Type 2 diabetes: simple, dual or multiple pathogenetic defects?

Abstract

Insulin resistance and defective beta-cell function are both required for the development of Type 2 diabetes. However, the discussion on whether one event may precede the other is still ongoing. This may be an academic more than a physiopathologic question, because Type 2 diabetes is a heterogeneous disease both in terms of clinical and pathogenetic aspects. The involvement of insulin resistance and impaired insulin secretion can vary from subject to subject. The mechanisms causing defective insulin action and secretion may be very distinct as well as very similar. With this picture in mind, we examined different pathogenetic models that take into account such heterogeneity. In one case, we speculate that insulin resistance in the face of preserved beta-cell function leads to the development of the metabolic syndrome. In a second case, we speculate that distinct defect at the level of insulin-dependent tissues and at the level of the beta cell will lead to glucose intolerance. The derangement of the metabolic environment will then contribute to the development of overt hyperglycemia. Finally, recent literature data will be used to make the case that the same intimate alteration (i.e., impaired insulin signalling) may be a common cause for insulin resistance and impaired insulin secretion.