Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes

Cell Metab. 2016 Jun 14;23(6):1067-1077. doi: 10.1016/j.cmet.2016.04.009. Epub 2016 May 12.


Type 2 diabetes (T2D) is a global pandemic. Genome-wide association studies (GWASs) have identified >100 genetic variants associated with the disease, including a common variant in the melatonin receptor 1 b gene (MTNR1B). Here, we demonstrate increased MTNR1B expression in human islets from risk G-allele carriers, which likely leads to a reduction in insulin release, increasing T2D risk. Accordingly, in insulin-secreting cells, melatonin reduced cAMP levels, and MTNR1B overexpression exaggerated the inhibition of insulin release exerted by melatonin. Conversely, mice with a disruption of the receptor secreted more insulin. Melatonin treatment in a human recall-by-genotype study reduced insulin secretion and raised glucose levels more extensively in risk G-allele carriers. Thus, our data support a model where enhanced melatonin signaling in islets reduces insulin secretion, leading to hyperglycemia and greater future risk of T2D. The findings also imply that melatonin physiologically serves to inhibit nocturnal insulin release.

Keywords: RNA sequencing; gene targeting; insulin; islets; recall-by-genotype.

MeSH terms

  • Animals
  • Cyclic AMP / metabolism
  • Diabetes Mellitus, Type 2 / metabolism*
  • Genetic Predisposition to Disease
  • Glucose / metabolism
  • Heterozygote
  • Humans
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Melatonin / metabolism*
  • Melatonin / pharmacology
  • Mice, Knockout
  • Polymorphism, Single Nucleotide / genetics
  • Quantitative Trait Loci / genetics
  • Receptors, Melatonin / genetics
  • Risk Factors
  • Signal Transduction* / drug effects


  • Insulin
  • Receptors, Melatonin
  • Cyclic AMP
  • Glucose
  • Melatonin