Several lines of evidence have suggested that triglyceride accumulation in skeletal muscle and pancreatic islets is causally related to type 2 diabetes mellitus. We recently showed that alpha-lipoic acid (ALA), a potent antioxidant and cofactor of mitochondrial respiratory enzymes, reduces body weight of rodents by suppressing food intake and increasing energy expenditure. We sought to determine if ALA can prevent the development of diabetes mellitus in obese Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Most (78%) untreated OLETF rats showed glycosuria at 40 weeks of age, but this was completely prevented by ALA. Compared with untreated OLETF rats, ALA reduced body weight and protected pancreatic beta-cells from destruction. ALA also reduced triglyceride accumulation in skeletal muscle and pancreatic islets. These results indicate that ALA prevents diabetes mellitus in obese diabetes-prone rats by reducing lipid accumulation in non-adipose tissue as well as in adipose tissue.