The Circadian Rhythm–Related MTNR1B Genotype, Gestational Weight Gain, and Postpartum Glycemic Changes

Nisa, Hoirun; Qi, Kevin H T; Leng, Junhong; Zhou, Tao; Liu, Huikun; Li, Weiqin; Wang, Leishen; Li, Nan; Hu, Gang; Qi, Lü

doi:10.1210/jc.2018-00071

Cited by 15 publications

(12 citation statements)

References 26 publications

(23 reference statements)

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“…While it is known that disrupted circadian rhythms can be detrimental to reproductive success (Dolatshad et al, 2005;Mahoney, 2010), it remains largely unknown how they change from the non-pregnant state to pregnancy. Understanding the role of circadian rhythms in regulating both behavior and tissue-specific circadian function during the estrous cycle and in pregnancy is an essential first step toward elucidating the underlying mechanisms associated with infertility and pregnancy complications, which are more prevalent in women with disrupted circadian rhythms (Goldberg et al, 2012;Nisa et al, 2018;Pappa et al, 2013;Zornoza-Moreno et al, 2013). We hypothesize that circadian timekeeping during late pregnancy influences mouse behavior and reproductive tissue circadian function in preparation for labor.…”

Section: Introductionmentioning

confidence: 99%

Circadian rhythms in the mouse reproductive axis during the estrous cycle and pregnancy

Yaw

Duong

Nguyen

et al. 2020

J of Neuroscience Research

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Molecular and behavioral timekeeping is regulated by the circadian system which includes the brain's suprachiasmatic nucleus (SCN) that translates environmental light information into neuronal and endocrine signals aligning peripheral tissue rhythms to the time of day. Despite the critical role of circadian rhythms in fertility, it remains unexplored how circadian rhythms change within reproductive tissues during pregnancy. To determine how estrous cycle and pregnancy impact phase relationships of reproductive tissues, we used PER2::Luciferase (PER2::LUC) circadian reporter mice and determined the time of day of PER2::LUC peak (phase) in the SCN, pituitary, uterus, and ovary. The relationships between reproductive tissue PER2::LUC phases changed throughout the estrous cycle and late pregnancy and were accompanied by changes to PER2::LUC period in the SCN, uterus, and ovary. To determine if the phase relationship adaptations were driven by sex steroids, we asked if progesterone, a hormone involved in estrous cyclicity and pregnancy, could regulate Per2‐luciferase expression. Using an in vitro transfection assay, we found that progesterone increased Per2‐luciferase expression in immortalized SCN (SCN2.2) and arcuate nucleus (KTAR) cells. In addition, progesterone shortened PER2::LUC period in ex vivo uterine tissue recordings collected during pregnancy. As progesterone dramatically increases during pregnancy, we evaluated wheel‐running patterns in PER2::LUC mice. We confirmed that activity levels decrease during pregnancy and found that activity onset was delayed. Although SCN, but not arcuate nucleus, PER2::LUC period changed during late pregnancy, onset of locomotor activity did not correlate with SCN or arcuate nucleus PER2::LUC period.

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Section: Introductionmentioning

confidence: 99%

Circadian rhythms in the mouse reproductive axis during the estrous cycle and pregnancy

Yaw

Duong

Nguyen

et al. 2020

J of Neuroscience Research

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“…Although our study results in the Mediterranean population might not be generalized to other populations, future studies, taking into account pregnancy and other variables (sleep, etc.) related to this polymorphism [76,77] in different populations are warranted.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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.

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“…Interestingly, rs10830963 was associated with reduced β‐cell function (as determined by homeostatic model assessment of β‐cell function) and a higher level of fasting plasma glucose in a Chinese pregnant population . Furthermore, Nisa et al found that the rs10830963 G risk allele was associated with postpartum glycemic changes among women with a history of GDM. Of note, another study reported that individuals with the rs10830963 G allele have higher MTNR1B expression in pancreatic β‐cells, which is thus correlated with reduced insulin secretion, leading to the greater risk of T2D .…”

Section: Discussionmentioning

confidence: 99%

Genetic predisposition to gestational glucose metabolism and gestational diabetes mellitus risk in a Chinese population

Xie

Zhang

Wen

et al. 2019

Journal of Diabetes

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Background Genome‐wide association studies (GWAS) have identified several genetic variants affecting gestational glucose metabolism. However, information regarding their known associations with gestational diabetes mellitus (GDM) risk remains scarce. Methods This study examined the associations of 12 gestational glucose metabolism‐related variants with GDM risk in a Chinese population (964 GDM cases, 1021 controls). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression analysis. Results Rs10830963 in melatonin receptor 1B (MTNR1B) was found to be associated with an increased risk of GDM, after adjusting for age, prepregnancy body mass index, parity, abnormal pregnancy history, and family history of diabetes (OR 1.20; 95% CI 1.05‐1.36; P = 0.007). Compared with women with a family history of diabetes, there was a significant association of rs7936247 with GDM risk among pregnant women without a family history of diabetes (OR 1.20; 95% CI 1.04‐1.38; P = 0.014; Pheterogeneity = 0.035). Further functional annotations showed that rs10830963 and rs7936247 fell in the functional elements of human pancreatic islets. Genotype‐phenotype associations indicated that the variants may contribute to GDM risk by affecting the expression of nearby or distant genes. Conclusions The findings of this study suggest that rs10830963 and rs7936247 may be markers for susceptibility to GDM in a Chinese population. Additional studies are warranted to validate our findings and clarify the underlying mechanism.

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The Circadian Rhythm–Related MTNR1B Genotype, Gestational Weight Gain, and Postpartum Glycemic Changes

Abstract: Our findings suggest that gestational weight gain may modify the circadian rhythm-related MTNR1B genetic variant on long-term glycemic changes, highlighting the significance of gestational weight management in diabetes prevention among women with GDM.

Cited by 15 publications

References 26 publications

Circadian rhythms in the mouse reproductive axis during the estrous cycle and pregnancy

Circadian rhythms in the mouse reproductive axis during the estrous cycle and pregnancy

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

Genetic predisposition to gestational glucose metabolism and gestational diabetes mellitus risk in a Chinese population

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