Impaired fatty acid metabolism in type 2 diabetic skeletal muscle cells is reversed by PPARgamma agonists.
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 microM 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-gamma (PPARgamma) 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. beta-Oxidation of both long-chain (palmitate) and medium-chain (octanoate) fatty acids in T2D muscle cells was reduced by approximately 40% compared with ND cells. Palmitate oxidation occurred primarily in mitochondrial ( approximately 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 beta-oxidation. These defects can be corrected by treatment with PPARgamma 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.
Cha
Bong-Soo
BS
Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA.
Ciaraldi
Theodore P
TP
Park
Kyong-Soo
KS
Carter
Leslie
L
Mudaliar
Sunder R
SR
Henry
Robert R
RR
D000328:Adult; D002210:Caprylates / Q000378:metabolism*; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D008875:Middle Aged; D032448:Myoblasts, Skeletal / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism*; D010168:Palmitates / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone
D002210:Caprylates; D002839:Chromans; D005227:Fatty Acids; D047495:PPAR gamma; D010168:Palmitates; D045162:Thiazolidinediones; D000077288:Troglitazone; C031492:octanoic acid