Insulin receptor substrate-2 amino acid polymorphisms are not associated with random type 2 diabetes among Caucasians.

Bernal, Dolores; Almind, Katrine; Yenush, Lynne; Ayoub, Melissa A.; Zhang, Yitao; Rosshani, Leyla; Larsson, Catharina; Pedersen, Oluf; White, Morris F.

doi:10.2337/diabetes.47.6.976

Cited by 78 publications

(57 citation statements)

References 9 publications

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“…A possible effect of the latter amino acid substitution for the function of IRS-2 is difficult to predict from the primary structure of the protein. We failed to show an association of the codon 1057 polymorphism with an increased prevalence of Type II diabetes [2]. The purpose of the present study, therefore, was to elucidate whether the prevalent polymorphism at codon 1057 in human IRS-2 was associated with intermediary pre-diabetic phenotypes by studying insulin secretion and insulin sensitivity in glucose tolerant subjects from four Scandinavian population samples.…”

Section: : 1244±1249]mentioning

confidence: 99%

“…the IRS-2 deficient mice therefore suggests that IRS-2 plays a unique part in the regulation of beta-cell neogenesis, proliferation and survival. We have previously studied the genetic variability of the coding region of human IRS-2 [2] and reported on two nucleotide substitutions that predicted amino acid changes. One of these was a rare variant at codon 879 which resulted in a glycine to a serine substitution; the other was at codon 1057, had an allelic frequency of 34 % in both control subjects and Type II diabetic patients and predicted a replacement of glycine by aspartic acid.…”

Section: : 1244±1249]mentioning

confidence: 99%

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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

et al. 1999

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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

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Section: : 1244±1249]mentioning

confidence: 99%

Section: : 1244±1249]mentioning

confidence: 99%

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

et al. 1999

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“…SNP genotypes were determined by the analysis of PCR products. In a control group of lean and healthy Caucasians, the allelic frequency of these variants was 7 and 30% respectively, as reported (4,13). Procedures.…”

Section: Methodsmentioning

confidence: 99%

“…In contrast, combined heterozygous IRS-1 ϩ/-IRS-2 ϩ/Ϫ mice showed marked insulin resistance, indicating the importance of combined gene dosage effects of the IRS proteins. Because postreceptor defects are characteristic features of type 2 diabetes, variations in the coding regions of IRS-1 and IRS-2 genes have been studied extensively (3,4). There has been no report of monogenic forms of type 2 diabetes due to mutations of these genes.…”

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confidence: 99%

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

2002

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“…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].…”

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

et al. 2002

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Aims/hypothesis. To understand the transcriptional regulation and to investigate the pathological influence upon Type II (non-insulin-dependent) diabetes mellitus of insulin receptor substrate 2 (IRS2), the 5′ flanking region of the human IRS2 gene was cloned and screened in Japanese diabetic patients. Methods. Luciferase reporter assay and electrophoretic mobility shift assay (EMSA) were combined in HepG2, Fao, RINm5F, and HeLa cells to characterise the human IRS2 promoter region. Single nucleotide polymorphisms (SNPs) were identified in Japanese Type II diabetic patients by sequencing and were genotyped. Results. The proximal 2399 bp of the 5′ flanking region of the human IRS2 gene was cloned. A core promoter region was extended between nucleotide positions -834 and -557 (relative to the translation initiation site). The region [(-758)AGGGGGAGGG (-749)] that appears important in the positive regulation of IRS2 transcription was identified by EMSA with 32 Plabelled double-stranded oligonucleotides encompassing regions protected from DNase I digestion by nuclear extract of HepG2 cells. Two SNPs (-765C/T and -2062T/C), identified by screening Japanese Type II diabetic patients, were not associated with Type II diabetes. IRS2-driven reporter activity in the plasmid containing thymine at -765 was not suppressed by insulin when measured in Fao cells. Conclusion/interpretation. The 5′ flanking sequence of the human IRS2 was investigated and two SNPs were identified. The SNP at -765 was suggested to be involved in the insulin-mediated regulation of the transcriptional activity of IRS2. [Diabetologia (2002) The insulin receptor substrate (IRS) proteins are phosphorylated by the insulin receptor (IR) and mediate the actions of insulin by acting as adapter or scaffolding molecules [1]. To date, four IRS proteins (IRS1 to IRS4) have been identified, all of which possess a conserved domain structure that includes pleckstrin homology and phosphotyrosine-binding domains in the NH 2 -terminal region [2,3,4,5,6]. The COOHterminal region of these proteins is poorly conserved, with the exception of the presence of multiple motifs that undergo tyrosine phosphorylation in response to insulin and serve as docking sites for Src homology 2 domain-containing proteins, such as phosphatidylinositol 3-kinase (PI3K), SH2 domain-containing phosphotyrosine phosphatase (SHP2), and Grb2. These motifs are therefore thought to mediate most IR downstream signalling events that cause insulin action.

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Insulin receptor substrate-2 amino acid polymorphisms are not associated with random type 2 diabetes among Caucasians.

Cited by 78 publications

References 9 publications

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

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

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

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

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