Some have proposed the ‘equilibrium hypothesis’ which submits that either exaggerated or dampened melatonin signaling in common and rare variant carriers, respectively, becomes detrimental for glucose homeostasis. While the most common hypothesis is based on the action of melatonin on impairing glucose homeostasis by inhibiting insulin secretion, an explanation is still missing for the contradictory results. Unexpectedly, even among human research, seeming contradictions exist with studies showing that elevated melatonin concentrations are associated with improved glucose control and others with impaired glucose control. Thus, it is not surprising that it can be very difficult to translate melatonin research from laboratory rodent models into human. Moreover, the widely-used mice models often have severe defects in melatonin synthesis. Laboratory rodent models are usually nocturnal and eat when their endogenous melatonin levels are high. Despite the substantial scientific effort to understand this role of melatonin, different studies reach conflicting conclusions which have not been reconciled. This raises the question whether melatonin contributes to the circadian regulation of glucose metabolism. In humans, the nighttime rise in circulating melatonin levels coincides with the trough of the endogenous circadian rhythm in glucose tolerance ( Box 1), which also happens to be a naturally fasting period. Melatonin, as a circadian hormone, peaks during the nighttime. This is partly due to the discovery of T2D risk variants in MTNR1B, and partly because of the compelling evidence for the adverse impact of circadian disruption on glucose metabolism. However, in recent years its role in glucose control and in T2D risk or treatment has received increasing attention. Melatonin has been investigated mostly for its role in sleep and circadian regulation, including acute effects as well as circadian phase-shifting effects ( Box 1). We thus believe clarification is urgently needed in this fast-moving field. Even so, companies are already initiating programs to develop melatonin-based therapies in the fight against type 2 diabetes (T2D). As a result, currently there are opposing recommendations for the use of melatonin, melatonin agonists, and melatonin antagonists for the purposes of glycemic management. These conflicting data are not limited to one research field or methodology, but span across controlled trials and genome-wide association studies (GWAS), in vivo and in vitro approaches. Despite intensive research, there exists conflicting human data regarding the effects of melatonin and MTNR1B on glucose control, and disagreement on whether melatonin may be metabolically ‘beneficial’ or ‘deleterious’.
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