Thioctic acid and glucose metabolism: Studies using insulin-resistant skeletal muscle of the fatty Zucker rat

Insulin resistance of skeletal muscle glucose metabolism underlies numerous pathological conditions, most notably non-insulin-dependent diabetes mellitus, but also conditions of hyperinsulinemia associated with hypertension, dyslipidemia, and central adiposity ('syndrome X' or the 'insulin resistance syndrome'). Thioctic acid (TA) has been used to treat diabetic polyneuropathy and recent clinical evidence indicates that it may also be effective in increasing insulin-mediated glucose disposal in insulin-resistant humans. The information presented in this brief review article summarizes our recent efforts in identifying a possible cellular site of action for this beneficial effect of TA. To this end, we have investigated the effects of chronic parenteral TA treatment on in vitro glucose metabolism in the epitrochlearis muscle of a well-established animal model of severe insulin resistance, hyperinsulinemia, dyslipidemia, and central obesity: the fatty Zucker rat. Fatty Zucker rats were chronically treated intraperitoneally with vehicle or a racemic mixture of TA (30 mg/kg body weight/day for 10 days). Chronic TA treatment maximally increased insulin-stimulated glucose transport by 29% and both insulin-stimulated glucose oxidation (+35%) and glycogen synthesis (+22%) (all p < 0.05). In vivo glycogen levels were 21% greater (p < 0.05) in muscle from the TA-treated animals. Collectively, these studies indicate that, in this animal model of severe insulin resistance, the primary sites of the beneficial action of TA are the skeletal muscle glucose transport system and both the non-oxidative and oxidative glucose metabolism systems.