Insulin Sensitivity Is Not Affected by Mutation of Codon 972 of the Human IRS-1 Gene

Abstract

We investigated the relationship of codon 972 polymorphism of the insulin receptor substrate-1 (IRS-1) gene with insulin resistance in the Japanese population. Among 130 patients with type-2 diabetes mellitus (DM), we identified 6 who were heterozygous for the Gly972Arg mutation. Among 144 healthy subjects, 6 were heterozygous and 1 was homozygous for the mutation. A hyperinsulinemic euglycemic clamp study was performed in 3 of 6 diabetic patients with the heterozygous Gly972Arg mutation and in 60 without it. Both groups showed almost the same levels of insulin sensitivity (glucose infusion rate, GIR = 50.2 ± 3.0 vs. 51.3 ± 12.1 μmol/kg/min). Similarly, there was no difference in insulin sensitivity between healthy subjects with and without the mutation using the homeostasis model assessment (HOMA index = 1.14 ± 0.50 vs. 1.02 ± 0.63). The frequency of the Gly972Arg allele was not increased in diabetic patients compared with control subjects even in aged (>50 years old) or obese (BMI ≥25) subjects. Among healthy subjects, we identified a 25-year-old male with the homozygous Gly972Arg allele. He was slightly obese (BMI = 25.5) but showed relatively high insulin sensitivity, almost equal to that of healthy subjects without the mutation (GIR = 67.2 vs. 71.8 ± 22.0 μmol/kg/min). Because the GIR in healthy subjects was significantly higher compared with that in type-2 DM patients, we speculate that another genetic or environmental factor producing a more deleterious effect on insulin sensitivity may exist in diabetic patients. We conclude that this gene abnormality does not play a role in the pathogenesis of insulin resistance and type-2 DM.

Microarray profiling of skeletal muscle tissues from equally obese, non-diabetic insulin-sensitive and insulin-resistant Pima Indians

“…This explanation, together with the gene location on 2q36 in the vicinity of a suggestive linkage to insulin action in Pima Indians [7], lead to the possibility of a polymorphism(s) in the IRS1 gene that regulates its expression. The frequency of the Gly972Arg polymorphism in the IRS1 gene is higher in Type II diabetic patients of some, but not all, studied ethnic groups [25,26,27,28]. This polymorphism is absent, or at least very rare, in Pima Indians [29]; thus, the differentially regulated IRS1 expression in the subjects of our study was not associated with Gly972Arg polymorphism.…”

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

“…This additional information was provided by nine authors on ten study populations [8,13,15,16,17,18,19,20,23].…”

“…Of the studies five were population-based studies [5,8,19,21] and 22 studies were hospital-based studies [2,3,4,6,9,10,11,12,13,14,15,16,17,18,20,22,23,26]. Seventeen studies included Caucasian subjects [2,3,4,5,8,11,12,14,15,18,19,20,22,23,26], eight studies included Asian subjects [6,8,9,10,13,16,17], and three studies black or South American subjects [15,21,23] (Fig.…”

“…Based on seven studies published up to 1996 [2,3,4,5,8,12], a combined odds ratio of 1.49 has been reported [12]. However, since then a number of other studies have been published in which no association was observed [15,16,17,19,20,21,22,23]. Besides study power and other methodological issues, interaction with important diabetic risk factors such as body weight could have resulted in heterogeneous findings.…”

“…Polymorphisms in the IRS-1 gene were identified for the first time in 1993 [2]. Since then, many case control studies have examined the association between the Gly972Arg variant and Type 2 diabetes [2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26]. Results, however, are not association between the Gly972Arg variant in the IRS-1 gene and the prevalence of Type 2 diabetes.…”