Molecular scanning of the insulin receptor substrate-1 (IRS-1) gene in Japanese patients with NIDDM: identification of five novel polymorphisms
| Autor: | Ryohei Yoshimura, Eiichi Araki, Kohji Matsuda, Nobuhiro Miyamura, Hideki Kishikawa, S. Isami, Seiya Shimoda, Motoaki Shichiri, Tetsuya Shirotani, Mikio Todaka, S. Motoyoshi, S. Ura, C R Kahn |
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| Rok vydání: | 1996 |
| Předmět: |
Blood Glucose
Male medicine.medical_specialty endocrine system diseases Endocrinology Diabetes and Metabolism Molecular Sequence Data Polymerase Chain Reaction Insulin resistance Japan Polymorphism (computer science) Reference Values Diabetes mellitus Internal medicine Internal Medicine medicine Humans Point Mutation Amino Acid Sequence Deoxyribonucleases Type II Site-Specific Polymorphism Single-Stranded Conformational DNA Primers Polymorphism Genetic biology Base Sequence Single-strand conformation polymorphism Glucose clamp technique Middle Aged medicine.disease Phosphoproteins Introns IRS1 Insulin receptor Endocrinology Diabetes Mellitus Type 2 biology.protein Glucose Clamp Technique Insulin Receptor Substrate Proteins Female GLUT4 Polymorphism Restriction Fragment Length |
| Zdroj: | Diabetologia. 39(5) |
| ISSN: | 0012-186X |
| Popis: | 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%, p0.05), 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. |
| Databáze: | OpenAIRE |
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