More than 40 genetic risk variants for type 2 diabetes have been validated. We aimed to test if a genetic risk score associates with the incidence of type 2 diabetes and with 5-year changes in glycemic traits and if the effects were modulated by changes in BMI and lifestyle.The Inter99 study population was genotyped for 46 variants and a genetic risk score was constructed. During a median follow-up of 11 years 327 of 5,850 individuals developed diabetes. Physical examinations and oral glucose tolerance tests were performed at baseline and after 5 years (n=3,727).The risk of incident type 2 diabetes was increased with a hazard ratio of 1.06 [95%CI 1.03-1.08] per risk allele. While the population in general improved their glucose regulation during the 5-year follow-up period, each additional allele in the genetic risk score was associated with a relative increase in fasting, 30-min and 120-min plasma glucose values and a relative decrease in measures of beta-cell function over the 5-year period, whereas indices of insulin sensitivity were unaffected. The effect of the genetic risk score on 5-year changes in fasting plasma glucose was stronger in individuals who increased their BMI.In conclusion, a genetic risk score based on 46 variants associated strongly with incident type 2 diabetes and 5-year changes in plasma glucose and beta-cell function. Individuals who gain weight may be more susceptible to the cumulative impact of type 2 diabetes risk variants on fasting plasma glucose.