Clinical and molecular genetic determinants of the development of gestational diabetes mellitus
The molecular mechanisms of the pathogenesis of gestational diabetes mellitus (GDM) remain insufficiently studied, which is largely determined by its heterogeneous nature. The paper reviews the data available in the current literature on studies of the molecular genetic determinants of the development of gestational diabetes mellitus. It describes predictors for GDM, their relationship to obstetric and neonatal outcomes, as well as associations with other types of diabetes and with the risk of their development.Khodzhaeva Z.S., Snetkova N.V., Klimenchenko N.I., Abramova M.E., Degtyareva E.I., Donnikov A.E.
Conclusion. Further investigations are needed to identify virtually significant molecular genetic biomarkers for GDM.
Keywords
gestational diabetes mellitus
pregnancy
genetics
diabetic fetopathy
fetal macrosomia
oral glucose tolerance test
insulin resistance
References
- Hod M., Kapur A., Sacks D.A., Hadar E., Agarwal M., Di Renzo G.C. et al. The International Federation of Gynecology and Obstetrics (FIGO) Initiative on gestational diabetes mellitus: A pragmatic guide for diagnosis, management, and care. Int. J. Gynaecol. Obstet. 2015; 131(Suppl. 3): S173-211.
- ВОЗ. Диагностические критерии и классификация гипергликемии, впервые выявленной при беременности. Женева: Всемирная организация здравоохранения; 2013. [WHO. Diagnostic criteria and classification of hyperglycemia, first identified during pregnancy. Geneva: World Health Organization; 2013. (in Russian)].
- Kharroubi A.T., Darwish H.M. Diabetes mellitus: The epidemic of the century. World J. Diabetes. 2015; 6(6): 850-67.
- Webber J., Charlton M., Johns N. Diabetes in pregnancy: management of diabetes and its complications from preconception to the postnatal period (NG3). Br. J. Diabetes. 2015; 15(3): 107-11.
- Mackeen A.D., Lott M. Gestational diabetes. In: Berghella V., ed. Maternal-fetal evidence based guidelines. 3rd ed. CRC Press; 2017: ch 5.
- Ornoy A., Reece E.A., Pavlinkova G., Kappen C., Miller R.K. Effect of maternal diabetes on the embryo, fetus, and children: congenital anomalies, genetic and epigenetic changes and developmental outcomes. Birth Defects Res. C Embryo Today. 2015; 105(1): 53-72.
- Бурумкулова Ф.Ф., Петрухин В.А. Гестационный сахарный диабет: вчера, сегодня, завтра. Терапевтический архив. 2014; 86(10): 109-15. [Burumkulova F.F. , Petrukhin V.A. Gestational diabetes: yesterday, today, tomorrow. Therapeutic archive. 2014; 86 (10): 109-15. (in Russian)].
- Дедов И.И., Сухих Г.Т., Краснопольский В.И., ред. Гестационный сахарный диабет: диагностика, лечение и послеродовое наблюдение. Клинические рекомендации (протокол). М.; 2014. [Grandfathers I.I., Sukhikh G.T., Krasnopolsky V.I., ed. Gestational diabetes mellitus: diagnosis, treatment and postpartum observation. Clinical recommendations (protocol). M .; 2014. (in Russian)].
- Lenin M., Ramasamy R., Kulkarani S., Ghose S., Srinivasan A.R.S. Association of KCNJ11(RS5219) gene polymorphism with biochemical markers of glycemic status and insulin resistance in gestational diabetes mellitus. Meta Gene. 2018; 16: 134-8.
- Huopio H., Hakkarainen H., Pääkkönen M., Kuulasmaa T., Heinonen S., Laakso M. Association of risk variants for type 2 diabetes and hyperglycemia with gestational diabetes. Eur. J. Endocrinol. 2013; 169(3): 291-7.
- Ding M., Chavarro J., Olsen S., Lin Y., Ley S.H., Bao W. et al. Genetic variants of gestational diabetes mellitus: A study of 112 SNPs among 8722 women in two independent populations. Diabetologia. 2018; 61(8): 1758-68.
- Franzago M., Fraticelli F., Marchetti D., Celentano C., Liberati M., Stuppia L., Vitacolonna E. Nutrigenetic variants and cardio-metabolic risk in women with or without gestational diabetes. Diabetes Res. Clin. Pract. 2018; 137: 64-71.
- Nobrega M.A. TCF7L2 and Glucose metabolism: time to look beyond the pancreas. Diabetes. 2013; 62(3): 706-8.
- Pilgaard K., Jensen C.B., Schou J.H., Lyssenko V., Wegner L., Brøns C. et al. The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men. Diabetologia. 2009; 52(7): 1298-307.
- Tarnowski M., Wieczorek A., Dziedziejko V., Safranow K., Ustianowski P., Celewicz Z., Pawlik A. IL16 and IL18 gene polymorphisms in women with gestational diabetes. Ginekol. Pol. 2017; 88(5): 249-54.
- Guinan K.J. Worldwide distribution of type 2 diabetes-associated TCF7L2 SNPs: evidence for stratification in Europe. Biochem. Genet. 2012; 50(3-4): 159-79.
- Ao D., Wang H.J., Wang L.F., Song J.Y., Yang H.X., Wang Y. The rs2237892 polymorphism in KCNQ1 influences gestational diabetes mellitus and glucose levels: A case-control study and meta-analysis. PLoS One. 2015; 10(6): e0128901.
- Tian C., Chang H., La X., Li J.A. Wushenziye formula improves skeletal muscle insulin resistance in type 2 diabetes mellitus via PTP1B-IRS1-Akt-GLUT4 signaling pathway. Evid. Based Complement. Alternat. Med. 2017; 2017: 4393529.
- Alharbi K.K., Khan I.A., Abotalib Z., Al-Hakeem M.M. Insulin receptor substrate-1 (IRS-1) Gly927Arg: Correlation with gestational diabetes mellitus in Saudi women. Biomed. Res. Int. 2014; 2014:146695.
- Popova P.V., Klyushina A.A., Vasilyeva L.B., Tkachuk A.S., Bolotko Y.A., Gerasimov A.S. et al. Effect of gene-lifestyle interaction on gestational diabetes risk. Oncotarget. 2017; 8(67): 112024-35.
- Rosta K., Al-Aissa Z., Hadarits O., Harreiter J., Nádasdi A., Kelemen F. et al. Association study with 77 SNPs confirms the robust role for the rs10830963/G of MTNR1B variant and identifies two novel associations in gestational diabetes mellitus development. PLoS One. 2017; 12(1):e0169781.
- Petry C.J., Mooslehner K., Prentice P., Hayes M.G., Nodzenski M., Scholtens D.M. et al. Associations between a fetal imprinted gene allele score and late pregnancy maternal glucose concentrations. Diabetes Metab. 2017; 43(4): 323-31.
- White V., Jawerbaum A., Mazzucco M.B., Gauster M., Desoye G., Hiden U. IGF2 stimulates fetal growth in a sex- and organ-dependent manner. Pediatr. Res. 2018; 83(1-1): 183-9.
- Su R., Wang C., Feng H., Lin L., Liu X., Wei Y. Alteration in expression and methylation of IGF2/H19 in placenta and umbilical cord blood are associated with macrosomia exposed to intrauterine hyperglycemia. PLoS One. 2016; 11(2): e0148399.
- Wang X., Li W., Ma L., Ping F., Liu J., Wu X. et al. Investigation of miRNA-binding site variants and risk of gestational diabetes mellitus in Chinese pregnant women. Acta Diabetol. 2017; 54(3): 309-16.
- Sun H., Wang X., Chen J., Gusdon A.M., Song K., Li L., Qu S. Melatonin Treatment improves insulin resistance and pigmentation in obese patients with acanthosis nigricans. Int. J. Endocrinol. 2018; 2018:2304746.
- Tarnowski M., Malinowski D., Safranow K., Dziedziejko V., Pawlik A. MTNR1A and MTNR1B gene polymorphisms in women with gestational diabetes. Gynecol. Endocrinol. 2017; 33(5): 395-8.
- Huopio H., Cederberg H. Association of risk variants for type 2 diabetes and hyperglycemia with gestational diabetes. Eur. J. Endocrinol. 2013; 169(3): 291-7.
- Prokopenko I., Langenberg C., Florez J.C., Saxena R., Soranzo N., Thorleifsson G. et al. Variants in MTNR1B influence fasting glucose levels. Nat. Genet. 2009; 41: 77-81.
- Pappa K.I., Gazouli M., Economou K., Daskalakis G., Anastasiou E., Anagnou N.P., Antsaklis A. Gestational diabetes mellitus shares polymorphisms of genes associated with insulin resistance and type 2 diabetes in the Greek population. Gynecol. Endocrinol. 2011; 27(4): 267-72.
- Heude B., Pelloux V., Forhan A., Bedel J.F., Lacorte J.M., Clement K., Charles M.A. Association of the Pro12Ala and C1431 T varisnts of PPARgamma and their haplotypes with susceptibility to gestational diabetes. J. Clin. Endocrinol. Metab. 2011; 96(10): E1656-60.
- Mao H., Li Q., Gao S. Meta-analysis of the relationship between common type 2 diabetes risk gene variants with gestational diabetes mellitus. PLoS One. 2012; 7(9): e45882.
- Bao W., Baecker A., Song Y., Kiely M., Liu S., Zhang C. Adipokine levels during the first or early second trimester of pregnancy and subsequent risk of gestational diabetes mellitus: A systematic review. Metabolism. 2015; 64(6): 756-64.
- Feng Y ., Jiang C.D., Chang A.M., Shi Y., Gao J., Zhu L., Zhang Z . 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. 2019; 32(2): 339-47.
- Han Y., Zheng Y.L., Fan Y.P., Liu M.H., Lu X.Y., Tao Q. Association of adiponectin gene polymorphism 45TG with gestational diabetes mellitus diagnosed on the new IADPSG criteria, plasma adiponectin levels and adverse pregnancy outcomes. Clin. Exp. Med. 201; 15(1): 47-53.
- Pawlik A., Teler J., Maciejewska A., Sawczuk M., Safranow K., Dziedziejko V. Adiponectin and leptin gene polymorphisms in women with gestational diabetes mellitus. J. Assist. Reprod. Genet. 2017; 34(4): 511-6.
- Wang H., Dong S., Xu H., Qian J., Yang J. Genetic variants in FTO associated with metabolic syndrome: A meta- and gene-based analysis. Mol. Biol. Rep. 2012; 39(5): 5691-8.
- Merkestein M., Sellayah D. Role of FTO in adipocyte development and function: recent insights. Int. J. Endocrinol. 2015; 2015: 521381.
- De Melo S.F., Frigeri H.R., dos Santos-Weiss I.C.R., Réa R.R., de Souza E.M., Alberton D. Polymorphisms in FTO and TCF7L2 genes of Euro-Brazilian women with gestational diabetes. Clin. Biochem. 2015; 48(16-17): 1064-7.
- Anghebem-Oliveira M.I., Martins B.R., Alberton D., de Souza Ramos E.A., Picheth G., Rego F.G.M. Type 2 diabetes-associated genetic variants of FTO, LEPR, PPARg, and TCF7l2 in gestational diabetes in a Brazilian population. Arch. Endocrinol. Metab. 2017; 61(3): 238-48.
- Saucedo R., Valencia J., Gutierrez C., Basurto L., Hernandez M., Puello E. et al. Gene variants in the FTO gene are associated with adiponectin and TNF-alpha levels in gestational diabetes mellitus. Diabetol. Metab. Syndr. 2017; 9: 32.
- Iynedjian P.B. Molecular physiology of mammalian glucokinase. Cell. Mol. Life Sci. 2009; 66(1): 27-42.
- Santos I.C., Frigeri H.R., Rea R.R., Almeida A.C., Souza E.M., Pedrosa F.O. et al. The glucokinase gene promoter polymorphism −30G>A (rs1799884) is associated with fasting glucose in healthy pregnant women but not with gestational diabetes. Clin. Chim. Acta. 2010; 411(11-12): 892-3.
- Gjesing A.P., Rui G., Lauenborg J., Have C.T., Hollensted M., Andersson E. et al. High prevalence of diabetes-predisposing variants in MODY genes among Danish women with gestational diabetes mellitus. J. Endocr. Soc. 2017; 1(6): 681-90.
- Freathy R.M., Hayes M.G., Urbanek M., Lowe L.P., Lee H., Ackerman C. et al. Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study: common genetic variants in GCK and TCF7L2 are associated with fasting and postchallenge glucose levels in pregnancy and with the new consensus definition of gestational diabetes mellitus from the International Association of Diabetes and Pregnancy Study Groups. Diabetes. 2010;59(10): 2682-9.
- Han X., Cui H., Chen X., Xie W., Chang Y. Association of the glucokinase gene promoter polymorphism -30G > A (rs1799884) with gestational diabetes mellitus susceptibility: A case-control study and meta-analysis. Arch. Gynecol. Obstet. 2015; 292(2): 291-8.
- Stuebe A., Wise A., Nguyen T., Herring A., North K., Siega-Riz A. Maternal genotype and gestational diabetes. Am. J. Perinatol. 2013; 31(1): 69-76.
- Anghebem-Oliveira M.I., Webber S., Alberton D., de Souza E.M., Klassen G., Picheth G., Rego F.G.D.M. The GCKR gene polymorphism rs780094 is a risk factor for gestational diabetes in a Brazilian population. J. Clin. Lab. Anal. 2017; 31(2): e22035.
- Jamalpour S., Zain S.M., Mosavat M., Mohamed Z., Omar S.Z. A case-control study and meta-analysis confirm glucokinase regulatory gene rs780094 is a risk factor for gestational diabetes mellitus. Gene. 2018; 650: 34-40.
- Kleinberger J.W., Maloney K.A., Pollin T.I. The genetic architecture of diabetes in pregnancy: implications for clinical practice. Am. J. Perinatol. 2016; 33(13): 1319-26.
- Cieza-Borrella C., Díaz-Soto G., Martínez-Pino I., Puig-Domingo M., González-Sarmiento R. Early-onset type 2 diabetes mellitus is associated to HNF4A T130I polymorphism in families of central Spain. J. Investig. Med. 2014; 62(8): 968-74.
- Kwak S.H., Kim S.H., Cho Y.M., Go M.J., Cho Y.S., Choi S.H. et al. A genome-wide association study of gestational diabetes mellitus in Korean women. Diabetes. 2012; 61(2): 531-41.
- Ju H., Lin R., Yuan Z., Sun Y., Zeng L., Su Z., Jin L. No association detected between seven common variants in the CDKAL1 gene and gestational glycemic traits. Mol. Cell. Probes. 2017; 34: 64-7.
- Sun X.F., Xiao X.H., Zhang Z.X., Liu Y., Xu T., Zhu X.L. et al. Positive association between type 2 diabetes risk alleles near CDKAL1 and reduced birthweight in Chinese Han individuals. Chin. Med. J. 2015; 128(14): 1873-8.
- Artunc-Ulkumen B., Ulucay S., Pala H.G., Cam S. Maternal serum ADAMTS-9 levels in gestational diabetes: a pilot study. J. Matern. Fetal Neonatal Med. 2017; 30(12): 1442-5.
- Franzago M., Fraticelli F., Marchetti D., Celentano C., Liberati M., Stuppia L., Vitacolonna E. Nutrigenetic variants and cardio-metabolic risk in women with or without gestational diabetes. Diabetes Res. Clin. Pract. 2018; 137: 64-71.
- Cheng Y ., Ma Y., Peng T., Wang J., Lin R., Cheng HD. Genotype discrepancy between maternal and fetal Pro12Ala polymorphism of PPARG2 gene and its association with gestational diabetes mellitus. Zhonghua Fu Chan Ke Za Zhi. 2010; 45(3): 170-3.
- Tarnowski M., Tkacz M., Dziedziejko V., Safranow K., Pawlik A. COX2 and NOS3 gene polymorphisms in women with gestational diabetes. J. Gene Med. 2017; 19(8): e2959.
- Kang J., Lee C.N., Li H.Y., Hsu K.H., Lin S.Y. Genome-wide DNA methylation variation in maternal and cord blood of gestational diabetes population. Diabetes Res. Clin. Pract. 2017; 132: 127-36.
- Wu P., Farrell W.E., Haworth K.E., Emes R.D., Kitchen M.O., Glossop J.R. et al. Maternal genome-wide DNA methylation profiling in gestational diabetes shows distinctive disease-associated changes relative to matched healthy pregnancies. Epigenetics. 2018; 13: 122-8.
- Lowe W.L., Scholtens D.M., Sandler V., Hayes M.G. Genetics of gestational diabetes mellitus and maternal metabolism. Curr. Diab. Rep. 2016; 16(2): 15.
- Lekva T., Roland M.C.P., Michelsen A.E., Friis C.M., Aukrust P., Bollerslev J. et al. Large reduction in adiponectin during pregnancy is associated with large-for-gestational-age newborns. J. Clin. Endocrinol. Metab. 2017; 102(7): 2552-9.
- Beaumont R.N., Warrington N.M., Cavadino A., Tyrrell J., Nodzenski M., Horikoshi M. et al. Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics. Hum. Mol. Genet. 2018;27(4): 742-56.
- Iljas J.D., Guanzon D., Elfeky O., Rice G.E., Salomon C. Review: Bio-compartmentalization of microRNAs in exosomes during gestational diabetes mellitus. Placenta. 2017; 54: 76-82.
- Li J., Song L., Zhou L., Wu J., Sheng C., Chen H. et al. A microRNA signature in gestational diabetes mellitus associated with risk of macrosomia. Cell. Physiol. Biochem. 2015; 37(1): 243-52.
- Tagoma A., Alnek K., Kirss A., Uibo R., Haller-Kikkatalo K. MicroRNA profiling of second trimester maternal plasma shows upregulation of miR-195-5p in patients with gestational diabetes. Gene. 2018; 672: 137-42.
- Zhu Y., Tian F., Li H., Zhou Y., Lu J., Ge Q. Profiling maternal plasma microRNA expression in early pregnancy to predict gestational diabetes mellitus. Int. J. Gynaecol. Obstet. 2015; 130(1): 49-53.
- Cao Y.L., Jia Y.J., Xing B.H. , Shi D.D., Dong XJ. Plasma microRNA-16-5p, -17-5p and -20a-5p: Novel diagnostic biomarkers for gestational diabetes mellitus. J. Obstet. Gynaecol. Res. 2017; 43(6): 974-91.
- Shek N.W., Ngai C.S., Lee C.P., Chan J.Y., Lao T.T. Lifestyle modifications in the development of diabetes mellitus and metabolic syndrome in Chinese women who had gestational diabetes mellitus: a randomized interventional trial. Arch. Gynecol. Obstet. 2014; 289(2): 319-27.
Received 14.09.2018
Accepted 21.09.2018
About the Authors
Khodzhaeva, Zulfiya S., MD, professor, head of the 1st Department of Patology of Pregnancy, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov Ministry of Health of Russia. 117997, Russia, Moscow, Ac. Oparina str. 4. Tel.: +74954380788. E-mail: zkhodjaeva@mail.ruSnetkova, Nina V., postgraduate student, 1st Department of Pathology of Pregnancy, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov Ministry of Health of Russia. 117997, Russia, Moscow, Ac. Oparina str. 4. Tel.: +749543806741. E-mail: n_snetkova@mail.ru
Abramova, Mariya E., clinical intern, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov
Ministry of Health of Russia. 117997, Russia, Moscow, Ac. Oparina str. 4. Tel.: +749543806741. E-mail: n_snetkova@mail.ru
Klimenchenko, Natalia I., senior researcher, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov
Ministry of Health of Russia. 117997, Russia, Moscow, Ac. Oparina str. 4. E-mail:n_klimenchenko@oparina4.ru
Degtyareva, Elena I., PhD, Outpatient Department, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov Ministry of Health of Russia. 117997, Russia, Moscow, Ac. Oparina str. 4. Tel.: +74954387700. E-mail: e_degtyareva@oparina4.ru
Donnikov, Andrey E., PhD, head of the Department of Laboratory and Genetic Methods, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov Ministry of Health of Russia. 117997, Russia, Moscow, Ac. Oparina str. 4. Tel.: +74954387700. E-mail: a_donnikov@oparina4.ru
For citation: Khodzhaeva Z.S., Snetkova N.V., Klimenchenko N.I., Abramova M.E., Degtyareva E.I., Donnikov A.E. Clinical and molecular genetic determinants of the development of gestational diabetes mellitus. Akusherstvo i Ginekologiya/Obstetrics and Gynecology.2019; (4): 18-24. (in Russian)
https://dx.doi.org/10.18565/aig.2019.4.18-24