DataSheet_1_The rs10830963 Polymorphism of the MTNR1B Gene: Association With Abnormal Glucose, Insulin and C-peptide Kinetics.pdf

BackgroundThe MTNR1B gene encodes a receptor for melatonin, a hormone regulating biorhythms. Disruptions in biorhythms contribute to the development of type 2 diabetes mellitus (T2DM). Genetic studies suggest that variability in the MTNR1B gene affects T2DM development. Our aim was to compare the distribution of the genetic variant rs10830963 between persons differing in glucose tolerance in a sample of the Czech population (N=1206). We also evaluated possible associations of the polymorphism with insulin sensitivity, beta cell function, with the shape of glucose, insulin and C-peptide trajectories measured 7 times during a 3-hour oral glucose tolerance test (OGTT) and with glucagon response. In a subgroup of 268 volunteers we also evaluated sleep patterns and biorhythm.
Results13 persons were diagnosed with T2DM, 119 had impaired fasting blood glucose (IFG) and/or impaired glucose tolerance (IGT). 1074 participants showed normal results and formed a control group. A higher frequency of minor allele G was found in the IFG/IGT group in comparison with controls. The GG constellation was present in 23% of diabetics, in 17% of IFG/IGT probands and in 11% of controls. Compared to CC and CG genotypes, GG homozygotes showed higher stimulated glycemia levels during the OGTT. Homozygous as well as heterozygous carriers of the G allele showed lower very early phase of insulin and C-peptide secretion with unchanged insulin sensitivity. These differences remained significant after excluding diabetics and the IFG/IGT group from the analysis. No associations of the genotype with the shape of OGTT-based trajectories, with glucagon or with chronobiological patterns were observed. However, the shape of the trajectories differed significantly between men and women.
ConclusionIn a representative sample of the Czech population, the G allele of the rs10830963 polymorphism is associated with impaired early phase of beta cell function, and this is evident even in healthy individuals.

研究背景：MTNR1B基因编码褪黑素受体，褪黑素是一种调控生物节律的激素。生物节律紊乱会促进2型糖尿病（T2DM）的发生发展。遗传学研究表明，MTNR1B基因的变异会影响T2DM的发病风险。本研究旨在在捷克人群队列（N=1206）中，比较不同糖耐量状态个体间遗传变异rs10830963的分布差异；同时评估该多态性与胰岛素敏感性、β细胞功能、3小时口服葡萄糖耐量试验（OGTT）中7次检测的血糖、胰岛素及C肽轨迹形态，以及胰高血糖素反应的关联。在268名志愿者组成的亚组中，本研究还评估了睡眠模式与生物节律特征。

研究结果：本队列中共13人被诊断为T2DM，119人存在空腹血糖受损（IFG）和/或糖耐量减低（IGT），剩余1074名参与者糖耐量正常，作为对照组。相较于对照组，IFG/IGT组中次要等位基因G的携带频率更高。GG基因型在糖尿病患者中占比23%，在IFG/IGT组受试者中占17%，在对照组中占11%。与CC及CG基因型携带者相比，GG纯合子在OGTT过程中表现出更高的刺激后血糖水平。G等位基因的纯合及杂合携带者，其胰岛素及C肽的早期第一相分泌水平更低，但胰岛素敏感性未发生改变。在排除糖尿病患者及IFG/IGT组人群后，上述差异仍具有统计学意义。未观察到该基因型与OGTT轨迹形态、胰高血糖素反应或生物节律模式存在关联。不过，不同性别间的轨迹形态存在显著差异。

研究结论：在具有代表性的捷克人群队列中，rs10830963多态性的G等位基因与β细胞早期分泌功能受损相关，且这一关联在健康个体中同样显著。