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Impact of Common Diabetes Risk Variant in MTNR1B on Sleep, Circadian, and Melatonin Physiology.

ABSTRACT: The risk of type 2 diabetes (T2D) is increased by abnormalities in sleep quantity and quality, circadian alignment, and melatonin regulation. A common genetic variant in a receptor for the circadian-regulated hormone melatonin (MTNR1B) is associated with increased fasting blood glucose and risk of T2D, but whether sleep or circadian disruption mediates this risk is unknown. We aimed to test if MTNR1B diabetes risk variant rs10830963 associates with measures of sleep or circadian physiology in intensive in-laboratory protocols (n = 58-96) or cross-sectional studies with sleep quantity and quality and timing measures from self-report (n = 4,307-10,332), actigraphy (n = 1,513), or polysomnography (n = 3,021). In the in-laboratory studies, we found a significant association with a substantially longer duration of elevated melatonin levels (41 min) and delayed circadian phase of dim-light melatonin offset (1.37 h), partially mediated through delayed offset of melatonin synthesis. Furthermore, increased T2D risk in MTNR1B risk allele carriers was more pronounced in early risers versus late risers as determined by 7 days of actigraphy. Our results provide the surprising insight that the MTNR1B risk allele influences dynamics of melatonin secretion, generating a novel hypothesis that the MTNR1B risk allele may extend the duration of endogenous melatonin production later into the morning and that early waking may magnify the diabetes risk conferred by the risk allele.

SUBMITTER: Lane JM

PROVIDER: S-EPMC4878414 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Common type 2 diabetes risk variant in MTNR1B worsens the deleterious effect of melatonin on glucose tolerance in humans.

Project description:AimsThe common MTNR1B genetic variant rs10830963 is associated with an increased risk of type 2 diabetes (T2D). To date, no experimental study has tested the effect of the MTNR1B variant on glucose metabolism in humans during exposure of the melatonin receptors to their ligand. The aim of this study was to investigate whether this MTNR1B variant influenced the effect of melatonin (5mg) on glucose tolerance assessed by an oral glucose tolerance test (OGTT; 75 g) at different times of the day (morning and evening) as compared to a placebo.MethodsSeventeen normoglycemic women (24 ± 6 years; BMI 23.0 ± 3.3 kg/m(2)) completed the study (11 carriers of the risk allele [CG] and 6 noncarriers [CC]).ResultsThe effect of melatonin on glucose tolerance depended on the genotype. In the morning, the effect of melatonin (melatonin-placebo) on the glucose area under the curve (AUC) above baseline differed significantly (P=0.036) between the carriers and noncarriers. This effect of melatonin in the carriers was six times as large as that in the noncarriers. The MTNR1B SNP explained over one-quarter (26%) of the inter-individual differences in the effect of melatonin on glucose AUC. However, in the evening, the effect of melatonin on glucose AUC of the carriers and noncarriers did not differ significantly (P>0.05).ConclusionsMTNR1B rs10830963 risk variant worsens the effect of melatonin on glucose tolerance, suggesting the importance of genotyping and personalized recommendations, especially in people consuming food when melatonin levels are elevated. Large-scale studies in vulnerable populations are necessary to translate these results into real-world, clinically relevant recommendations.

| S-EPMC4856010 | biostudies-literature

Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion.

Project description:Genome-wide association studies have shown that variation in MTNR1B (melatonin receptor 1B) is associated with insulin and glucose concentrations. Here we show that the risk genotype of this SNP predicts future type 2 diabetes (T2D) in two large prospective studies. Specifically, the risk genotype was associated with impairment of early insulin response to both oral and intravenous glucose and with faster deterioration of insulin secretion over time. We also show that the MTNR1B mRNA is expressed in human islets, and immunocytochemistry confirms that it is primarily localized in beta cells in islets. Nondiabetic individuals carrying the risk allele and individuals with T2D showed increased expression of the receptor in islets. Insulin release from clonal beta cells in response to glucose was inhibited in the presence of melatonin. These data suggest that the circulating hormone melatonin, which is predominantly released from the pineal gland in the brain, is involved in the pathogenesis of T2D. Given the increased expression of MTNR1B in individuals at risk of T2D, the pathogenic effects are likely exerted via a direct inhibitory effect on beta cells. In view of these results, blocking the melatonin ligand-receptor system could be a therapeutic avenue in T2D.

| S-EPMC3725650 | biostudies-literature

Common genetic variation near melatonin receptor MTNR1B contributes to raised plasma glucose and increased risk of type 2 diabetes among Indian Asians and European Caucasians.

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| S-EPMC2768158 | biostudies-literature

Increased Risk of Myocardial Infarction Among Patients With Type 2 Diabetes Who Carry the Common rs10830963 Variant in the <i>MTNR1B</i> Gene.

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| S-EPMC7440907 | biostudies-literature

Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes.

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| S-EPMC3773908 | biostudies-literature

Melatonin is required for the circadian regulation of sleep.

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| S-EPMC4851458 | biostudies-literature

Sleep, circadian dysrhythmia, obesity and diabetes.

Project description:Synchrony of biological processes with environmental cues developed over millennia to match growth, reproduction and senescence. This entails a complex interplay of genetic, metabolic, chemical, light, hormonal and hedonistic factors across life forms. Sleep is one of the most prominent rhythms where such a match is established. Over the past 100 years or so, it has been possible to disturb the synchrony between sleep-wake cycle and environmental cues. Development of electric lights, shift work and continual accessibility of the internet has disrupted this match. As a result, many non-communicable diseases such as obesity, insulin resistance, type 2 diabetes, coronary artery disease and malignancies have been attributed in part to such disruption. In this presentation a review is made of the origin and evolution of sleep studies, the pathogenic mediators for such asynchrony, clinical evidence and relevance and suggested management options to deal with the disturbances.

| S-EPMC5107711 | biostudies-literature

Common genetic variation in the melatonin receptor 1B gene (MTNR1B) is associated with decreased early-phase insulin response.

Project description:Aims/hypothesisWe investigated whether variation in MTNR1B, which was recently identified as a common genetic determinant of fasting glucose levels in healthy, diabetes-free individuals, is associated with measures of beta cell function and whole-body insulin sensitivity.MethodsWe studied 1,276 healthy individuals of European ancestry at 19 centres of the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study. Whole-body insulin sensitivity was assessed by euglycaemic-hyperinsulinaemic clamp and indices of beta cell function were derived from a 75 g oral glucose tolerance test (including 30 min insulin response and glucose sensitivity). We studied rs10830963 in MTNR1B using additive genetic models, adjusting for age, sex and recruitment centre.ResultsThe minor (G) allele of rs10830963 in MTNR1B (frequency 0.30 in HapMap Centre d'Etude du Polymorphisme [Utah residents with northern and western European ancestry] [CEU]; 0.29 in RISC participants) was associated with higher levels of fasting plasma glucose (standardised beta [95% CI] 0.17 [0.085, 0.25] per G allele, p = 5.8 x 10(-5)), consistent with recent observations. In addition, the G-allele was significantly associated with lower early insulin response (-0.19 [-0.28, -0.10], p = 1.7 x 10(-5)), as well as with decreased beta cell glucose sensitivity (-0.11 [-0.20, -0.027], p = 0.010). No associations were observed with clamp-assessed insulin sensitivity (p = 0.15) or different measures of body size (p > 0.7 for all).Conclusions/interpretationGenetic variation in MTNR1B is associated with defective early insulin response and decreased beta cell glucose sensitivity, which may contribute to the higher glucose levels of non-diabetic individuals carrying the minor G allele of rs10830963 in MTNR1B.

| S-EPMC2709880 | biostudies-literature

A common variant in the MTNR1b gene is associated with increased risk of impaired fasting glucose (IFG) in youth with obesity.

Project description:ObjectiveTo explore the role of MTNR1B rs10830963 and G6PC2 rs560887 variants in the pathogenesis of impaired fasting glucose (IFG) in obese adolescents.MethodsA total of 346 Caucasians, 218 African-Americans, and 217 Hispanics obese children and adolescents underwent an oral glucose tolerance test (OGTT) and 518 underwent the evaluation of insulin secretion by the oral minimal model (OMM). Also, 274 subjects underwent a second OGTT after 3.0 ± 2.1 years.ResultsThe MTNR1B rs10830963 variant was associated with higher fasting glucose levels and lower dynamic beta-cell response in Caucasians and Hispanics (P < 0.05) and conferred an increased risk of showing IFG to Caucasians (P = 0.05), African-Americans (P = 0.0066), and Hispanics (P = 0.024). Despite the association between the G6PC2 rs560887 and higher fasting glucose levels (P < 0.05), there was no association between this variant and IFG at baseline or at follow-up (all P > 0.10).ConclusionsIt has been shown for the first time in obese youth that the MTNR1B variant is associated with an increased risk of IFG.

| S-EPMC4414047 | biostudies-literature

Melatonin alleviates LPS-induced abnormal pregnancy through MTNR1B regulation of m6A

Project description:In this study, the protective effect of melatonin and m6A on mouse pregnancy was studied by constructing an LPS-induced abnormal early pregnancy model in mice. Pregnant ICR mice were selected and intraperitoneal injection of LPS on D3 and D4 of pregnancy, melatonin was found to alleviated LPS-induced reductions in the number of implantation sites. Besides, melatonin alleviated the activation of inflammation, autophagy and apoptosis pathways, thereby protecting the pregnancy process of mice. We monitored m6A methylation by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and m6A-sequencing (m6A-seq), we found that melatonin regulated m6A methylation levels.

2024-01-31 | GSE216994 | GEO

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