ABSTRACT

Insulin resistance is a key factor in the pathogenesis of obesity and type 2 diabetes, the world’s most prevalent metabolic disorder. Insulin resistance is also the cause of insulin resistance syndrome, syndrome X, in which physiological abnormalities such as renal failure, hypertension and neuropathy cluster together. Insulin resistance is characterized by the failure of tissues to respond to insulin, resulting in reduced glucose intake to peripheral tissue and increased hepatic glucose output. Since the major portion of ‘whole body’ glucose is metabolized into glycogen (Bogardus et al., 1984; Roden and Shulman, 1999), defects in its metabolism may represent an important factor underlying the development of insulin resistance and type 2 diabetes. Glycogen synthase is the rate-limiting enzyme for glycogen synthesis, and its regulation is one of the few examples of complex, hierarchical, multisite phosphorylation. Studies to date have not fully uncovered the in vivo mechanisms regulating glycogen synthase; they have, however, established important concepts in cellular regulation such as enzyme regulation by reversible phosphorylation, the role of targeting molecules and function of signaling cascades.