Insulin resistance: interactions between obesity and a common variant of insulin receptor substrate-1

J. O. Clausen, T. Hansen, C. Bj o rbaek, S. M. Echwald, S. A. Urhammer, S. Rasmussen, C. B. Andersen, L. Hansen, K. Almind, O. Pedersen*, J. O. Clausen, K. Borch-Johnsen, K. Winther, J. Haraldsdòttir

*Corresponding author af dette arbejde

    Publikation: Bidrag til tidsskriftArtikelForskningpeer review

    Abstract

    Summary. We previously discovered two aminoacid polymorphisms in codons 513 and 972 of the protein insulin receptor substrate-1 (IRS-1), which is important in cellular insulin action. We have investigated whether these polymorphisms are associated with changes in insulin sensitivity in a random sample of young healthy adults. Insulin sensitivity and secretion were measured during a combined intravenous glucose and tolbutamide tolerance test in 380 unrelated white subjects aged 18-32. IRS-1 polymorphisms were examined by single-strand conformation polymorphism and verified by restriction-enzyme digestion. No homozygous carrier of the codon-513 variant was identified, but one non-obese man had the codon-972 mutation on both alleles. He had low fasting-serum insulin and C-peptide concentrations and low insulin sensitivity and glucose effectiveness. During a 24 h dexamethasone test, he developed transient diabetes. In their heterozygous forms the codon-513 and codon-972 variants of IRS-1 were found in 3% and 9% of the subjects. Non-obese carriers of either polymorphism had similar insulin sensitivity and pancreatic β-cell function to non-obese wild-type subjects (no known variants of IRS-1). Analysis of variance showed, however, a significant interaction between obesity (body-mass index ≥25 kg/m2) and the heterozygous form of the codon-972 variant (p<0·003); obese polymorphism carriers had lower insulin sensitivity than obese non-carriers (mean 6·0 [SD 3·3] vs 12·3 [9·5] ×10-5 L min-1 pmol-1). The obese carriers of the codon-972 variant were also characterised by a clustering of metabolic cardiovascular risk factors, with raised fasting concentrations of plasma glucose, serum triglyceride, and plasma tissue-plasminogen-activator and its fast-acting inhibitor. With adjustment for known modulators of insulin sensitivity, multivariate analyses showed that the combination of obesity and the codon-972 variant was associated with a 50% reduction in insulin sensitivity (p=0·0008). Our results suggest that the codon-972 IRS-1 gene variant may interact with obesity in the pathogenesis of common insulin-resistant disorders.

    OriginalsprogEngelsk
    Sider (fra-til)397-402
    Antal sider6
    TidsskriftThe Lancet
    Vol/bind346
    Udgave nummer8972
    DOI
    StatusUdgivet - 12 aug. 1995

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