Molecular scanning for mutations in the insulin receptor substrate-1 (IRS-1) gene in Mexican Americans with Type 2 diabetes mellitus

Celi, Francesco S.; Negri, Carlo; Tanner, Kandice; Raben, Nina; Pablo, Flora de; Rovira, Adela; Pallardo, Luís Felipe; Martín-Vaquero, Pilar; Stern, Michael P.; Mitchell, Braxton D.; Shuldiner, Alan R.

doi:10.1002/1520-7560(2000)9999:9999<::aid-dmrr129>3.0.co;2-b

Cited by 30 publications

(11 citation statements)

References 57 publications

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“…In this study, we observed a frequency of about 4% for Arg972, which is similar to the one reported in another Mexican American population (40). Similarly, Gly(972)Arg failed to show an association with T2DM as reported (40). …”

Section: Discussionsupporting

confidence: 91%

“…The Arg972 variant of IRS1 was found to be more common in Caucasians (20%) (37) compared with African Americans (11%) (38), Asians (4%) (39), and Mexican Americans (4%) (40). In this study, we observed a frequency of about 4% for Arg972, which is similar to the one reported in another Mexican American population (40). Similarly, Gly(972)Arg failed to show an association with T2DM as reported (40).…”

Section: Discussionmentioning

confidence: 99%

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The Gly(972)Arg Variant of Human IRS1 Gene Is Associated With Variation in Glomerular Filtration Rate Likely Through Impaired Insulin Receptor Signaling

et al. 2012

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The objective of this study is to identify and characterize the genetic variants related to the glomerular filtration rate (GFR) linkage on 2q37. Of the positional candidate genes, we selected IRS1 and resequenced its 2-kb promoter region and exons for sequence variants in 32 subjects. A total of 11 single nucleotide polymorphisms (SNPs) were identified. To comprehensively cover the 59-kb-long intron-1, eight additional tagging SNPs were selected from the HapMap. All the 19 SNPs were genotyped by TaqMan Assay in the entire data set (N = 670; 39 families). Association analyses between the SNPs and GFR and type 2 diabetes–related traits were performed using the measured genotype approach. Of the SNPs examined for association, only the Gly(972)Arg variant of IRS1 exhibited a significant association with GFR (P = 0.0006) and serum triglycerides levels (P = 0.003), after accounting for trait-specific covariate effects. Carriers of Arg972 had significantly decreased GFR values. Gly(972)Arg contributed to 26% of the linkage signal on 2q. Expression of IRS1 mutant Arg972 in human mesangial cells significantly reduced the insulin-stimulated phosphorylation of IRS1 and Akt kinase. Taken together, the data provide the first evidence that genetic variation in IRS1 may influence variation in GFR probably through impaired insulin receptor signaling.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

The Gly(972)Arg Variant of Human IRS1 Gene Is Associated With Variation in Glomerular Filtration Rate Likely Through Impaired Insulin Receptor Signaling

et al. 2012

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“…So far, many polymorphisms described in IRS1 gene, located in 2q36-37, especially Gly972Arg substitution, are shown to be associated with insulin resistance in studies with different several populations and meta-analyses about type 2 diabetes ( Aileen et al, 2005 , Burguete-Garcia et al, 2010 , Celi et al, 2000 , Jellema et al, 2003 , Martínez-Gómez et al, 2011 , Zaman Huri et al, 2012 ). The single nucleotide polymorphisms (SNPs) Gly972Arg, Pro170Arg and Met209Thr in IRS1 gene have been reported to be associated with a reduction in phosphatidylinositol 3 kinase (PI3K) activity ( Yoshimura et al, 1997 ) and subsequently development of insulin resistance ( Armstrong et al, 1996 , Garcia et al, 1993 , Yoshimura et al, 1997 ).…”

Section: Introductionmentioning

confidence: 99%

IRS1 gene polymorphisms Gly972Arg and Ala513Pro are not associated with insulin resistance and type 2 diabetes risk in non-obese Turkish population

et al. 2014

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Insulin receptor substrate 1 (IRS1), plays a critical role in insulin signaling and its control has an important place in the development of insulin resistance. The tyrosine phosphorylation of IRS1 serves as docking molecules for downstream effectors such as Phosphatidylinositol 3-kinase and phosphotyrosine phosphatase-2. We focused on the Gly972Arg and Ala513Pro variants of the IRS1 gene, since these specific allelic variants are located near the Tyr-Met-X-Met (YMXM) motifs around Tyr987 and Tyr612. Thus, we aimed to investigate the effects of Gly972Arg/Ala513Pro polymorphisms in IRS1 gene on development of insulin resistance and the risk of type 2 diabetes in a non-obese Turkish population. This work included 306 individuals comprising 178 subjects with type 2 diabetes and 128 healthy subjects matched for body mass index. Gly972Arg/Ala513Pro polymorphisms had no effect on type 2 diabetes risk and its phenotypes (P > 0.05). Although IRS1 gene and its variants are associated with type 2 diabetes and insulin resistance in several studies worldwide, our data showed that there is no association between Gly972Arg and Ala513Pro variants in IRS1 and disease in Turkish population.

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“…The gene is encoded on chromosome 2q36 as a single exon. To date, several amino acid variants in the IRS-1 gene have been identified in humans [87][88][89][90][91].…”

Section: The Pc-1 Genementioning

confidence: 92%

“…In some studies, Gly971Arg IRS-1 was weakly associated with type 2 diabetes [87,88], particularly in obese subjects [92,93], whereas in other studies no significant associations were found [89][90][91]94]. In vitro expression and functional studies of the Gly971Arg IRS-1 variant are controversial.…”

Section: The Pc-1 Genementioning

confidence: 99%

Genetics of insulin resistance

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McLenithan²,

Silver³

et al. 2002

Curr Diab Rep

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Insulin resistance, defined as the decreased ability of insulin to perform its biological functions, is likely to represent the primary physiologic defect underlying the insulin resistance syndrome (IRS), which includes insulin resistance/hyperinsulinemia, glucose intolerance and/or type 2 diabetes mellitus, visceral obesity, hypertension, and dyslipidemia. This constellation of traits is a leading cause of cardiovascular mortality and morbidity. Insulin sensitivity varies widely among individuals. Although environmental provocations including physical inactivity and caloric excess play an important role in the development of obesity and thus insulin resistance, epidemiologic and family studies show that there are also moderate genetic influences on the development of insulin resistance. Extreme forms of insulin resistance may be caused rarely by mutations in the genes for the insulin receptor and peroxisome proliferator-activated receptor gamma. However, the genetic basis for common more moderate forms of insulin resistance is likely to be polygenic and heterogeneous. Evidence further suggests that gene variants may have phenotypic influences on more than one IRS trait (so-called pleiotrophy), which may explain, in part, the clustering of these traits. This article reviews the evidence that insulin resistance has a genetic basis. Progress to date toward identifying specific gene variants are reviewed. Ultimately, the identification of specific gene variants that influence insulin resistance and other IRS traits will have profound influences on our understanding of the molecular and pathophysiologic basis of these disorders, from which new and more effective preventive and therapeutic interventions will be possible.

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Molecular scanning for mutations in the insulin receptor substrate-1 (IRS-1) gene in Mexican Americans with Type 2 diabetes mellitus

Abstract: Ala94Thr, Ala512Pro and Ser892Gly mutation are rare in the populations studied. Gly971Arg, is more common in Mexican Americans and Caucasians, but is not a major contributor to genetic susceptibility to Type 2 diabetes.

Cited by 30 publications

References 57 publications

The Gly(972)Arg Variant of Human IRS1 Gene Is Associated With Variation in Glomerular Filtration Rate Likely Through Impaired Insulin Receptor Signaling

The Gly(972)Arg Variant of Human IRS1 Gene Is Associated With Variation in Glomerular Filtration Rate Likely Through Impaired Insulin Receptor Signaling

IRS1 gene polymorphisms Gly972Arg and Ala513Pro are not associated with insulin resistance and type 2 diabetes risk in non-obese Turkish population

Genetics of insulin resistance

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