Despite considerable advances in the past few years, obesity and type 2 diabetes mellitus (T2DM) remain two major challenges for public health systems globally. In the past 9 years, genome-wide association studies (GWAS) have established a major role for genetic variation within the MTNR1B locus in regulating fasting plasma levels of glucose and in affecting the risk of T2DM. This discovery generated a major interest in the melatonergic system, in particular the melatonin MT2 receptor (which is encoded by MTNR1B). In this Review, we discuss the effect of melatonin and its receptors on glucose homeostasis, obesity and T2DM. Preclinical and clinical post-GWAS evidence of frequent and rare variants of the MTNR1B locus confirmed its importance in regulating glucose homeostasis and T2DM risk with minor effects on obesity. However, these studies did not solve the question of whether melatonin is beneficial or detrimental, an issue that will be discussed in the context of the peculiarities of the melatonergic system. Melatonin receptors might have therapeutic potential as they belong to the highly druggable G protein-coupled receptor superfamily. Clarifying the precise role of melatonin and its receptors on glucose homeostasis is urgent, as melatonin is widely used for other indications, either as a prescribed medication or as a supplement without medical prescription, in many countries in Europe and in the USA.
The rs10830963 single-nucleotide polymorphism (SNP) in the MTNR1B locus is associated with increased fasting plasma glucose levels and impaired insulin secretion, as well as increased risk of type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus.
Obesity seems to not be associated with the rs10830963 SNP in adults but might have a role in fetal birth weight.
The phenotype of rs10830963 risk allele carriers includes increased MTNR1B mRNA expression, altered melatonin secretion and possibly further effects associated with the enhancer activity of the region surrounding the rs10830963 SNP.
Loss-of-function of rare MT2 receptor variants, in particular of melatonin-induced Gi1 and Gz and spontaneous β-arrestin 2 recruitment, is associated with increased risk of T2DM.
Lifestyle recommendations are emerging for rs10830963 risk allele carriers and further clinical evidence has to be gathered to evaluate the prescription of melatonin for patients with T2DM.
The wide use of melatonin by millions of people, both as a supplement and as a medicine, calls for a rapid assessment of the effect of melatonin on glucose homeostasis.
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We thank Julie Dam and Erika Cecon (Institut Cochin, France) for their valuable expert advice during the preparation of the manuscript. The authors were supported by the Agence Nationale de la Recherche (ANR-2011-BSV1-012-01 “MLT2D” and ANR-2011-META “MELA-BETES”), the Fondation de la Recherche Médicale (Equipe FRM DEQ20130326503), Institut National de la Santé et de la Recherche Médicale (INSERM) and Centre National de la Recherche Scientifique (CNRS).
Nature Reviews Endocrinology thanks J. Cipolla-Neto and other anonymous reviewers for their contribution to the peer review of this work.
The authors declare no competing interests.
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Karamitri, A., Jockers, R. Melatonin in type 2 diabetes mellitus and obesity. Nat Rev Endocrinol 15, 105–125 (2019). https://doi.org/10.1038/s41574-018-0130-1
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