Metformin and exercise reduce muscle FAT/CD36 and lipid accumulation and blunt the progression of high-fat diet-induced hyperglycemia

Mar 22, 2007American journal of physiology. Endocrinology and metabolism

Metformin and exercise lower muscle fat intake and buildup and slow the development of high-fat diet-related high blood sugar

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Abstract

Hyperglycemia in HF-fed ZDF rats reached a mean of 24.4 +/- 2.1 mM.

Decreased fatty acid oxidation and increased lipid accumulation, including ceramides and diacylglycerol, are associated with insulin resistance in obesity.
All interventions (metformin, exercise, or both) significantly reduced hyperglycemia and the content of ceramide and diacylglycerol in ZDF rats.
Improvements in insulin-stimulated glucose transport and GLUT4 expression occurred only with exercise training.
Therapeutic interventions did not alter reduced fatty acid oxidation and increased triacylglycerol synthesis compared to lean rats.
Exercise training led to modest increases in specific metabolic enzyme activities, indicating some improvement in muscle metabolism.

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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 +/- 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-1alpha, 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.

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Metformin and exercise reduce muscle FAT/CD36 and lipid accumulation and blunt the progression of high-fat diet-induced hyperglycemia

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