Insulin receptor substrate 2 plays a crucial role in β cells and the hypothalamus

Abstract

We previously demonstrated that insulin receptor substrate 2 (Irs2) KO mice develop diabetes associated with hepatic insulin resistance, lack of compensatory beta cell hyperplasia, and leptin resistance. To more precisely determine the roles of Irs2 in beta cells and the hypothalamus, we generated beta cell-specific Irs2 KO and hypothalamus-specific Irs2 knockdown (betaHT-IRS2) mice. Expression of Irs2 mRNA was reduced by approximately 90% in pancreatic islets and was markedly reduced in the arcuate nucleus of the hypothalamus. By contrast, Irs2 expression in liver, muscle, and adipose tissue of betaHT-IRS2 mice was indistinguishable from that of control mice. The betaHT-IRS2 mice displayed obesity and leptin resistance. At 4 weeks of age, the betaHT-IRS2 mice showed normal insulin sensitivity, but at 8 and 12 weeks, they were insulin resistant with progressive obesity. Despite their normal insulin sensitivity at 8 weeks with caloric restriction, the betaHT-IRS2 mice exhibited glucose intolerance and impaired glucose-induced insulin secretion. beta Cell mass and beta cell proliferation in the betaHT-IRS2 mice were reduced significantly at 8 and 12 weeks but not at 10 days. Insulin secretion, normalized by cell number per islet, was significantly increased at high glucose concentrations in the betaHT-IRS2 mice. We conclude that, in beta cells and the hypothalamus, Irs2 is crucially involved in the regulation of beta cell mass and leptin sensitivity.

Pancreatic deletion of insulin receptor substrate 2 reduces beta and alpha cell mass and impairs glucose homeostasis in mice

“…Our analysis shows that PIrs2KO mice have a reduced beta cell mass with reduced beta cell proliferation, confirming the key role of IRS2 in this process. No alteration in beta cell mass was seen before weaning, consistent with previous observations [8][9][10] demonstrating that IRS2 is not required for beta cell development. Our findings also suggest that IRS2-dependent mechanisms are required not only for beta cell compensation under conditions of increased insulin The absence of insulin resistance in our model also permitted analysis of the effects of Irs2 deletion upon insulin secretory function.…”

“…However, many of these studies have been compromised by two key features of the RIPCre (B6.Cg-tg(Ins2-cre)25Mgn/J) transgenic mice used to delete the floxed alleles. First, in this animal there was extensive expression in hypothalamic neurons, which resulted in obesity, hyperleptinaemia and hyperinsulinaemia when either Irs2 or indeed Insr was deleted in these cells [8][9][10]20]. Second, it has been suggested that the RIPCre mouse is intrinsically glucose intolerant [12].…”

“…Through the use of both global and conditional mouse gene targeting strategies we and others have demonstrated that IRS2 plays a key role in the maintenance of pancreatic beta cell mass [3,4,[8][9][10]. Furthermore both INSR and IGF1R have also been demonstrated to act as key regulators of beta cell function using Cre/loxP techniques [5][6][7].…”

“…Deletion of the insulin-like growth factor 1 receptor gene (Igf1r) likewise impairs insulin synthesis and secretion and combined deletion of the insulin receptor gene (Insr) and Igf1r causes marked beta cell failure [6,7]. Using similar techniques, we and others have recently generated 'beta cell-specific' Irs2-null mice that have utilised a rat insulin promoter 2 Cre recombinase transgenic mouse (RIPCre or B6.Cg-tg(Ins2-cre)25Mgn/J) to delete the floxed alleles of Irs2 [8][9][10][11]. Our studies and those of others have demonstrated that beta cell deletion of Irs2 reduces beta cell mass and impairs glucose tolerance.…”

“…However, the interpretation of all these studies with respect to the precise role of INSR and IRS2 signalling in beta cell function has been complicated by features of the RIPCre transgenic mouse used to delete the floxed Insr and Irs2 alleles. First, significant Cre recombinase expression in the hypothalamus resulted in the development of obesity, hyperleptinaemia and insulin resistance, which together per se will alter beta cell function [8][9][10]. Second, RIPCre mice themselves have been reported to display mild glucose intolerance, although it was unclear whether this was due to the influence of genetic background or the effects of Cre recombinase expression in beta cells [12].…”