title: 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.
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.
  
  
  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 x 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 >or=11 vs. <or=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.
authors.affiliation: Department of Medicine, University of Kuopio and Kuopio University Hospital, Kuopio, Finland.
authors.forename: Alena
authors.initials: A
authors.lastname: Stancáková
authors.forename: Teemu
authors.initials: T
authors.lastname: Kuulasmaa
authors.forename: Jussi
authors.initials: J
authors.lastname: Paananen
authors.forename: Anne U
authors.initials: AU
authors.lastname: Jackson
authors.forename: Lori L
authors.initials: LL
authors.lastname: Bonnycastle
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
authors.forename: Michael
authors.initials: M
authors.lastname: Boehnke
authors.forename: Johanna
authors.initials: J
authors.lastname: Kuusisto
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
mesh_terms: D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000235:genetics* / Q000378:metabolism; D005387:Finland / Q000453:epidemiology; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005838:Genotype; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011384:Proinsulin / Q000378:metabolism*; D012307:Risk Factors
chemical_list: D007328:Insulin; D011384:Proinsulin