Polymorphisms within the Novel Type 2 Diabetes Risk Locus MTNR1B Determine [beta]-Cell Function

• Published in: PloS one Vol. 3; no. 12; p. e3962
• Main Authors: Staiger, Harald, Machicao, Fausto, Schäfer, Silke A, Kirchhoff, Kerstin, Kantartzis, Konstantinos, Guthoff, Martina, Silbernagel, Günther, Stefan, Norbert, Häring, Hans-Ulrich, Fritsche, Andreas
• Format: Journal Article
• Language: English
• Published: Public Library of Science 17.12.2008
• Subjects: Chromosomes; Genetic aspects; Glucose; Glucose tolerance test; Insulin; Insulin resistance; Obesity; Pancreatic beta cells; Prediabetic state; Risk factors; Single nucleotide polymorphisms; Type 2 diabetes
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0003962

Very 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. We 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[less than or equal to]0.0007 and p[less than or equal to]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[less than or equal to]0.0002, respectively). Moreover, SNP rs3781638 revealed significant association with elevated fasting- and OGTT-derived insulin sensitivity (p[less than or equal to]0.0021). None of the MTNR1B tagging SNPs altered proinsulin-to-insulin conversion. In conclusion, common genetic variation within MTNR1B determines glucose-stimulated insulin secretion and plasma glucose concentrations. Their impact on [beta]-cell function might represent the prevailing pathomechanism how MTNR1B variants increase the type 2 diabetes risk.