PATHOPHYSIOLOGY OF INSULIN-RESISTANCE

Insulin resistance of skeletal muscle, liver and fat combined with an abnormality of insulin secretion characterizes Type 2 (non-insulin-dependent) diabetes mellitus. There is increasing evidence that the insulin resistance of the skeletal muscle plays a key role early in the development of Type 2 diabetes. As a consequence recent research efforts have focussed on the characterization of insulin signal transduction elements in the muscle which are candidates for a localization of a defect causing insulin resistance, i.e. the insulin receptor, phosphatases related to insulin action, glycogen synthase and the glucose transporters. In this review we attempt to summarize present knowledge about abnormalities of these systems in skeletal muscle of Type 2 diabetic and pre-diabetic individuals. We try to classify abnormalities as secondary events or as candidates for putative primary molecular defects which might initiate the development of insulin resistance as early as in the ''pre-diabetic'' state. Insulin resistance is combined with abnormalities of insulin secretion. Compensatory hypersecretion of insulin is typically found in early stages of the development of the ''Metabolic Endocrine Syndrome'' and the pre-diabetic state. The transition from this pre-diabetic state to the clinically overt Type 2 diabetes is accompanied or even caused by declining insulin secretion. The molecular mechanism causing declining insulin secretion is not understood in detail. Beside genetically determined factors regulatory events might be important.