Table 1. Controversies in the literature and potential explanations by the Timing Model.

This table captures the published literature through multiple human controlled trials, genetic experimental studies, and genome wide association studies (GWAS) which support either the beneficial or deleterious roles of melatonin in glucose control and T2D risk. It includes the hypothesized mechanism that explains this apparent contradiction based on the Timing Model.

Study design/model	Seemingly beneficial effects on glucose control	Hypothesized mechanism (circadian model)	Seemingly deleterious effects on glucose control	Hypothesized mechanism (circadian model)
Association study	low nighttime melatonin (urinary 6-sulphatoxy melatonin) prospectively associated with increased insulin resistance and T2D risk 6,7	low nighttime melatonin signaling during fasting impairs beta-cell recovery and/or sleep
Open label study	long term (5mo) nighttime administration in T2D w/insomnia decreased HbA1C (however, no effect in RCT) 8	high nighttime melatonin signaling during fasting improves beta-cell recovery and/or sleep
Genetics	rare loss-of-function MTNR1B variation associated with increased T2D risk (observation has not been replicated)9,11,81	low nighttime melatonin signaling during fasting impairs beta-cell recovery and/or sleep	common gain-of-function MTNR1B variant impairs insulin secretion and increases T2D risk 12–17	high melatonin signaling and longer window of melatonin production with gain-of-function variant impair glucose tolerance if eating in late evening, night, or early morning
Placebo-controlled study			daytime melatonin administration impairs glucose tolerance 12,20,21	high (exogenous) melatonin impairs glucose tolerance
Placebo-controlled genetic study			daytime melatonin administration impairs glucose tolerance more in carriers of common MTNR1B variant 12,22	high (exogenous) melatonin with gain-of function variant impairs glucose tolerance
Experimental study			late dinner timing, when endogenous melatonin concentrations elevated, impairs glucose tolerance (RCT) 23	high (endogenous) melatonin impairs glucose tolerance
Experimental genetic study			late dinner timing, when endogenous melatonin concentrations elevated, impairs glucose tolerance more in carriers of common MTNR1B variant (RCT) 23	high (endogenous) nighttime melatonin with gain-of function variant impairs glucose tolerance

T2D: Type 2 Diabetes; RCT: Randomized controlled trial.