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1 VA San Diego Healthcare System, San Diego, California, USA; Department of Medicine, University of California, San Diego, La Jolla, California, USA
* To whom correspondence should be addressed. E-mail: rrhenry{at}vapop.ucsd.edu.
We examined the regulation of free fatty acid (FFA, palmitate) uptake into skeletal muscle cells of non-diabetic and type 2 diabetic subjects. Palmitate uptake included a protein-mediated component that was inhibited by phloretin. The protein-mediated component of uptake in muscle cells from type 2 diabetic subjects (78 ± 13 nmol/mg protein/min) was reduced compared to that in non-diabetic muscle (150 ± 17, p<0.01). Acute insulin exposure caused a modest (16 ± 5%, p<0.025) but significant increase in protein-mediated uptake in non-diabetic muscle. There was no significant insulin effect in diabetic muscle (+19 ± 19%, p=NS). Chronic (4d) treatment with a series of thiazolidinediones, troglitazone (Tgz), rosiglitazone (Rgz) and pioglitazone (Pio), increased FFA uptake. Only the phloretin-inhibitable component was increased by treatment, which normalized this activity in diabetic muscle cells. Under the same conditions FFA oxidation was also increased by thiazolidinedione treatment. Increases in FFA uptake and oxidation were associated with upregulation of fatty acid translocase (FAT/CD36) expression. FAT/CD36 protein was increased by Tgz (90 ± 22% over control), Rgz (146 ± 42%) and Pio (111 ± 37%, p<0.05 for all 3) treatment. Tgz treatment had no effect on fatty acid transporter protein (FATP-1) and membrane-associated plasmalemmal fatty acid-binding protein (FABPpm) mRNA expression. We conclude that FFA uptake into cultured muscle cells is, in part, protein-mediated and acutely insulin responsive. The basal activity of FFA uptake is impaired in type 2 diabetes. In addition, chronic thiazolidinedione treatment increased FFA uptake and oxidation into cultured human skeletal muscle cells in concert with upregulation of FAT/CD36 expression. Increased FFA uptake and oxidation may contribute to lower circulating FFA levels and reduced insulin resistance in skeletal muscle of individuals with type 2 diabetes following thiazolidinedione treatment.
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