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

OBJECTIVEWe 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 METHODSA total of 5,327 nondiabetic men (age 58 ± 7 years, BMI 27.0 ± 3.8 kg/m2) 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.RESULTSSix 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 (InsAUC0–30/GluAUC0–30), adjusted for age, BMI, and insulin sensitivity (Matsuda ISI). Combined effects of these eight SNPs reached −32% reduction in InsAUC0–30/GluAUC0–30 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 InsAUC0–30/GluAUC0–30. Nine SNPs did not show any associations with examined traits.CONCLUSIONSEight 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.

The suppressor of cytokine signalling 2 (SOCS2) is a key repressor of insulin secretion

“…As previously mentioned, SOCS proteins are potent negative modulators of Jak/STAT signalling. While our most urgent challenge is to understand how SOCS proteins can affect expression of genes involved in proinsulin processing, our observations are particularly intriguing in light of recent reports showing that the confirmed type 2 diabetes-related genetic loci, TCF7L2, CDKAL1 and SLC30A8, are associated with impaired proinsulin conversion [52,53].…”

Association of indices of liver and adipocyte insulin resistance with 19 confirmed susceptibility loci for type 2 diabetes in 6,733 non-diabetic Finnish men

“…For the study of liver and adipose tissue insulin sensitivity (Study 1), 8,460 non-diabetic participants (Table 1) from our ongoing population-based cross-sectional Metabolic Syndrome in Men (METSIM) study [16,17] were included. Participants, aged from 45 to 70 years, were randomly selected from the population register of Kuopio town, Eastern Finland (population 95,000).…”

Pharmacogenetics for T2DM and Anti-Diabetic Drugs

“…In Asian Indian descent subjects also found the -cell defect [34]. Trend toward lower -cell function could be observed in Caucasians population [35,38,52]. SNP rs12779790 variation carriers showed a lower insulin response to glucose stimulation and noted a trend toward a reduced insulin response after arginine stimulation.…”

“…The OR values of the three SNPs rs1111875, rs5015480 and rs7923837 genotyped in HHEX (1.20-1.46) were higher in Japanese than those of the European population (1.20) [64]. HHEX variant was associated with impaired proinsulin conversion [38]. SNP rs1111875 and rs7923837 was associated with T2DM independent of body fat [65].…”

“…Rare mutations in WFS1 cause Wolfram syndrome, variation in WFS1 also predisposes to common T2DM. It has been reported that WFS1 gene variants were associated with reduced insulin response to oral but not intravenous glucose [35][36][37][38][39]. WFS1 gene was associated with estimates of a decreased pancreatic -cell function among middle-aged individuals with abnormal glucose regulation [37].…”