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Common genetic variants have been recently associated with fasting glucose and insulin levels in white populations. Whether these associations replicate in pre-diabetes is not known. We extended these findings to the Diabetes Prevention Program, a clinical trial in which participants at high risk for diabetes were randomized to placebo, lifestyle modification or metformin for diabetes prevention. We genotyped previously reported polymorphisms (or their proxies) in/near  G6PC2 ,  MTNR1B ,  GCK ,  DGKB ,  GCKR ,  ADCY5 ,  MADD ,  CRY2 ,  ADRA2A ,  FADS1 ,  PROX1 ,  SLC2A2 ,  GLIS3 ,  C2CD4B ,  IGF1 , and  IRS1  in 3,548 Diabetes Prevention Program participants. We analyzed variants for association with baseline glycemic traits, incident diabetes and their interaction with response to metformin or lifestyle intervention. We replicated associations with fasting glucose at  MTNR1B  ( P <0.001),  G6PC2  ( P  = 0.002) and  GCKR  ( P  = 0.001). We noted impaired β-cell function in carriers of glucose-raising alleles at  MTNR1B  ( P <0.001), and an increase in the insulinogenic index for the glucose-raising allele at  G6PC2  ( P <0.001). The association of  MTNR1B  with fasting glucose and impaired β-cell function persisted at 1 year despite adjustment for the baseline trait, indicating a sustained deleterious effect at this locus. We also replicated the association of  MADD  with fasting proinsulin levels ( P <0.001). We detected no significant impact of these variants on diabetes incidence or interaction with preventive interventions. The association of several polymorphisms with quantitative glycemic traits is replicated in a cohort of high-risk persons. These variants do not have a detectable impact on diabetes incidence or response to metformin or lifestyle modification in the Diabetes Prevention Program.

Effects of Genetic Variants Previously Associated with Fasting Glucose and Insulin in the Diabetes Prevention Program