title: 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.
authors: Department of Metabolic Medicine, Kumamoto University School of Medicine, Japan.
authors: S
authors: S
authors: Ura
authors: E
authors: E
authors: Araki
authors: H
authors: H
authors: Kishikawa
authors: T
authors: T
authors: Shirotani
authors: M
authors: M
authors: Todaka
authors: S
authors: S
authors: Isami
authors: S
authors: S
authors: Shimoda
authors: R
authors: R
authors: Yoshimura
authors: K
authors: K
authors: Matsuda
authors: S
authors: S
authors: Motoyoshi
authors: N
authors: N
authors: Miyamura
authors: C R
authors: CR
authors: Kahn
authors: M
authors: M
authors: Shichiri
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism; D017931:DNA Primers; D015252:Deoxyribonucleases, Type II Site-Specific; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007438:Introns; D007564:Japan; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000235:genetics*; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D018807:Polymorphism, Single-Stranded Conformational; D012016:Reference Values
chemical_list: D001786:Blood Glucose; D017931:DNA Primers; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; C046545:CCWGG-specific type II deoxyribonucleases; D015252:Deoxyribonucleases, Type II Site-Specific