Mechanisms of insulin resistance and new pharmacological approaches to metabolism and diabetic complications.

1. Resistance to insulin-mediated glucose transport and metabolism has been identified as a primary mechanism in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM) and as a target for drug development. The aetiology of insulin resistance is likely to be multifactorial, but the present review focuses on candidate post-receptor mechanisms of insulin resistance, particularly protein kinase C (PKC), and the metabolic and genetic significance of beta3-adrenoceptors (beta3-AR) in adipose tissue. 2. Multiple lines of evidence suggest that isoform-selective activation of PKC phosphorylates and down-regulates one or more substrates involved in glucose transport and metabolism (e.g. glycogen synthase and the insulin receptor) and recent studies have shown increased expression of calcium-independent isozymes (PKC-epsilon and PKC-theta) in the membrane fraction of skeletal muscle in fructose- and fat-fed rat models of insulin resistance. In addition, there is separate evidence that glucose-induced PKC activation plays an important role in the micro- and macrovascular complications of diabetes. 3. New pharmacological approaches to NIDDM and obesity have focused on insulin-sensitizing agents (e.g. troglitazone), beta3-AR agonists, anti-lipolytic drugs (e.g. the adenosine A1 receptor agonist GR79236) and selective inhibitors of PKC isoforms (e.g. the inhibitor of PKC-beta LY333531). Experimental studies with GR79236 show that this drug ameliorates the hypertriglyceridaemia induced by fructose feeding and that the reduction in fatty acid levels is associated with secondary improvements in glucose tolerance. 4. Recent insights into the pathogenesis of NIDDM and its associated complications have been used to develop a range of new therapeutic agents that are currently showing promise in clinical and preclinical development.