Melatonin Impairs Glucose Tolerance, First-Phase Insulin Secretion, and Insulin Feedback Inhibition; Interaction With MTNR1B Diabetes Risk Variant.
Level 2 - randomized trial
Individual randomized, double-blind, placebo-controlled crossover trial
PubMed 42346809 · doi:10.2337/dc26-0164
What was done
Twenty-one healthy participants of European ancestry (10 MTNR1B G-allele risk carriers and 11 noncarriers) completed a randomized, double-blind, placebo-controlled crossover trial in a 5-day laboratory protocol. Participants received a single dose of 5 mg oral melatonin or placebo in randomized order across two nonconsecutive days. Glycemic dynamics, first- and second-phase beta-cell responsivity, and insulin feedback were assessed using insulin-modified intravenous glucose tolerance tests analyzed with minimal modeling.
What was found
In MTNR1B risk carriers, melatonin worsened glucose tolerance by 11.7% (95% CI 1.0 to 22.3; Padj < 0.05) and reduced early C-peptide responses by 19.2% (95% CI -33.9 to -1.2; Padj < 0.05) compared to placebo, with no significant effects observed in noncarriers. In carriers, melatonin suppressed glucose-stimulated first-phase beta-cell responsivity by 40% (95% CI -52.4 to -24.3; Padj = 0.0003), slowed the insulin-induced decline in second-phase insulin secretion rate by 64.3% (95% CI 23.1 to 119.2; Padj = 0.001), and prevented exogenous insulin-induced hypoglycemia (zero events vs. seven with placebo, P = 0.001).
Why it matters
These findings identify specific beta-cell mechanisms explaining how melatonin can impair glucose regulation in individuals carrying the common MTNR1B risk allele. This highlights the need for personalized, genotype-informed guidance regarding melatonin supplementation.
Limits
The sample size was small (n = 21) and restricted to healthy individuals of European ancestry. The study tested an acute 5 mg pharmacological dose during a brief laboratory protocol, leaving the metabolic impacts of chronic, lower-dose, or habitual use unmeasured.
Cited by
- supports Melatonin rises approximately 3 hours before natural bedtime and reduces pancreatic insulin secretion, lowering insulin sensitivity in the evening.