752 © 2004 Diabetes UK. Diabetic Medicine, 21, 752– 758 DOI: 10.1111/j.1464-5491.2004.01229.x Introduction Insulin receptor substrate-1 (IRS-1) mediates the metabolic and growth promoting effects of insulin and insulin growth factor-I by acting as a docking protein between the insulin receptor and intracellular signalling molecules [1]. IRS-1 knockout mice show insulin resistance, defects in glucose- induced insulin secretion, mild glucose intolerance, and features of the insulin resistance syndrome [1]. The common IRS-1 Gly972Arg polymorphism is among the most exten- sively studied genetic variants in relation to Type 2 diabetes. In vitro, the variant was related to lower insulin sensitivity in Correspondence to: Rob M. van Dam, Department of Nutrition and Health, Faculty of Earth and Life Sciences, Vrije Universiteit Amsterdam, de Boelelaan 1085, 1081 HV Amsterdam, the Netherlands. E-mail: rob.van.dam@falw.vu.nl Abstract Aims The insulin receptor substrate-1 (IRS-1) gene is among the most frequently studied candidate genes for Type 2 diabetes, but findings have been inconsistent. This may have been due to generally small study sizes, or to interaction with body fatness as suggested by studies of insulin sensitivity. The aim of this study was to test the hypothesis that the IRS-1 Gly972Arg variant increases risk of Type 2 diabetes. Methods We conducted two large population-based studies including a total of 725 cases and 742 control subjects, who were Caucasian Dutch men and women aged 40–70 years. We calculated odds ratios adjusted for body mass index, study centre, sex and age. Results Carriers of the Arg allele did not have a higher prevalence of newly detected (OR 0.49, 95% CI 0.24 –1.01) or treated (OR 0.71, 0.37–1.35) Type 2 diabetes in the first study, or a higher prevalence of glucose intolerance (OR 1.07, 0.71–1.59) in the second study. The summary odds ratio was 0.86 (0.62–1.17) for carrying the Arg allele as compared with the Gly/Gly genotype. Associations did not differ appreciably by degree of obesity. Also, the Arg variant was not associated with detrimental values for body mass index, waist circumference, plasma HDL-and total cholesterol or hypertension. Conclusions Our findings indicate that the IRS-1 Gly972Arg variant does not substantially increase risk of common Type 2 diabetes, or Type 2 diabetes in obese persons. Diabet. Med. 21, 752–758 (2004) Keywords cardiovascular risk factors, genetics, obesity, population-based study, Type 2 diabetes Abbreviations BMI, body mass index; CI, confidence interval; HDL, high- density lipoprotein; IRS-1, insulin receptor substrate-1; OR, odds ratio Blackwell Publishing, Ltd. Oxford, UK DME Diabetic Medicine 0742-3071 Blackwell Publishing, 2004 21 Original Article Original article IRS-1 Gly972Arg and Type 2 diabetes R. M. van Dam et al. The insulin receptor substrate-1 Gly972Arg polymorphism is not associated with Type 2 diabetes mellitus in two population-based studies R. M. van Dam*†, B. Hoebee‡, J. C. Seidell†, M. M. Schaap‡, E. E. Blaak§ and E. J. M. Feskens* *Center of Nutrition and Health, National Institute for Public Health and the Environment, Bilthoven, †Department of Nutrition and Health, Vrije Universiteit Amsterdam, ‡Laboratory of Health Effects Research, National Institute for Public Health and the Environment, Bilthoven, §Department of Human Biology, Nutrition Research Center, Maastricht University, Maastricht, the Netherlands Accepted 30 September 2003