β-cell–specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter β-cell mass

Abstract

Regulation of glucose homeostasis by insulin depends on the maintenance of normal beta-cell mass and function. Insulin-like growth factor 1 (Igf1) has been implicated in islet development and differentiated function, but the factors controlling this process are poorly understood. Pancreatic islets produce Igf1 and Igf2, which bind to specific receptors on beta-cells. Igf1 has been shown to influence beta-cell apoptosis, and both Igf1 and Igf2 increase islet growth; Igf2 does so in a manner additive with fibroblast growth factor 2 (ref. 10). When mice deficient for the Igf1 receptor (Igf1r(+/-)) are bred with mice lacking insulin receptor substrate 2 (Irs2(-/-)), the resulting compound knockout mice show a reduction in mass of beta-cells similar to that observed in pancreas of Igf1r(-/-) mice (ref. 11), suggesting a role for Igf1r in growth of beta-cells. It is possible, however, that the effects in these mice occur secondary to changes in vascular endothelium or in the pancreatic ductal cells, or because of a decrease in the effects of other hormones implicated in islet growth. To directly define the role of Igf1, we have created a mouse with a beta-cell-specific knockout of Igf1r (betaIgf1r(-/-)). These mice show normal growth and development of beta-cells, but have reduced expression of Slc2a2 (also known as Glut2) and Gck (encoding glucokinase) in beta-cells, which results in defective glucose-stimulated insulin secretion and impaired glucose tolerance. Thus, Igf1r is not crucial for islet beta-cell development, but participates in control of differentiated function.

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

“…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. Insr-, Igf1r-and Irs1-null islets display defective glucose-stimulated insulin release in vitro [6,21,22]. In contrast, in both global Irs2-null mice and RIPCreIrs2KO mice, insulin secretion from isolated islets has been reported to be enhanced [4,9].…”

“…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]. 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.…”

“…Furthermore, cell-specific gene targeting in mice using Cre/loxP-mediated recombination strategies has shown that beta cell deletion of the insulin receptor reduces first-phase insulin release and beta cell insulin content and causes a progressive deterioration in glucose tolerance [5]. 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].…”

Enhanced mitochondrial metabolism may account for the adaptation to insulin resistance in islets from C57BL/6J mice fed a high-fat diet

“…This has become even more evident when identical genetic manipulations, i.e. gene knock-outs, have been analysed in different genetic backgrounds, in many instances yielding dissimilar results with respect to glucose homeostasis [33,34].…”

Glucose concentration and AMP-dependent kinase activation regulate expression of insulin receptor family members in rat islets and INS-1E beta cells

“…In transgenic mice, beta cell expression of IGF-I leads to recovery from streptozotocin-induced diabetes [14] while overexpression of IGF-II leads to an increased beta cell mass at birth [15]. On the other hand, beta-cell-specific knock-out of IGF-IR or IR in mice leads to altered glucose sensing and glucose intolerance in adult mice but only the IR knock-out mice display a reduced beta cell mass in adult life [16][17][18]. Furthermore, in vitro knock-down studies applying a small-interfering-RNA technique allowed detailed comparison of the specific function that each receptor, IR and IGF-IR, plays in beta cell function [11].…”