Association of 18 Confirmed Susceptibility Loci for Type 2 Diabetes With Indices of Insulin Release, Proinsulin Conversion, and Insulin Sensitivity in 5,327 Nondiabetic Finnish Men Alena Stančáková 1 , Teemu Kuulasmaa 1 , Jussi Paananen 1 , Anne U. Jackson 2 , Lori L. Bonnycastle 3 , Francis S. Collins 3 , Michael Boehnke 2 , Johanna Kuusisto 1 and Markku Laakso 1 1 Department of Medicine, University of Kuopio and Kuopio University Hospital, Kuopio, Finland; 2 Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan; 3 National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland. Corresponding author: Markku Laakso, markku.laakso{at}kuh.fi . Abstract OBJECTIVE We investigated the effects of 18 confirmed type 2 diabetes risk single nucleotide polymorphisms (SNPs) on insulin sensitivity, insulin secretion, and conversion of proinsulin to insulin. RESEARCH DESIGN AND METHODS A total of 5,327 nondiabetic men (age 58 ± 7 years, BMI 27.0 ± 3.8 kg/m 2 ) from a large population-based cohort were included. Oral glucose tolerance tests and genotyping of SNPs in or near PPARG , KCNJ11 , TCF7L2 , SLC30A8 , HHEX , LOC387761 , CDKN2B , IGF2BP2 , CDKAL1 , HNF1B , WFS1 , JAZF1, CDC123 , TSPAN8 , THADA , ADAMTS9 , NOTCH2 , KCNQ1 , and MTNR1B were performed. HNF1B rs757210 was excluded because of failure to achieve Hardy-Weinberg equilibrium. RESULTS Six SNPs ( TCF7L2 , SLC30A8, HHEX , CDKN2B , CDKAL1 , and MTNR1B ) were significantly ( P < 6.9 × 10 −4 ) and two SNPs ( KCNJ11 and IGF2BP2 ) were nominally ( P < 0.05) associated with early-phase insulin release (InsAUC 0–30 /GluAUC 0–30 ), adjusted for age, BMI, and insulin sensitivity (Matsuda ISI). Combined effects of these eight SNPs reached −32% reduction in InsAUC 0–30 /GluAUC 0–30 in carriers of ≥11 vs. ≤3 weighted risk alleles. Four SNPs ( SLC30A8 , HHEX , CDKAL1 , and TCF7L2 ) were significantly or nominally associated with indexes of proinsulin conversion. Three SNPs ( KCNJ11 , HHEX , and TSPAN8 ) were nominally associated with Matsuda ISI (adjusted for age and BMI). The effect of HHEX on Matsuda ISI became significant after additional adjustment for InsAUC 0–30 /GluAUC 0–30 . Nine SNPs did not show any associations with examined traits. CONCLUSIONS Eight type 2 diabetes–related loci were significantly or nominally associated with impaired early-phase insulin release. Effects of SLC30A8 , HHEX , CDKAL1 , and TCF7L2 on insulin release could be partially explained by impaired proinsulin conversion. HHEX might influence both insulin release and insulin sensitivity. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received January 27, 2009. Accepted May 27, 2009. © 2009 by the American Diabetes Association.