Polymorphisms of the Insulin Receptor Subtrate-2 in Patients with Type 2 Diabetes

Abstract

We investigated the significance of Gly1057Asp and Leu647Val insulin receptor substrate (IRS)-2 polymorphisms in two Italian cohorts comprising 186 glucose-tolerant subjects and 240 subjects with type 2 diabetes from the Lazio region (i.e. representative of central Italy), and 123 glucose-tolerant subjects from the Sicily region (i.e. representative of south Italy). The allelic frequency of Gly1057Asp variant did not differ between diabetics (32.9%) and nondiabetic subjects, whatever their ethnicity was (35.8% and 33.7% from Lazio and Sicily, respectively). As compared with Gly/Gly subjects within each group, Asp/Asp individuals showed no differences in quantitative traits, including fasting insulin and C-peptide, and several indices of insulin sensitivity and secretion. Only one of the diabetic patients was heterozygous for the Leu647Val variant, and none of the control subjects carried this variant. This patient had three children who were also heterozygous for this variant. They were glucose tolerant, and their insulin sensitivity and insulin secretion indices were within the range of age-matched controls. We also analyzed IRS-2 function in fibroblasts from carriers of Gly1057Asp or Leu647Val variant. No defects in IRS-2 expression, insulin-stimulated phosphorylation, or binding to the p85 subunit of phosphatidylinositol 3-kinase were observed. These results strongly argue against a major role of IRS-2 polymorphisms in the pathogenesis of type 2 diabetes.

Polymorphism Study of the Insulin Receptor Substrate IRS1 and IRS2 Genes Associated with Type 2 Diabetes in Ethnic Groups of Djerba Island

“…Our conclusion is in agreement with other studies 17,18 showing that a polymorphic marker in the IRS2 gene was not linked to T2DM in Ashkenazi Jewish and Italian Caucasian families excluding the IRS2 gene as a major predisposing gene for this disease. Indeed polymorphisms in the regions encoding codons 513 and 972 of IRSl, although present in some European Caucasians, is not responsible for T2DM in Djerbian studied groups.…”

The G1057D polymorphism of IRS-2 gene and its relationship with obesity in conferring susceptibility to type 2 diabetes in Asian Indians

“…24,25 Thus, there appears to be marked difference in the association of the D1057 allele and diabetes, emphasising the need for studies in other populations. The molecular mechanism by which the nonconservative G1057D variant affects insulin action is not clear, but it is hypothesised that this introduces a charged amino acid (D) in place of a neutral one (G) in the domain of IRS-2 molecule located in between two putative tyrosine phosphorylation sites (at positions 1042 & 1072) of the protein which could produce alterations in downstream signalling through IRS-2.…”

The PTEN–PI3K pathway: of feedbacks and cross-talks

“…p85 levels are found increased in some patients with insulin resistance (Bandyopadhyay et al, 2005) Moreover, polymorphism of PI3KR1 (which encodes for p85) together with those found in IRS-1 and IRS-2 has been associated with diabetes (Almind et al, 1996;Kawanishi et al, 1997;D'Alfonso et al, 2003;Esposito et al, 2003). On the other hand, AKT2 has been found to be mutated in familiar insulin resistance (George et al, 2004), thereby enforcing the concept that PI3K, through modulation of targets involved in metabolic regulation, fine-tunes glucose metabolism in response to extracellular stimuli.…”