Melatonin Impairs Glucose Tolerance, First-Phase Insulin Secretion, and Insulin Feedback Inhibition; Interaction With MTNR1B Diabetes Risk Variant
Abstract
Objective: 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…
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Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 2 of 5 (High · randomized trial). Randomized trials of a reasonable size are the strongest single-study design.
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