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. 2009 Sep;58(9):2129-36.
doi: 10.2337/db09-0117. Epub 2009 Jun 5.

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 Stancáková  1 , Teemu Kuulasmaa, Jussi Paananen, Anne U Jackson, Lori L Bonnycastle, Francis S Collins, Michael Boehnke, Johanna Kuusisto, Markku Laakso
Affiliations
Free PMC article

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 Stancáková et al. Diabetes. 2009 Sep.
Free PMC article

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 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.

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Figures

FIG. 1.
FIG. 1.
Early-phase insulin release (InsAUC0–30/GluAUC0–30) according to the number of risk alleles in eight insulin secretion–related SNPs (KCNJ11 rs5219, TCF7L2 rs7903146, SLC30A8 rs13266634, HHEX rs1111875, CDKN2B rs10811661, IGF2BP2 rs4402960, CDKAL1 rs7754840, and MTNR1B rs10830963). For each subject, the number of type 2 diabetes risk alleles (0, 1, 2) per SNP was weighted for their effect sizes (shown in Table 1; average effect size per risk allele among eight SNPs was 1.58, which was considered as one weighted risk allele). Effect of the number of the risk alleles on InsAUC0–30/GluAUC0–30 was significant (P = 9.3 × 10−44, adjusted for age, BMI, and Matsuda ISI). Data are shown as means ± SE (adjusted for age, BMI, and Matsuda ISI). Bars show numbers of subjects in each category.
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