Search for variants of the gene-promoter and the potential phosphotyrosine encoding sequence of the insulin receptor substrate-2 gene: evaluation of their relation with alterations in insulin secretion and insulin sensitivity

Abstract

The importance of the insulin receptor substrate-2 (IRS-2) has recently been investigated in mice in which the homozygous deficiency of IRS-2 causes a Type II (non-insulin-dependent) diabetes-like phenotype due to both insulin resistance and pancreatic beta-cell failure [1]. The insulin resistance is profound in both skeletal muscle and liver. Morphometric analysis of the pancreas showed that the mice have considerably reduced beta-cell mass which consequently prevents an adequate insulin secretion to compensate for the insulin resistance. The study of Diabetologia (1999) Abstract Aims/hypothesis. The aim of this study was to screen part of the putative promoter sequence in addition to 14 potential phosphotyrosine residues of human IRS-2 for genetic variability which might cause changes in protein expression or function. Furthermore, the potential impact on insulin secretion and sensitivity of a previously identified IRS-2 variant (Gly1057Asp) was analysed Methods. The screenings were carried out by the SSCP-heteroduplex technique on DNA from Type II (non-insulin-dependent) diabetic patients. The impact of the Gly1057Asp variant was analysed in four glucose-tolerant Scandinavian study groups. Results. The results showed no nucleotide substitutions in the promoter sequence, however, a novel heterozygous amino acid variant was identified (Leu647-Val). In an association study, the new variant was found in 3 of 413 diabetic patients and in none of 280 glucose tolerant subjects. The variant did not affect the binding of IRS-2 to the insulin receptor or p85a of phosphatidylinositol 3-kinase when measured in the yeast two-hybrid system. Examination of the common Gly1057Asp variant in 363 young healthy subjects and in 228 glucose tolerant offspring of one diabetic parent showed no differences in insulin secretion or insulin sensivity after an intravenous glucose tolerance test. Glucose tolerant middle-aged subjects homozygous for the polymorphism (n = 31), however, had on average a 25 % decrease in fasting serum insulin concentrations (p = 0.009) and 28 % (p = 0.01) and 34 % (p = 0.003) reductions in serum insulin concentrations at 30 and 60 min, respectively, during an OGTT compared with wildtype carriers (n = 107). In a cohort of 639 elderly Swedish men the amino acid variant did not have any detectable impact on insulin secretion after an OGTT. Conclusion/interpretation. No genetic variability was found in the IRS-2 promoter. A rare IRS-2 variant at codon 647 has been identified in Type II diabetic patients. The prevalent codon 1057 polymorphism had no consistent effect on insulin secretion or insulin sensitivity. [Diabetologia (1999

Increased Insulin Resistance in Obese Children Who Have Both 972 IRS-1 and 1057 IRS-2 Polymorphisms

“…Asp1057Gly, a common IRS-2 variant, has not been associated with changes in insulin sensitivity in lean or obese adults (12). Its prevalence is not increased in type 2 diabetes (13).…”

“…Its prevalence is not increased in type 2 diabetes (13). It may, however, affect insulin physiology because subjects homozygous for both IRS-1 and IRS-2 wild-type proteins have serum insulin in the lower 5th percentile of the population (12).…”

IRS2 variants and syndromes of severe insulin resistance

“…rare non-synonymous variants, none of which appear to have a strong impact on insulin sensitivity [5,6].…”

Identification of a single nucleotide polymorphism showing no insulin-mediated suppression of the promoter activity in the human insulin receptor substrate 2 gene

“…Nucleotide substitutions have been detected in the coding region of the human IRS2 gene [14,15,16]. Among them, only the Gly 1057 → Asp is predicted to contribute to the prevalence of Type II diabetes mellitus since Asp 1057 carriers can have higher insulin sensitivity [16].…”

“…Among them, only the Gly 1057 → Asp is predicted to contribute to the prevalence of Type II diabetes mellitus since Asp 1057 carriers can have higher insulin sensitivity [16]. Given that genetic variability in promoter sequences potentially affects the level of protein expression, the organisation and 5′ flanking sequence of human IRS2 were recently examined [15,17,18]. However, the promoter sequence described was only partial and the genetic variability of this sequence in diabetic subjects was not intensively investigated.…”