Insulin-sensitising agents: beyond thiazolidinediones.

The global prevalence of Type 2 diabetes mellitus is increasing rapidly, at least in part as a function of obesity. The results of the United Kingdom Prospective Diabetes Study emphasise the importance of developing safe, efficacious new agents for the treatment of Type 2 diabetes. The pharmaceutical industry has recently focused on strategies to improve insulin resistance, particularly modulation of PPAR-gamma. Here we review current thinking on the mechanism of action of these agents, and consider future directions that may arise as a result of increasing understanding of the biology of these receptors and of insulin action. Studies of thiazolidinedione action in adipose tissue have revealed several novel adipocyte-derived hormones that may also be future pharmacological targets for increasing insulin sensitivity. The role of other hormones, such as cortisol and dehydroepiandrosterone, are also discussed in a therapeutic context, as are other novel approaches to the pharmacological management of patients with insulin resistance and Type 2 diabetes.