Skip to main content
SpringerLink
Log in

Mechanisms of Congenital Malformations in Pregnancies with Pre-existing Diabetes

  • Diabetes and Pregnancy (M-F Hivert and CE Powe, Section Editors)
  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Fetuses of diabetic mothers are at increased risk for congenital malformations. Research in recent decades using animal and embryonic stem cell models has revealed many embryonic developmental processes that are disturbed by maternal diabetes. The aim of this review is to give clinicians a better understanding of the reasons for rigorous glycemic control in early pregnancy, and to provide background to guide future research.

Recent Findings

Mouse models of diabetic pregnancy have revealed mechanisms for altered expression of tissue-specific genes that lead to malformations that are more common in diabetic pregnancies, such as neural tube defects (NTDs) and congenital heart defects (CHDs), and how altered gene expression causes apoptosis that leads to malformations. Embryos express the glucose transporter, GLUT2, which confers susceptibility to malformation, due to high rates of glucose uptake during maternal hyperglycemia and subsequent oxidative stress; however, the teleological function of GLUT2 for mammalian embryos may be to transport the amino sugar glucosamine (GlcN) from maternal circulation to be used as substrate for glycosylation reactions and to promote embryo cell growth. Malformations in diabetic pregnancy may be not only due to excess glucose uptake but also due to insufficient GlcN uptake.

Summary

Avoiding maternal hyperglycemia during early pregnancy should prevent excess glucose uptake via GLUT2 into embryo cells, and also permit sufficient GLUT2-mediated GlcN uptake.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

CNNC:

Cardiac neural crest cells

COHDs:

Cardiac outflow tract defects

CHDs:

Congenital heart defects

DNMT:

DNA methyltransferase

ESC:

Embryonic stem cell

GlcN:

Glucosamine

G6PD:

Glucose-6-PO4 dehydrogenase

Gln:

Glutamine

GSH-EE:

Glutathione-ethyl ester

GFP:

Green fluorescent protein

HBSP:

Hexosamine biosynthetic pathway

IRES:

Internal ribosome entry site

LMP:

Last menstrual period

NTDs:

Neural tube defects

1C:

One carbon

GSSG:

Oxidized glutathione

PPP:

Pentose phosphate pathway

GSH:

Reduced glutathione

SGLT:

Sodium/glucose cotransporter

SOD:

Superoxide dismutase

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Mills JL. Malformations in infants of diabetic mothers. Teratology. 1982;25(3):385–94. https://doi.org/10.1002/tera.1420250316.

    Article  CAS  PubMed  Google Scholar 

  2. Miodovnik M, Mimouni F, Dignan PSJ, Berk MA, Ballard JL, Siddiqi TA, et al. Major malformations in infants of IDDM women: vasculopathy and early first-trimester poor glycemic control. Diabetes Care. 1988;11:713–8.

    CAS  PubMed  Google Scholar 

  3. Schaefer-Graf UM, Buchanan TA, Xiang A, Songster G, Montoro M, Kjos SL. Patterns of congenital anomalies and relationship to initial maternal fasting glucose levels in pregnancies complicated by type 2 and gestational diabetes. Am J Obstet Gynecol. 2000;182(2):313–20.

    CAS  PubMed  Google Scholar 

  4. Ylinen K, Aula P, Stenman UH, Kesaniemi-Kuokkanen T, Teramo K. Risk of minor and major fetal malformations in diabetics with high haemoglobin A1c values in early pregnancy. Br Med J (Clin Res Ed). 1984;289(6441):345–6.

    CAS  Google Scholar 

  5. White P. Pregnancy complicating diabetes. Am J Med. 1949;7(5):609–16.

    CAS  PubMed  Google Scholar 

  6. Kucera J. Rate and type of congenital anomalies among offspring of diabetic women. J Reprod Med. 1971;7:61–70.

    Google Scholar 

  7. Loffredo CA, Wilson PD, Ferencz C. Maternal diabetes: an independent risk factor for major cardiovascular malformations with increased mortality of affected infants. Teratology. 2001;64(2):98–106.

    CAS  PubMed  Google Scholar 

  8. Sheffield JS, Butler-Koster EL, Casey BM, McIntire DD, Leveno KJ. Maternal diabetes mellitus and infant malformations. Obstet Gynecol. 2002;100(5 Pt 1):925–30.

    PubMed  Google Scholar 

  9. Wren C, Birrell G, Hawthorne G. Cardiovascular malformations in infants of diabetic mothers. Heart. 2003;89(10):1217–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Correa A, Gilboa SM, Besser LM, Botto LD, Moore CA, Hobbs CA, et al. Diabetes mellitus and birth defects. Am J Obstet Gynecol. 2008;199(3):237 e1–9. https://doi.org/10.1016/j.ajog.2008.06.028.

    Article  CAS  Google Scholar 

  11. Evers IM, de Valk HW, Visser GH. Risk of complications of pregnancy in women with type 1 diabetes: nationwide prospective study in the Netherlands. BMJ. 2004;328(7445):915–9.

    PubMed  PubMed Central  Google Scholar 

  12. Cea-Soriano L, Garcia-Rodriguez LA, Brodovicz KG, Masso Gonzalez E, Bartels DB, Hernandez-Diaz S. Safety of non-insulin glucose-lowering drugs in pregnant women with pre-gestational diabetes: a cohort study. Diabetes Obes Metab. 2018;20:1642–51. https://doi.org/10.1111/dom.13275.

    Article  CAS  PubMed  Google Scholar 

  13. Ludvigsson JF, Neovius M, Soderling J, Gudbjornsdottir S, Svensson AM, Franzen S, et al. Periconception glycaemic control in women with type 1 diabetes and risk of major birth defects: population based cohort study in Sweden. BMJ. 2018;362:k2638. https://doi.org/10.1136/bmj.k2638.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Oyen N, Diaz LJ, Leirgul E, Boyd HA, Priest J, Mathiesen ER, et al. Pre-pregnancy diabetes and offspring risk of congenital heart disease: a nation-wide cohort study. Circulation. 2016;133:2243–53. https://doi.org/10.1161/CIRCULATIONAHA.115.017465.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Becerra JE, Khoury MJ, Cordero JF, Erickson JD. Diabetes mellitus during pregnancy and the risks for specific birth defects: a population-based case-control study. Pediatrics. 1990;85(1):1–9.

    CAS  PubMed  Google Scholar 

  16. Gilboa SM, Correa A, Botto LD, Rasmussen SA, Waller DK, Hobbs CA, et al. Association between prepregnancy body mass index and congenital heart defects. Am J Obstet Gynecol. 2010;202(1):51 e1–e10. https://doi.org/10.1016/j.ajog.2009.08.005.

    Article  Google Scholar 

  17. Watkins ML, Rasmussen SA, Honein MA, Botto LD, Moore CA. Maternal obesity and risk for birth defects. Pediatrics. 2003;111(5 Part 2):1152–8.

    PubMed  Google Scholar 

  18. Shaw GM, Velie EM, Schaffer D. Risk of neural tube defect-affected pregnancies among obese women. JAMA. 1996;275:1093–6.

    CAS  PubMed  Google Scholar 

  19. Werler MM, Louik C, Shapiro S, Mitchell AA. Prepregnant weight in relation to risk of neural tube defects. JAMA. 1996;275(14):1089–92. https://doi.org/10.1001/jama.1996.03530380031027.

    Article  CAS  PubMed  Google Scholar 

  20. Helle EIT, Biegley P, Knowles JW, Leader JB, Pendergrass S, Yang W, et al. First trimester plasma glucose values in women without diabetes are associated with risk for congenital heart disease in offspring. J Pediatr. 2017;195:275–8. https://doi.org/10.1016/j.jpeds.2017.10.046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bell R, Glinianaia SV, Tennant PW, Bilous RW, Rankin J. Peri-conception hyperglycaemia and nephropathy are associated with risk of congenital anomaly in women with pre-existing diabetes: a population-based cohort study. Diabetologia. 2012;55(4):936–47. https://doi.org/10.1007/s00125-012-2455-y.

    Article  CAS  Google Scholar 

  22. Kitzmiller JL, Wallerstein R, Correa A, Kwan S. Preconception care for women with diabetes and prevention of major congenital malformations. Birth Defects Res A Clin Mol Teratol. 2010;88(10):791–803. https://doi.org/10.1002/bdra.20734.

    Article  CAS  PubMed  Google Scholar 

  23. Robertson H, Pearson DW, Gold AE. Severe hypoglycaemia during pregnancy in women with type 1 diabetes is common and planning pregnancy does not decrease the risk. Diabet Med. 2009;26(8):824–6. https://doi.org/10.1111/j.1464-5491.2009.02769.x.

    Article  CAS  PubMed  Google Scholar 

  24. Evers IM, ter Braak EW, de Valk HW, van Der Schoot B, Janssen N, Visser GH. Risk indicators predictive for severe hypoglycemia during the first trimester of type 1 diabetic pregnancy. Diabetes Care. 2002;25(3):554–9.

    PubMed  Google Scholar 

  25. Nielsen LR, Pedersen-Bjergaard U, Thorsteinsson B, Johansen M, Damm P, Mathiesen ER. Hypoglycemia in pregnant women with type 1 diabetes: predictors and role of metabolic control. Diabetes Care. 2008;31(1):9–14. https://doi.org/10.2337/dc07-1066.

    Article  PubMed  Google Scholar 

  26. Temple RC, Aldridge VJ, Murphy HR. Prepregnancy care and pregnancy outcomes in women with type 1 diabetes. Diabetes Care. 2006;29(8):1744–9. https://doi.org/10.2337/dc05-2265.

    Article  PubMed  Google Scholar 

  27. Horii KI, Watanabe GI, Ingalls TH. Experimental diabetes in pregnant mice. Prevention of congenital malformations in offspring by insulin. Diabetes. 1966;15(3):194–204.

    CAS  PubMed  Google Scholar 

  28. Sadler T. Effects of maternal diabetes on early embryogenesis: II. Hyperglycemia-induced exencephaly. Teratology. 1980;21(3):349–56.

    CAS  PubMed  Google Scholar 

  29. Sadler TW, et al. Teratology. 1980;21(3):339–47.

    CAS  PubMed  Google Scholar 

  30. Cockroft DL, Coppola PT. Teratogenic effects of excess glucose on head-fold rat embryos in culture. Teratology. 1977;16:141–6.

    CAS  PubMed  Google Scholar 

  31. Buchanan TA, Denno KM, Sipos GF, Sadler TW. Diabetic teratogenesis. In vitro evidence for a multifactorial etiology with little contribution from glucose per se. Diabetes. 1994;43(5):656–60.

    CAS  PubMed  Google Scholar 

  32. Wentzel P, Eriksson UJ. Insulin treatment fails to abolish the teratogenic potential of serum from diabetic rats. Eur J Endocrinol. 1996;134:459–66.

    CAS  PubMed  Google Scholar 

  33. Eriksson UJ, Dahlstrom E, Larsson KS, Hellerstrom C. Increased incidence of congenital malformations in the offspring of diabetic rats and their prevention by maternal insulin therapy. Diabetes. 1982;31:1–6.

    CAS  PubMed  Google Scholar 

  34. Strieleman PJ, Metzger BE. Glucose and scyllo-inositol impair phosphoinositide hydrolysis in the 10.5-day cultured rat conceptus--a role in dysmorphogenesis? Teratology. 1993;48:267–78.

    CAS  PubMed  Google Scholar 

  35. Phelan SA, Ito M, Loeken MR. Neural tube defects in embryos of diabetic mice: role of the Pax-3 gene and apoptosis. Diabetes. 1997;46(7):1189–97.

    CAS  PubMed  Google Scholar 

  36. Chalepakis G, Goulding M, Read A, Strachan T, Gruss P. Molecular basis of splotch and Waardenburg Pax-3 mutations. Proc Natl Acad Sci U S A. 1994;91:3685–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Auerbach R. Analysis of the developmental effects of a lethal mutation in the house mouse. J Exp Zool. 1954;127:305–29.

    Google Scholar 

  38. Fine E, Horal M, Chang T, Fortin G, Loeken M. Evidence that hyperglycemia causes altered gene expression, apoptosis, and neural tube defects in a mouse model of diabetic pregnancy. Diabetes. 1999;48:2454–62.

    CAS  PubMed  Google Scholar 

  39. Hogan A, Heyner S, Charron MJ, Copeland NG, Gilbert DJ, Jenkins NA, et al. Glucose transporter gene expression in early mouse embryos. Development. 1991;113(1):363–72.

    CAS  PubMed  Google Scholar 

  40. Trocino RA, Akazawa S, Takino H, Takao Y, Matsumoto K, Maeda Y, et al. Cellular-tissue localization and regulation of the GLUT-1 protein in both the embryo and the visceral yolk sac from normal and experimental diabetic rats during the early postimplantation period. Endocrinology. 1994;134(2):869–78.

    CAS  PubMed  Google Scholar 

  41. Matsumoto K, Akazawa S, Ishibashi M, Trocino RA, Matsuo H, Yamasaki H, et al. Abundant expression of GLUT1 and GLUT3 in rat embryo during the early organogenesis period. Biochem Biophys Res Commun. 1995;209(1):95–102.

    CAS  PubMed  Google Scholar 

  42. Li R, Thorens B, Loeken MR. Expression of the gene encoding the high Km glucose transporter 2 by the early postimplantation mouse embryo is essential for neural tube defects associated with diabetic embryopathy. Diabetologia. 2007;50(3):682–9. https://doi.org/10.1007/s00125-006-0579-7.

    Article  CAS  PubMed  Google Scholar 

  43. Siman CM, Eriksson UJ. Vitamin E decreases the occurrence of malformations in the offspring of diabetic rats. Diabetes. 1997;46:1054–61.

    CAS  PubMed  Google Scholar 

  44. Sivan E, Reece EA, Wu Y-K, Homko CJ, Polansky M, Borenstein M. Dietary vitamin E prophylaxis and diabetic embryopathy: morphologic and biochemical analysis. Am J Obstet Gynecol. 1996;175:793–9.

    CAS  PubMed  Google Scholar 

  45. Viana M, Herrera E, Bonet B. Terotogenic effects of diabetes mellitus in the rat. Prevention by vitamin E. Diabetologia. 1996;39:1041–6.

    CAS  PubMed  Google Scholar 

  46. Hagay ZJ, Weiss Y, Zusman I, Peled-Kamar M, Reece EA, Eriksson UJ, et al. Prevention of diabetes-associated embryopathy by overexpression of the free radical scavenger copper zinc superoxide dismutase in transgenic mouse embryos. Am J Obstet Gynecol. 1995;173:1036–41.

    CAS  PubMed  Google Scholar 

  47. Yang P, Zhao Z, Reece EA. Activation of oxidative stress signaling that is implicated in apoptosis with a mouse model of diabetic embryopathy. Am J Obstet Gynecol. 2008;198(1):130 e1–7. https://doi.org/10.1016/j.ajog.2007.06.070.

    Article  CAS  Google Scholar 

  48. Trocino RA, Akazawa S, Ishibashi M, Matsumoto K, Matsuo H, Yamamoto H, et al. Significance of glutathione depletion and oxidative stress in early embryogenesis in glucose-induced rat embryo culture. Diabetes. 1995;44:992–8.

    CAS  PubMed  Google Scholar 

  49. Eriksson UJ, Borg LAH. Protection by free oxygen radical scavenging enzymes against glucose-induced embryonic malformations in vitro. Diabetologia. 1991;34:325–31.

    CAS  PubMed  Google Scholar 

  50. Forsberg H, Borg LA, Cagliero E, Eriksson UJ. Altered levels of scavenging enzymes in embryos subjected to a diabetic environment. Free Radic Res. 1996;24:451–9.

    CAS  PubMed  Google Scholar 

  51. Chang TI, Horal M, Jain S, Wang F, Patel R, Loeken MR. Oxidant regulation of gene expression and neural tube development: insights gained from diabetic pregnancy on molecular causes of neural tube defects. Diabetologia. 2003;46:538–45.

    CAS  PubMed  Google Scholar 

  52. Akazawa S, Unterman T, Metzger BE. Glucose metabolism in separated embryos and investing membranes during organogenesis in the rat. Metabolism. 1994;43(7):830–5.

    CAS  PubMed  Google Scholar 

  53. Shepard TH, Tanimura T, Robkin MA. Energy metabolism in early mammalian embryos. Symp Soc Dev Biol. 1970;29:42–58.

    CAS  PubMed  Google Scholar 

  54. Fischer B, Bavister BD. Oxygen tension in the oviduct and uterus of rhesus monkeys, hamsters and rabbits. J Reprod Fertil. 1993;99(2):673–9.

    CAS  PubMed  Google Scholar 

  55. Rodesch F, Simon P, Donner C, Jauniaux E. Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy. Obstet Gynecol. 1992;80(2):283–5.

    CAS  PubMed  Google Scholar 

  56. Quinn P, Harlow GM. The effect of oxygen on the development of preimplantation mouse embryos in vitro. J Exp Zool. 1978;206(1):73–80.

    CAS  PubMed  Google Scholar 

  57. Paddenberg R, Ishaq B, Goldenberg A, Faulhammer P, Rose F, Weissmann N, et al. Essential role of complex II of the respiratory chain in hypoxia-induced ROS generation in the pulmonary vasculature. Am J Phys Lung Cell Mol Phys. 2003;284(5):L710–9.

    CAS  Google Scholar 

  58. Li R, Chase M, Jung SK, Smith PJS, Loeken MR. Hypoxic stress in diabetic pregnancy contributes to impaired embryo gene expression and defective development by inducing oxidative stress. Am J Physiol Endocrinol Metab. 2005;289(4):E591–9.

    CAS  PubMed  Google Scholar 

  59. Kanji MI, Toews ML, Carper WR. A kinetic study of glucose-6-phosphate dehydrogenase. J Biol Chem. 1976;251(8):2258–62.

    CAS  PubMed  Google Scholar 

  60. Uldry M, Ibberson M, Hosokawa M, Thorens B. GLUT2 is a high affinity glucosamine transporter. FEBS Lett. 2002;524(1–3):199–203.

    CAS  PubMed  Google Scholar 

  61. Horal M, Zhang Z, Virkamaki A, Stanton R, Loeken MR. Activation of the hexosamine pathway causes oxidative stress and abnormal embryo gene expression: involvement in diabetic teratogenesis. Birth Defects Res Part A Clin Mol Teratol. 2004;70:519–27.

    CAS  PubMed  Google Scholar 

  62. Fan J, Ye J, Kamphorst JJ, Shlomi T, Thompson CB, Rabinowitz JD. Quantitative flux analysis reveals folate-dependent NADPH production. Nature. 2014;510(7504):298–302. https://doi.org/10.1038/nature13236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. •• Ryall JG, Cliff T, Dalton S, Sartorelli V. Metabolic reprogramming of stem cell epigenetics. Cell Stem Cell. 2015;17(6):651–62. https://doi.org/10.1016/j.stem.2015.11.012. This paper reviews how metabolites generated during glycolytic and oxidative processes of stem cells regulated enzymes that stimulate epigenetic modifications affecting transcriptional regulation during differentiation and lineage commitment.

  64. Sperber H, Mathieu J, Wang Y, Ferreccio A, Hesson J, Xu Z, et al. The metabolome regulates the epigenetic landscape during naive-to-primed human embryonic stem cell transition. Nat Cell Biol. 2015;17(12):1523–35. https://doi.org/10.1038/ncb3264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. •• Lewis CA, Parker SJ, Fiske BP, McCloskey D, Gui DY, Green CR, et al. Tracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells. Mol Cell. 2014;55(2):253–63. https://doi.org/10.1016/j.molcel.2014.05.008. This paper shows how folate-mediated 1 Carbon metabolism in cytosol and mitochondria compartments regulates NADPH production.

  66. Oyama K, Sugimura Y, Murase T, Uchida A, Hayasaka S, Oiso Y, et al. Folic acid prevents congenital malformations in the offspring of diabetic mice. Endocr J. 2008;56(1):29–37.

    PubMed  Google Scholar 

  67. Wentzel P, Eriksson UJ. A diabetes-like environment increases malformation rate and diminishes prostaglandin E(2) in rat embryos: reversal by administration of vitamin E and folic acid. Birth Defects Res A Clin Mol Teratol. 2005;73(7):506–11. https://doi.org/10.1002/bdra.20145.

    Article  CAS  PubMed  Google Scholar 

  68. Wlodarczyk BJ, Tang LS, Triplett A, Aleman F, Finnell RH. Spontaneous neural tube defects in splotch mice supplemented with selected micronutrients. Toxicol Appl Pharmacol. 2006;213(1):55–63. https://doi.org/10.1016/j.taap.2005.09.008.

    Article  CAS  PubMed  Google Scholar 

  69. Hardie DG. Roles of the AMP-activated/SNF1 protein kinase family in the response to cellular stress. Biochem Soc Symp. 1999;64:13–27.

    CAS  PubMed  Google Scholar 

  70. Choi SL, Kim SJ, Lee KT, Kim J, Mu J, Birnbaum MJ, et al. The regulation of AMP-activated protein kinase by H(2)O(2). Biochem Biophys Res Commun. 2001;287(1):92–7.

    CAS  PubMed  Google Scholar 

  71. Yang W, Hong YH, Shen XQ, Frankowski C, Camp HS, Leff T. Regulation of transcription by AMP-activated protein kinase: phosphorylation of p300 blocks its interaction with nuclear receptors. J Biol Chem. 2001;276(42):38341–4.

    CAS  PubMed  Google Scholar 

  72. Hong YH, Varanasi US, Yang W, Leff T. AMP-activated protein kinase regulates HNF4alpha transcriptional activity by inhibiting dimer formation and decreasing protein stability. J Biol Chem. 2003;278(30):27495–501.

    CAS  PubMed  Google Scholar 

  73. Bergeron R, Ren JM, Cadman KS, Moore IK, Perret P, Pypaert M, et al. Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. Am J Physiol Endocrinol Metab. 2001;281(6):E1340–6.

    CAS  PubMed  Google Scholar 

  74. Lee M, Hwang JT, Lee HJ, Jung SN, Kang I, Chi SG, et al. AMP-activated protein kinase activity is critical for hypoxia-inducible factor-1 transcriptional activity and its target gene expression under hypoxic conditions in DU145 cells. J Biol Chem. 2003;278(41):39653–61.

    CAS  PubMed  Google Scholar 

  75. Wu Y, Viana M, Thirumangalathu S, Loeken MR. AMP-activated protein kinase mediates effects of oxidative stress on embryo gene expression in a mouse model of diabetic embryopathy. Diabetologia. 2012;55(1):245–54. https://doi.org/10.1007/s00125-011-2326-y.

    Article  CAS  PubMed  Google Scholar 

  76. Meissner A, Mikkelsen TS, Gu H, Wernig M, Hanna J, Sivachenko A et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature. 2008;454(7205):766–70. https://doi.org/10.1038/nature07107.

  77. Borgel J, Guibert S, Li Y, Chiba H, Schubeler D, Sasaki H et al. Targets and dynamics of promoter DNA methylation during early mouse development. Nat Genet. 2010;42(12):1093–100. https://doi.org/10.1038/ng.708.

  78. Smith ZD, Meissner A. DNA methylation: roles in mammalian development. Nature reviews Genetics. 2013;14(3):204–20. https://doi.org/10.1038/nrg3354.

  79. Fouse SD, Shen Y, Pellegrini M, Cole S, Meissner A, Van Neste L et al. Promoter CpG methylation contributes to ES cell gene regulation in parallel with Oct4/Nanog, PcG complex, and histone H3 K4/K27 trimethylation. Cell Stem Cell. 2008;2(2):160–9. https://doi.org/10.1016/j.stem.2007.12.011.

  80. Mikkelsen TS, Ku M, Jaffe DB, Issac B, Lieberman E, Giannoukos G et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature. 2007;448(7153):553–60. https://doi.org/10.1038/nature06008.

  81. Wei D, Loeken MR. Increased DNA methyltransferase 3b (dnmt3b)-mediated CpG island methylation stimulated by oxidative stress inhibits expression of a gene required for neural tube and neural crest development in diabetic pregnancy. Diabetes. 2014;63(10):3512–22. https://doi.org/10.2337/db14-0231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Robson EJ, He SJ, Eccles MR. A PANorama of PAX genes in cancer and development. Nat Rev Cancer. 2006;6(1):52–62.

    CAS  PubMed  Google Scholar 

  83. Kwang SJ, Brugger SM, Lazik A, Merrill AE, Wu LY, Liu YH, et al. Msx2 is an immediate downstream effector of Pax3 in the development of the murine cardiac neural crest. Development. 2002;129(2):527–38.

    CAS  PubMed  Google Scholar 

  84. Borycki AG, Li J, Jin F, Emerson CP, Epstein JA. Pax3 functions in cell survival and in pax7 regulation. Development. 1999;126(8):1665–74.

    CAS  PubMed  Google Scholar 

  85. Moase CE, Trasler DG. N-CAM alterations in splotch neural tube defect mouse embryos. Development. 1991;113(3):1049–58.

    CAS  PubMed  Google Scholar 

  86. Kioussi C, Gross MK, Gruss P. Pax3: a paired domain gene as a regulator in PNS myelination. Neuron. 1995;15:553–62.

    CAS  PubMed  Google Scholar 

  87. Tajbakhsh S, Rocancourt D, Cossu G, Buckingham M. Redefining the genetic heirarchies controlling skeletal myogenesis: Pax-3 and Myf-5 act upstream of MyoD. Cell. 1997;89:127–38.

  88. Maroto M, Reshef R, Munsterberg AE, Koester S, Goulding M, Lassar AB. Ectopic Pax-3 activates MyoD and Myf-5 expression in embryonic mesoderm and neural tissue. Cell. 1997;89:139–48.

    CAS  PubMed  Google Scholar 

  89. Epstein JA, Shapiro DN, Chang J, Lam PYP, Maas RL. Pax3 modulates expression of the c-Met receptor during limb muscle development. Proc Natl Acad Sci U S A. 1996;93:4213–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Laborda J. 36B4 cDNA used as an estradiol-independent mRNA control is the cDNA for human acidic ribosomal phosphoprotein PO. Nucleic Acids Res. 1991;19:3998.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Hill AL, Phelan SA, Loeken MR. Reduced expression of Pax-3 is associated with overexpression of cdc46 in the mouse embryo. Dev Genes Evol. 1998;208:128–34.

    CAS  PubMed  Google Scholar 

  92. Cai J, Phelan SA, Hill AL, Loeken MR. Identification of Dep-1, a new gene that is regulated by the transcription factor, Pax-3, as a marker for altered embryonic gene expression during diabetic pregnancy. Diabetes. 1998;47:1803–5.

  93. Maulbecker CC, Gruss P. The oncogenic potential of Pax genes. EMBO J. 1993;12:2361–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Pani L, Horal M, Loeken MR. Rescue of neural tube defects in Pax-3-deficient embryos by p53 loss of function: implications for Pax-3- dependent development and tumorigenesis. Genes Dev. 2002;16(6):676–80. https://doi.org/10.1101/gad.969302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Ferencz C, Rubin JD, McCarter RJ, Clark EB. Maternal diabetes and cardiovascular malformations: predominance of double outlet right ventricle and truncus arteriosus. Teratology. 1990;41(3):319–26. https://doi.org/10.1002/tera.1420410309.

    Article  CAS  PubMed  Google Scholar 

  96. Kirby ML, Turnage KL 3rd, Hays BM. Characterization of conotruncal malformations following ablation of “cardiac” neural crest. Anat Rec. 1985;213(1):87–93.

    CAS  PubMed  Google Scholar 

  97. Conway SJ, Henderson DJ, Copp AJ. Pax3 is required for cardiac neural crest migration in the mouse: evidence from the splotch (Sp2H) mutant. Development. 1997;124:505–14.

    CAS  PubMed  Google Scholar 

  98. Morgan SC, Relaix F, Sandell LL, Loeken MR. Oxidative stress during diabetic pregnancy disrupts cardiac neural crest migration and causes outflow tract defects. Birth Defects Res A Clin Mol Teratol. 2008;82(6):453–63. https://doi.org/10.1002/bdra.20457.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Morgan SC, Lee HY, Relaix F, Sandell LL, Levorse JM, Loeken MR. Cardiac outflow tract septation failure in Pax3-deficient embryos is due to p53-dependent regulation of migrating cardiac neural crest. Mech Dev. 2008;125(9–10):757–67. https://doi.org/10.1016/j.mod.2008.07.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. •• Wang XD, Morgan SC, Loeken MR. Pax3 stimulates p53 ubiquitination and degradation independent of transcription. PLoS One. 2011;6(12):e29379. https://doi.org/10.1371/journal.pone.0029379. This paper demonstrated that PAX3 DNA-binding domains associate with MDM2 and p53 and stimulate p53 degradation separate from PAX3's activity as a transcription factor.

  101. Ma W, Sung HJ, Park JY, Matoba S, Hwang PM. A pivotal role for p53: balancing aerobic respiration and glycolysis. J Bioenerg Biomembr. 2007;39(3):243–6.

    CAS  PubMed  Google Scholar 

  102. Lundberg AS, Hahn WC, Gupta P, Weinberg RA. Genes involved in senescence and immortalization. Curr Opin Cell Biol. 2000;12(6):705–9.

    CAS  PubMed  Google Scholar 

  103. Hong H, Takahashi K, Ichisaka T, Aoi T, Kanagawa O, Nakagawa M, et al. Suppression of induced pluripotent stem cell generation by the p53-p21 pathway. Nature. 2009;460(7259):1132–5. https://doi.org/10.1038/nature08235.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Kawamura T, Suzuki J, Wang YV, Menendez S, Morera LB, Raya A, et al. Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature. 2009;460(7259):1140–4. https://doi.org/10.1038/nature08311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Kondoh H, Lleonart ME, Gil J, Wang J, Degan P, Peters G, et al. Glycolytic enzymes can modulate cellular life span. Cancer Res. 2005;65(1):177–85.

    CAS  PubMed  Google Scholar 

  106. Li M, He Y, Dubois W, Wu X, Shi J, Huang J. Distinct regulatory mechanisms and functions for p53-activated and p53-repressed DNA damage response genes in embryonic stem cells. Mol Cell. 2012;46(1):30–42. https://doi.org/10.1016/j.molcel.2012.01.020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Lin T, Chao C, Saito S, Mazur SJ, Murphy ME, Appella E, et al. p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression. Nat Cell Biol. 2005;7(2):165–71.

    CAS  PubMed  Google Scholar 

  108. Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, et al. p53 regulates mitochondrial respiration. Science. 2006;312(5780):1650–3. https://doi.org/10.1126/science.1126863.

    Article  CAS  PubMed  Google Scholar 

  109. Pan G, Thomson JA. Nanog and transcriptional networks in embryonic stem cell pluripotency. Cell Res. 2007;17(1):42–9. https://doi.org/10.1038/sj.cr.7310125.

    Article  CAS  PubMed  Google Scholar 

  110. Qin H, Yu T, Qing T, Liu Y, Zhao Y, Cai J, et al. Regulation of apoptosis and differentiation by p53 in human embryonic stem cells. J Biol Chem. 2007;282(8):5842–52. https://doi.org/10.1074/jbc.M610464200.

    Article  CAS  PubMed  Google Scholar 

  111. Solozobova V, Blattner C. Regulation of p53 in embryonic stem cells. Exp Cell Res. 2010;316(15):2434–46. https://doi.org/10.1016/j.yexcr.2010.06.006.

    Article  CAS  PubMed  Google Scholar 

  112. Utikal J, Polo JM, Stadtfeld M, Maherali N, Kulalert W, Walsh RM, et al. Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature. 2009;460(7259):1145–8. https://doi.org/10.1038/nature08285.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Yang A, Shi G, Zhou C, Lu R, Li H, Sun L, et al. Nucleolin maintains embryonic stem cell self-renewal by suppression of the p53-dependent pathway. J Biol Chem. 2011;286:43370–82. https://doi.org/10.1074/jbc.M111.225185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Mandal S, Lindgren AG, Srivastava AS, Clark AT, Banerjee U. Mitochondrial function controls proliferation and early differentiation potential of embryonic stem cells. Stem Cells. 2011;29(3):486–95. https://doi.org/10.1002/stem.590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Facucho-Oliveira JM, St John JC. The relationship between pluripotency and mitochondrial DNA proliferation during early embryo development and embryonic stem cell differentiation. Stem Cell Rev. 2009;5(2):140–58. https://doi.org/10.1007/s12015-009-9058-0.

    Article  CAS  Google Scholar 

  116. Ellington SK. In vitro analysis of glucose metabolism and embryonic growth in postimplantation rat embryos. Development. 1987;100(3):431–9.

    CAS  PubMed  Google Scholar 

  117. Conway SJ, Bundy J, Chen J, Dickman E, Rogers R, Will BM. Decreased neural crest stem cell expansion is responsible for the conotruncal heart defects within the splotch (Sp(2H))/Pax3 mouse mutant. Cardiovasc Res. 2000;47(2):314–28.

    CAS  PubMed  Google Scholar 

  118. Fleming A, Copp AJ. Embryonic folate metabolism and mouse neural tube defects. Science. 1998;280(5372):2107–9.

    CAS  PubMed  Google Scholar 

  119. Sudiwala S, Palmer A, Massa V, Burns AJ, Dunlevy LPE, de Castro SCP, et al. Cellular mechanisms underlying Pax3-related neural tube defects and their prevention by folic acid. Dis Model Mech. 2019;12(11). https://doi.org/10.1242/dmm.042234.

  120. Burren KA, Savery D, Massa V, Kok RM, Scott JM, Blom HJ, et al. Gene-environment interactions in the causation of neural tube defects: folate deficiency increases susceptibility conferred by loss of Pax3 function. Hum Mol Genet. 2008;17(23):3675–85. https://doi.org/10.1093/hmg/ddn262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Ichi S, Costa FF, Bischof JM, Nakazaki H, Shen YW, Boshnjaku V, et al. Folic acid remodels chromatin on Hes1 and Neurog2 promoters during caudal neural tube development. J Biol Chem. 2010;285(47):36922–32. https://doi.org/10.1074/jbc.M110.126714.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Spiro RG. Role of insulin in two pathways of glucose metabolism: in vivo glucosamine and glycogen synthesis. Ann N Y Acad Sci. 1959;82:366–73.

    CAS  PubMed  Google Scholar 

  123. Setnikar I, Rovati LC. Absorption, distribution, metabolism and excretion of glucosamine sulfate. A review. Arzneimittel-Forschung. 2001;51(9):699–725. https://doi.org/10.1055/s-0031-1300105.

    Article  CAS  PubMed  Google Scholar 

  124. Fleischer B. Mechanism of glycosylation in the Golgi apparatus. J Histochem Cytochem. 1983;31(8):1033–40.

    CAS  PubMed  Google Scholar 

  125. Abbondanzo S, Gadi I, Stewart C. Derivation of embryonic stem cell lines. In: Wasserman PM, Pamphilis MLD, editors. Methods in enzymology. New York: Academic Press; 1993. p. 803–23.

    Google Scholar 

  126. Wang F, Thirumangalathu S, Loeken MR. Establishment of new mouse embryonic stem cell lines is improved by physiological glucose and oxygen. Cloning Stem Cells. 2006;8(2):108–16.

  127. •• Jung JH, Wang XD, Loeken MR. Mouse embryonic stem cells established in physiological-glucose media express the high KM Glut2 glucose transporter expressed by normal embryos. Stem Cells Transl Med. 2013;2(12):929–34. https://doi.org/10.5966/sctm.2013-0093. This paper describes glucose transport kinetics and sensitivity to high glucose concentrations of LG-ESC lines that were islated in physiological glucose media.

  128. •• Jung JH, Iwabuchi K, Yang Z, Loeken MR. Embryonic stem cell proliferation stimulated by altered anabolic metabolism from glucose transporter 2-transported glucosamine. Sci Rep. 2016;6:28452. https://doi.org/10.1038/srep28452. This paper provides functional evidence that GLUT2 may function as a glucosamine transporter for embryo cells to stimulate growth.

  129. Shang J, Korner C, Freeze H, Lehrman MA. Extension of lipid-linked oligosaccharides is a high-priority aspect of the unfolded protein response: endoplasmic reticulum stress in Type I congenital disorder of glycosylation fibroblasts. Glycobiology. 2002;12(5):307–17.

    CAS  PubMed  Google Scholar 

  130. Wang F, Reece EA, Yang P. Superoxide dismutase 1 overexpression in mice abolishes maternal diabetes-induced endoplasmic reticulum stress in diabetic embryopathy. Am J Obstet Gynecol. 2013;209(4):345 e1–7. https://doi.org/10.1016/j.ajog.2013.06.037.

    Article  CAS  Google Scholar 

  131. Wang F, Wu Y, Gu H, Reece EA, Fang S, Gabbay-Benziv R, et al. Ask1 gene deletion blocks maternal diabetes-induced endoplasmic reticulum stress in the developing embryo by disrupting the unfolded protein response signalosome. Diabetes. 2015;64(3):973–88. https://doi.org/10.2337/db14-0409.

    Article  CAS  PubMed  Google Scholar 

  132. Zhao Z, Yang P, Eckert RL, Reece EA. Caspase-8: a key role in the pathogenesis of diabetic embryopathy. Birth Defects Res B Dev Reprod Toxicol. 2009;86(1):72–7. https://doi.org/10.1002/bdrb.20185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Lupo PJ, Mitchell LE, Canfield MA, Shaw GM, Olshan AF, Finnell RH, et al. Maternal-fetal metabolic gene-gene interactions and risk of neural tube defects. Mol Genet Metab. 2014;111(1):46–51. https://doi.org/10.1016/j.ymgme.2013.11.004.

    Article  CAS  PubMed  Google Scholar 

  134. Ruggiero JE, Northrup H, Au KS. Association of facilitated glucose transporter 2 gene variants with the myelomeningocele phenotype. Birth Defects Res A Clin Mol Teratol. 2015;103:479–87. https://doi.org/10.1002/bdra.23358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the National Institutes of Health (R01 DK052865, R01 DK058300, R01 DK104649 to MRL, and P30 DK036836 to the Joslin Diabetes Center).

Author information

Authors and Affiliations

  1. Section on Islet Cell and Regenerative Biology, Department of Medicine, Joslin Diabetes Center and Harvard Medical School, One Joslin Place, Boston, MA, 02215, USA

    Mary R. Loeken

Authors
  1. Mary R. Loeken
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mary R. Loeken.

Ethics declarations

Conflict of Interest

Mary R. Loeken declares that she has no conflicts of interest.

Human and Animal Rights and Informed Consent

All reported studies/experiments with animal subjects performed by the author have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Diabetes and Pregnancy

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Loeken, M.R. Mechanisms of Congenital Malformations in Pregnancies with Pre-existing Diabetes. Curr Diab Rep 20, 54 (2020). https://doi.org/10.1007/s11892-020-01338-4

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11892-020-01338-4

Keywords

Search

Navigation