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.

Keywords: Diabetic complications; Eye; Heart; Insulin; Insulin receptor substrate; Kidney; Neuron; Review.

Fig. 1

IRS proteins in organs affected by diabetic complications. A selection of data from animal and human studies supporting changes in IRS proteins during diabetic heart disease (pink panel), diabetic nephropathy (purple panel), diabetic retinopathy (green panel), diabetic vascular disease (yellow panel), diabetic neuropathy (orange panel) and Alzheimer’s disease (blue panel). Details and supporting references are provided in the text. Red T-bar represents inhibition; green arrow represents activation; black arrow represents ‘leading to’. AngII, angiotensin II; βAR, β-adrenergic receptor; PDN, painful diabetic neuropathy