MOLECULAR-BIOLOGY OF INSULIN RESISTANCE

Insulin resistance is an essential feature of a great variety of clini cal disorders, like diabetes mellitus, obesity, essential hypertension , and is primarily due to a defect in hormone action at the cellular l evel. In the past decade application of novel research techniques incl uding recombinant DNA technology have paved the way to understand the mechanisms of insulin action and its alterations at the molecular leve l. The first step in insulin action is the activation of the insulin r eceptor. The insulin receptor is a tetrameric protein consisting of tw o extracellular alpha- and two transmembrane beta-subunits. Binding of insulin to the alpha-subunit causes autophosphorylation of the intrac ellular beta-subunit region on tyrosine residues thereby activating th e receptor. How the hormonal signal is subsequently transduced within the cell is still quiet unclear. The activated insulin receptor appear s to couple to cytosolic receptor substrates which can affect differen t signaling cascades eliciting the pleiotropic hormone response on cel l metabolism and growth. Most proteins involved in the signal transduc tion pathway of insulin are not known yet, but each of them might play a role in the various forms of insulin resistance. Taking the insulin receptor as an exemplary protein involved in insulin action we review molecular mechanisms regulating insulin receptor activity, gene expre ssion, and the role of natural occuring insulin receptor gene mutation s in patients with insulin resistant diabetes mellitus. It is outlined how the combination of both clinical medicine and molecular biology n ot only helps to understand insulin action and the pathogenesis of ins ulin resistance, but also leads to new avenues in the differential dia gnosis, therapy, and possibly prevention of this heterogenous but most frequent metabolic and endocrine disorder.