Molecular scanning of the insulin receptor substrate-1 (IRS-1) gene in Japanese patients with NIDDM: identification of five novel polymorphisms

Abstract

Since the insulin receptor substrate-1 (IRS-1) is the major substrate of the insulin receptor tyrosine kinase and has been shown to activate phosphatidylinositol (PI) 3-kinase and promote GLUT4 translocation, the IRS-1 gene is a potential candidate for development of non-insulin-dependent diabetes mellitus (NIDDM). In this study, we have identified IRS-1 gene polymorphisms, evaluated their frequencies in Japanese subjects, and analysed the contribution of these polymorphisms to the development of NIDDM. The entire coding region of the IRS-1 gene of 94 subjects (47 NIDDM and 47 control subjects) was screened by polymerase chain reaction-single stranded conformation polymorphism (PCR-SSCP) analysis. Seven SSCP polymorphisms were identified. These corresponded to two previously identified polymorphisms [Gly971 --> Arg (GGG --> AGG) and Ala804 (GCA --> GCG)] as well as five novel polymorphisms [Pro190 --> Arg (CCC --> CGC), Met209 --> Thr (ATG --> ACG), Ser809 --> Phe (TCT --> TTT), Leu142 (CTT --> CTC), and Gly625 (GGC --> GGT)]. Although the prevalence of each of these polymorphisms was not statistically different between NIDDM and control subjects, the prevalence of the four IRS-1 polymorphisms with an amino acid substitution together was significantly higher in NIDDM than in control subjects (23.4 vs 8.5%, p < 0.05), and two substitutions (Met 209 --> Thr and Ser809 --> Phe) were found only in NIDDM patients. Equilibrium glucose infusion rates during a euglycaemic clamp in NIDDM and control subjects with the IRS-1 polymorphisms decreased by 29.5 and 22.0%, respectively on the average when compared to those in comparable groups without polymorphisms, although they were not statistically significant. Thus, IRS-1 polymorphisms may contribute in part to the insulin resistance and development of NIDDM in Japanese subjects; however, they do not account for the major part of the decrease in insulin-stimulated glucose uptake which is observed in subjects with clinically apparent NIDDM.

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.…”

“…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. 1).…”

“…Diagnostic tests to exclude diabetes in the control subjects were a single fasting blood glucose test in ten studies [2,3,8,14,18,19,20,21,22] and a glucose tolerance test in nine studies [5, 6, 8, 9, 10, 16, . In nine studies no diagnostic test has been used or reported [4,11,12,13,15,23,26]. SSCP analysis was used in three studies to determine the polymorphism [6,15], fifteen studies used direct enzyme digestion [8,10,12,14,16,17,18,19,20,21,22,26], and seven studies used both [2,4,5,9,11,13,23].…”

“…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.…”