Melatonin Impairs Glucose Tolerance, First-Phase Insulin Secretion, and Insulin Feedback Inhibition; Interaction With MTNR1B Diabetes Risk Variant
Jingyi Qian, Darko Stefanovski, Phillip A.K. Andersen, Nina Vujovic, Lauren Kelly, Joshua Lepson, Hoa Nguyen, Sean Byrne, Wei Wang, Thomas Mandrup-Poulsen, Gail Adler, Marta Garaulet, Richa Saxena, Frank A.J.L. ScheerOBJECTIVE
Melatonin use quintupled in recent decades. The common melatonin receptor 1B gene (MTNR1B) variant increases risk of type 2 diabetes, raising concerns about melatonin’s adverse metabolic effects and highlighting the need for a genotype-based personalized approach. We aimed to comprehensively characterize the actions of melatonin on glucose homeostasis, including first- and second-phase β-cell responsivity to glucose, β-cell negative feedback by exogeneous insulin, insulin sensitivity, and whether such effects are stronger in MTNR1B G-allele risk carriers compared with noncarriers.
RESEARCH DESIGN AND METHODS
Twenty-one healthy participants of European ancestry were studied in a randomized, double-blind, placebo-controlled, crossover trial, including 10 MTNR1B risk carriers and 11 noncarriers. Each participant underwent a highly controlled 5-day laboratory protocol, during which they received 5 mg oral melatonin or placebo in randomized order on two nonconsecutive days. Glycemic dynamics were assessed using insulin-modified intravenous glucose tolerance tests with minimal-model analysis.
RESULTS
Melatonin worsened glucose tolerance and reduced early C-peptide responses in risk allele carriers (vs. placebo: 11.7% [95% CI 1.0–22.3] and −19.2% [−33.9 to −1.2], respectively; Padj < 0.05) but not in noncarriers. In carriers, impairments stemmed from a 40% (−52.4 to −24.3; Padj = 0.0003) suppression of glucose-stimulated first-phase β-cell responsivity, along with a slower insulin-induced decline in second-phase insulin secretion rate (64.3% [23.1–119.2]; Padj = 0.001). In carriers, melatonin also prevented exogenous insulin-induced hypoglycemia compared with placebo (zero vs. seven events, P = 0.001), but not in noncarriers.
CONCLUSIONS
These findings identify blunted β-cell responsivity to glucose and dysregulated insulin negative feedback as key mechanisms linking melatonin signaling to diabetes risk.