Melatonin Impairs Glucose Tolerance, First-Phase Insulin Secretion, and Insulin Feedback Inhibition; Interaction With MTNR1B Diabetes Risk Variant.

Summary

In a randomized, double-blind crossover study of 21 healthy adults, melatonin acutely worsened glucose tolerance and suppressed first-phase beta-cell responsivity by ~40% in MTNR1B risk-allele carriers, but not in noncarriers. Melatonin also attenuated insulin’s negative feedback on secretion and prevented insulin-induced hypoglycemia in carriers, delineating genotype-specific mechanisms linking melatonin signaling to diabetes risk.

Key Findings

• Melatonin worsened glucose tolerance in MTNR1B risk carriers but not in noncarriers.
• First-phase beta-cell responsivity to glucose was suppressed by ~40% in carriers under melatonin.
• Melatonin slowed insulin-induced decline in second-phase insulin secretion and prevented insulin-induced hypoglycemia in carriers.

Clinical Implications

Clinicians should exercise caution with melatonin in individuals at high diabetes risk—particularly MTNR1B G-allele carriers—and consider counseling on timing/dose or alternatives. The findings motivate pharmacogenomic consideration when recommending sleep aids in prediabetes/metabolic risk.

Limitations

• Small sample size and short-term laboratory exposure limit generalizability to chronic, real-world use.
• Participants were healthy Europeans; effects in patients with prediabetes/diabetes and other ancestries remain to be established.

Future Directions

Test chronic melatonin effects across genotypes in at-risk populations, evaluate dose and timing, and assess whether MTNR1B-guided recommendations mitigate dysglycemia.