The Antihyperglycemic Drug α-Lipoic Acid Stimulates Glucose Uptake via Both GLUT4 Translocation and GLUT4 Activation

Abstract

The cofactor of mitochondrial dehydrogenase complexes and potent antioxidant ␣-lipoic acid has been shown to lower blood glucose in diabetic animals. ␣-Lipoic acid enhances glucose uptake and GLUT1 and GLUT4 translocation in 3T3-L1 adipocytes and L6 myotubes, mimicking insulin action. In both cell types, insulin-stimulated glucose uptake is reduced by inhibitors of p38 mitogen-activated protein kinase (MAPK). Here we explore the effect of ␣-lipoic acid on p38 MAPK, phosphatidylinositol (PI) 3-kinase, and Akt1 in L6 myotubes. ␣-Lipoic acid (2.5 mmol/l) increased PI 3-kinase activity (31-fold) and Akt1 (4.9-fold). Both activities were inhibited by 100 nmol/l wortmannin. ␣-Lipoic acid also stimulated p38 MAPK phosphorylation by twofold within 10 min. The phosphorylation persisted for at least 30 min. Like insulin, ␣-lipoic acid increased the kinase activity of the ␣ (2.8-fold) and ␤ (2.1-fold) isoforms of p38 MAPK, measured by an in vitro kinase assay. Treating cells with 10 mol/l of the p38 MAPK inhibitors SB202190 or SB203580 reduced the ␣-lipoic acid-induced stimulation of glucose uptake by 66 and 55%, respectively. In contrast, SB202474, a structural analog that does not inhibit p38 MAPK, was without effect on glucose uptake. In contrast to 2-deoxyglucose uptake, translocation of GLUT4myc to the cell surface by either ␣-lipoic acid or insulin was unaffected by 20 mol/l of SB202190 or SB203580. The results suggest that inhibition of 2-deoxyglucose uptake in response to ␣-lipoic acid by inhibitors of p38 MAPK is independent of an effect on GLUT4 translocation. Instead, it is likely that regulation of transporter activity is sensitive to these inhibitors.

α-Lipoic acid regulates AMP-activated protein kinase and inhibits insulin secretion from beta cells

“…Treatment of islets with 2.0 mmol/l α-LA (a concentration similar to that used in other in vitro studies [8,9]) for 15 min led to an increase in phosphorylation of the AMPK α-subunit at Thr172 (2.54±0.14 fold) compared with untreated islets (p<0.001) (Fig. 1a,b).…”

“…Bitar et al [5] demonstrated that α-LA could partly ameliorate insulin resistance in type 2 diabetic rats, while others had reported additional antidiabetic effects in earlier rodent [4,6], and human studies [7]. In vitro approaches have also shown that α-LA can enhance glucose disposal in skeletal muscle [8] and adipocytes [9], and suppress hepatic gluconeogen-esis [10]. The exact molecular mechanisms responsible for these effects are currently not known.…”

Troglitazone causes acute mitochondrial membrane depolarisation and an AMPK-mediated increase in glucose phosphorylation in muscle cells

“…The stimulation of glucose uptake would supply substrate for this increased demand on glycolysis. Troglitazone rapidly (in 30 min) stimulates 2-deoxyglucose uptake into muscle cells [16], and hence we were intrigued by a potential connection between stimulation of glucose uptake by troglitazone and its effect on mitochondrial function.…”

A Dominant-negative p38 MAPK Mutant and Novel Selective Inhibitors of p38 MAPK Reduce Insulin-stimulated Glucose Uptake in 3T3-L1 Adipocytes without Affecting GLUT4 Translocation

“…It is remarkable that stimuli that increase p38 phosphorylation such as insulin-like growth factor-1 (18), muscle contraction (19 -21), lipoic acid (22), 5-aminoimidazole-4-carboxamide ribonucleoside (23), pro-inflammatory cytokines (18), protein synthesis inhibitors (24, 25), hyperosmolar stress (26), and preconditioning (ischemia/reperfusion) (27) also elevate glucose uptake. Importantly, the pyridinylimidazole inhibitor of p38, SB203580, reduced the stimulation of glucose uptake by all of the above stimuli including insulin in skeletal muscle and/or various cell lines, suggesting that p38 may be a component in the signaling pathway leading to the stimulation of glucose uptake (18,19,22,23,25,28).Insulin stimulates glucose uptake in mature skeletal muscle, adipose tissue, and insulin-responsive cells in culture by recruiting glucose transporter 4 (GLUT4) to the plasma membrane. Interestingly, although SB203580 reduced insulin-mediated glucose in 3T3-L1 adipocytes and L6 muscle cells, it did not diminish GLUT4 translocation to the plasma membrane (13,14).…”