Inhibition of acetyl-CoA carboxylase 2 enhances skeletal muscle fatty acid oxidation and improves whole-body glucose homeostasis in db/db mice.

AIMS/HYPOTHESIS: Excessive ectopic lipid deposition contributes to impaired insulin action in peripheral tissues and is considered an important link between obesity and type 2 diabetes mellitus. Acetyl-CoA carboxylase 2 (ACC2) is a key regulatory enzyme controlling skeletal muscle mitochondrial fatty acid oxidation; inhibition of ACC2 results in enhanced oxidation of lipids. Several mouse models lacking functional ACC2 have been reported in the literature. However, the phenotypes of the different models are inconclusive with respect to glucose homeostasis and protection from diet-induced obesity. METHODS: Here, we studied the effects of pharmacological inhibition of ACC2 using as a selective inhibitor the S enantiomer of compound 9c ([S]-9c). Selectivity was confirmed in biochemical assays using purified human ACC1 and ACC2. RESULTS: (S)-9c significantly increased fatty acid oxidation in isolated extensor digitorum longus muscle from different mouse models (EC(50) 226 nmol/l). Accordingly, short-term treatment of mice with (S)-9c decreased malonyl-CoA levels in skeletal muscle and concomitantly reduced intramyocellular lipid levels. Treatment of db/db mice for 70 days with (S)-9c (10 and 30 mg/kg, by oral gavage) resulted in improved oral glucose tolerance (AUC -36%, p < 0.05), enhanced skeletal muscle 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) uptake, as well as lowered prandial glucose (-31%, p < 0.01) and HbA(1c) (-0.7%, p < 0.05). Body weight, liver triacylglycerol, plasma insulin and pancreatic insulin content were unaffected by the treatment. CONCLUSIONS/INTERPRETATION: In conclusion, the ACC2-selective inhibitor (S)-9c revealed glucose-lowering effects in a mouse model of diabetes mellitus.

Nitric oxide increases cyclic GMP levels, AMP-activated protein kinase (AMPK)alpha1-specific activity and glucose transport in human skeletal muscle.

AIMS/HYPOTHESIS: We investigated the direct effect of a nitric oxide donor (spermine NONOate) on glucose transport in isolated human skeletal muscle and L6 skeletal muscle cells. We hypothesised that pharmacological treatment of human skeletal muscle with N-(2-aminoethyl)-N-(2-hydroxy-2-nitrosohydrazino)-1,2-ethylenediamine (spermine NONOate) would increase intracellular cyclic GMP (cGMP) levels and promote glucose transport. METHODS: Skeletal muscle strips were prepared from vastus lateralis muscle biopsies obtained from seven healthy men. Muscle strips were incubated in the absence or presence of 5 mmol/l spermine NONOate or 120 nmol/l insulin. The L6 muscle cells were treated with spermine NONOate (20 micromol/l) and incubated in the absence or presence of insulin (120 nmol/l). The direct effect of spermine NONOate and insulin on glucose transport, cGMP levels and signal transduction was determined. RESULTS: In human skeletal muscle, spermine NONOate increased glucose transport 2.4-fold (p < 0.05), concomitant with increased cGMP levels (80-fold, p < 0.001). Phosphorylation of components of the canonical insulin signalling cascade was unaltered by spermine NONOate exposure, implicating an insulin-independent signalling mechanism. Consistent with this, spermine NONOate increased AMP-activated protein kinase (AMPK)-alpha1-associated activity (1.7-fold, p < 0.05). In L6 muscle cells, spermine NONOate increased glucose uptake (p < 0.01) and glycogen synthesis (p < 0.001), an effect that was in addition to that of insulin. Spermine NONOate also elicited a concomitant increase in AMPK and acetyl-CoA carboxylase phosphorylation. In the presence of the guanylate cyclase inhibitor LY-83583 (10 micromol/l), spermine NONOate had no effect on glycogen synthesis and AMPK-alpha1 phosphorylation. CONCLUSIONS/INTERPRETATION: Pharmacological treatment of skeletal muscle with spermine NONOate increases glucose transport via insulin-independent signalling pathways involving increased intracellular cGMP levels and AMPK-alpha1-associated activity.

Role of interleukin-6 signalling in glucose and lipid metabolism.

Derangements in whole body glucose and lipid metabolism, accompanied by insulin resistance, are key features of obesity and the metabolic syndrome. A role for inflammation as a causative factor is an emerging concept in the field of metabolic disease. Research has centred on identifying important inflammatory markers, and tumour necrosis factor-alpha has been highlighted as a key mediator of insulin resistance, as well as interleukin-6 (IL-6). A parallel ongoing endeavour is the unravelling of molecular mechanisms underlying the beneficial effects of physical exercise on whole body glucose and lipid metabolism. Release of IL-6 from the contracting skeletal muscle has been proposed to be one of the molecular signals promoting the beneficial exercise-induced effects. These two opposing views of IL-6 underscore that the role of IL-6 in whole body physiology is incompletely resolved. This review aims at summarizing the current data on mechanisms by which IL-6 may impact on glucose and lipid metabolism.

Exercise training increases insulin-stimulated glucose disposal and GLUT4 (SLC2A4) protein content in patients with type 2 diabetes.

AIMS/HYPOTHESIS: Exercise enhances insulin-stimulated glucose transport in skeletal muscle through changes in signal transduction and gene expression. The aim of this study was to assess the impact of acute and short-term exercise training on whole-body insulin-mediated glucose disposal and signal transduction along the canonical insulin signalling cascade. METHODS: A euglycaemic-hyperinsulinaemic clamp, with vastus lateralis skeletal muscle biopsies, was performed at baseline and 16 h after an acute bout of exercise and short-term exercise training (7 days) in obese non-diabetic (n=7) and obese type 2 diabetic (n=8) subjects. RESULTS: Insulin-mediated glucose disposal was unchanged following acute exercise in both groups. Short-term exercise training increased insulin-mediated glucose disposal in obese type 2 diabetic (p<0.05), but not in obese non-diabetic subjects. Insulin activation of (1) IRS1, (2) IRS2, (3) phosphotyrosine-associated phosphatidylinositol-3 kinase activity and (4) the substrate of phosphorylated Akt, AS160, a functional Rab GTPase activating protein important for GLUT4 (now known as solute carrier family 2 [facilitated glucose transporter], member 4 [SLC2A4]) translocation, was unchanged after acute or chronic exercise in either group. GLUT4 protein content was increased in obese type 2 diabetic subjects (p<0.05), but not in obese non-diabetic subjects following chronic exercise. CONCLUSIONS/INTERPRETATION: Exercise training increased whole-body insulin-mediated glucose disposal in obese type 2 diabetic patients. These changes were independent of functional alterations in the insulin-signalling cascade and related to increased GLUT4 protein content.

Modulation of susceptibility to weight gain and insulin resistance in low birthweight rats by treatment of their mothers with leptin during pregnancy and lactation.

OBJECTIVES: To investigate whether administration of leptin to rats during pregnancy and lactation affects placental 11beta-hydroxysteroid dehydrogenase (11beta-HSD2) activity and the susceptibility of their offspring to weight gain and insulin resistance. DESIGN: Pregnant rats fed on a low-protein diet were administered leptin or saline by subcutaneous minipump from day 14 of gestation and throughout lactation. A further group was fed a normal diet and given saline. After weaning, the offspring of each group were fed on a normal diet until 6 weeks of age and then half of each group was transferred to a high-fat diet until 12 months of age. RESULTS: Plasma leptin levels were raised two-fold on days 16-18 of pregnancy in the leptin-treated dams, but, despite a constant rate of infusion, at parturition they dipped to control levels before rising again. The activity of placental 11beta-HSD2 was reduced by the low-protein diet; this reduction was prevented by treating the dams with leptin. The male offspring of the saline-treated dams gained more weight and had higher plasma leptin levels on the high fat than the chow diet, but the offspring of the leptin-treated dams did not. Fasting blood glucose and intraperitoneal glucose tolerance at 6 and 12 months of age was unaffected by the high-fat diet, but only the offspring of the leptin-treated dams achieved this control without raised insulin levels. CONCLUSIONS: The rate of leptin clearance appears to increase at parturition. The administration of leptin to rats during late pregnancy and lactation makes their male offspring less susceptible to high-fat-diet-induced weight gain and insulin resistance.