Minireview: Toward the establishment of a link between melatonin and glucose homeostasis: association of melatonin MT2 receptor variants with type 2 diabetes

Mol Endocrinol. 2013 Aug;27(8):1217-33. doi: 10.1210/me.2013-1101. Epub 2013 Jun 24.

Abstract

The existence of interindividual variations in G protein-coupled receptor sequences has been recognized early on. Recent advances in large-scale exon sequencing techniques are expected to dramatically increase the number of variants identified in G protein-coupled receptors, giving rise to new challenges regarding their functional characterization. The current minireview will illustrate these challenges based on the MTNR1B gene, which encodes the melatonin MT2 receptor, for which exon sequencing revealed 40 rare nonsynonymous variants in the general population and in type 2 diabetes (T2D) cohorts. Functional characterization of these MT2 mutants revealed 14 mutants with loss of Gi protein activation that associate with increased risk of T2D development. This repertoire of disease-associated mutants is a rich source for structure-activity studies and will help to define the still poorly understood role of melatonin in glucose homeostasis and T2D development in humans. Defining the functional defects in carriers of rare MT2 mutations will help to provide personalized therapies to these patients in the future.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism*
  • Glucose / metabolism*
  • Humans
  • Melatonin / metabolism*
  • Mice
  • Molecular Sequence Data
  • Obesity / metabolism
  • Pineal Gland / metabolism
  • Polymorphism, Single Nucleotide
  • Rats
  • Receptor, Melatonin, MT1 / genetics
  • Receptor, Melatonin, MT1 / metabolism
  • Receptor, Melatonin, MT2 / genetics
  • Receptor, Melatonin, MT2 / metabolism*
  • Structure-Activity Relationship

Substances

  • MTNR1B protein, human
  • Receptor, Melatonin, MT1
  • Receptor, Melatonin, MT2
  • Glucose
  • Melatonin

Grant support

This work was supported by grants from the Agence Nationale de la Recherche (ANR 2011 -BSV1–012-01 “MLT2D” and ANR-2011-META “MELA-BETES”), the Fondation Recherche Médicale (Equipe FRM DEQ20130326503, to R.J.), Institut National de la Santé et de la Recherche Médicale and Centre National de la Recherche Scientifique. A.K. holds a postdoctoral fellowship from the Fondation pour la Recherche Médicale.