We propose to perform a placebo-controlled study of Alpha Lipoic Acid (LA) administration in a cohort of non-obese, non-diabetic, insulin resistant subjects. The insulin sensitivity of 180 subjects will be initially estimated by measuring fasting glucose and insulin levels (homeostasis model assessment) and oral glucose tolerance test (OGTT). The 60 most insulin resistant subjects will then be randomized to 6 weeks of therapy with either 600 mg three times a day of LA or placebo. To quantitate the ALA-induced improvements, euglycemic hyperinsulinemic clamps to evaluate insulin sensitivity, OGTT using deuterated glucose to evaluate glycolytic glucose disposal, and muscle biopsies to evaluate insulin signaling pathways, will be performed before and after treatment. We believe these studies will (1) confirm the beneficial effect of CR-ALA on insulin sensitivity; (2) further our understanding of the molecular mechanisms of LA action; and (3) because these insulin resistant subjects are at risk for the development of type 2 diabetes, the Metabolic Syndrome, and coronary artery disease (CAD), a demonstration of the beneficial effects of LA on insulin action could ultimately have important public health consequences.
