Melatonin Effects on Glucose Metabolism: Time To Unlock the Controversy

The past decade has witnessed a revival of interest in the hormone melatonin, partly attributable to the discovery that genetic variation in MTNR1B – the melatonin receptor gene – is a risk factor for impaired fasting glucose and type 2 diabetes (T2D). Despite intensive investigation, there is considerable confusion and seemingly conflicting data on the metabolic effects of melatonin and MTNR1B variation, and disagreement on whether melatonin is metabolically beneficial or deleterious, a crucial issue for melatonin agonist/antagonist drug development and dosing time. We provide a conceptual framework – anchored in the dimension of 'time' – to reconcile paradoxical findings in the literature. We propose that the relative timing between elevated melatonin concentrations and glycemic challenge should be considered to better understand the mechanisms and therapeutic opportunities of melatonin signaling in glycemic health and disease. Melatonin has been investigated mostly for its role in sleep and circadian regulation. The recent discovery of MTNR1B as a novel T2D risk gene has sparked great interest in the role of melatonin in glucose control among diabetologists and basic researchers alike.Despite intensive research, there are seemingly conflicting data regarding the effects of melatonin and MTNR1B genotype on glucose control, and disagreement on whether melatonin may increase or decrease fasting glucose, glucose tolerance, and T2D risk.The concurrence of elevated melatonin concentrations with food intake in human decreases glucose tolerance, whereas high melatonin during fasting may facilitate β cell recovery.Shift workers, night eaters, and melatonin users are susceptible to the adverse effects brought about by the concurrence of food intake and high melatonin levels.