IRS proteins and diabetic complications

Abstract

IRS proteins are cellular adaptor molecules that mediate many of the key metabolic actions of insulin. When tyrosine is phosphorylated by the activated insulin receptor, IRS proteins recruit downstream effectors, such as phosphoinositide 3-kinase and mitogen-activated protein kinase, in order to elicit cellular responses such as glucose uptake, lipid metabolism and cell proliferation. There are two main IRS proteins in humans (IRS1 and IRS2), both of which are widely expressed. Given their central role in the insulin signalling pathway, it is not surprising that male mice lacking Irs1 or Irs2 present with elevated blood glucose or type 2 diabetes, respectively. For reasons yet to be identified, female Irs2 −/− mice do not develop type 2 diabetes. A number of organs are affected by complications of diabetes; macrovascular complications include stroke and coronary artery disease, while nephropathy, neuropathy and retinopathy fall into the category of microvascular complications. Given the serious consequences of these complications on patient morbidity and mortality, it is essential to identify the molecular pathogenesis underlying diabetic complications, with a view to improving therapeutic intervention and patient outcomes. A number of recently published papers have converged on the hypothesis that the loss of insulin signalling and IRS proteins is instrumental to the development and/or progression of diabetic complications. This review will summarise some highlights from the published work in which this hypothesis is discussed.

Umbilical Cord Cells Treatment with Metadichol® IRS Proteins and GLUT4 Expression and Implications for Diabetes

“…Since adult stem cells are present in PBMCs which have similar expression profiles to UBC [39], one could expect similar actions by Metadichol on these cells leading to observed improvements that we have documented in diabetes patients [21][22][23]. The study shows highly related biologically functional gene clusters are the key in targeting diseases.…”

“…We recently presented clinical case studies that showed the effectiveness of Metadichol in treatment of diabetes and related complications like wound healing [20][21][22]. IRS1 and IRS2 have been shown to play an essential role in the insulin signaling pathway [23]. Increase in IRS2 expression in β-cells has been shown to be essential for growth and function [24].…”

Association of Perilipin and Insulin Receptor Substrate-1 Genes Polymorphism with Lipid Profiles, Central Obesity, and Type 2 Diabetes in a Sample of an Iranian Population

“…However, the effects of the IRS-1 genotype on prediabetic mediated features were not known. Recently the researchers showed that this gene is not only associated with Type 2 diabetes in different populations but also it may have a significant correlation with diabetic complications, particularly with coronary artery disease (CAD) and obesity (9)(10)(11). Another gene that was investigated in this study was perilipin (PLIN) (rs4578621).…”

The insulin receptor adaptor IRS2 is an APC/C substrate that promotes cell cycle protein expression and a robust spindle assembly checkpoint

“…Though IRS1 and IRS2 share similar structural and functional features, 43 they have complementary roles and expression patterns that depend on tissue type and 44 physiological state (Haeusler et al, 2017). These differences are illustrated by divergent 45 phenotypes in knockout mice: whereas IRS1 knockout mice exhibit insulin resistance that 46 is compensated by increased pancreatic β cell mass, IRS2 knockout mice exhibit β cell 47 failure and resultant diabetes (Lavin et al, 2016). Distinct roles for IRS1 and IRS2 can 48 also be observed within the same tissue.…”