Understanding the pathogenesis and treatment of insulin resistance and type 2 diabetes mellitus: What can we learn from transgenic and knockout mice?

The development of type 2 diabetes is linked to insulin resistance coupled with a failure of pancreatic beta -cells to compensate by adequate insulin secretion. Here, we review studies obtained from genetically engineered mic e that have helped dissect the pathophysiology of this disease. Transgenic/ knockout models with monogenic impairment in insulin action and insulin sec retion have highlighted potential molecular mechanisms for insulin resistan ce and suggested a mechanism for the development of MODY in humans. Polygen ic models have strengthened the idea that minor defects in insulin secretio n and insulin action, when combined, can lead to diabetes, pointing out the importance of interactions of different genetic loci in the production of diabetes. Tissue specific knockouts of the insulin receptor have challenged current concepts on the regulation of glucose homeostasis and have highlig hted the importance of insulin action in pancreatic beta -cells and brain. The impact of the genetic background on insulin action, insulin secretion a nd the incidence of diabetes is also evident in these models. These finding s highlight potential new therapeutic targets in the treatment of type 2 di abetes.