The melatonin receptor 1B gene links circadian rhythms and type 2 diabetes mellitus: an evolutionary story

Abstract

Disturbed circadian rhythms have been a risk factor for type 2 diabetes mellitus (T2DM). Melatonin is the major chronobiotic hormone regulating both circadian rhythm and glucose homeostasis. The rs10830963 (G allele) of the melatonin receptor 1B ( MTNR1B ) gene has the strongest genetic associations with T2DM according to several genome-wide association studies. The MTNR1B rs10830963 G allele is also associated with disturbed circadian phenotypes and altered melatonin secretion, both factors that can elevate the risk of diabetes. Furthermore, evolutionary studies implied the presence of selection pressure and ethnic diversity in MTNR1B , which was consistent with the “thrifty gene” hypothesis in T2DM. The rs10830963 G risk allele is associated with delayed melatonin secretion onset in dim-light and prolonged duration of peak melatonin. This delayed melatonin secretion may help human ancestors adapt to famine or food shortages during long nights and early mornings and avoid nocturnal hypoglycemia but confers susceptibility to T2DM due to adequate energy intake in modern society. We provide new insight into the role of MTNR1B variants in T2DM via disturbed circadian rhythms from the perspective of the “thrifty gene” hypothesis; these data indicate a novel target for the prevention and treatment of susceptible populations with the thrifty genotype.

Blue Light and Temperature Actigraphy Measures Predicting Metabolic Health Are Linked to Melatonin Receptor Polymorphism

“…Associations between the carriage of the MTNR1B rs10830963 minor G-allele and the affected modulation of the metabolic response to melatonin and light were evident in previous studies [42][43][44]. Carriers of the minor G-allele of the MTNR1B rs10830963 snp represent a large part of populations that have elevated fasting glucose and higher risks of metabolic disorders, particularly type 2 diabetes mellitus [41]. They also have changed and prolonged patterns of melatonin secretion [42] that can be related to chronotype [43] or reduced light signaling due to retinal ganglion cell loss [44].…”

“…This SNP is associated with disrupted circadian phenotypes and also with altered melatonin secretion [42][43][44]. Both factors are prerequisites for metabolic disturbances and diabetes [41].…”

“…MTNR1B also mediates the effect of melatonin on insulin gene expression [95]. The MTNR1B rs10830963 G-allele may be a link between circadian rhythm alterations, metabolic disorders and diabetes [41,96]. This SNP is associated with disrupted circadian phenotypes and also with altered melatonin secretion [42][43][44].…”

“…We included the rs10830963 polymorphism of the melatonin receptor MTNR1B gene since it is associated with metabolic risks and circadian rhythms [41][42][43][44][45][46] and may serve as a connection between circadian disruption due to impaired light signaling and metabolic response [41,46], including the circadian rhythm of temperature [44]. The pineal gland hormone melatonin is a well-documented substance that mediates the influence of outdoor light cues on the inner circadian machinery.…”

Glycemic Variability in Patients with Type 2 Diabetes Mellitus (T2DM): The Role of Melatonin in a Crossover, Double-Blind, Placebo-Controlled, Randomized Study

“…One study revealed that individuals with prediabetes and insulin resistance exhibit lower excretion levels of melatonin metabolites in their urine (6-sulfatoxymelatonin) [ 16 ]. Numerous studies have also investigated the relationship between polymorphisms in the gene responsible for expressing melatonin MTNR1B receptors and elevated susceptibility to developing type 2 diabetes mellitus (T2DM) and circadian disorders [ 17 , 18 ]. Melatonin is a hormone that signals the circadian rhythm.…”