New therapeutic agents for the treatment of NIDDM.

Non-insulin dependent diabetes mellitus (NIDDM) is a heterogeneous disease with a world wide growing prevalence. Insulin resistance, particularly an impaired action of insulin on the glucose metabolism in skeletal muscles, has been assumed to be the primary factor in the pathophysiology of this disease and it is observed years before the precipitation of overt NIDDM. Almost half of the patient population already suffer from macroangiopathy at the time of diagnosis and the overall mortality rate primarily due to coronary heart disease is approximately 2.5 times higher as compared with healthy individuals. It can be assumed that these complications are closely linked to insulin resistance and a result of the "metabolic syndrome". Insulin resistance is obviously a strong predictive factor for NIDDM, but it is not sufficient for the development of overt diabetes. For the precipitation of overt NIDDM an impaired function of the pancreatic B-cells is also required which seems to be a consequence of the excessive demand for insulin in insulin resistant individuals. Increasing knowledge about the pathophysiology of type II diabetes led to completely new approaches for the treatment of this disease. In this context compounds exhibiting an effect on the peripheral insulin resistance are of special interest and the promising results of clinical trials with troglitazone, a thiazolidinedione derivative, can be regarded as a proof of this newly discovered therapeutic concept. Since the primary effect of this compound is to improve the response of peripheral target tissues to insulin, this should result in a better glycemic control and a concomitant decrease of the circulating insulin levels. Although troglitazone can be regarded as a first approach to a new therapeutic regimen, we are only at the beginning of a new and very exciting area. Future research efforts should be focussed on the discovery of therapeutic agents with higher potency and the fact that not all patients can be treated with troglitazone (non-responder) leads to the assumption that different patient populations may require different therapeutic agents. The effect of insulin sensitizers on insulin resistance and hyperinsulinemia may be of important consequence since insulin resistance has been linked to an increased risk of coronary artery disease as a major cause of mortality in NIDDMs.