Irs-2 coordinates Igf-1 receptor-mediated β-cell development and peripheral insulin signalling

Abstract

Insulin receptor substrates (Irs proteins) mediate the pleiotropic effects of insulin and Igf-1 (insulin-like growth factor-1), including regulation of glucose homeostasis and cell growth and survival. We intercrossed mice heterozygous for two null alleles (Irs1+/- and Irs2+/-) and investigated growth and glucose metabolism in mice with viable genotypes. Our experiments revealed that Irs-1 and Irs-2 are critical for embryonic and post-natal growth, with Irs-1 having the predominant role. By contrast, both Irs-1 and Irs-2 function in peripheral carbohydrate metabolism, but Irs-2 has the major role in beta-cell development and compensation for peripheral insulin resistance. To establish a role for the Igf-1 receptor in beta-cells, we intercrossed mice heterozygous for null alleles of Igf1r and Irs2. Our results reveal that Igf-1 receptors promote beta-cell development and survival through the Irs-2 signalling pathway. Thus, Irs-2 integrates the effects of insulin in peripheral target tissues with Igf-1 in pancreatic beta-cells to maintain glucose homeostasis.

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

“…For example, in Irs2−/ − mice there is diminished β cell mass with impaired glucose tolerance [89,91]; in this model, superposition of haploinsufficiency of the Forkhead transcription factor Foxo1 causes activation of Pdx1 expression in duct cells, and the subsequent recovery of β cell mass [92]. In support of this observation, overexpression of Pdx1 alone in Irs2−/− animals promotes recovery of β cell mass and correction of glucose tolerance throughout life [93].…”

“…Amongst the most wellstudied pathways that regulate β cell mass include the insulin receptor substrate 1 and 2 (IRS1 and IRS2) branch of insulin receptor (IR)/insulin-like growth factor 1 receptor (IGF1R) signaling [83,83,84]. Several studies suggest that Pdx1 may act downstream of the IR/IGF1R signaling to promote β cell proliferation [83,[85][86][87][88][89]. Studies of Kulkarni, et al reveal that haploinsufficiency of Pdx1 in two mouse models of insulin resistance-insulin receptor/IRS1 double heterozygous mice and liver insulin receptor knockout mice-virtually completely abrogated the adaptive islet hyperplastic response, resulting instead in β cell apoptosis and premature death of the animals [88].…”

The intrauterine metabolic environment modulates the gene expression pattern in fetal rat islets: prevention by maternal taurine supplementation

“…IGF-2 exerts its mitogenic and antiapoptotic action via its binding to the IGF-1 receptor. IGF-1 receptor knockout mice have 50% reduction in their beta cell mass [40] and deletion of the IGF-1 and insulin receptors in the beta cell induced reduced beta cell mass and increased apoptosis and default in insulin secretion, three alterations that were also observed in the LP fetal islets [8,11,14].…”

Defective IGF2 and IGF1R protein production in embryonic pancreas precedes beta cell mass anomaly in the Goto–Kakizaki rat model of type 2 diabetes

“…Igf2 overexpression in transgenic mice has a profound effect on pancreas morphology and causes islets hyperplasia [11]. Deletion of the gene encoding IGF1R in mice, which is lethal after birth, was responsible for 50% fewer beta cells on E16 and E18.5 [21]. Global knockout of Irs2 or S6 kinase 1 gene (also known as ribosomal protein S6 kinase, polypeptide 1), effectors of the IGF signalling pathway, led to smaller beta cell masses [22,23].…”