Insulin resistance and its impact on the approach to therapy of type 2 diabetes

Insulin resistance is a core defect in Type 2 diabetes, occurring in peripheral organs (skeletal muscle and adipose tissue) leading to decreased glucose uptake and utilisation and in liver leading to increased hepatic glucose production. As long as the beta-cell can compensate for this by producing more insulin, glucose tolerance remains normal. However, as insulin resistance worsens, the beta-cell starts to fail to compensate leading to impaired glucose tolerance and then frank diabetes. The exact pathophysiology of insulin resistance is not clear but it probably involves a combination of genetic and environmental factors. These factors may result in changes in the number of insulin receptors, their affinity for insulin or a defect in post-receptor signalling or a combination of these. Insulin resistance also affects lipid metabolism such that there is increased production of triglycerides from the liver, which in turn both amplifies insulin resistance and exacerbates atherogenesis. The promotion of atherosclerosis by insulin resistance means that patients with Type 2 diabetes are at particularly high risk of cardiovascular disease. Therefore, treatment of insulin resistance with thiazolidinediones has the potential to offer improvements both in glycaemic control and in cardiovascular events.