Abstract: Melatonin receptor 1B (MT2, encoded by the MTNR1B gene), a high-affinity receptor for melatonin, is associated with glucose homeostasis including glucose uptake and transport. The rs10830963 variant in the MTNR1B gene is linked to glucose metabolism disorders including gestational diabetes mellitus (GDM); however, the relationship between MT2-mediated melatonin signaling and a high birth weight of GDM infants from maternal glucose abnormality remains poorly understood. This article aims to investigate the relationship between rs10830963 variants and GDM development, as well as the effects of MT2 receptor on glucose uptake and transport in trophoblasts. TaqMan-MGB (minor groove binder) probe quantitative real-time polymerase chain reaction (qPCR) assays were used for rs10930963 genotyping. MT2 expression in the placenta of GDM and normal pregnant women was detected by immunofluorescence, western blot, and qPCR. The relationship between MT2 and glucose transporters (GLUTs) or peroxisome proliferator-activated receptor γ (PPARγ) was established by western blot, and glucose consumption of trophoblasts was measured by a glucose assay kit. The results showed that the genotype and allele frequencies of rs10830963 were significantly different between GDM and normal pregnant women (P<0.05). The fasting, 1-h and 2-h plasma glucose levels of G-allele carriers were significantly higher than those of C-allele carriers (P<0.05). Besides, the protein and messenger RNA (mRNA) expression of MT2 in the placenta of GDM was significantly higher than that of normal pregnant women (P<0.05). Melatonin could stimulate glucose uptake and GLUT4 and PPARγ protein expression in trophoblasts, which could be attenuated by MT2 receptor knockdown. In conclusion, the rs10830963 variant was associated with an increased risk of GDM. The MT2 receptor is essential for melatonin to raise glucose uptake and transport, which may be mediated by PPARγ.

褪黑素受体1B基因多态性及其对葡萄糖转运的调控在妊娠期糖尿病中的作用

[1]ACOG, 2020. Macrosomia: ACOG practice bulletin, number 216. Obstet Gynecol, 135(1):e18-e35.

[2]AlharbiKK, Al-SulaimanAM, ShedaidMKB, et al., 2019. MTNR1B genetic polymorphisms as risk factors for gestational diabetes mellitus: a case-control study in a single tertiary care center. Ann Saudi Med, 39(5):309-318.

[3]AlharbiKK, AlsaikhanAS, AlshammaryAF, et al., 2022. Screening of mitochondrial mutations in Saudi women diagnosed with gestational diabetes mellitus: a non-replicative case-control study. Saudi J Biol Sci, 29(1):360-365.

[4]BeaumontRN, WarringtonNM, CavadinoA, et al., 2018. Genome-wide association study of offspring birth weight in 86577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics. Hum Mol Genet, 27(4):742-756.

[5]BellamyL, CasasJP, HingoraniAD, et al., 2009. Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis. Lancet, 373(9677):1773-1779.

[6]BorgesMH, PullockaranJ, CatalanoPM, et al., 2019. Human placental GLUT1 glucose transporter expression and the fetal insulin-like growth factor axis in pregnancies complicated by diabetes. Biochim Biophys Acta Mol Basis Dis, 1865(9):2411-2419.

[7]BrownK, HellerDS, ZamudioS, et al., 2011. Glucose transporter 3 (GLUT3) protein expression in human placenta across gestation. Placenta, 32(12):1041-1049.

[8]BrüningJC, MichaelMD, WinnayJN, et al., 1998. A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol Cell, 2(5):559-569.

[9]Castillo-CastrejonM, PowellTL, 2017. Placental nutrient transport in gestational diabetic pregnancies. Front Endocrinol (Lausanne), 8:306.

[10]FadlH, MagnusonA, ÖstlundI, et al., 2014. Gestational diabetes mellitus and later cardiovascular disease: a Swedish population based case-control study. BJOG, 121(12):1530-1536.

[11]FengY, JiangCD, ChangAM, et al., 2019. Interactions among insulin resistance, inflammation factors, obesity-related gene polymorphisms, environmental risk factors, and diet in the development of gestational diabetes mellitus. J Matern Fetal Neonatal Med, 32(2):339-347.

[12]GuanQY, WangZX, CaoJ, et al., 2021. Mechanisms of melatonin in obesity: a review. Int J Mol Sci, 23(1):218.

[13]HaE, YimSV, ChungJH, et al., 2006. Melatonin stimulates glucose transport via insulin receptor substrate-1/phosphatidylinositol 3-kinase pathway in C₂C₁₂ murine skeletal muscle cells. J Pineal Res, 41(1):67-72.

[14]HaggartyP, AllstaffS, HoadG, et al., 2002. Placental nutrient transfer capacity and fetal growth. Placenta, 23(1):86-92.

[15]IllsleyNP, BaumannMU, 2020. Human placental glucose transport in fetoplacental growth and metabolism. Biochim Biophys Acta Mol Basis Dis, 1866(2):165359.

[16]James-AllanLB, ArbetJ, TealSB, et al., 2019. Insulin stimulates GLUT4 trafficking to the syncytiotrophoblast basal plasma membrane in the human placenta. J Clin Endocrinol Metab, 104(9):4225-4238.

[17]KaramitriA, JockersR, 2019. Melatonin in type 2 diabetes mellitus and obesity. Nat Rev Endocrinol, 15(2):105-125.

[18]KhanIA, MovvaS, ShaikNA, et al., 2014. Investigation of Calpain 10 (rs2975760) gene polymorphism in Asian Indians with Gestational Diabetes Mellitus. Meta Gene, 2:299-306.

[19]LiC, ZhouYB, QiaoBL, et al., 2019. Association between a melatonin receptor IB genetic polymorphism and its protein expression in gestational diabetes mellitus. Reprod Sci, 26(10):1382-1388.

[20]LiTJ, NiL, ZhaoZW, et al., 2018. Melatonin attenuates smoking-induced hyperglycemia via preserving insulin secretion and hepatic glycogen synthesis in rats. J Pineal Res, 64(4):e12475.

[21]LiangZX, LiuHK, WangLS, et al., 2020. Maternal MTNR1B genotype, maternal gestational weight gain, and childhood obesity. Am J Clin Nutr, 111(2):360-368.

[22]LiaoW, NguyenMTA, YoshizakiT, et al., 2007. Suppression of PPAR-γ attenuates insulin-stimulated glucose uptake by affecting both GLUT1 and GLUT4 in 3T3-L1 adipocytes. Am J Physiol Endocrinol Metab, 293(1):E219-E227.

[23]LingY, LiXM, GuQ, et al., 2011. A common polymorphism rs3781637 in MTNR1B is associated with type 2 diabetes and lipids levels in Han Chinese individuals. Cardiovasc Diabetol, 10:27.

[24]MontaigneD, ButruilleL, StaelsB, 2021. PPAR control of metabolism and cardiovascular functions. Nat Rev Cardiol, 18(12):809-823.

[25]OwinoS, BuonfiglioDDC, TchioC, et al., 2019. Melatonin signaling a key regulator of glucose homeostasis and energy metabolism. Front Endocrinol (Lausanne), 10:488.

[26]PatelR, RathwaN, PalitSP, et al., 2018. Association of melatonin & MTNR1B variants with type 2 diabetes in Gujarat population. Biomed Pharmacother, 103:429-434.

[27]PettittDJ, BennettPH, KnowlerWC, et al., 1985. Gestational diabetes mellitus and impaired glucose tolerance during pregnancy: long-term effects on obesity and glucose tolerance in the offspring. Diabetes, 34(Suppl 2):119-122.

[28]PoweCE, NodzenskiM, TalbotO, et al., 2018. Genetic determinants of glycemic traits and the risk of gestational diabetes mellitus. Diabetes, 67(12):2703-2709.

[29]RenJ, XiangAH, TrigoE, et al., 2014. Genetic variation in MTNR1B is associated with gestational diabetes mellitus and contributes only to the absolute level of beta cell compensation in Mexican Americans. Diabetologia, 57(7): 1391-1399.

[30]ShenLL, JinY, 2019. Effects of MTNR1B genetic variants on the risk of type 2 diabetes mellitus: a meta-analysis. Mol Genet Genomic Med, 7(5):e611.

[31]SolimanA, LacasseAA, LanoixD, et al., 2015. Placental melatonin system is present throughout pregnancy and regulates villous trophoblast differentiation. J Pineal Res, 59(1):38-46.

[32]StanirowskiPJ, SzukiewiczD, PyzlakM, et al., 2019. Analysis of correlations between the placental expression of glucose transporters GLUT-1, GLUT-4 and GLUT-9 and selected maternal and fetal parameters in pregnancies complicated by diabetes mellitus. J Matern Fetal Neonatal Med, 32(4):650-659.

[33]The HAPO Study Cooperative Research Group, 2008. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med, 358(19):1991-2002.

[34]VlassiM, GazouliM, PaltoglouG, et al., 2012. The rs10830963 variant of melatonin receptor MTNR1B is associated with increased risk for gestational diabetes mellitus in a Greek population. Hormones (Athens), 11(1):70-76.

[35]WuYT, ZhangCJ, MolBW, et al., 2021. Early prediction of gestational diabetes mellitus in the Chinese population via advanced machine learning. J Clin Endocrinol Metab, 106(3):e1191-e1205.

[36]XueBZ, KahnBB, 2006. AMPK integrates nutrient and hormonal signals to regulate food intake and energy balance through effects in the hypothalamus and peripheral tissues. J Physiol, 574(1):73-83.

[37]YaoG, ZhangYF, WangD, et al., 2017. GDM-induced macrosomia is reversed by Cav-1 via AMPK-mediated fatty acid transport and GLUT1-mediated glucose transport in placenta. PLoS ONE, 12(1):e0170490.

[38]ZhangL, YuXY, WuY, et al., 2021. Gestational diabetes mellitus-associated hyperglycemia impairs glucose transporter 3 trafficking in trophoblasts through the downregulation of AMP-activated protein kinase. Front Cell Dev Biol, 9:722024.

[39]ZhouML, JiJS, XieN, et al., 2022. Prediction of birth weight in pregnancy with gestational diabetes mellitus using an artificial neural network. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 23(5):432-436.

[40]ZhuB, MaZX, ZhuYN, et al., 2021. Reduced glycodeoxycholic acid levels are associated with negative clinical outcomes of gestational diabetes mellitus. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 22(3):223-232.