Disruption of insulin receptor substrate-2 impairs growth but not insulin function in rats

Abstract

<jats:p>Insulin receptor substrate (IRS)-2, along with IRS-1, is a key signaling molecule that mediates the action of insulin and insulin-like growth factor (IGF)-I. The activated insulin and IGF-I receptors phosphorylate IRSs on tyrosine residues, leading to the activation of downstream signaling pathways and the induction of various physiological functions of insulin and IGF-I. Studies using IRS-2 knockout (KO) mice showed that the deletion of IRS-2 causes type 2 diabetes due to peripheral insulin resistance and impaired β-cell function. However, little is known about the roles of IRS-2 in other animal models. Here, we created IRS-2 KO rats to elucidate the physiological functions of IRS-2 in rats. The body weights of IRS-2 KO rats at birth were lower compared to those of their wild-type (WT) littermates. The postnatal growth of both male and female IRS-2 KO rats was also suppressed. Compared to male WT rats, the glucose and insulin tolerance of male IRS-2 KO rats were slightly enhanced, whereas a similar difference was not observed between female WT and IRS-2 KO rats. Besides the modestly increased insulin sensitivity, male IRS-2 KO rats displayed the enhanced insulin-induced activation of the mammalian target of rapamycin complex 1 pathway in the liver compared to WT rats. Taken together, these results indicate that in rats, IRS-2 plays important roles in the regulation of growth but is not essential for the glucose-lowering effects of insulin.</jats:p>

Integrating genome-wide association studies and population genomics analysis reveals the genetic architecture of growth and backfat traits in pigs

“…In this region, both combined-population and cross-population GWAS simultaneously identified anoctamin 1 (ANO1) gene, which was also known as TMEM16A. ANO1 and IRS2 played positive roles in insulin secretion (Dong et al, 2006;Xu et al, 2014;Hashimoto et al, 2015;Toyoshima et al, 2020), which could affect growth rate and fat deposition in pigs. ANO1 gene defects or its expression in pancreatic islets might influence cytokine expression and elicit an immune response that could result in death of β cell (Xu et al, 2014).…”

NADPH-Oxidase Derived Hydrogen Peroxide and Irs2b Facilitate Re-oxygenation-Induced Catch-Up Growth in Zebrafish Embryo

“…So far, studies in mice have reported that Irs1 is essential for body growth (11), but Irs2 contributed to normal body growth only a little (13). On the other hand, recent studies have shown that Irs2 is required for normal body growth in rats (14) and that Irs2 protein potentially plays a role in the growthpromoting mechanism with some specific interacting molecule(s) (50). Irs2 is crucial for various physiological functions, including maintaining energy homeostasis (12,51), and the Erk1/2 contributes to various cell-fate determinations such as proliferation and differentiation (52), the elucidation of the H 2 O 2 -induced Irs2b-MAPK function should be a crucial research subject.…”

“…Instead, Irs2 deficient mice show severe hepatic insulin resistance, impaired beta-cell proliferation, insulin secretion, and diabetic symptoms caused outside of growth (12,13). However, a recent knockout study has shown that deletion of the Irs2 gene in rats causes significant growth retardation (14). In addition, the role of Irs1 was examined in a catch-up growth model using zebrafish and found it was responsible for the survival of multipotent cells vital for the growth spurt (15).…”