IMPAIRED GLUCOSE-TOLERANCE IN MICE WITH A TARGETED IMPAIRMENT OF INSULIN ACTION IN MUSCLE AND ADIPOSE-TISSUE

Type 2 diabetes is a complex metabolic disorder characterized by perip heral insulin resistance and impaired beta cell function(1,2) Insulin resistance is inherited as a non-mendelian trait(3). In genetically pr edisposed individuals, resistance of skeletal muscle and adipose tissu e to insulin action precedes the onset of clinical diabetes, and is th ought to contribute to hyperglycaemia by leading to impaired beta cell function and increased hepatic glucose production(4,5). It is not cle ar whether beta cell and liver defects are also genetically determined (2). To test the hypothesis that insulin resistance in muscle and fat is sufficient to cause type 2 diabetes in the absence of intrinsic bet a cell and liver abnormality, we generated transgenic mice that were i nsulin-resistant in skeletal muscle and adipose tissue. These mice dev eloped all the prodromal features of type 2 diabetes hut, despite the compounded effect of peripheral insulin resistance and a mild impairme nt of beta cell function, failed to become diabetic. These findings in dicate the need for a critical re-examination of the primary site(s) o f insulin resistance in diabetes.