D aLipoic Acid Stimulation of Glucose Uptake via Components of the Insulin Signaling Pathway

As previously mentioned, a-lipoic acid is a naturally occurring cofactor of oxidative metabolism, which is found as lipoamide covalently bound to a lysyl residue in five eukaryotic proteins, including mitochondrial dehydrogenase complexes (107). A natural antioxidant, lipoic acid has been used for the treatment of diabetic neuropathy (108) and ischemia-reperfusion injury (109) and has been indicated to improve glucose metabolism (110). In vitro and in vivo studies have demonstrated that exogenously supplied a-lipoic acid is taken up and reduced to DHLA by NADH- or NADPH-dependent enzymes in a variety of cells and tissues (111,112). Furthermore, a-lipoic acid has the ability to decrease the NADH/NAD+ ratios elevated as a result of sorbitol oxidation to fructose under hyperglycemic conditions by the consumption of NADH (113). Further antioxidant properties attributed to a-lipoic acid include its ability to directly scavenge ROS and to recycle thioredoxin, glutathione, vitamin E, and vitamin C (114). However, it is not known whether these potent antioxidant properties of a-lipoic acid contribute to its ability to improve glucose utilization.

a-Lipoic acid has been shown in vitro to stimulate glucose utilization in isolated rat diaphragms (115), to enhance insulin-stimulated glucose metabolism in insulin-resistant skeletal muscle of obese Zucker rats (116), and to stimulate glucose transport activity in skeletal muscle isolated from both lean and obese Zucker rats (117). In streptozotocin-diabetic rats, chronic a-lipoic acid treatment reduced blood glucose concentrations by enhancement of muscle GLUT4 content and increased muscle glucose utilization (118). In addition, acute and repeated parenteral administration of a-lipoic acid improved insulin-stimulated glucose disposal in individuals with type 2 diabetes (110,119), strengthening its therapeutic value as an antidiabetic agent. Estrada et al. (120) established the ability of a-lipoic acid to stimulate glucose uptake into the insulin-responsive L6 skeletal muscle cells and 3T3-L1 adipocytes in culture. The naturally occurring (R)+ isoform of lipoic acid was shown to have a significantly greater effect on the stimulation of glucose uptake in L6 cells in comparison with the (S)- isoform or the racemic mixture (120). In addition, (R)+ lipoic acid had a positive effect on both basal and insulin-stimulated glucose uptake but did not improve the sensitivity of glucose uptake to submaximal concentrations of insulin (120). It was suggested that this increase in glucose uptake could not be entirely attributed to the antioxidant abilities of this agent alone. The increase in glucose uptake was mediated by a rapid translocation of the GLUT1 and GLUT4 glucose transporter isoforms from the internal membrane fraction to the plasma membrane of L6 myotubes (120).

We have recently shown that a-lipoic acid similarly stimulates the translocation of GLUT1 and GLUT4 from the internal membrane fractions to the plasma membrane in 3T3-L1 adipocytes (K. Yaworsky, unpublished data). To account for the mechanism by which a-lipoic acid could stimulate this increase in glucose uptake via rapid glucose transporter translocation, an inhibitor of PI 3-kinase, wortmannin, was used. As stated earlier, PI 3-kinase activity is essential for the propagation of the insulin signal responsible for the mediation of insulin-stimulated glucose uptake as a result of the translocation of glucose transporters (121). Wortmannin significantly lowered the a-lipoic acid stimulated increase in glucose uptake in L6 myotubes, suggesting the involvement of PI 3-kinase in lipoic acid's mechanism of action (120). More recent evidence has shown that a-lipoic acid directly stimulates IRS-1 immunopre-cipitated PI 3-kinase activity in L6 myotubes, and this increase in PI 3-kinase activity is wortmannin sensitive (R. Somwar, K. Yaworsky, and A. Klip, unpublished data). These data suggest that a-lipoic acid engages components of the insulin signaling pathway in its ability to stimulate glucose uptake in L6 myotubes. This differs from other stimuli of glucose uptake such as the exercise and/or hypoxia pathway that do not use PI 3-kinase in their ability to stimulate glucose uptake, although they require glucose transporter translocation (122,133). The unique action of a-lipoic acid to increase glucose uptake

Insulin Receptor a-Lipoic Acid

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