Abstract
Increased accumulation of fatty acids and their derivatives can impair insulin-stimulated glucose disposal by skeletal muscle. To characterize the nature of the defects in lipid metabolism and to evaluate the effects of thiazolidinedione treatment, we analyzed the levels of triacylglycerol, long-chain fatty acyl-coA, malonyl-CoA, fatty acid oxidation, AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), malonyl-CoA decarboxylase, and fatty acid transport proteins in muscle biopsies from nondiabetic lean, obese, and type 2 subjects before and after an euglycemic-hyperinsulinemic clamp as well as pre-and post-3-month rosiglitazone treatment. We observed that low AMPK and high ACC activities resulted in elevation of malonyl-CoA levels and lower fatty acid oxidation rates. These conditions, along with the basal higher expression levels of fatty acid transporters, led accumulation of long-chain fatty acyl-coA and triacylglycerol in insulin-resistant muscle. During the insulin infusion, muscle fatty acid oxidation was reduced to a greater extent in the lean compared with the insulin-resistant subjects. In contrast, isolated muscle mitochondria from the type 2 subjects exhibited a greater rate of fatty acid oxidation compared with the lean group. All of these abnormalities in the type 2 diabetic group were reversed by rosiglitazone treatment. In conclusion, these studies have shown that elevated malonyl-CoA levels and decreased fatty acid oxidation are key abnormalities in insulin-resistant muscle, and, in type 2 diabetic patients, thiazolidinedione treatment can reverse these abnormalities.
Highlights
Increased accumulation of fatty acids and their derivatives can impair insulin-stimulated glucose disposal by skeletal muscle
We have examined intracellular fatty acid metabolism and mitochondrial oxidative capacity in skeletal muscle samples in normal subjects, obese nondiabetic subjects, and patients with type 2 diabetes
The major finding in this article is that there is a decrease in AMP kinase activity and an increase in acetyl-CoA carboxylase (ACC) activity in insulin-resistant muscle that results in elevated intracellular levels of malonyl-CoA
Summary
Increased accumulation of fatty acids and their derivatives can impair insulin-stimulated glucose disposal by skeletal muscle. Basal fatty acid levels of FAT/CD36 and FATP4 remained elevated, but the effect of insulin to induce translocation to the plasma membrane fraction was completely restored (Fig. 5C and D).
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