Amélie Bonnefond1, Philippe Froguel2,3. 1. 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. amelie.bonnefond@inserm.fr. 2. 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. 3. Genomics of Common Disease, Imperial College London, London, W12 0NN, UK.
Abstract
PURPOSE OF REVIEW: 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 FINDINGS: 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.
PURPOSE OF REVIEW: 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 FINDINGS: 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.
Entities:
Keywords:
Circadian rhythm; Clock; Expression quantitative trait loci (eQTL); Genome-wide association study (GWAS); Insulin secretion; MTNR1B; Melatonin; Pancreatic beta cell; Rare genetic variant
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