a-Lipoic Acid: A Multifunctional Antioxidant That Improves Insulin Sensitivity in Patients with Type 2 Diabetes

a-Lipoic acid (LA) is a disulfide compound that is produced in small quantities in cells, and functions naturally as a co-enzyme in the pyruvate dehydrogenase and a-ketoglutarate dehydrogenase mitochondrial enzyme complexes. In pharmacological doses, LA is a multifunctional antioxidant. LA has been used in Germany for over 30 years for the treatment of diabetes-induced neuropathy. In patients with type 2 diabetes, recent studies have reported that intravenous (i.v.) infusion of LA increases insulin-mediated glucose disposal, whereas oral administration of LA has only marginal effects. If the limitations of oral therapy can be overcome, LA could emerge as a safe and effective adjunctive antidiabetic agent with insulin sensitizing activity. 401 GENERAL OVERVIEW OF a-LIPOIC ACID IN 1937, A COMPONENT OF POTATO EXTRACT, named “potato growth factor,” was discovered to be necessary for the growth of Lactobacillus.1 Subsequent work by a number of laboratories led to the isolation and purification of the active compound in 1951.2 The compound was identified as a-lipoic acid (LA; occasionally referred to as thioctic acid), an eight-carbon disulfide containing a single chiral center (Fig. 1). LA is reduced in vivo to its dithiol form, dihydrolipoic acid (DHLA), a compound that also possesses biological activity.3 LA is synthesized in organisms ranging from bacteria to man. In humans, it is synthesized in liver and other tissues, where it functions as a natural co-factor in multienzyme dehydrogenase complexes, such as pyruvate dehydrogenase (PDH) and a-ketoglutarate dehydrogenase.4 Pyruvate dehydrogenase is localized in mitochondria where it catalyzes the oxidative decarboxylation of pyruvate to acetyl-CoA, a critical step in oxidative glucose metabolism.5 In the PDH complex, LA is covalently attached to a lysine side chain of the dihydrolipoyl transacetylase component (E2), where it forms the lipoamide prosthetic group that accepts an acetyl group and transfers it CoA. Thus, LA plays an essential role in mitochondrial-specific pathways that generate energy from glucose. LA and DHLA are also potent antioxidants.6 As shown in Figure 2, four distinct antioxidant actions of LA and DHLA have been observed: (1) reactive oxygen species (free radical) scavenging activity, (2) capacity to regenerate endogenous antioxidants such as glutathione, vitamin C and vitamin E, (3) metal chelating 1Medical Research Institute, San Bruno, California. 2Diabetes Research Laboratory, Mount Zion Hospital, San Francisco, California. Review Article