Total insulin and IGF-I resistance in pancreatic β cells causes overt diabetes

An appropriate beta cell mass is pivotal for the maintenance of glucose homeostasis(1). Both insulin and IGF-1 are important in regulation of beta cell growth and function ( reviewed in ref. 2). To define the roles of these hormones directly, we created a mouse model lacking functional receptors for both insulin and IGF-1 only in beta cells (beta DKO), as the hormones have overlapping mechanisms of action and activate common downstream proteins. Notably, bDKO mice were born with a normal complement of islet cells, but 3 weeks after birth, they developed diabetes, in contrast to mild phenotypes observed in single mutants(3,4). Normoglycemic 2-week-old beta DKO mice manifest reduced beta cell mass, reduced expression of phosphorylated Akt and the transcription factor MafA, increased apoptosis in islets and severely compromised b cell function. Analyses of compound knockouts showed a dominant role for insulin signaling in regulating beta cell mass. Together, these data provide compelling genetic evidence that insulin and IGF-I-dependent pathways are not critical for development of beta cells but that a loss of action of these hormones in b cells leads to diabetes. We propose that therapeutic improvement of insulin and IGF-I signaling in beta cells might protect against type 2 diabetes.