Insulin action and type 2 diabetes: lessons from knockout mice

Recent evidence from a number of knockout mouse models has not only provided novel insights into mechanisms by which insulin signal transduction pathways regulate glucose homeostasis in classical insulin target tissues, but has revealed previously unsuspected roles for these pathways in pancreatic beta cell function. A most striking example is that insulin receptor substrate 2-dependent signaling pathways, long implicated in peripheral insulin action, have now been demonstrated to mediate the beta cell compensatory mechanisms that occur in response to insulin resistance. Further evidence that insulin signaling pathways are important in beta cell function comes from the recent finding that beta cell-specific deletion of the insulin receptor results in defects in insulin secretion. Additional models aimed at abrogating insulin signaling in muscle and adipose tissue show that these defects are insufficient to result in a marked disturbance of glucose homeostasis. Taken together these new experimental models challenge the classical views of insulin signaling pathways in glucose disposal and identify novel mechanisms for the pathogenesis of type 2 diabetes.