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agonists
Veterans Affairs San Diego Healthcare System, San Diego, and Department of Medicine, University of California, San Diego, La Jolla, California
Submitted 25 March 2004 ; accepted in final form 14 February 2005
The impact of type 2 diabetes on the ability of muscle to accumulate and dispose of fatty acids and triglycerides was evaluated in cultured muscle cells from nondiabetic (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 days) with the peroxisome proliferator-activated receptor-
(PPAR) agonist troglitazone 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 troglitazone treatment. 
-Oxidation of both long-chain (palmitate) and medium-chain (octanoate) fatty acids in T2D muscle cells was reduced by 
40% compared with 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. Troglitazone 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 -oxidation. These defects can be corrected by treatment with PPAR agonists. Augmentation of fatty acid disposal in skeletal muscle, potentially reducing intramyocellular triglyceride content, may represent one mechanism for the lipid-lowering and insulin-sensitizing effects of thiazolidinediones.
type 2 diabetes mellitus; fatty acid oxidation; thiazolidinediones; mitochondria
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