Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes

Area of Science:

• Endocrinology
• Genetics
• Metabolic Diseases

Background:

• Type 2 diabetes (T2D) is a global health crisis with over 100 identified genetic risk variants.
• A common variant in the melatonin receptor 1B (MTNR1B) gene is linked to T2D susceptibility.

Purpose of the Study:

• To investigate the functional impact of the MTNR1B risk variant on insulin secretion and T2D pathogenesis.
• To elucidate the role of melatonin signaling in regulating glucose homeostasis.

Main Methods:

• Assessed MTNR1B gene expression in human pancreatic islets from individuals with different genotypes.
• Utilized insulin-secreting cell models and mouse models with disrupted MTNR1B.
• Conducted a human recall-by-genotype study involving melatonin administration.

Main Results:

• Increased MTNR1B expression was observed in islets from risk G-allele carriers.
• Melatonin reduced cAMP levels and inhibited insulin release in a manner exaggerated by MTNR1B overexpression.
• Mice lacking the MTNR1B receptor showed enhanced insulin secretion.
• Melatonin treatment led to more pronounced reductions in insulin secretion and greater glucose elevation in risk G-allele carriers.

Conclusions:

• Enhanced melatonin signaling via MTNR1B in pancreatic islets reduces insulin secretion, contributing to hyperglycemia and increased T2D risk.
• The findings suggest melatonin physiologically inhibits nocturnal insulin release.
• Targeting melatonin signaling could offer a novel therapeutic strategy for T2D.