Polymorphisms within the Novel Type 2 Diabetes Risk Locus MTNR1B Determine β-Cell Function

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.

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

“…In agreement with our result, a previous study showed an association between a different SNP and decreased HOMA-IR [34]. In contrast, a study based on the hyperinsulinaemic-euglycaemic clamp showed that the MTNR1B risk allele reduced suppression of hepatic glucose production, suggesting that it could be associated with hepatic IR [35].…”

The role of melatonin in diabetes: therapeutic implications

“…Furthermore, a polymorphic allele was identified in CRY2 associated with type 2 diabetes (85). A group of researchers reported that the MTNR1B-associated Single Nucleotide Polymorphisms rs10830962, rs4753426 and the aforementioned rs10830963 were all significantly associated with higher fasting glucose concentrations in the blood and decreased insulin secretion in German cohorts (86).…”

“…Moreover, diabetes is coupled with lower melatonin levels as reduction in serum melatonin and higher insulin level is observed in type 2 diabetic Goto Kakizaki rats (6). Genome-wide association studies has shown that specific single-nucleotide polymorphisms of the melatonin receptor 2 (MTNR1B) locus is linked with an increased blood glucose concentration and type 2 diabetes (8)(9)(10)(11)(12)(13). Melatonin can be able to bring anti-hyperglycemic effect either by improving insulin sensitization or by improvement of insulin secretion, or both.…”

Genetic and environmental factors associated with type 2 diabetes and diabetic vascular complications

“…On the other hand, common variants in melatonin receptor type 1 B gene (MTNR1B) are associated with the risk of T2D independent of BMI [34,35]. Receptors for melatonin (MTNR1A and MTNR1B) are expressed in pancreatic islet cells, and carriers of the risk genotype exhibit impaired glucose-stimulated insulin secretion [36,37].…”