Defects of the insulin receptor substrate (IRS) system in human metabolic disorders

Abstract

Insulin receptor substrate (IRS) molecules are key mediators in insulin signaling and play a central role in maintaining basic cellular functions such as growth, survival, and metabolism. They act as docking proteins between the insulin receptor and a complex network of intracellular signaling molecules containing Src homology 2 (SH2) domains. Four members (IRS-1, IRS-2, IRS-3, IRS-4) of this family have been identified that differ as to tissue distribution, subcellular localization, developmental expression, binding to the insulin receptor, and interaction with SH2 domain-containing proteins. Results from targeted disruption of the IRS genes in mice have provided important clues to the functional differences among these related molecules, suggesting they play different and specific roles in vivo. The available data are consistent with the notion that IRS-1 and IRS-2 are not functionally interchangeable in tissues that are responsible for glucose production (liver), glucose uptake (skeletal muscle and adipose tissue), and insulin production (pancreatic beta cells). In fact, IRS-1 appears to have its major role in skeletal muscle whereas IRS-2 appears to regulate hepatic insulin action as well as pancreatic beta cell development and survival. By contrast, IRS-3 and IRS-4 genes appear to play a redundant role in the IRS signaling system. Defects in muscle IRS-1 expression and function have been reported in insulin-resistant states such as obesity and type 2 diabetes. Several polymorphisms in the IRS genes have been identified, but only the Gly-->Arg972 substitution of IRS-1, interacting with environmental factors, seems to have a pathogenic role in the development of type 2 diabetes. In contrast, polymorphisms of the other IRS genes do not appear to contribute to type 2 diabetes.

A/ASP/VAL allele combination of IGF1R, IRS2, and UCP2 genes is associated with better metabolic profile, preserved energy expenditure parameters, and low mortality rate in longevity

“…Indeed, we have previously demonstrated that allele A variant at codon 1013 of IGF1R is associated with longevity and with low levels of free plasma IGF-1 ) and more recently an overrepresentation of heterozygotes for mutation in IGF1R gene has been found among Jewish female centenarians (Suh et al 2008). Furthermore, some, but not all, studies have indicated a role for IRS2 gene variants in the pathogenesis of obesity and obesity-associated insulin resistance (Sesti et al 2001;Stefan et al 2003). Indeed, we have recently found that subjects with one or two IRS2 Asp alleles displayed a greater chance of living between 96 and 104 years of age (Barbieri et al 2010) Recent experimental evidences suggest that the effect of the insulin IGF1 signaling pathway on life span may be partially mediated by regulating the expression of uncoupling protein 2 (UCP2) (Bratic and Trifunovic 2010;Andrews et al 2005) In flies, over-expressing human UCP2 (hUCP2) to adult neurons resulted in decreased oxidative damage and extended life span without compromising fertility or physical activity (Fridell et al 2005).…”

Resistin disrupts glycogen synthesis under high insulin and high glucose levels by down-regulating the hepatic levels of GSK3β

“…IRS1 and IRS2 are two major insulin receptor effectors that contribute to the signaling that regulates glucose homeostasis (Thirone et al 2006), while tumor necrosis factor-alpha (TNFα) is an important mediator of insulin resistance in obesity and diabetes, as it induces insulin resistance at the level of the IRS proteins (Ishizuka et al 2007;Lorenzo et al 2008;Nieto-Vazquez et al 2008). IRS-1 primarily functions in skeletal muscle and adipose tissues (Sesti et al 2001;Thirone et al 2006), while IRS2 contributes to hepatic insulin sensitivity and resistance in the liver (Sesti et al 2001;Dominici et al 2002;Thirone et al 2006). IRS1, however, might cooperate with IRS2 in the regulation of insulin signaling in the liver (Thirone et al 2006).…”

Association testing of common variants in the insulin receptor substrate-1 gene (IRS1) with type 2 diabetes

“…Tissue-specific knockout experiments in mice have shown that IRS1 is a necessary component of insulin action in skeletal muscle, adipose tissue and pancreatic beta cells [3]. Its gene IRS1 has therefore been proposed as a candidate gene that might cause diabetes in humans [4].…”