Thiazolidinediones upregulate impaired fatty acid uptake in skeletal muscle of type 2 diabetic subjects

Abstract

We examined the regulation of free fatty acid (FFA, palmitate) uptake into skeletal muscle cells of nondiabetic 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-1 · min-1) was reduced compared with that in nondiabetic 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 nondiabetic muscle. There was no significant insulin effect in diabetic muscle (+19 ± 19%, P = not significant). Chronic (4 day) 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-1 and membrane-associated plasmalemmal fatty acid-binding protein 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.

Heterogeneity in limb fatty acid kinetics in type 2 diabetes

“…Reduced fatty acid uptake has been observed in the forearm [8] and in the leg [7,27] of type 2 diabetic patients. A lower capacity for fatty acid uptake in the diabetic leg muscles is also in agreement with similar findings in human cultured vastus lateralis muscle cells [28]. However, subsequent data on human cultured myotubes from the vastus lateralis did not indicate substantial differences between myotubes from diabetic patients and matched controls [29].…”

“…Moreover, in rat skeletal muscle, in- sulin has been proved to translocate FAT/CD36 from the intracellular pool to the plasma membrane, causing increased fatty acid uptake. Interestingly, protein-mediated fatty acid transport in human cultured muscle cells from the vastus lateralis has been shown to be stimulated by insulin in non-diabetic but not in type 2 diabetic subjects [28]. In the light of the results of the present study, it would be of interest to investigate the possibility of a different effect of type 2 diabetes on protein-mediated fatty acid transport in arm and leg muscles under both basal and insulin-stimulated conditions.…”

“…The decrease of palmitate uptake with insulin has been reported previously for the leg [7,30] and the arm [31] of healthy subjects. Nevertheless, when fatty acid levels were maintained during the insulin infusion, the fatty acid uptake by skeletal muscle was actually increased in rat muscle preparations [32,33] and in cultured cells from the vastus lateralis muscle [28,29]. These observations imply that the reduction in limb fatty acid uptake with insulin is caused more by reduced limb fatty acid availability than by lessened skeletal muscle insulin sensitivity.…”

CD36: Implications in cardiovascular disease

“…Both up and down regulation of CD36 can have pathological sequellae, as these reports indicate. Thiazolidinediones, a major new class of drugs to treat diabetes, up regulate CD36 in monocytes/macrophages, adipose and muscle (Wilmsen, Ciaraldi, Carter, Reehman, Mudaliar, & Henry, 2003, Kolak, et al, 2006, Hirakata, Tozawa, Imura, & Sugiyama, 2004,Llaverias, et al, 2006, and may therefore contribute to the insulin-sensitizing effects of these drugs as a result of plasma fatty acid clearance, but also potentially to atherosclerosis and obesity in these patients. Interestingly, glucose/insulin appears to increase CD36 expression (Sampson, Davies, Braschi, Ivory, & Hughes, 2003,Griffin, et al, 2001,Chabowski, et al, 2004,Chen, Yang, Loux, Georgeson, & Harmon, 2006, and because CD36 is expressed on tissues important in fatty acid metabolism (heart, skeletal muscle, fat, and in pathological states, liver) this may imply an important role for CD36 in insulin resistance (see later).…”

“…Less is known about CD36 regulation in other tissues, although PPAR species are apparently important to regulation in adipocytes, smooth muscle cells and liver (Wilmsen, Ciaraldi, Carter, Reehman, Mudaliar, & Henry, 2003,Motojima, Passilly, Peters, Gonzalez, & Latruffe, 1998,Lim, et al, 2006. In adipose tissue, CD36 expression coincides with differentiation from pre-adipocyte to adipocyte, and capacity to take up fatty acids (Sfeir, Ibrahimi, Amri, Grimaldi, & Abumrad, 1997).…”