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Background  A meta-analysis of genome-wide data reported the discovery of the rs35767 polymorphism near IGF1 with genome-wide significant association with fasting insulin levels. However, it is unclear whether the effects of this polymorphism on fasting insulin are mediated by a reduced insulin sensitivity or impaired insulin clearance. We investigated the effects of the rs35767 polymorphism on circulating IGF-1 levels, insulin sensitivity, and insulin clearance.Methodology/Principal Findings  Two samples of adult nondiabetic white Europeans were studied. In sample 1 (n=569), IGF-1 levels were lower in GG genotype carriers compared with A allele carriers (190±77 vs. 218±97 ng/ml, respectively;  P =0.007 after adjusting for age, gender, and BMI). Insulin sensitivity assessed by euglycaemic-hyperinsulinemic clamp was lower in GG genotype carriers compared with A allele carriers (8.9±4.1 vs. 10.1±5.1 mg x Kg -1  free fat mass x min -1 , respectively;  P =0.03 after adjusting for age, gender, and BMI). The rs35767 polymorphism did not show significant association with insulin clearance. In sample 2 (n=859), IGF-1 levels were lower in GG genotype carriers compared with A allele carriers (155±60 vs. 164±63 ng/ml, respectively;  P =0.02 after adjusting for age, gender, and BMI). Insulin sensitivity, as estimated by the HOMA index, was lower in GG genotype carriers compared with A allele carriers (2.8±2.2 vs. 2.5±1.3, respectively;  P =0.03 after adjusting for age, gender, and BMI).    Conclusion/Significance  The rs35767 polymorphism near  IGF1  was associated with circulating IGF-1 levels, and insulin sensitivity with carriers of the GG genotype exhibiting lower IGF-1 concentrations and insulin sensitivity as compared with subjects carrying the A allele.

A Fasting Insulin–Raising Allele at IGF1 Locus Is Associated with Circulating Levels of IGF-1 and Insulin Sensitivity