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Derangements in skeletal muscle fatty acid (FA) metabolism associated with insulin resistance in obesity appear to involve decreased FA oxidation and increased accumulation of lipids such as ceramides and diacylglycerol (DAG). We investigated potential lipid-related mechanisms of metformin (Met) and/or exercise for blunting the progression of hyperglycemia/ hyperinsulinemia and skeletal muscle insulin resistance in female Zucker diabetic fatty rats (ZDF), a high-fat (HF) diet-induced model of diabetes. Lean and ZDF rats consumed control or HF diet (48 kcal %fat) alone or with Met (500 mg/kg), with treadmill exercise, or with both exercise and Met interventions for 8 wk. HF-fed ZDF rats developed hyperglycemia (mean: 24.4 [+ or -] 2.1 mM), impairments in muscle insulin-stimulated glucose transport, increases in the FA transporter FAT/CD36, and increases in total ceramide and DAG content. The development of hyperglycemia was significantly attenuated with all interventions, as was skeletal muscle FAT/CD36 abundance and ceramide and DAG content. Interestingly, improvements in insulin-stimulated glucose transport and increased GLUT4 transporter expression in isolated muscle were seen only in conditions that included exercise training. Reduced FA oxidation and increased triacylglycerol synthesis in isolated muscle were observed with all ZDF rats compared with lean rats (P < 0.01) and were unaltered by therapeutic intervention. However, exercise did induce modest increases in peroxisome proliferator-activated receptor-[gamma] coactivator-1[alpha], citrate synthase, and [beta]-hydroxyacyl-CoA dehydrogenase activity. Thus reduction of skeletal muscle FAT/CD36 and content of ceramide and DAG may be important mechanisms by which exercise training blunts the progression of diet-induced insulin resistance in skeletal muscle. Zucker diabetic fatty rat; lipid metabolism; glucose transport; diacylglycerol; ceramide; adenosine 5'-monophosphate-activated protein kinase doi:10.1152/ajpendo.00677.2006

High-fat (HF) diets induce insulin resistance and alter lipid metabolism, although controversy exists regarding the impact of saturated vs. polyunsaturated fats. Adiponectin (Ad) stimulates fatty acid (FA) oxidation and improves insulin sensitivity in humans and rodents, due in part to the activation of AMP-activated protein kinase (AMPK) and subsequent deactivation of acetyl coenzyme A carboxylase (ACC). In genetically obese, diabetic mice, this acute stimulatory effect on AMPK in muscle is lost. The ability of a HF diet to induce skeletal muscle Ad resistance has not been examined. The purpose of this study was to determine whether Ad's effects on FA oxidation and AMPK/ACC would be reduced following different HF diets, and if this coincided with the development of impaired maximal insulin-stimulated glucose transport. Rats were fed a control (10% kcal fat, CON), high unsaturated fat (60% kcal safflower oil, SAFF), or high saturated fat diet (60% kcal lard, LARD) for 4 wk. Following the dietary intervention, glucose transport, lipid metabolism, and AMPK/ACC phosphorylation were measured in the presence and absence of globular Ad (gAd, 2.5 [micro]g/ml) in isolated soleus muscle. LARD rats showed reduced rates of maximal insulin-stimulated glucose transport compared with CON and SAFF (+68 vs. +172 and +184%, P [less than or equal to] 0.001). gAd increased pACC (+25%, P [less than or equal to] 0.01) and FA oxidation (+28%, P [less than or equal to] 0.05) in CON rats, but not in either HF group. Thus 4 wk of HF feeding results in the loss of gAd stimulatory effect on ACC phosphorylation and muscle FA oxidation, and this can occur independently of impaired maximal insulin-stimulated glucose transport. fatty acid metabolism; glucose transport; adenosine 5'-monophosphate-activated protein kinase; acetyl coenzyme A carboxylase doi:10.1152/ajpendo.00545.2006

The present study examined the acute effects of metformin on fatty acid (FA) metabolism in oxidative soleus (SOL) and glycolytic epitrochlearis (EPT) rodent muscle. SOL and EPT were incubated for either 30 or 180 min in the absence or presence of 2 mM metformin and with or without insulin (10 mU/ml). Metformin did not alter basal FA metabolism but countered the effects of insulin on FA oxidation and incorporation into triacylglyerol (TAG). Specifically, metformin prevented the insulin-induced suppression of FA oxidation in SOL but did not alter FA incorporation into lipid pools. In contrast, in EPT metformin blunted the incorporation of FA into TAG when insulin was present but did not alter FA oxidation. In SOL, metformin resulted in a 50% increase in AMP-activated protein kinase [alpha]2 activity and prevented the insulin-induced increase in malonyl-CoA content. In both fiber types, basal and insulin-stimulated glucose oxidation were not significantly altered by metformin. All effects were similar regardless of whether they were measured after 30 or 180 min. Because increased muscle lipid storage and impaired FA oxidation have been associated with insulin resistance in this tissue, the ability of metformin to reverse these abnormalities in muscle FA metabolism may be a part of the mechanism by which metformin improves glucose clearance and insulin sensitivity. The present data also suggest that increased glucose clearance is not due to its enhanced subsequent oxidation. Additional studies are warranted to determine whether chronic metformin treatment has similar effects on muscle FA metabolism. obesity; diabetes; lipid; adenosine 5'-monophosphate-activated protein kinase

Leptin acutely stimulates skeletal muscle fatty acid (FA) metabolism in lean rodents and humans. This stimulatory effect is eliminated following the feeding of high-fat diets in rodents as well as in obese humans. The mechanism(s) responsible for the development of skeletal muscle leptin resistance is unknown; however, a role for increased suppressor of cytokine signaling-3 (SOCS3) inhibition of the leptin receptor has been demonstrated in other rodent tissues. Furthermore, whether exercise intervention is an effective strategy to prevent or attenuate the development of skeletal muscle leptin resistance has not been investigated. Toward this end, 48 Sprague-Dawley rats (175-190 g; ~2-3 mo of age) were fed control or high-fat (60% kcal) diets for 4 wk and either remained sedentary or were treadmill trained. In control diet-fed animals that remained sedentary (CS) or were endurance trained (CT), leptin stimulated FA oxidation (CS +32 [+ or -] 15%, CT +30 [+ or -] 17%; P < 0.05), suppressed triacylglycerol (TAG) esterification (CS - 17 [+ or -] 7%, CT -24 [+ or -] 8%; P < 0.05), and reduced the esterification-to-oxidation ratio (CS - 19 [+ or -] 13%, CT - 29 [+ or -] 10%; P < 0.001) in soleus muscle. High-fat feeding induced leptin resistance in the soleus of sedentary rats (FS), whereas endurance exercise training (FT) restored the ability of leptin to suppress TAG esterification (-19 [+ or -] 9%, P = 0.038). Training did not completely restore the ability of leptin to stimulate FA oxidation. High-fat diets stimulated SOCS3 mRNA expression irrespective of training status (FS +451 [+ or -] 120%, P = 0.024; FT +381 [+ or -] 141%, P = 0.023). Thus the development of skeletal muscle leptin resistance appears to involve an increase in SOCS3 mRNA expression. Endurance training was generally effective in preventing the development of leptin resistance, although this did not appear to require a decrease in SOCS3 expression. Future studies should examine changes in the actual protein content of SOCS3 in muscle and establish whether aerobic exercise is also effective in treating leptin resistance in humans. suppressor of cytokine signaling-3; tracer; triacylglycerol; glycogen; treadmill running

Two complementary pharmacological approaches that enhance incretin action for the treatment of Type 2 diabetes mellitus have recently been developed, ie injectable GLP-1R agonists with prolonged plasma half-life and orally available inhibitors of dipeptidyl peptidase (DPP)-4, the main enzyme responsible for the rapid degradation and inactivation of circulating GLP-1 and GIP. The mechanism of action of these two pharmacotherapies, however, differs and is not yet fully understood. Here we investigated whether acute exendin-4 or DPP-4 inhibition differentially affect insulin sensitivity in vivo in chow-fed, C57BL/6 mice using a (4mU/kg/min insulin infusion) euglycemic, hyperinsulinemic clamp technique with somatostatin infusion to suppress endogenous insulin secretion. To this aim, the effect of a single iv bolus of DPP-4 inhibitor (11 mpk des-F-sitagliptin, Merck, N J, USA) was administered to n=6 chow-fed, C57BL/6 mice 15 minutes after the start of the clamp and the effect was compared to a 50 ng iv bolus of exendin-4 (Ex-4, n=6) or the same volume of saline (SAL, n=5). Despite matched plasma glucose and insulin concentrations, within 15 minutes the glucose infusion rate (GINF) required to maintain euglycemia was significantly greater after des-F-sitagliptin compared to saline and Ex-4 (mean GINF between 90 and 120 mins after start of clamp in SAL: 42.0 ± 2.7 mg/kg/min, Ex-4:46.5 ± 2.9, des-F-sitagliptin: 60.5 ± 3.3, p< 0.001 for des-F-sitagliptin vs SAL and Ex-4, p=ns for Ex-4 vs SAL). This profound difference in insulin sensitivity was entirely due to enhancement of insulin-mediated suppression of endogenous (which is mainly hepatic) glucose production (EGP) by des-F-sitagliptin, with no difference in glucose disposal rate (% suppression of EGP in SAL: 38±15%, Ex-4: 19±14%, des-F-sitagiiptin: 121±13%, p< 0.001 for des-F-sitagliptin vs SAL and Ex-4, p=ns for Ex-4 vs SAL). In conclusion, this is the first demonstration that acute DPP-4 inhibition but not GLP-1R agonist administration induces profound insulin sensitization by rapidly enhancing insulin-mediated suppression of endogenous glucose production. These findings highlight emerging differences between the mechanism of action of these two new therapeutic modalities for the treatment of Type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]