Impaired Fatty Acid Metabolism in Type 2 Diabetic Skeletal Muscle Cells is Reversed by PPARγ Agonists

The impact of type 2 diabetes (T2D) on the ability of muscle to accumulate and dispose of fatty acids and triglycerides (TG) was evaluated in cultured muscle cells from non-diabetic (ND) and Type 2 diabetic (T2D) subjects. In the presence of 5 µM palmitate T2D muscle cells accumulated less lipid than ND cells (11.5±1.2 vs 15.1±1.4 nmol/mg protein, p<0.05). Chronic treatment (4 d) with a PPAR agonist (troglitazone, TGZ) increased palmitate accumulation, normalizing uptake in T2D cells. There were no significant differences between groups with regard to the relative incorporation of palmitate into neutral lipid species. This distribution was also unaffected by TGZ treatment. ß-oxidation of both long-chain (palmitate) and medium chain (octanoate) fatty acids in T2D muscle cells was reduced by ~40% compared to ND cells. Palmitate oxidation occurred primarily in mitochondrial (~40-50% of total) and peroxisomal (20-30%) compartments. The diabetes-related defect in palmitate oxidation was localized to the mitochondrial component. Both palmitate and octanoate oxidation were stimulated by a series of thiazolidinediones. Oxidation in T2D muscle cells was normalized after treatment. TGZ increased the mitochondrial component of palmitate oxidation. Skeletal muscle cells from T2D subjects express defects in free fatty acid metabolism that are retained in vitro, most importantly defects in ß-oxidation. These defects can be corrected by treatment with PPAR agonists. Augmentation of fatty acid disposal in skeletal muscle, potentially reducing intramyocellular TG content, may represent one mechanism for the lipid lowering and insulin sensitizing effects of