Bonnefond Amélie, Froguel Philippe
CNRS UMR 8199. European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Pôle Recherche-1er - 1er étage Aile Ouest, 1 place de Verdun, 59045, Lille Cedex, France.
Genomics of Common Disease, Imperial College London, London, W12 0NN, UK.
Curr Diab Rep. 2017 Oct 23;17(12):122. doi: 10.1007/s11892-017-0957-1.
Type 2 diabetes (T2D) is a complex genetic metabolic disorder. T2D heritability has been estimated around 40-70%. In the last decade, exponential progress has been made in identifying T2D genetic determinants, through genome-wide association studies (GWAS). Among single-nucleotide polymorphisms mostly associated with T2D risk, rs10830963 is located in the MTNR1B gene, encoding one of the two receptors of melatonin, a neurohormone involved in circadian rhythms. Subsequent studies aiming to disentangle the role of MTNR1B in T2D pathophysiology led to controversies. In this review, we will tackle them and will try to give some directions to get a better view of MTNR1B contribution to T2D pathophysiology.
Recent studies either based on genetic/genomic analyses, clinical/epidemiology data, functional analyses at rs10830963 locus, insulin secretion assays in response to melatonin (involving or not MTNR1B) or animal model analyses have led to strong controversies at each level of interpretation. We discuss possible caveats in these studies and present ways to go beyond these issues, towards a better understanding of T2D molecular mechanisms, keeping in mind that melatonin is a versatile hormone and regulates many functions via its primary role in the body clock.
2型糖尿病（T2D）是一种复杂的遗传代谢紊乱疾病。T2D的遗传度估计在40%-70%左右。在过去十年中，通过全基因组关联研究（GWAS），在识别T2D遗传决定因素方面取得了指数级进展。在与T2D风险最相关的单核苷酸多态性中，rs10830963位于MTNR1B基因中，该基因编码褪黑素的两种受体之一，褪黑素是一种参与昼夜节律的神经激素。随后旨在阐明MTNR1B在T2D病理生理学中作用的研究引发了争议。在本综述中，我们将解决这些争议，并尝试给出一些方向，以便更好地了解MTNR1B对T2D病理生理学的贡献。
最近的研究，无论是基于遗传/基因组分析、临床/流行病学数据、rs10830963位点的功能分析、对褪黑素（涉及或不涉及MTNR1B）的胰岛素分泌测定，还是动物模型分析，在每个解释层面都引发了强烈争议。我们讨论了这些研究中可能存在的问题，并提出了超越这些问题的方法，以更好地理解T2D的分子机制，同时要记住褪黑素是一种多功能激素，通过其在生物钟中的主要作用调节许多功能。
