Chronological Age Interacts with the Circadian Melatonin Receptor 1B Gene Variation, Determining Fasting Glucose Concentrations in Mediterranean Populations. Additional Analyses on Type-2 Diabetes Risk

Gene-age interactions have not been systematically investigated on metabolic phenotypes and this modulation will be key for a better understanding of the temporal regulation in nutrigenomics. Taking into account that aging is typically associated with both impairment of the circadian system and a decrease in melatonin secretion, we focused on the melatonin receptor 1B (MTNR1B)-rs10830963 C>G variant that has been associated with fasting glucose concentrations, gestational diabetes, and type-2 diabetes. Therefore, our main aim was to investigate whether the association between the MTNR1B-rs10830963 polymorphism and fasting glucose is age dependent. Our secondary aims were to analyze the polymorphism association with type-2 diabetes and explore the gene-pregnancies interactions on the later type-2 diabetes risk. Three Mediterranean cohorts (n = 2823) were analyzed. First, a cross-sectional study in the discovery cohort consisting of 1378 participants (aged 18 to 80 years; mean age 41 years) from the general population was carried out. To validate and extend the results, two replication cohorts consisting of elderly individuals were studied. In the discovery cohort, we observed a strong gene-age interaction (p = 0.001), determining fasting glucose in such a way that the increasing effect of the risk G-allele was much greater in young (p = 5.9 × 10−10) than in elderly participants (p = 0.805). Consistently, the association of the MTNR1B-rs10830963 polymorphism with fasting glucose concentrations in the two replication cohorts (mean age over 65 years) did not reach statistical significance (p > 0.05 for both). However, in the elderly cohorts, significant associations between the polymorphism and type-2 diabetes at baseline were found. Moreover, in one of the cohorts, we obtained a statistically significant interaction between the MTNR1B polymorphism and the number of pregnancies, retrospectively assessed, on the type-2 diabetes risk. In conclusion, the association of the MTNR1B-rs10830963 polymorphism with fasting glucose is age-dependent, having a greater effect in younger people. However, in elderly subjects, associations of the polymorphism with type-2 diabetes were observed and our exploratory analysis suggested a modulatory effect of the number of past pregnancies on the future type-2 diabetes genetic risk.

Role of Melatonin in Monochromatic Light Affecting the Expression of Somatostatin in Hypothalamus and Pituitary of Chicks

Background: Melatonin (MEL) plays an important role in regulating the growth and development of organism and the metabolism of cells. A study was conducted to explore the effect of MEL-mediated monochromatic light on the secretion of somatostatin (SST) in the hypothalamus and pituitary.Results: The newly hatched broilers were exposed to white (WL), red (RL), green (GL) and blue (BL) lights through the pinealectomy model. The results showed that SST immunoreactive neurons and fibers were distributed in hypothalamus. The mRNA and protein levels of SST and SST receptor 2 (SSTR2) in hypothalamus and pituitary in RL were higher than those of in GL and BL. After pinealectomy, mRNA and protein levels of SST and SSTR2 in hypothalamus and pituitary in different light groups were increased and the differences were disapeared. Meanwhile, the trend of SSTR5 mRNA in pituitary is the same as the SSTR2 mRNA in pituitary. In vitro, the exogenous SST inhibited the growth hormone (GH) secretion, and SSTR2 and SSTR5 selective antogonists promoted GH secretion. While, melatonin receptor 1b (Mel1b) and Mel1c selective antagonists increased relative concentraitons of SST in adenohypophysis cells.Conclusion: Monochromatic light affected the expression of SST in chick hypothalamus and pituitary. MEL via Mel1b and Mel1c decreased SST secretion under GL, which is related to inhibiting the combination of SST, SSTR2 and SSTR5 in adenohypophysis cells.

Reply to Comments on ‘A functional polymorphism rs10830963 in melatonin receptor 1B associated with the risk of gestational diabetes mellitus’

Th authors of ‘A functional polymorphism rs10830963 in melatonin receptor 1B associated with the risk of gestational diabetes mellitus’ (Bioscience Reports (2019) 39, 12) have written a reply in response to the correspondence piece by Rosta et al. (Bioscience Reports (2020) 40, 2).

Comments on: A functional polymorphism rs10830963 in melatonin receptor 1B associated with the risk of gestational diabetes mellitus

We have read with great interest the accepted manuscript of the meta-analysis performed by Huang, et al. titled “A functional polymorphism rs10830963 in melatonin receptor 1B associated with the risk of gestational diabetes mellitus” published online in the 2019 December 6 issue of Bioscience Reports (https://doi.org/10.1042/BSR20190744). We do agree with the authors’ final conclusion that such a meta-analysis should eventually confirm that the MTNR1B rs10830963 G allele is significantly associated with increased risk of gestational diabetes mellitus (GDM) development in pregnant populations with Asian and European ancestry. However we have surprisingly found that our genetic association study (PLoS One (2017), https://doi.org/10.1371/journal.pone.0169781) was included in this meta-analysis, but with mistakenly calculated odds ratios (OR). Therefore we would suggest to use the correct OR values based on our original publication that were already indicating a high genetic effect size for the MTNR1B rs10830963 risk variant on GDM development.

A functional polymorphism rs10830963 in melatonin receptor 1B associated with the risk of gestational diabetes mellitus

The melatonin receptor 1B (MTNR1B) polymorphism rs10830963 C>G has been reported to be associated with the risk of gestational diabetes mellitus (GDM) with inconsistent results. To clarify the effect of the polymorphism on the risk of GDM, a meta-analysis therefore was performed. Pooled OR with its corresponding 95%CI was used to estimate the strength of the association. Totally 14 eligible studies with a number of 5033 GDM patients and 5614 controls were included in this meta-analysis. Results indicated that the variant G allele was significantly associated with an increased GDM risk (CG vs. CC: OR = 1.25, 95% CI = 1.11−1.40, P < 0.001; GG vs. CC: OR = 1.78, 95% CI = 1.45−2.19, P < 0.001; G vs. C: OR = 1.33, 95% CI = 1.21−1.47, P < 0.001). In the stratified analysis by ethnicity, similar results were found in Asians (CG vs. CC: OR = 1.15, 95%CI = 1.02−1.28, P = 0.020; GG vs. CC: OR = 1.52, 95% CI = 1.23−1.89, P < 0.001; G vs. C: OR = 1.23, 95% CI = 1.10−1.37, P < 0.001) and in Caucasians (CG vs. CC: OR = 1.40, 95% CI = 1.16−1.70, P < 0.001; GG vs. CC: OR = 2.21, 95% CI = 1.54−3.17, P < 0.001; G vs. C: OR = 1.47, 95% CI = 1.24−1.73, P < 0.001). FPRP and TSA analyses confirmed findings support that the rs10830963 G allele increases the risk of GDM, and further functional experimental studies are warranted to explore and clarify the potential mechanism.

Effects of MTNR1B Genetic Variants on Individual Susceptibility to Gestational Diabetes Mellitus: A Meta-Analysis

Objective Whether melatonin receptor 1B (MTNR1B) variants are implicated in gestational diabetes mellitus (GDM) remains unclear. Therefore, we performed this meta-analysis to obtain a more conclusive result on associations between MTNR1B variants and GDM. Study Design Literature research was performed in PubMed, Web of Science, Embase, and China National Knowledge Infrastructure. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Results A total of 17 studies were eligible for analyses. Pooled overall analyses showed that rs1387153 (dominant model: p = 0.0002, OR = 0.78, 95% CI: 0.68–0.89; recessive model: p < 0.0001, OR = 1.46, 95% CI: 1.24–1.73; allele model: p < 0.0001, OR = 0.78, 95% CI: 0.72–0.84), rs4753426 (recessive model: p = 0.01, OR = 1.75, 95% CI: 1.14–2.68; allele model: p = 0.01, OR = 0.69, 95% CI: 0.51–0.93), and rs10830963 (dominant model: p < 0.0001, OR = 0.72, 95% CI: 0.65–0.78; recessive model: p < 0.0001, OR = 1.56, 95% CI: 1.40–1.74; allele model: p < 0.0001, OR = 0.73, 95% CI: 0.69–0.78) variants were all significantly associated with the susceptibility to GDM. Further subgroup analyses by ethnicity of participants yielded similar positive results. Conclusion Our findings indicated that MTNR1B rs1387153, rs4753426, and rs10830963 variants might serve as genetic biomarkers of GDM.