The melatonin receptor 1B, encoded by the MTNR1B gene, is a member of the melatonin receptor family expressed in many tissues, including pancreatic islets (1). Single nucleotide polymorphisms in MTNR1B have been revealed to be associated with increased blood glucose levels and type 2 diabetes (T2D) incidence according to several genome-wide association studies (GWAS) (2,3), and some of the variants of MTNR1B have been proved to be the proper causal variants in functional studies (4). Additionally, rare loss-of-function variants of MTNR1B were proved to contribute to T2D (5). These association studies in genetics have provided a link between MTNR1B and T2D, but the exact mechanism underlying the association between MTNR1B and T2D risk remains unclear.

As a circulating hormone released from the pineal gland, melatonin is an important contributor of seasonal and circadian rhythms (6), and there are complex interplays between melatonin secretion, circadian rhythm, and the circadian master clock of the suprachiasmatic nucleus in the brain (7). The existing literature implies that melatonin plays a role in glucose metabolism (8) and insulin secretion from pancreatic β-cells (9), although the role of melatonin in humans is very complex. According to previous research, impaired glucose metabolism and insulin secretion occurred when the circadian clock was disrupted (10,11), and the quality and quantity of sleep could have affected T2D incidence (12). Studying the associations among MTNR1B variants, sleep status, circadian rhythms, and melatonin traits might link MTNR1B variants to T2D risk considering that melatonin endocrinology, circadian rhythms, and sleep status are associated with T2D risk. Melatonin is the main regulator of sleep status and circadian rhythms, and sleep status is a prominent manifestation of circadian rhythms.

In this issue of Diabetes, Lane et al. (13) aim to evaluate the associations of MTNR1B rs10830963, a risk variant of T2D, with sleep status, circadian rhythms, and melatonin traits, thus exploring the link between MTNR1B variants and T2D. This study was composed of two parts: an intensive in-laboratory protocol evaluating the association of rs10830963 with circadian phenotypes and melatonin traits under a fixed sleep duration schedule and the Candidate-gene Association Resource (CARe) study involving rs10830963 genotypes, sleep (quantity, quality, and timing), and T2D risk. According to the in-laboratory studies, the G allele of rs10830963 was correlated with later dim-light melatonin offset and longer high-melatonin duration. Additionally, the association between rs10830963 and dim-light melatonin offset was mediated by sleep timing, not sleep duration, but whether rs10830963 affected sleep timing via melatonin modulation remained unknown. In the CARe study, there was a significant association between rs10830963 and fasting blood glucose and T2D, but no significant association between rs10830963 and sleep quantity, quality, or timing was observed. When the participants were further classified according to sleep timing, the association between rs10830963 and T2D risk was more significant in early sleep timing compared with late sleep timing.

Lane et al. (13) has confirmed the significant correlation between the G allele of rs10830963 for diabetes risk and longer duration of elevated levels of melatonin, which was a circadian contributor in the in-laboratory study, suggesting that MTNR1B rs10830963 is likely associated with sleep and circadian rhythms, although these associations were not significant. According to biological circadian rhythm, melatonin secretion follows a diurnal pattern with increased secretion after sleep onset at night and low secretion during daylight (7), thus inhibiting insulin secretion at night and avoiding hypoglycemia. The effect of the rs10830963 melatonin risk allele on T2D risk was magnified by early sleep timing in the CARe study, probably due to increased melatonin level in the morning accompanied by concomitant food intake, which is contrary to the natural circadian rhythms (14). Therefore, people with the melatonin risk allele of MTNR1B rs10830963 accompanied by early sleep timing are more susceptible to develop T2D due to circadian rhythm disturbance.

The depth and breadth of phenotypes and precise endogenous circadian rhythm measurements are the main strengths of the study by Lane et al. (13), and this is the first large observational study linking MTNR1B variants to T2D via circadian rhythms. Probably due to limited sample size, MTNR1B rs10830963 was likely but not significantly associated with sleep or circadian rhythms in this study. Further evaluation in a larger sample size may provide more convincing evidence of these associations. As melatonin secretion is reduced by aging and diseases (15), and glucose levels are increased in aged people, the in-laboratory study has excluded the influence of aging and disease by enrolling only young, healthy participants. However, the age and disease status of the participants in the CARe study were not controlled. Further study in different age stages with controlled disease status might offer more clues for the associations among MTNR1B, melatonin, and T2D. Melatonin levels were not measured in the CARe study, and melatonin measurement accompanied with genotype, circadian rhythm, and glucose levels will clarify more details of the association among MTNR1B variants, circadian rhythm, and T2D in future studies. Besides, this study was not to elucidate the pathophysiology of T2D onset in MTNR1B variant carriers; it was an observational study linking MTNR1B to diabetes risk via circadian rhythms, which offers more clues for functional studies on the pathophysiology of T2D.

In the study by Lane et al. (13), participants with the MTNR1B diabetes risk allele G of rs10830963 accompanied by circadian rhythm disturbance had higher T2D risk compared with the carriers of the MTNR1B nondiabetes risk allele C of rs10830963, emphasizing the importance of keeping biological circadian rhythms in these individuals. This study also provides novel clues for T2D therapy by alterations of melatonin dynamics or food intake timing based on the adverse effects on circadian rhythm disturbance, including increased melatonin levels and concomitant food intake on glucose metabolic disorders. It is likely that studies based on these intervention treatments might help to confirm this hypothesis.

In conclusion, MTNR1B variants were linked to diabetes risk via circadian rhythms (Fig. 1), and more studies in different populations are essential to replicate this association. Further functional and interventional studies involving the exact effect of MTNR1B variants on melatonin endocrinology, circadian rhythms, and T2D risk are obligatory to confirm the exact link between MTNR1B, circadian rhythms, and T2D.

Figure 1

The detailed pathway linking MTNR1B rs10830963 risk allele to T2D risk. The G allele of rs10830963 was associated with elevated melatonin level accompanied by early sleep timing and concomitant food intake, which is contrary to the natural circadian rhythms, leading to decreased glucose tolerance, thus resulting in increased T2D risk. The dotted line between melatonin and sleep timing indicate that whether rs10830963 affects sleep timing via melatonin modulation remains unknown.

Figure 1

The detailed pathway linking MTNR1B rs10830963 risk allele to T2D risk. The G allele of rs10830963 was associated with elevated melatonin level accompanied by early sleep timing and concomitant food intake, which is contrary to the natural circadian rhythms, leading to decreased glucose tolerance, thus resulting in increased T2D risk. The dotted line between melatonin and sleep timing indicate that whether rs10830963 affects sleep timing via melatonin modulation remains unknown.

See accompanying article, p. 1741.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

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