Abstract
BackgroundVery recently, a novel type 2 diabetes risk gene, i.e., MTNR1B, was identified and reported to affect fasting glycemia. Using our thoroughly phenotyped cohort of subjects at an increased risk for type 2 diabetes, we assessed the association of common genetic variation within the MTNR1B locus with obesity and prediabetes traits, namely impaired insulin secretion and insulin resistance.Methodology/Principal FindingsWe genotyped 1,578 non-diabetic subjects, metabolically characterized by oral glucose tolerance test, for five tagging single nucleotide polymorphisms (SNPs) covering 100% of common genetic variation (minor allele frequency >0.05) within the MTNR1B locus (rs10830962, rs4753426, rs12804291, rs10830963, rs3781638). In a subgroup (N = 513), insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and in a further subgroup (N = 301), glucose-stimulated insulin secretion was determined by intravenous glucose tolerance test. After appropriate adjustment for confounding variables and Bonferroni correction for multiple comparisons, none of the tagging SNPs was reliably associated with measures of adiposity. SNPs rs10830962, rs4753426, and rs10830963 were significantly associated with higher fasting plasma glucose concentrations (p<0.0001) and reduced OGTT- and IVGTT-induced insulin release (p≤0.0007 and p≤0.01, respectively). By contrast, SNP rs3781638 displayed significant association with lower fasting plasma glucose levels and increased OGTT-induced insulin release (p<0.0001 and p≤0.0002, respectively). Moreover, SNP rs3781638 revealed significant association with elevated fasting- and OGTT-derived insulin sensitivity (p≤0.0021). None of the MTNR1B tagging SNPs altered proinsulin-to-insulin conversion.Conclusions/SignificanceIn conclusion, common genetic variation within MTNR1B determines glucose-stimulated insulin secretion and plasma glucose concentrations. Their impact on β-cell function might represent the prevailing pathomechanism how MTNR1B variants increase the type 2 diabetes risk.
Highlights
During the last two years, genome-wide association (GWA) studies based on tens of thousands of human cases and controls identified a series of novel type 2 diabetes risk loci including SLC30A8, HHEX, CDKAL1, IGF2BP2, and CDKN2A/B [1,2,3,4,5] which were subsequently replicated in other human cohorts and ethnicities [6,7,8,9,10,11,12,13]
single nucleotide polymorphisms (SNPs) rs3781638 displayed opposite effects (Table 4): this SNP was associated with reduced fasting plasma glucose concentrations (p,0.0001), with higher values in all oral glucose tolerance test (OGTT)-derived measures of insulin release (p#0.0002), and with a higher value of the disposition index (p,0.0001)
SNP rs3781638 showed significant associations with increased OGTTderived insulin sensitivity (p,0.0021 after adjustment for gender, age, Body mass index (BMI), and family history of diabetes) and correspondingly decreased Homeostasis model assessment of insulin resistance (HOMA-IR) (p#0.0015 after analogous adjustment; Table 4). We tested whether this SNP affects hepatic insulin clearance, a close correlate of liver insulin sensitivity, using the ratios area under the curve (AUC) C-peptide/AUC insulin and mean C-peptide/mean insulin during the OGTT as estimates
Summary
During the last two years, genome-wide association (GWA) studies based on tens of thousands of human cases and controls identified a series of novel type 2 diabetes risk loci including SLC30A8, HHEX, CDKAL1, IGF2BP2, and CDKN2A/B [1,2,3,4,5] which were subsequently replicated in other human cohorts and ethnicities [6,7,8,9,10,11,12,13]. An additional type 2 diabetes risk gene, i.e., MTNR1B, was identified and reported to affect fasting plasma glucose concentrations [21;22]. As certain sleep disorders, such as obstructive sleep apnea, result from obesity and are associated with insulin resistance [24;25], MTNR1B could represent a new interesting candidate gene linking sleep disorders with type 2 diabetes. A novel type 2 diabetes risk gene, i.e., MTNR1B, was identified and reported to affect fasting glycemia. Using our thoroughly phenotyped cohort of subjects at an increased risk for type 2 diabetes, we assessed the association of common genetic variation within the MTNR1B locus with obesity and prediabetes traits, namely impaired insulin secretion and insulin resistance
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