Mechanisms linking hyperglycemia in pregnancy to the offspring cardiovascular system dysfunction
Hyperglycemia in pregnancy (HIP) is a high-glycemic state that occurs during pregnancy, and gestational diabetes mellitus (GDM) is the major cause of it. Studies reveal that GDM has long-term adverse impacts on mothers and offspring, such as maternal type 2 diabetes, premature birth and stillbirth in newborns, cardiovascular disease, and metabolic disorders in adult offspring. In recent years, studies on the transcription level of GDM and metabonomics have provided new insights into the pathophysiological mechanism of GDM. This article reviews the transcriptional levels and metabolomics studies involving GDM and cardiovascular dysfunction in the offspring, which may provide insight to the long-term health of pregnant women and offspring.
Butte NF. Carbohydrate and lipid metabolism in pregnancy: normal compared with gestational diabetes mellitus. Am J Clin Nutr. 2000, 71(5 Suppl):1256S-61S.
Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002, 346(6):393–403.
American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018, 41(Suppl 1):S13–27.
Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, Ilanne-Parikka P, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med., 344(18):1343–50.
Herman WH, Hoerger TJ, Brandle M, Hicks K, Sorensen S, Zhang P, et al. The cost-effectiveness of lifestyle modification or metformin in preventing type 2 diabetes in adults with impaired glucose tolerance. Ann Intern Med. 2005,142(5):323–32.
Lavery JA, Friedman AM, Keyes KM, Wright JD, Ananth CV. Gestational diabetes in the United States: temporal changes in prevalence rates between 1979 and 2010. BJOG Int J Obstet Gynaecol. 2017, 124(5):804–13.
Goldstein RF, Abell SK, Ranasinha S, Misso M, Boyle JA, Black MH, et al. Association of gestational weight gain with maternal and infant outcomes: a systematic review and meta-analysis. JAMA. 2017, 317(21):2207–25.
Hedderson MM, Williams MA, Holt VL, Weiss NS, Ferrara A. Body mass index and weight gain prior to pregnancy and risk of gestational diabetes mellitus. Am J Obstet Gynecol. 2008, 198(4):409.e1-7.
Sacks DA, Hadden DR, Maresh M, Deerochanawong C, Dyer AR, Metzger BE, et al. Frequency of gestational diabetes mellitus at collaborating centers based on IADPSG consensus panel–recommended criteria: the hyperglycemia and adverse pregnancy outcome (HAPO) study. Diabetes Care. 2012, 35(3):526–8.
Cheng YW, Block-Kurbisch I, Caughey AB. Carpenter-Coustan criteria compared with the national diabetes data group thresholds for gestational diabetes mellitus. Obstet Gynecol. 2009, 114(2 Pt 1):326–32.
Malcolm J. Through the looking glass: gestational diabetes as a predictor of maternal and offspring long-term health. Diabetes Metab Res Rev. 2012, 28(4):307–11.
Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS, et al. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med. 2005, 352(24):2477–86.
Catalano PM, McIntyre HD, Cruickshank JK, McCance DR, Dyer AR, Metzger BE, et al. The hyperglycemia and adverse pregnancy outcome study: associations of GDM and obesity with pregnancy outcomes. Diabetes Care. 2012, 35(4):780–6.
Michael Weindling A. Offspring of diabetic pregnancy: short-term outcomes. Semin Fetal Neonatal Med. 2009, 14(2):111–8.
Krishnaveni GV, Veena SR, Hill JC, Kehoe S, Karat SC, Fall CHD. Intrauterine exposure to maternal diabetes is associated with higher adiposity and insulin resistance and clustering of cardiovascular risk markers in Indian children. Diabetes Care. 2010, 33(2):402–4.
West NA, Crume TL, Maligie MA, Dabelea D. Cardiovascular risk factors in children exposed to maternal diabetes in utero. Diabetologia. 2011, 54(3):504–7.
Gautier JF, Wilson C, Weyer C, Mott D, Knowler WC, Cavaghan M, et al. Low acute insulin secretory responses in adult offspring of people with early onset type 2 diabetes. Diabetes. 2001, 50(8):1828–33.
Nijs H, Benhalima K. Gestational diabetes mellitus and the long-term risk for glucose intolerance and overweight in the offspring: a narrative review. J Clin Med. 2020, 22;9(2).
Tam WH, Ma RCW, Ozaki R, Li AM, Chan MHM, Yuen LY, et al. In utero exposure to maternal hyperglycemia increases childhood cardiometabolic risk in offspring. Diabetes Care. 2017, 40(5):679–86.
Lambrinoudaki I, Vlachou SA, Creatsas G. Genetics in gestational diabetes mellitus: association with incidence, severity, pregnancy outcome and response to treatment. Curr Diabetes Rev. 2010, 6(6):393–9.
Sorenson RL, Brelje TC. Prolactin receptors are critical to the adaptation of islets to pregnancy. Endocrinology. 2009, 150(4):1566–9.
Butler AE, Cao-Minh L, Galasso R, Rizza RA, Corradin A, Cobelli C, et al. Adaptive changes in pancreatic beta cell fractional area and beta cell turnover in human pregnancy. Diabetologia. 2010, 53(10):2167–76.
Huang C, Snider F, Cross JC. Prolactin receptor is required for normal glucose homeostasis and modulation of beta-cell mass during pregnancy. Endocrinology. 2009, 150(4):1618–26.
Karnik SK, Chen H, McLean GW, Heit JJ, Gu X, Zhang AY, et al. Menin controls growth of pancreatic beta-cells in pregnant mice and promotes gestational diabetes mellitus. Science. 2007, 318(5851):806–9.
Zhang H, Zhang J, Pope CF, Crawford LA, Vasavada RC, Jagasia SM, et al. Gestational diabetes mellitus resulting from impaired beta-cell compensation in the absence of FoxM1, a novel downstream effector of placental lactogen. Diabetes. 2010, 59(1):143–52.
Kim H, Toyofuku Y, Lynn FC, Chak E, Uchida T, Mizukami H, et al. Serotonin regulates pancreatic beta cell mass during pregnancy. Nat Med. 2010, 16(7):804–8.
Schraenen A, Lemaire K, de Faudeur G, Hendrickx N, Granvik M, Van Lommel L, et al. Placental lactogens induce serotonin biosynthesis in a subset of mouse beta cells during pregnancy. Diabetologia. 2010, 53(12):2589–99.
Baek D, Villén J, Shin C, Camargo FD, Gygi SP, Bartel DP. The impact of microRNAs on protein output. Nature. 2008, 455(7209):64–71.
Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009, 136(2):215–33.
Mattick JS, Makunin IV. Non-coding RNA. Hum Mol Genet. 2006, 15 Spec No 1:R17-29.
Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, et al. Landscape of transcription in human cells. Nature. 2012, 489(7414):101–8.
ENCODE Project Consortium. The ENCODE (ENCyclopedia Of DNA Elements) Project. Science. 2004, 306(5696):636–40.
Anastasiadou E, Jacob LS, Slack FJ. Non-coding RNA networks in cancer. Nat Rev Cancer. 2018, 18(1):5–18.
Anfossi S, Babayan A, Pantel K, Calin GA. Clinical utility of circulating non-coding RNAs - an update. Nat Rev Clin Oncol. 2018, 15(9):541–63.
Chen B, Huang S. Circular RNA: An emerging non-coding RNA as a regulator and biomarker in cancer. Cancer Lett. 2018, 418:41–50.
Chen X, Liang H, Zhang J, Zen K, Zhang C-Y. Secreted microRNAs: a new form of intercellular communication. Trends Cell Biol. 2012, 22(3):125–32.
Guarino E, Delli Poggi C, Grieco GE, Cenci V, Ceccarelli E, Crisci I, et al. Circulating microRNAs as biomarkers of gestational diabetes mellitus: updates and perspectives. Int J Endocrinol. 2018;2018:6380463.
Lynn FC, Skewes-Cox P, Kosaka Y, McManus MT, Harfe BD, German MS. MicroRNA expression is required for pancreatic islet cell genesis in the mouse. Diabetes. 2007, 56(12):2938–45.
Filardi T, Catanzaro G, Mardente S, Zicari A, Santangelo C, Lenzi A, et al. Non-Coding RNA: role in gestational diabetes pathophysiology and complications. Int J Mol Sci. 2020, 21(11).
Li J, Du B, Geng X, Zhou L. lncRNA SNHG17 is Downregulated in Gestational Diabetes Mellitus (GDM) and Has Predictive Values. Diabetes Metab Syndr Obes Targets Ther. 2021, 14:831–8.
Zhang H. Mechanism associated with aberrant lncRNA MEG3 expression in gestational diabetes mellitus. Exp Ther Med. 2019, 18(5):3699–706.
Ye H-H, Yang S-H, Zhang Y. MEG3 damages fetal endothelial function induced by gestational diabetes mellitus via AKT pathway. Eur Rev Med Pharmacol Sci. 2018, 22(24):8553–60.
Zhang W, Cao D, Wang Y, Ren W. LncRNA MEG8 is upregulated in gestational diabetes mellitus (GDM) and predicted kidney injury. J Diabetes Complications. 2021 Jan;35(1):107749.
Zhang Y, Wu H, Wang F, Ye M, Zhu H, Bu S. Long non-coding RNA MALAT1 expression in patients with gestational diabetes mellitus. Int J Gynaecol Obstet Off Organ Int Fed Gynaecol Obstet. 2018, 140(2):164–9.
Zhang Y, Qu L, Ni H, Wang Y, Li L, Yang X, et al. Expression and function of lncRNA MALAT1 in gestational diabetes mellitus. Adv Clin Exp Med Off Organ Wroclaw Med Univ. 2020, 29(8):903–10.
Poy MN, Hausser J, Trajkovski M, Braun M, Collins S, Rorsman P, et al. miR-375 maintains normal pancreatic alpha- and beta-cell mass. Proc Natl Acad Sci U S A. 2009, 106(14):5813–8.
Grygiel-Górniak B. Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications--a review. Nutr J. 2014, 13:17.
Muralimanoharan S, Maloyan A, Myatt L. Mitochondrial function and glucose metabolism in the placenta with gestational diabetes mellitus: role of miR-143. Clin Sci Lond Engl 1979. 2016, 130(11):931–41.
Cao J-L, Zhang L, Li J, Tian S, Lv X-D, Wang X-Q, et al. Up-regulation of miR-98 and unraveling regulatory mechanisms in gestational diabetes mellitus. Sci Rep. 2016, 6:32268.
Jacovetti C, Abderrahmani A, Parnaud G, Jonas J-C, Peyot M-L, Cornu M, et al. MicroRNAs contribute to compensatory β cell expansion during pregnancy and obesity. J Clin Invest. 2012, 122(10):3541–51.
Nair S, Jayabalan N, Guanzon D, Palma C, Scholz-Romero K, Elfeky O, et al. Human placental exosomes in gestational diabetes mellitus carry a specific set of miRNAs associated with skeletal muscle insulin sensitivity. Clin Sci Lond Engl 1979. 2018, 132(22):2451–67.
Hivert MF, Perng W, Watkins SM, Newgard CS, Kenny LC, Kristal BS, et al. Metabolomics in the developmental origins of obesity and its cardiometabolic consequences. J Dev Orig Health Dis. 2015, 6(2):65–78.
Spalding KL, Arner E, Westermark PO, Bernard S, Buchholz BA, Bergmann O, et al. Dynamics of fat cell turnover in humans. Nature. 2008, 453(7196):783–7.
Alberga AS, Sigal RJ, Goldfield G, Prud’homme D, Kenny GP. Overweight and obese teenagers: why is adolescence a critical period? Pediatr Obes. 2012, 7(4):261–73.
Huynh J, Xiong G, Bentley-Lewis R. A systematic review of metabolite profiling in gestational diabetes mellitus. Diabetologia. 2014, 57(12):2453–64.
Perng W, Ringham BM, Smith HA, Michelotti G, Kechris KM, Dabelea D. A prospective study of associations between in utero exposure to gestational diabetes mellitus and metabolomic profiles during late childhood and adolescence. Diabetologia. 2020, 63(2):296–312.
Diaz SO, Pinto J, Graça G, Duarte IF, Barros AS, Galhano E, et al. Metabolic biomarkers of prenatal disorders: an exploratory NMR metabonomics study of second trimester maternal urine and blood plasma. J Proteome Res. 2011, 10(8):3732–42.
Enquobahrie DA, Denis M, Tadesse MG, Gelaye B, Ressom HW, Williams MA. Maternal Early Pregnancy Serum Metabolites and Risk of Gestational Diabetes Mellitus. J Clin Endocrinol Metab. 2015, 100(11):4348–56.
Chen X, Scholl TO, Leskiw M, Savaille J, Stein TP. Differences in maternal circulating fatty acid composition and dietary fat intake in women with gestational diabetes mellitus or mild gestational hyperglycemia. Diabetes Care. 2010, 33(9):2049–54.
Dudzik D, Zorawski M, Skotnicki M, Zarzycki W, Kozlowska G, Bibik-Malinowska K, et al. Metabolic fingerprint of Gestational Diabetes Mellitus. J Proteomics. 2014, 103:57–71.
Cetin I, de Santis MSN, Taricco E, Radaelli T, Teng C, Ronzoni S, et al. Maternal and fetal amino acid concentrations in normal pregnancies and in pregnancies with gestational diabetes mellitus. Am J Obstet Gynecol. 2005, 192(2):610–7.
Vaughn PR, Lobo C, Battaglia FC, Fennessey PV, Wilkening RB, Meschia G. Glutamine-glutamate exchange between placenta and fetal liver. Am J Physiol. 1995, 268(4 Pt 1):E705-711.
Cetin I, Fennessey PV, Quick AN, Marconi AM, Meschia G, Battaglia FC, et al. Glycine turnover and oxidation and hepatic serine synthesis from glycine in fetal lambs. Am J Physiol. 1991, 260(3 Pt 1):E371-378.
Kalkhoff RK, Kandaraki E, Morrow PG, Mitchell TH, Kelber S, Borkowf HI. Relationship between neonatal birth weight and maternal plasma amino acid profiles in lean and obese nondiabetic women and in type I diabetic pregnant women. Metabolism. 1988, 37(3):234–9.
Pappa KI, Vlachos G, Theodora M, Roubelaki M, Angelidou K, Antsaklis A. Intermediate metabolism in association with the amino acid profile during the third trimester of normal pregnancy and diet-controlled gestational diabetes. Am J Obstet Gynecol. 2007, 196(1):65.e1-5.
McCormack SE, Shaham O, McCarthy MA, Deik AA, Wang TJ, Gerszten RE, et al. Circulating branched-chain amino acid concentrations are associated with obesity and future insulin resistance in children and adolescents. Pediatr Obes. 2013, 8(1):52–61.
Friedrich N. Metabolomics in diabetes research. J Endocrinol. 2012, 215(1):29–42.
Roberts LD, Koulman A, Griffin JL. Towards metabolic biomarkers of insulin resistance and type 2 diabetes: progress from the metabolome. Lancet Diabetes Endocrinol. 2014, 2(1):65–75.
Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 2009, 9(4):311–26.
Metzger BE, Phelps RL, Freinkel N, Navickas IA. Effects of gestational diabetes on diurnal profiles of plasma glucose, lipids, and individual amino acids. Diabetes Care. 1980 , 3(3):402–9.
Bentley-Lewis R, Huynh J, Xiong G, Lee H, Wenger J, Clish C, et al. Metabolomic profiling in the prediction of gestational diabetes mellitus. Diabetologia. 2015, 58(6):1329–32.
de Seymour JV, Conlon CA, Sulek K, Villas Bôas SG, McCowan LME, Kenny LC, et al. Early pregnancy metabolite profiling discovers a potential biomarker for the subsequent development of gestational diabetes mellitus. Acta Diabetol. 2014, 51(5):887–90.
Graca G, Duarte IF, Barros AS, Goodfellow BJ, Diaz SO, Pinto J, et al. Impact of prenatal disorders on the metabolic profile of second trimester amniotic fluid: a nuclear magnetic resonance metabonomic study. J Proteome Res. 2010, 9(11):6016–24.
Nevalainen J, Sairanen M, Appelblom H, Gissler M, Timonen S, Ryynänen M. First-Trimester Maternal Serum Amino Acids and Acylcarnitines Are Significant Predictors of Gestational Diabetes. Rev Diabet Stud RDS. 2016, 13(4):236–45.
Mannino GC, Pezzilli S, Averta C, Fuoco A, Spiga R, Mancuso E, et al. A functional variant of the dimethylarginine dimethylaminohydrolase-2 gene is associated with myocardial infarction in type 2 diabetic patients. Cardiovasc Diabetol. 2019, 18(1):102.
Lu T-M, Ding Y-A, Lin S-J, Lee W-S, Tai H-C. Plasma levels of asymmetrical dimethylarginine and adverse cardiovascular events after percutaneous coronary intervention. Eur Heart J. 2003, 24(21):1912–9.
Valkonen VP, Päivä H, Salonen JT, Lakka TA, Lehtimäki T, Laakso J, et al. Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine. Lancet Lond Engl. 2001, 358(9299):2127–8.
Meinitzer A, Seelhorst U, Wellnitz B, Halwachs-Baumann G, Boehm BO, Winkelmann BR, et al. Asymmetrical dimethylarginine independently predicts total and cardiovascular mortality in individuals with angiographic coronary artery disease (the Ludwigshafen Risk and Cardiovascular Health study). Clin Chem. 2007 , 53(2):273–83.
Böger RH. Asymmetric dimethylarginine (ADMA) and cardiovascular disease: insights from prospective clinical trials. Vasc Med Lond Engl. 2005, 10 Suppl 1:S19-25.
Akturk M, Altinova A, Mert I, Dincel A, Sargin A, Buyukkagnici U, et al. Asymmetric dimethylarginine concentrations are elevated in women with gestational diabetes. Endocrine. 2010, 38(1):134–41.
Telejko B, Zonenberg A, Kuzmicki M, Modzelewska A, Niedziolko-Bagniuk K, Ponurkiewicz A, et al. Circulating asymmetric dimethylarginine, endothelin-1 and cell adhesion molecules in women with gestational diabetes. Acta Diabetol. 2009, 46(4):303–8.
Sertkaya AC, Kafkasli A, Turkcuoglu I, Karabulut AB. Asymmetric dimethylarginine level in hyperglycemic gestation. Endocrine. 2011, 40(2):237–42.
Paradisi G, Biaggi A, Ferrazzani S, De Carolis S, Caruso A. Abnormal carbohydrate metabolism during pregnancy : association with endothelial dysfunction. Diabetes Care. 2002, 25(3):560–4.
Dani C, Bresci C, Berti E, Ottanelli S, Mello G, Mecacci F, et al. Metabolomic profile of term infants of gestational diabetic mothers. J Matern-Fetal Neonatal Med Off J Eur Assoc Perinat Med Fed Asia Ocean Perinat Soc Int Soc Perinat Obstet. 2014, 27(6):537–42.
Peng S, Zhang J, Liu L, Zhang X, Huang Q, Alamdar A, et al. Newborn meconium and urinary metabolome response to maternal gestational diabetes mellitus: a preliminary case-control study. J Proteome Res. 2015, 14(4):1799–809.
Mitanchez D, Yzydorczyk C, Simeoni U. What neonatal complications should the pediatrician be aware of in case of maternal gestational diabetes? World J Diabetes. 2015, 6(5):734–43.
Copyright (c) 2021 Zemeng Xiao
This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors retain full copyright to their individual works, and publishing rights without restrictions.
In accordance with the Budapest Open Access Initiative, articles published in STEMedicine are freely available "on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited."
Except where otherwise noted, all content on this website is licensed under a Creative Commons Attribution 4.0 License. This license allows for commercial and non-commercial redistribution as well as modifications of the work as long as attribution is given to the authors and STEMedicine as the original publication source, and a link to the article on the STEMedicine website is provided.