Linking MTNR1B Variants to Diabetes: The Role of Circadian Rhythms.

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-offunction 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 b-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.