that the decreased production of adiponectin in lipoatrophic adipose tissue may contribute to hepatic insulin resistance in these patients.

Several studies have demonstrated an association in humans between plasma levels or production capacity of the antiinflammatory cytokine IL-10 and insulin sensitivity. The aim of our study was to investigate the protective role of endogenous IL-10 availability in the development of diet-induced insulin resistance. We compared parameters of glucose and lipid metabolism between IL-10(-/-) mice and wild-type (wt) mice fed a high-fat diet for 6 wk. This diet has previously been shown to induce steatosis and insulin resistance. After 6 wk on the high-fat diet, no differences in body weight, basal metabolism (measured by indirect calorimetry), or plasma levels of glucose, triglycerides, or cholesterol were observed between IL-10(-/-) and wt mice. Nonetheless, in IL-10(-/-) mice, plasma free fatty acid levels were 75% increased compared with wt mice after overnight fasting (P < 0.05). In addition, hepatic triglyceride content was 54% increased in IL-10(-/-) mice (P < 0.05). During a hyperinsulinemic euglycemic clamp, no differences were observed in whole-body or hepatic insulin sensitivity between both groups. We conclude that basal IL-10 production protects against hepatic steatosis but does not improve hepatic or whole-body insulin sensitivity, during high-fat feeding.

Acquired obesity independent of genetic influences is able to increase expression of macrophage and inflammatory markers and decrease adiponectin expression in adipose tissue.

Aims/hypothesis: We determined the response of selected genes to in vivo insulin in adipose tissue in 21 non-diabetic women. Materials and methods: The women were divided into insulin-sensitive and -resistant groups based on their median whole-body insulin sensitivity (8.7±0.4 vs 4.2±0.3 mg kg −1 min −1 for insulin-sensitive vs -resistant group). Subcutaneous adipose tissue biopsies were obtained before and after 3 and 6 h of i.v. maintained euglycaemic hyperinsulinaemia. Adipose tissue mRNA concentrations of facilitated glucose transporter, member 1 (SLC2A1, previously known as GLUT1), facilitated glucose transporter, member 4 (SLC2A4, previously known as GLUT4), peroxisome proliferator-activated receptor γ (PPARG), peroxisome proliferator-activated receptor γ co-activator 1α (PPARGC1A), 11β-hydroxysteroid dehydrogenase-1 (HSD11B1), TNF, adiponectin (ADIPOQ), IL6 and the macrophage marker CD68 were measured using real-time PCR. Results: Basal expression of 'insulin-sensitivity genes' SLC2A4 and ADIPOQ was lower while that of 'insulin-resistance genes', HSD11B1 and IL6 was significantly higher in the insulin-resistant than in the insulinsensitive group. Insulin significantly increased expression of 'insulin-sensitivity genes' SLC2A4, PPARG, PPARGC1Aand ADIPOQ in the insulin-sensitive group, while only expression of PPARG and PPARGC1A was increased in the insulin-resistant group. The expression of 'insulin-resistance genes' HSD11B1 and IL6 was increased by insulin in the insulin-resistant group, but insulin failed to increase HSD11B1 expression in the insulin-sensitive group. At 6 h, expression of HSD11B1, TNF and IL6 was significantly higher in the insulin-resistant than in the insulin-sensitive group. IL6 expression increased significantly more in response to insulin in the insulin-resistant than in the insulin-sensitive group. CD68 was overexpressed in the insulin-resistant as compared with the insulin-sensitive group at both 0 and 6 h. Conclusions/interpretation: These data suggest that genes adversely affecting insulin sensitivity hyperrespond to insulin, while genes enhancing insulin sensitivity hyporespond to insulin in insulin-resistant human adipose tissue in vivo.

Objective-Patients with highly active antiretroviral therapy-associated lipodystrophy (HAARTϩLDϩ) have high plasminogen activator inhibitor-1 (PAI-1) concentrations for unknown reasons. We determined whether (1) plasma PAI-1 antigen concentrations are related to liver fat content (LFAT) independently of the size of other fat depots and (2) rosiglitazone decreases PAI-1 and LFAT in these patients. Methods and Results-In the cross-sectional study, 3 groups were investigated: 30 HIV-positive patients with HAARTϩLDϩ, 13 HIV-positive patients without lipodystrophy (HAARTϩLDϪ), and 15 HIV-negative subjects (HIVϪ). In the treatment study, the HAARTϩLDϩ group received either rosiglitazone (8 mg, nϭ15) or placebo (nϭ15) for 24 weeks. Plasma PAI-1 was increased in HAARTϩLDϩ (28Ϯ2 ng/mL) compared with the HAARTϩLDϪ (18Ϯ3, PϽ0.02) and HIVϪ (10Ϯ3, PϽ0.001) groups. LFAT was higher in HAARTϩLDϩ (7.6Ϯ1.7%) than in the HAARTϩLDϪ (2.1Ϯ1.1%, PϽ0.001) and HIVϪ (3.6Ϯ1.2%, PϽ0.05) groups. Within the HAARTϩLDϩ group, plasma PAI-1 was correlated with LFAT (rϭ0.49, PϽ0.01) but not with subcutaneous or intra-abdominal fat or serum insulin or triglycerides. In subcutaneous adipose tissue, PAI-1 mRNA was 2-to 3-fold higher in the HAARTϩLDϩ group than in either the HAARTϩLDϪ or HIVϪ group. Rosiglitazone decreased LFAT, serum insulin, and plasma PAI-1 and increased serum triglycerides but had no effect on intra-abdominal or subcutaneous fat mass or PAI-1 mRNA. Conclusions-Plasma PAI-1 concentrations are increased in direct proportion to LFAT in HAARTϩLDϩ patients.Rosiglitazone decreases LFAT, serum insulin, and plasma PAI-1 without changing the size of other fat depots or PAI-1 mRNA in subcutaneous fat. These data suggest that liver fat contributes to plasma PAI-1 concentrations in these patients.