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

• Published in: The Lancet (British edition) Vol. 346; no. 8972; pp. 397 - 402
• Main Authors: Clausen, J.O., Hansen, T., Bjørbaek, C., Echwald, S.M., Urhammer, S.A., Rasmussen, S., Andersen, C.B., Hansen, L., Almind, K., Pedersen, O., Borch-Johnsen, K., Winther, K., Haraldsdòttir, J.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 12.08.1995; Elsevier Limited
• Subjects: Adolescent; Adult; Adults; Amino acids; Cardiovascular diseases; Clustering; Codon - genetics; Codons; Dexamethasone; Diabetes mellitus; Fasting; Female; Gene polymorphism; Glucose; Glucose tolerance; Glucose Tolerance Test; Health risks; Heterozygote; Humans; Insulin; Insulin receptor substrate 1; Insulin Receptor Substrate Proteins; Insulin Resistance; Intravenous administration; IRS-1 gene; Male; Medical research; Modulators; Mutation; Obesity; Obesity - genetics; Obesity - metabolism; Pancreas; Pathogenesis; Phosphoproteins - genetics; Polymorphism; Polymorphism, Genetic; Proteins; Risk analysis; Risk factors; Secretion; Sensitivity analysis; Substrates; Tolbutamide; Variance analysis
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(95)92779-4

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.