Molecular scanning of the insulin receptor substrate 1 gene in subjects with severe insulin resistance: detection and functional analysis of a naturally occurring mutation in a YMXM motif.

Whitehead, Jonathan P.; Humphreys, P; Krook, Anna; Jackson, R.; Hayward, Amanda C.; Lewis, Helen M.; Siddle, Kenneth; O’Rahilly, Stephen

doi:10.2337/diabetes.47.5.837

Cited by 34 publications

(22 citation statements)

References 8 publications

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“…To the extent one can extrapolate from mice to humans, this lack of IRS-3 in humans might produce an increased dependence on IRS-1 in both adipocyte differentiation and control of insulin sensitivity. If this is the case, then mutations or sequence variants of IRS-1 such as those reported in a number of studies (Almind et al 1993;Imai et al 1994;Laakso et al 1994;Whitehead et al 1998) may lead to more exaggerated effects than would occur if IRS-3 were also present.…”

Section: Discussionmentioning

confidence: 99%

Lipoatrophic diabetes in Irs1^−/−/Irs3^−/− double knockout mice

Laustsen¹,

Michael²,

Crute³

et al. 2002

Genes Dev.

116

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Section: Discussionmentioning

confidence: 99%

Lipoatrophic diabetes in Irs1^−/−/Irs3^−/− double knockout mice

Laustsen¹,

Michael²,

Crute³

et al. 2002

Genes Dev.

116

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“…We identified 44 articles published until January 2002 on the Gly972Arg polymorphism in Type 2 diabetic patients and control subjects. We excluded five studies because they examined the expression of the mutation instead of the prevalence [29,30,31,32,33]. We excluded seven studies because case subjects were relatives of Type 2 diabetic patients [34,35,36,37] or were obese subjects [27,38,39] instead of Type 2 diabetic patients.…”

Section: Methodsmentioning

confidence: 99%

Gly972Arg variant in the insulin receptor substrate-1 gene and association with Type 2 diabetes: a meta-analysis of 27 studies

et al. 2003

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Aims/hypothesis. Several case-control studies have examined the association between the Gly972Arg variant in the IRS-1 gene and Type 2 diabetes, but most had limited power and results could therefore be conflicting. Methods. We systematically reviewed the literature by means of a meta-analysis and investigated sources of heterogeneity in results of different studies.Results. The summary risk ratio, based on 3408 cases and 5419 control cases from 27 studies, was 1.25 (95% CI 1.05-1.48). The results, however, differed according to the type of study, method of verifying non-diabetic status of the control subjects, and age of the case subjects. Population-based studies reported lower odds ratios than hospital-based studies (OR 0.98, 95% CI 0.74-1.30 vs OR 1.43, 95% CI 1.17-1.74). Also, the diagnostic test to exclude diabetes amongst control subjects interacted with the association between the IRS-1 Gly972Arg variant and Type 2 diabetes (p=0.03). Finally, the odds ratio reduced with increasing age (p=0.03). Conclusion/interpretation. Overall, carriers of the 972Arg variant of the IRS-1 gene are at a 25% increased risk of having Type 2 diabetes compared with non-carriers. The odds ratios are generally higher in hospital-based studies, including relatively young, symptomatic, cases. [Diabetologia (2003) 46:990-995]

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“…Apart from insulin receptor gene mutations, monogenic causes of severe insulin resistance have been elusive. Mutations in IRS-1 are uncommon in severe insulin resistance, although one person with a missense mutation in IRS-1 has been described [47]. The Gly 972 Arg IRS-1 polymorphism has been associated with Type II diabetes [48,49] as have mutations in the PTB domain of IRS-1 [50].…”

Section: Discussionmentioning

confidence: 99%

Natural variants of human p85α phosphoinositide 3-kinase in severe insulin resistance: a novel variant with impaired insulin-stimulated lipid kinase activity

et al. 2000

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Severe insulin resistance is found in a heterogeneous group of uncommon disorders characterised by acanthosis nigricans, impaired glucose tolerance or diabetes mellitus and in women, features of hyperandrogenism such as oligomenorrhoea and hirsutism [1±3]. The mechanisms underlying severe insulin resistance in human disease remain poorly understood, but mutations in the insulin receptor gene or autoantibodies to the insulin receptor are responsible in only a small minority of cases [4±6]. The increasing knowledge of the complexity of intracellular insulin signalling path- Diabetologia (2000) AbstractAims/hypothesis. Phosphoinositide 3-kinase (PI 3K) plays a central part in the mediation of insulin-stimulated glucose disposal. No genetic studies of this enzyme in human syndromes of severe insulin resistance have been previously reported. Methods. Phosphoinositide 3-kinase p85a regulatory subunit cDNA was examined in 20 subjects with syndromes of severe insulin resistance by single strand conformational polymorphism and restriction fragment length polymorphism analyses. Insulin-stimulated phosphoinositide 3-kinase activity and recruitment into phosphotyrosine complexes of variants of p85a were studied in transiently transfected HEK293 cells. Phosphopeptide binding characteristics of wild-type and mutant p85a-GST fusion proteins were examined by surface plasmon resonance. Results. The common p85a variant, Met 326 I1e, was identified in 9 of the 20 subjects. Functional studies of the Met 326 Ile variant showed it to have equivalent insulin-stimulated lipid kinase activity and phosphotyrosine recruitment as wild-type p85a. A novel heterozygous mutation, Arg 409 Gln, was detected in one subject. Within the proband's family, carriers of the mutation had a higher median fasting plasma insulin (218 pmol/l) compared with wild-type relatives (72 mol/l) (n = 8 subjects, p = 0.06). The Arg 409 Gln p85a subunit was associated with lower insulin-stimulated phosphoinositide 3-kinase activity compared with wild-type (mean reduction 15 %, p < 0.05, n = 5). The recruitment of Arg 409 Gln p85a into phosphotyrosine complexes was not significantly impaired. GST fusion proteins of wild-type and mutant p85a showed identical binding to phosphopeptides in surface plasmon resonance studies. Conclusion/interpretation. Mutations in p85a are uncommon in subjects with syndromes of severe insulin resistance. The Met 326 Ile p85a variant appears to have no functional effect on the insulin-stimulated phosphoinositide 3-kinase activity. The impaired phosphoinositide 3-kinase activity of the Arg 409 Gln mutant suggests that it could contribute to the insulin resistance seen in this family. [Diabetologia (2000) 43: 321±331] Keywords Keywords Genetics, insulin signalling, phosphatidylinositol 3-kinase.

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Molecular scanning of the insulin receptor substrate 1 gene in subjects with severe insulin resistance: detection and functional analysis of a naturally occurring mutation in a YMXM motif.

Cited by 34 publications

References 8 publications

Lipoatrophic diabetes in Irs1^−/−/Irs3^−/− double knockout mice

Lipoatrophic diabetes in Irs1^−/−/Irs3^−/− double knockout mice

Gly972Arg variant in the insulin receptor substrate-1 gene and association with Type 2 diabetes: a meta-analysis of 27 studies

Natural variants of human p85α phosphoinositide 3-kinase in severe insulin resistance: a novel variant with impaired insulin-stimulated lipid kinase activity

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Molecular scanning of the insulin receptor substrate 1 gene in subjects with severe insulin resistance: detection and functional analysis of a naturally occurring mutation in a YMXM motif.

Cited by 34 publications

References 8 publications

Lipoatrophic diabetes in Irs1−/−/Irs3−/− double knockout mice

Lipoatrophic diabetes in Irs1−/−/Irs3−/− double knockout mice

Gly972Arg variant in the insulin receptor substrate-1 gene and association with Type 2 diabetes: a meta-analysis of 27 studies

Natural variants of human p85α phosphoinositide 3-kinase in severe insulin resistance: a novel variant with impaired insulin-stimulated lipid kinase activity

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Lipoatrophic diabetes in Irs1^−/−/Irs3^−/− double knockout mice

Lipoatrophic diabetes in Irs1^−/−/Irs3^−/− double knockout mice