Endocrine Abstracts

Insulin resistance is an insulin signalling defect, defined as resistance of the body to the biological actions of insulin. It is present in around 25% of the UK adult population and, although genetic factors are involved, the major arbiters are obesity and sedentary lifestyle. The tendency of cardiovascular risk factors to co-occur in the same patient may relate to insulin resistance as a primary abnormality. This hypothesis remains controversial particularly as to whether there is a direct causal link between insulin resistance and cardiovascular disease.

A new group of oral antidiabetic agents has recently come on the market, the thiazolidinediones (glitazones). These agents are agonists of the intranuclear hormone receptor, peroxisome proliferator activated receptor gamma (PPAR gamma). They improve insulin sensitivity thereby reducing insulin resistance. In diabetic patients, they improve glycaemic control and may also have beneficial effects on other features of the insulin resistance (metabolic) syndrome. This includes improvement in blood pressure, dyslipidaemia, inflammatory markers, endothelial function and clotting parameters. They may also help preserve pancreatic beta cell function. Tantalising reports have also suggested that they may have similar effects in non-diabetic insulin resistant subjects.

Clinical trials are now ongoing to answer several questions:

1. Can these agents prevent/delay the onset of type 2 diabetes in those at high risk?

2. Can they slow/prevent disease progression in established type 2 diabetes?

3. Can they reduce cardiovascular risk, event rates, and mortality?

There is also presently much interest in several new compounds under development which improve insulin resistance. These include non-thiazolidinedione agonists of PPAR gamma and others which have a dual agonist role acting both on the PPAR alpha and PPAR gamma receptor. These latter agents are particularly interesting as they may have more profound effects on the typical dyslipidaemia of type 2 diabetes (low HDL and raised triglycerides).