Skip to main content
SpringerLink
Log in

Insulin Resistance in Pregnancy: Implications for Mother and Offspring

  • Chapter
  • First Online:
Book cover Insulin Resistance

Part of the book series: Contemporary Endocrinology ((COE))

Abstract

In normal pregnancy, maternal metabolism transforms to one characterized by insulin resistance (IR) to promote nutrient availability to the fetus while supporting maternal metabolic needs. The rising global epidemic of obesity and overweight now approaches 60%, and this has changed the landscape of the pregnancy phenotype. With pre-pregnancy obesity comes heightened IR and, when compounded by pregnancy-induced IR, the intrauterine environment becomes characterized by nutrient excess in the form of glucose, lipids, and amino acids in parallel with metabolic derangements, including inflammation and oxidative stress. When a sedentary lifestyle, poor nutrition, and excess gestational weight gain (GWG) are added, the maternal metabolome and microbiome are further altered. This chapter will provide a discussion of IR in pregnancy and its mechanisms, including genetic/epigenetic, cellular, metabolic, and lifestyle factors. Importantly, the implications of IR in pregnancy on maternal and offspring outcomes will be highlighted.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 139.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Devlieger R, Benhalima K, Damm P, Van Assche A, Mathieu C, Mahmood T, et al. Maternal obesity in Europe: where do we stand and how to move forward?: a scientific paper commissioned by the European Board and College of Obstetrics and Gynaecology (EBCOG). Eur J Obstet Gynecol Reprod Biol. 2016;201:203–8.

    Article  PubMed  Google Scholar 

  2. Nicklas JM, Barbour LA. Optimizing weight for maternal and infant health – tenable, or too late? Expert Rev Endocrinol Metab. 2015;10(2):227–42.

    Article  CAS  PubMed  Google Scholar 

  3. Gynecologists Acooa. Obesity in pregnancy committee opinion. Obstet Gynecol. 2013;121(1):210–2.

    Article  Google Scholar 

  4. Davies GA, Maxwell C, Mcleod L, Gagnon R, Basso M, Bos H, et al. SOGC clinical practice guidelines: obesity in pregnancy. No. 239, February 2010. Int J Gynaecol Obstet. 2010;110(2):167–73.

    Article  PubMed  Google Scholar 

  5. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011–2012. JAMA. 2014;311(8):806–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Flegal KM, Carroll MD, Kit BK, Ogden CL. Prevalence of obesity and trends in the distribution of body mass index among us adults, 1999–2010. JAMA. 2012;307(5):491–7.

    Article  PubMed  Google Scholar 

  7. Ogden CL, Carroll MD, Curtin LR, Mcdowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 1999–2004. JAMA. 2006;295(13):1549–55.

    Article  CAS  PubMed  Google Scholar 

  8. Handwerger S, Freemark M. The roles of placental growth hormone and placental lactogen in the regulation of human fetal growth and development. J Pediatr Endocrinol Metab. 2000;13(4):343–56.

    Article  CAS  PubMed  Google Scholar 

  9. Barbour LA, Mccurdy CE, Hernandez TL, Kirwan JP, Catalano PM, Friedman JE. Cellular mechanisms for insulin resistance in normal pregnancy and gestational diabetes. Diabetes Care. 2007;30(Supplement 2):S1–8.

    Article  CAS  Google Scholar 

  10. Koren O, Goodrich JK, Cullender TC, Spor A, Laitinen K, Backhed HK, et al. Host remodeling of the gut microbiome and metabolic changes during pregnancy. Cell. 2012;150(3):470–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. O’Keeffe M, St-Onge MP. Sleep duration and disorders in pregnancy: implications for glucose metabolism and pregnancy outcomes. Int J Obes. 2013;37(6):765–70.

    Article  CAS  Google Scholar 

  12. Di Cianni G, Miccoli R, Volpe L, Lencioni C, Del Prato S. Intermediate metabolism in normal pregnancy and in gestational diabetes. Diabetes Metab Res Rev. 2003;19(4):259–70.

    Article  PubMed  CAS  Google Scholar 

  13. Butte NF. Carbohydrate and lipid metabolism in pregnancy: normal compared with gestational diabetes mellitus. Am J Clin Nutr. 2000;71(5 Suppl):1256s–61s.

    Article  CAS  PubMed  Google Scholar 

  14. Catalano PM, Huston L, Amini SB, Kalhan SC. Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and gestational diabetes mellitus. Am J Obstet Gynecol. 1999;180(4):903–16.

    Article  CAS  PubMed  Google Scholar 

  15. Holme AM, Roland MC, Lorentzen B, Michelsen TM, Henriksen T. Placental glucose transfer: a human in vivo study. PLoS One. 2015;10(2):E0117084.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Illsley NP. Placental glucose transport in diabetic pregnancy. Clin Obstet Gynecol. 2000;43(1):116–26.

    Article  CAS  PubMed  Google Scholar 

  17. De Veciana M. Diabetes ketoacidosis in pregnancy. Semin Perinatol. 2013;37(4):267–73.

    Article  PubMed  Google Scholar 

  18. Lain KY, Catalano PM. Metabolic changes in pregnancy. Clin Obstet Gynecol. 2007;50(4):938–48.

    Article  PubMed  Google Scholar 

  19. Diderholm B, Stridsberg M, Ewald U, Lindeberg-Norden S, Gustafsson J. Increased lipolysis in non-obese pregnant women studied in the third trimester. BJOG. 2005;112(6):713–8.

    Article  CAS  PubMed  Google Scholar 

  20. Freinkel N. Banting Lecture 1980. Of pregnancy and progeny. Diabetes. 1980;29(12):1023–35.

    Article  CAS  PubMed  Google Scholar 

  21. Mcintyre HD, Zeck W, Russell A. Placental growth hormone, fetal growth and the IGF axis in normal and diabetic pregnancy. Curr Diabetes Rev. 2009;5(3):185–9.

    Article  CAS  PubMed  Google Scholar 

  22. Kirwan JP, Hauguel-De MS, Lepercq J, Challier JC, Huston-Presley L, Friedman JE, et al. TNF-alpha is a predictor of insulin resistance in human pregnancy. Diabetes. 2002;51(7):2207–13.

    Article  CAS  PubMed  Google Scholar 

  23. Barbour LA, Shao J, Qiao L, Pulawa LK, Jensen DR, Bartke A, et al. Human placental growth hormone causes severe insulin resistance in transgenic mice. Am J Obstet Gynecol. 2002;186(3):512–7.

    Article  CAS  PubMed  Google Scholar 

  24. Mesiano S. The endocrinology of human pregnancy and fetoplacental development. In: Barbieri JFSRL, editor. Yes and Jaffe’s reproductive endocrinology: physiology, pathophysiology, and clinical Management. Philadelphia: Saunders Elsevier; 2009. p. 249–82.

    Chapter  Google Scholar 

  25. Brelje TC, Scharp DW, Lacy PE, Ogren L, Talamantes F, Robertson M, et al. Effect of homologous placental lactogens, prolactins, and growth hormones on islet B-cell division and insulin secretion in rat, mouse, and human islets: implication for placental lactogen regulation of islet function during pregnancy. Endocrinology. 1993;132(2):879–87.

    Article  CAS  PubMed  Google Scholar 

  26. Baeyens L, Hindi S, Sorenson RL, German MS. Beta-cell adaptation in pregnancy. Diabetes Obes Metab. 2016;18(Suppl 1):63–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Iliodromiti S, Sassarini J, Kelsey TW, Lindsay RS, Sattar N, Nelson SM. Accuracy of circulating adiponectin for predicting gestational diabetes: a systematic review and meta-analysis. Diabetologia. 2016;59(4):692–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lacroix M, Battista MC, Doyon M, Menard J, Ardilouze JL, Perron P, et al. Lower adiponectin levels at first trimester of pregnancy are associated with increased insulin resistance and higher risk of developing gestational diabetes mellitus. Diabetes Care. 2013;36(6):1577–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Retnakaran R, Qi Y, Connelly PW, Sermer M, Hanley AJ, Zinman B. Low adiponectin concentration during pregnancy predicts postpartum insulin resistance, beta cell dysfunction and fasting glycaemia. Diabetologia. 2010;53(2):268–76.

    Article  CAS  PubMed  Google Scholar 

  30. Retnakaran R. Adiponectin and beta-cell adaptation in pregnancy. Diabetes. 2017;66(5):1121–2.

    Article  CAS  PubMed  Google Scholar 

  31. Harmon KA, Gerard L, Jensen DR, Kealey EH, Hernandez TL, Reece MS, et al. Continuous glucose profiles in obese and normal-weight pregnant women on a controlled diet: metabolic determinants of fetal growth. Diabetes Care. 2011;34(10):2198–204.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Sivan E, Homko CJ, Whittaker PG, Reece EA, Chen X, Boden G. Free fatty acids and insulin resistance during pregnancy. J Clin Endocrinol Metab. 1998;83(7):2338–42.

    CAS  PubMed  Google Scholar 

  33. Heerwagen MJ, De La Houssaye BE, Krause MA, Kramer A, Fisher B, Reece MS, et al. Human placental LPL activity is strongly associated with infant adiposity at birth. Diabetes. 2012;61(Suppl 1):A52.

    Google Scholar 

  34. Barbour LA, Hernandez TL, Hirsch N, Reece MS, Chartier-Logan C, Friedman JE, et al. Lipid predictors of infant adiposity in early and late pregnancy, fasting and fed. Diabetes. 2017;66(Suppl 1):A55.

    Google Scholar 

  35. Whyte K, Kelly H, O’Dwyer V, Gibbs M, O’Higgins A, Turner MJ. Offspring birth weight and maternal fasting lipids in women screened for gestational diabetes mellitus (GDM). Eur J Obstet Gynecol Reprod Biol. 2013;170(1):67–70.

    Article  CAS  PubMed  Google Scholar 

  36. Schaefer-Graf UM, Graf K, Kulbacka I, Kjos SL, Dudenhausen J, Vetter K, et al. Maternal lipids as strong determinants of fetal environment and growth in pregnancies with gestational diabetes mellitus. Diabetes Care. 2008;31(9):1858–63.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Hernandez TL, Friedman JE, Van Pelt RE, Barbour LA. Patterns of glycemia in normal pregnancy: should the current therapeutic targets be challenged? Diabetes Care. 2011;34(7):1660–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Siegmund T, Rad N, Ritterath C, Siebert G, Henrich W, Buhling KJ. Longitudinal changes in the continuous glucose profile measured by the CGMS in healthy pregnant women and determination of cut-off values. Eur J Obstet Gynecol Reprod Biol. 2008;139(1):46–52.

    Article  PubMed  Google Scholar 

  39. Yogev Y, Ben Haroush A, Chen R, Rosenn B, Hod M, Langer O. Diurnal glycemic profile in obese and normal weight nondiabetic pregnant women. Am J Obstet Gynecol. 2004;191(3):949–53.

    Article  CAS  PubMed  Google Scholar 

  40. Buchanan TA, Xiang AH. Gestational diabetes mellitus. J Clin Invest. 2005;115(3):485–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Barrett HL, Dekker NM, Mcintyre HD, Callaway LK. Normalizing metabolism in diabetic pregnancy: is it time to target lipids? Diabetes Care. 2014;37(5):1484–93.

    Article  CAS  PubMed  Google Scholar 

  42. Catalano PM, Shankar K. Obesity and pregnancy: mechanisms of short term and long term adverse consequences for mother and child. BMJ. 2017;356:J1.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Olmos PR, Rigotti A, Busso D, Berkowitz L, Santos JL, Borzone GR, et al. Maternal hypertriglyceridemia: a link between maternal overweight-obesity and macrosomia in gestational diabetes. Obesity (Silver Spring). 2014;22(10):2156–63.

    Article  CAS  Google Scholar 

  44. Barbour LA, Hernandez TL, Reece MS, Kahn B, Horton T, Galan HL, et al. Change in fasting triglycerides from early to late gestation are highly predictive of neonatal adiposity independent of maternal BMI. Diabetes. 2009;58(Suppl 1):A84.

    Google Scholar 

  45. 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.

    Article  CAS  PubMed  Google Scholar 

  46. Phelps RL, Metzger BE, Freinkel N. Carbohydrate metabolism in pregnancy. XVII. Diurnal profiles of plasma glucose, insulin, free fatty acids, triglycerides, cholesterol, and individual amino acids in late normal pregnancy. Am J Obstet Gynecol. 1981;140(7):730–6.

    Article  CAS  PubMed  Google Scholar 

  47. Ryckman KK, Donovan BM, Fleener DK, Bedell B, Borowski KS. Pregnancy-related changes of amino acid and acylcarnitine concentrations: the impact of obesity. AJP Rep. 2016;6(3):E329–36.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Newgard CB. Interplay between lipids and branched-chain amino acids in development of insulin resistance. Cell Metab. 2012;15(5):606–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Catalano PM, Nizielski SE, Shao J, Preston L, Qiao L, Friedman JE. Downregulated IRS-1 and PPARgamma in obese women with gestational diabetes: relationship to FFA during pregnancy. Am J Physiol Endocrinol Metab. 2002;282(3):E522–E33.

    Article  CAS  PubMed  Google Scholar 

  50. Zeghari N, Vidal H, Younsi M, Ziegler O, Drouin P, Donner M. Adipocyte membrane phospholipids and Ppar-gamma expression in obese women: relationship to hyperinsulinemia. Am J Physiol Endocrinol Metab. 2000;279(4):E736–E43.

    Article  CAS  PubMed  Google Scholar 

  51. Lappas M. Effect of pre-existing maternal obesity, gestational diabetes and adipokines on the expression of genes involved in lipid metabolism in adipose tissue. Metabolism. 2014;63(2):250–62.

    Article  CAS  PubMed  Google Scholar 

  52. Catalano PM, Hoegh M, Minium J, Huston-Presley L, Bernard S, Kalhan S, et al. Adiponectin in human pregnancy: implications for regulation of glucose and lipid metabolism. Diabetologia. 2006;49(7):1677–85.

    Article  CAS  PubMed  Google Scholar 

  53. Lowe LP, Metzger BE, Lowe WL Jr, Dyer AR, Mcdade TW, Mcintyre HD, et al. Inflammatory mediators and glucose in pregnancy: results from a subset of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. J Clin Endocrinol Metab. 2010;95(12):5427–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Aye IL, Powell TL, Jansson T. Review: adiponectin–the missing link between maternal adiposity, placental transport and fetal growth? Placenta. 2013;34(Suppl):S40–5.

    Article  CAS  PubMed  Google Scholar 

  55. Combs TP, Marliss EB. Adiponectin signaling in the liver. Rev Endocr Metab Disord. 2014;15(2):137–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Qiao L, Wattez JS, Lee S, Nguyen A, Schaack J, Hay WW Jr, et al. Adiponectin deficiency impairs maternal metabolic adaptation to pregnancy in mice. Diabetes. 2017;66(5):1126–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Howell KR, Powell TL. Effects of maternal obesity on placental function and fetal development. Reproduction. 2017;153(3):R97–R108.

    Article  CAS  PubMed  Google Scholar 

  58. Xiang A, Kawakubo M, Trigo E, Kjos SL, Buchanan TA. Declining beta-cell compensation for insulin resistance in hispanic women with recent gestational diabetes mellitus: association with changes in weight, adiponectin, and C-reactive protein. Diabetes Care. 2010;33(2):396–401.

    Article  CAS  PubMed  Google Scholar 

  59. Christou GA, Kiortsis DN. Adiponectin and lipoprotein metabolism. Obes Rev. 2013;14(12):939–49.

    Article  CAS  PubMed  Google Scholar 

  60. Ong GK, Hamilton JK, Sermer M, Connelly PW, Maguire G, Zinman B, et al. Maternal serum adiponectin and infant birthweight: the role of adiponectin isoform distribution. Clin Endocrinol. 2007;67(1):108–14.

    Article  CAS  Google Scholar 

  61. Lekva T, Roland MCP, Michelsen AE, Friis CM, 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.

    Article  PubMed  Google Scholar 

  62. Collado MC, Isolauri E, Laitinen K, Salminen S. Distinct composition of gut microbiota during pregnancy in overweight and normal-weight women. Am J Clin Nutr. 2008;88(4):894–9.

    Article  CAS  PubMed  Google Scholar 

  63. Basu S, Haghiac M, Surace P, Challier JC, Guerre-Millo M, Singh K, et al. Pregravid obesity associates with increased maternal endotoxemia and metabolic inflammation. Obesity (Silver Spring). 2011;19(3):476–82.

    Article  CAS  Google Scholar 

  64. Soderborg TK, Borengasser SJ, Barbour LA, Friedman JE. Microbial transmission from mothers with obesity or diabetes to infants: an innovative opportunity to interrupt a vicious cycle. Diabetologia. 2016;59(5):895–906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ma J, Prince AL, Bader D, Hu M, Ganu R, Baquero K, et al. High-fat maternal diet during pregnancy persistently alters the offspring microbiome in a primate model. Nat Commun. 2014;5:3889.

    Article  CAS  PubMed  Google Scholar 

  66. Russell SL, Gold MJ, Hartmann M, Willing BP, Thorson L, Wlodarska M, et al. Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma. EMBO Rep. 2012;13(5):440–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Prince AL, Antony KM, Chu DM, Aagaard KM. The microbiome, parturition, and timing of birth: more questions than answers. J Reprod Immunol. 2014;104–105:12–9.

    Article  PubMed  Google Scholar 

  68. Mueller NT, Shin H, Pizoni A, Werlang IC, Matte U, Goldani MZ, et al. Birth mode-dependent association between pre-pregnancy maternal weight status and the neonatal intestinal microbiome. Sci Rep. 2016;6:23133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Chu DM, Antony KM, Ma J, Prince AL, Showalter L, Moller M, et al. The early infant gut microbiome varies in association with a maternal high-fat diet. Genome Med. 2016;8(1):77.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Cotillard A, Kennedy SP, Kong LC, Prifti E, Pons N, Le Chatelier E, et al. Dietary intervention impact on gut microbial gene richness. Nature. 2013;500(7464):585–8.

    Article  CAS  PubMed  Google Scholar 

  71. Lemas DJ, Yee S, Cacho N, Miller D, Cardel M, Gurka M, et al. Exploring the contribution of maternal antibiotics and breastfeeding to development of the infant microbiome and pediatric obesity. Semin Fetal Neonatal Med. 2016;21(6):406–9.

    Article  PubMed  Google Scholar 

  72. Young BE, Patinkin ZW, Palmer C, De La Houssaye B, Barbour LA, Hernandez TL, et al. Human milk insulin is related to maternal plasma insulin and BMI–but other components of human milk do not differ by BMI. Eur J Clin Nutr. 2017;71(9):1094–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Goodrich JK, Waters JL, Poole AC, Sutter JL, Koren O, Blekhman R, et al. Human genetics shape the gut microbiome. Cell. 2014;159(4):789–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Yogev Y, Catalano PM. Pregnancy and obesity. Obstet Gynecol Clin North Am. 2009;36(2):285–300, viii.

    Article  PubMed  Google Scholar 

  75. Beard JH, Bell RL, Duffy AJ. Reproductive considerations and pregnancy after bariatric surgery: current evidence and recommendations. Obes Surg. 2008;18(8):1023–7.

    Article  PubMed  Google Scholar 

  76. Guelinckx I, Devlieger R, Vansant G. Reproductive outcome after bariatric surgery: a critical review. Hum Reprod Update. 2009;15(2):189–201.

    Article  PubMed  Google Scholar 

  77. Hackmon R, James R, O’Reilly Green C, Ferber A, Barnhard Y, Divon M. The impact of maternal age, body mass index and maternal weight gain on the glucose challenge test in pregnancy. J Matern Fetal Neonatal Med. 2007;20(3):253–7.

    Article  PubMed  Google Scholar 

  78. Saldana TM, Siega-Riz AM, Adair LS, Suchindran C. The relationship between pregnancy weight gain and glucose tolerance status among black and white women in central North Carolina. Am J Obstet Gynecol. 2006;195(6):1629–35.

    Article  CAS  PubMed  Google Scholar 

  79. Gibson KS, Waters TP, Catalano PM. Maternal weight gain in women who develop gestational diabetes mellitus. Obstet Gynecol. 2012;119(3):560–5.

    Article  PubMed  Google Scholar 

  80. Witter FR, Caulfield LE, Stoltzfus RJ. Influence of maternal anthropometric status and birth weight on the risk of cesarean delivery. Obstet Gynecol. 1995;85(6):947–51.

    Article  CAS  PubMed  Google Scholar 

  81. Young TK, Woodmansee B. Factors that are associated with cesarean delivery in a large private practice: the importance of prepregnancy body mass index and weight gain. Am J Obstet Gynecol. 2002;187(2):312–8; Discussion 8–20.

    Article  PubMed  Google Scholar 

  82. Cheng YW, Chung JH, Kurbisch-Block I, Inturrisi M, Shafer S, Caughey AB. Gestational weight gain and gestational diabetes mellitus: perinatal outcomes. Obstet Gynecol. 2008;112(5):1015–22.

    Article  PubMed  Google Scholar 

  83. Devader SR, Neeley HL, Myles TD, Leet TL. Evaluation of gestational weight gain guidelines for women with normal prepregnancy body mass index. Obstet Gynecol. 2007;110(4):745–51.

    Article  PubMed  Google Scholar 

  84. Kiel DW, Dodson EA, Artal R, Boehmer TK, Leet TL. Gestational weight gain and pregnancy outcomes in obese women: how much is enough? Obstet Gynecol. 2007;110(4):752–8.

    Article  PubMed  Google Scholar 

  85. Baird J, Fisher D, Lucas P, Kleijnen J, Roberts H, Law C. Being big or growing fast: systematic review of size and growth in infancy and later obesity. BMJ. 2005;331(7522):929.

    Article  PubMed  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

  87. Mojtabai R. Body mass index and serum folate in childbearing age women. Eur J Epidemiol. 2004;19(11):1029–36.

    Article  CAS  PubMed  Google Scholar 

  88. Laraia BA, Bodnar LM, Siega-Riz AM. Pregravid body mass index is negatively associated with diet quality during pregnancy. Public Health Nutr. 2007;10(9):920–6.

    Article  PubMed  Google Scholar 

  89. Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, Coustan DR, et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008;358(19):1991–2002.

    Article  PubMed  Google Scholar 

  90. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Ryan EA. Diagnosing gestational diabetes. Diabetologia. 2011;54(3):480–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Catalano PM, Thomas A, Huston-Presley L, Amini SB. Phenotype of infants of mothers with gestational diabetes. Diabetes Care. 2007;30(Suppl 2):S156–S60.

    Article  PubMed  Google Scholar 

  93. Defronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Phys. 1979;237(3):E214–E23.

    CAS  Google Scholar 

  94. Bergman RN, Phillips LS, Cobelli C. Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose. J Clin Invest. 1981;68(6):1456–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Bergman RN, Hope ID, Yang YJ, Watanabe RM, Meador MA, Youn JH, et al. Assessment of insulin sensitivity in vivo: a critical review. Diabetes Metab Rev. 1989;5(5):411–29.

    Article  CAS  PubMed  Google Scholar 

  96. Bergman RN. Lilly Lecture 1989. Toward physiological understanding of glucose tolerance. Minimal-model approach. Diabetes. 1989;38(12):1512–27.

    Article  CAS  PubMed  Google Scholar 

  97. Wallace TM, Matthews DR. The assessment of insulin resistance in man. Diabet Med. 2002;19(7):527–34.

    Article  CAS  PubMed  Google Scholar 

  98. Wallace TM, Levy JC, Matthews DR. Use and abuse of homa modeling. Diabetes Care. 2004;27(6):1487–95.

    Article  PubMed  Google Scholar 

  99. Crume TL, Shapiro AL, Brinton JT, Glueck DH, Martinez M, Kohn M, et al. Maternal fuels and metabolic measures during pregnancy and neonatal body composition: the Healthy Start study. J Clin Endocrinol Metab. 2015;100(4):1672–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Matsuda M, Defronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999;22(9):1462–70.

    Article  CAS  PubMed  Google Scholar 

  101. Kirwan JP, Huston-Presley L, Kalhan SC, Catalano PM. Clinically useful estimates of insulin sensitivity during pregnancy: validation studies in women with normal glucose tolerance and gestational diabetes mellitus. Diabetes Care. 2001;24(9):1602–7.

    Article  CAS  PubMed  Google Scholar 

  102. Abdul-Ghani MA, Matsuda M, Balas B, Defronzo RA. Muscle and liver insulin resistance indexes derived from the oral glucose tolerance test. Diabetes Care. 2007;30(1):89–94.

    Article  CAS  PubMed  Google Scholar 

  103. Utzschneider KM, Prigeon RL, Faulenbach MV, Tong J, Carr DB, Boyko EJ, et al. Oral disposition index predicts the development of future diabetes above and beyond fasting and 2-H glucose levels. Diabetes Care. 2009;32(2):335–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes. 2002;51(9):2796–803.

    Article  CAS  PubMed  Google Scholar 

  105. Hamilton JK, Odrobina E, Yin J, Hanley AJ, Zinman B, Retnakaran R. Maternal insulin sensitivity during pregnancy predicts infant weight gain and adiposity at 1 year of age. Obesity (Silver Spring). 2010;18(2):340–6.

    Article  Google Scholar 

  106. Shapiro AL, Schmiege SJ, Brinton JT, Glueck D, Crume TL, Friedman JE, et al. Testing the fuel-mediated hypothesis: maternal insulin resistance and glucose mediate the association between maternal and neonatal adiposity, the Healthy Start study. Diabetologia. 2015;58(5):937–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Isganaitis E, Woo M, Ma H, Chen M, Kong W, Lytras A, et al. Developmental programming by maternal insulin resistance: hyperinsulinemia, glucose intolerance, and dysregulated lipid metabolism in male offspring of insulin-resistant mice. Diabetes. 2014;63(2):688–700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Friedman JE. Obesity and gestational diabetes mellitus pathways for programming in mouse, monkey, and man-where do we go next? The 2014 Norbert Freinkel Award lecture. Diabetes Care. 2015;38(8):1402–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Margerison Zilko CE, Rehkopf D, Abrams B. Association of maternal gestational weight gain with short- and long-term maternal and child health outcomes. Am J Obstet Gynecol. 2010;202(6):574 E1–8.

    Article  Google Scholar 

  110. Jedrychowski W, Maugeri U, Kaim I, Budzyn-Mrozek D, Flak E, Mroz E, et al. Impact of excessive gestational weight gain in non-smoking mothers on body fatness in infancy and early childhood. Prospective prebirth cohort study in Cracow. J Physiol Pharmacol. 2011;62(1):55–64.

    CAS  PubMed  Google Scholar 

  111. Crozier SR, Inskip HM, Godfrey KM, Cooper C, Harvey NC, Cole ZA, et al. Weight gain in pregnancy and childhood body composition: findings from the southampton women’s survey. Am J Clin Nutr. 2010;91(6):1745–51.

    Article  CAS  PubMed  Google Scholar 

  112. Catalano PM, Thomas A, Huston-Presley L, Amini SB. Increased fetal adiposity: a very sensitive marker of abnormal in utero development. Am J Obstet Gynecol. 2003;189(6):1698–704.

    Article  PubMed  Google Scholar 

  113. Catalano PM, Roman NM, Tyzbir ED, Merritt AO, Driscoll P, Amini SB. Weight gain in women with gestational diabetes. Obstet Gynecol. 1993;81(4):523–8.

    CAS  PubMed  Google Scholar 

  114. Starling AP, Brinton JT, Glueck DH, Shapiro AL, Harrod CS, Lynch AM, et al. Associations of maternal BMI and gestational weight gain with neonatal adiposity in the Healthy Start study. Am J Clin Nutr. 2015;101(2):302–9.

    Article  CAS  PubMed  Google Scholar 

  115. Hernandez TL, Anderson MA, Chartier-Logan C, Friedman JE, Barbour LA. Strategies in the nutritional management of gestational diabetes. Clin Obstet Gynecol. 2013;56(4):803–15.

    Article  PubMed  PubMed Central  Google Scholar 

  116. Hernandez TL. Higher-complex carbohydrate diets in gestational diabetes. In: Rajendram R, Preedy VR, Patel V, editors. Nutrition and diet in maternal diabetes: an evidence-based approach. New York: Springer; 2018.

    Google Scholar 

  117. Lichtenstein AH, Schwab US. Relationship of dietary fat to glucose metabolism. Atherosclerosis. 2000;150(2):227–43.

    Article  CAS  PubMed  Google Scholar 

  118. Zhang C, Schulze MB, Solomon CG, Hu FB. A prospective study of dietary patterns, meat intake and the risk of gestational diabetes mellitus. Diabetologia. 2006;49(11):2604–13.

    Article  CAS  PubMed  Google Scholar 

  119. Zhang C, Liu S, Solomon CG, Hu FB. Dietary fiber intake, dietary glycemic load, and the risk for gestational diabetes mellitus. Diabetes Care. 2006;29(10):2223–30.

    Article  CAS  PubMed  Google Scholar 

  120. Mcgowan CA, Walsh JM, Byrne J, Curran S, Mcauliffe FM. The influence of a low glycemic index dietary intervention on maternal dietary intake, glycemic index and gestational weight gain during pregnancy: a randomized controlled trial. Nutr J. 2013;12(1):140.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Hernandez TL. Nutrition therapy in gestational diabetes: the case for complex carbohydrates. Diabetes Spectr. 2016;29(2):82–8.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Hernandez TL, Van Pelt RE, Anderson MA, Daniels LJ, West NA, Donahoo WT, et al. A higher-complex carbohydrate diet in gestational diabetes mellitus achieves glucose targets and lowers postprandial lipids: a randomized crossover study. Diabetes Care. 2014;37(5):1254–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Hernandez TL, Van Pelt RE, Anderson MA, Reece MS, Reynolds RM, De La Houssaye BA, et al. Women with gestational diabetes mellitus randomized to a higher-complex carbohydrate/low-fat diet manifest lower adipose tissue insulin resistance, inflammation, glucose, and free fatty acids: a pilot study. Diabetes Care. 2016;39(1):39–42.

    Article  CAS  PubMed  Google Scholar 

  124. Cunningham SA, Kramer MR, Narayan KM. Incidence of childhood obesity in the United States. N Engl J Med. 2014;370(5):403–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the global burden of disease study 2013. Lancet. 2014;384(9945):766–81.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Nicholas LM, Morrison JL, Rattanatray L, Zhang S, Ozanne SE, Mcmillen IC. The early origins of obesity and insulin resistance: timing, programming and mechanisms. Int J Obes. 2016;40(2):229–38.

    Article  CAS  Google Scholar 

  127. Hull HR, Thornton JC, Ji Y, Paley C, Rosenn B, Mathews P, et al. Higher infant body fat with excessive gestational weight gain in overweight women. Am J Obstet Gynecol. 2011;205(3):211.E1–7.

    Article  Google Scholar 

  128. Andersen CS, Gamborg M, Sorensen TI, Nohr EA. Weight gain in different periods of pregnancy and offspring’s body mass index at 7 years of age. Int J Pediatr Obes. 2011;6(2–2):E179–86.

    Article  PubMed  Google Scholar 

  129. Wu LL, Russell DL, Wong SL, Chen M, Tsai TS, St John JC, et al. Mitochondrial dysfunction in oocytes of obese mothers: transmission to offspring and reversal by pharmacological endoplasmic reticulum stress inhibitors. Development. 2015;142(4):681–91.

    Article  CAS  PubMed  Google Scholar 

  130. Mccurdy CE, Bishop JM, Williams SM, Grayson BE, Smith MS, Friedman JE, et al. Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman primates. J Clin Invest. 2009;119(2):323–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Thorn SR, Baquero KC, Newsom SA, El Kasmi KC, Bergman BC, Shulman GI, et al. Early life exposure to maternal insulin resistance has persistent effects on hepatic NAFLD in juvenile nonhuman primates. Diabetes. 2014;63(8):2702–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Kubo A, Ferrara A, Windham GC, Greenspan LC, Deardorff J, Hiatt RA, et al. Maternal hyperglycemia during pregnancy predicts adiposity of the offspring. Diabetes Care. 2014;37(11):2996–3002.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Mccurdy CE, Schenk S, Hetrick B, Houck J, Drew BG, Kaye S, et al. Maternal obesity reduces oxidative capacity in fetal skeletal muscle of Japanese macaques. JCI Insight. 2016;1(16):E86612.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Graus-Nunes F, Dalla Corte Frantz E, Lannes WR, Da Silva Menezes MC, Mandarim-De-Lacerda CA, Souza-Mello V. Pregestational maternal obesity impairs endocrine pancreas in male F1 and F2 progeny. Nutrition. 2015;31(2):380–7.

    Article  CAS  PubMed  Google Scholar 

  135. Saben JL, Boudoures AL, Asghar Z, Thompson A, Drury A, Zhang W, et al. Maternal metabolic syndrome programs mitochondrial dysfunction via germline changes across three generations. Cell Rep. 2016;16(1):1–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Seidler EA, Moley KH. Metabolic determinants of mitochondrial function in oocytes. Semin Reprod Med. 2015;33(6):396–400.

    Article  CAS  PubMed  Google Scholar 

  137. Welsh JA, Karpen S, Vos MB. Increasing prevalence of nonalcoholic fatty liver disease among United States adolescents, 1988–1994 to 2007–2010. J Pediatr. 2013;162(3):496–500 E1.

    Article  PubMed  Google Scholar 

  138. Alisi A, Manco M, Vania A, Nobili V. Pediatric nonalcoholic fatty liver disease in 2009. J Pediatr. 2009;155(4):469–74.

    Article  PubMed  Google Scholar 

  139. Dabelea D, Knowler WC, Pettitt DJ. Effect of diabetes in pregnancy on offspring: follow-up research in the Pima Indians. J Matern Fetal Med. 2000;9(1):83–8.

    CAS  PubMed  Google Scholar 

  140. Dabelea D, Hanson RL, Lindsay RS, Pettitt DJ, Imperatore G, Gabir MM, et al. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes. 2000;49(12):2208–11.

    Article  CAS  PubMed  Google Scholar 

  141. Brumbaugh DE, Tearse P, Cree-Green M, Fenton LZ, Brown M, Scherzinger A, et al. Intrahepatic fat is increased in the neonatal offspring of obese women with gestational diabetes. J Pediatr. 2013;162(5):930–6.e1.

    Article  CAS  PubMed  Google Scholar 

  142. Modi N, Murgasova D, Ruager-Martin R, Thomas EL, Hyde MJ, Gale C, et al. The influence of maternal body mass index on infant adiposity and hepatic lipid content. Pediatr Res. 2011;70(3):287–91.

    Article  PubMed  Google Scholar 

  143. Faupel-Badger JM, Mcelrath TF, Lauria M, Houghton LC, Lim KH, Parry S, et al. Maternal circulating angiogenic factors in twin and singleton pregnancies. Am J Obstet Gynecol. 2015;212(5):636 E1–8.

    Article  CAS  Google Scholar 

  144. Patel S, Lawlor DA, Callaway M, Macdonald-Wallis C, Sattar N, Fraser A. Association of maternal diabetes/glycosuria and pre-pregnancy body mass index with offspring indicators of non-alcoholic fatty liver disease. BMC Pediatr. 2016;16:47.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  145. Gaillard R, Welten M, Oddy WH, Beilin LJ, Mori TA, Jaddoe VW, et al. Associations of maternal prepregnancy body mass index and gestational weight gain with cardio-metabolic risk factors in adolescent offspring: a prospective cohort study. BJOG. 2016;123(2):207–16.

    Article  CAS  PubMed  Google Scholar 

  146. Newton KP, Feldman HS, Chambers CD, Wilson L, Behling C, Clark JM, et al. Low and high birth weights are risk factors for nonalcoholic fatty liver disease in children. J Pediatr. 2017;187:141–146.e1.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Goyal NP, Schwimmer JB. The progression and natural history of pediatric nonalcoholic fatty liver disease. Clin Liver Dis. 2016;20(2):325–38.

    Article  PubMed  Google Scholar 

  148. Heerwagen MJ, Stewart MS, De La Houssaye BA, Janssen RC, Friedman JE. Transgenic increase in N-3/N-6 fatty acid ratio reduces maternal obesity-associated inflammation and limits adverse developmental programming in mice. PLoS One. 2013;8(6):E67791.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Bruce KD, Cagampang FR, Argenton M, Zhang J, Ethirajan PL, Burdge GC, et al. Maternal high-fat feeding primes steatohepatitis in adult mice offspring, involving mitochondrial dysfunction and altered lipogenesis gene expression. Hepatology. 2009;50(6):1796–808.

    Article  CAS  PubMed  Google Scholar 

  150. Grant WF, Nicol LE, Thorn SR, Grove KL, Friedman JE, Marks DL. Perinatal exposure to a high-fat diet is associated with reduced hepatic sympathetic innervation in one-year old male Japanese macaques. PLoS One. 2012;7(10):E48119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Whitaker RC. Predicting preschooler obesity at birth: the role of maternal obesity in early pregnancy. Pediatrics. 2004;114(1):E29–36.

    Article  PubMed  Google Scholar 

  152. Boney CM, Verma A, Tucker R, Vohr BR. Metabolic syndrome in childhood: association with birth weight, maternal obesity, and gestational diabetes mellitus. Pediatrics. 2005;115(3):E290–E6.

    Article  PubMed  Google Scholar 

  153. Catalano PM, Farrell K, Thomas A, Huston-Presley L, Mencin P, De Mouzon SH, et al. Perinatal risk factors for childhood obesity and metabolic dysregulation. Am J Clin Nutr. 2009;90(5):1303–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Barisione M, Carlini F, Gradaschi R, Camerini G, Adami GF. Body weight at developmental age in siblings born to mothers before and after surgically induced weight loss. Surg Obes Relat Dis. 2012;8(4):387–91.

    Article  PubMed  Google Scholar 

  155. Kral JG, Biron S, Simard S, Hould FS, Lebel S, Marceau S, et al. Large maternal weight loss from obesity surgery prevents transmission of obesity to children who were followed for 2 to 18 years. Pediatrics. 2006;118(6):E1644–9.

    Article  PubMed  Google Scholar 

  156. Kizirian NV, Kong Y, Muirhead R, Brodie S, Garnett SP, Petocz P, et al. Effects of a low-glycemic index diet during pregnancy on offspring growth, body composition, and vascular health: a pilot randomized controlled trial. Am J Clin Nutr. 2016;103(4):1073–82.

    Article  CAS  PubMed  Google Scholar 

  157. Markovic TP, Muirhead R, Overs S, Ross GP, Louie JC, Kizirian N, et al. Randomized controlled trial investigating the effects of a low-glycemic index diet on pregnancy outcomes in women at high risk of gestational diabetes mellitus: the GI baby 3 study. Diabetes Care. 2016;39(1):31–8.

    Article  CAS  PubMed  Google Scholar 

  158. Barbour LA. Changing perspectives in pre-existing diabetes and obesity in pregnancy: maternal and infant short- and long-term outcomes. Curr Opin Endocrinol Diabetes Obes. 2014;21(4):257–63.

    Article  CAS  PubMed  Google Scholar 

  159. Jharap VV, Santos S, Steegers EA, Jaddoe VW, Gaillard R. Associations of maternal obesity and excessive weight gain during pregnancy with subcutaneous fat mass in infancy. Early Hum Dev. 2017;108:23–8.

    Article  PubMed  PubMed Central  Google Scholar 

  160. Rasmussen KM, Catalano PM, Yaktine AL. New guidelines for weight gain during pregnancy: what obstetrician/gynecologists should know. Curr Opin Obstet Gynecol. 2009;21(6):521–6.

    Article  PubMed  PubMed Central  Google Scholar 

  161. Rivera HM, Christiansen KJ, Sullivan EL. The role of maternal obesity in the risk of neuropsychiatric disorders. Front Neurosci. 2015;9:194.

    Article  PubMed  PubMed Central  Google Scholar 

  162. Sullivan EL, Rivera HM, True CA, Franco JG, Baquero K, Dean TA, et al. Maternal and postnatal high-fat diet consumption programs energy balance and hypothalamic melanocortin signaling in nonhuman primate offspring. Am J Physiol Regul Integr Comp Physiol. 2017;313(2):R169–79.

    Article  PubMed  PubMed Central  Google Scholar 

  163. Bajpeyi S, Myrland CK, Covington JD, Obanda D, Cefalu WT, Smith SR, et al. Lipid in skeletal muscle myotubes is associated to the donors’ insulin sensitivity and physical activity phenotypes. Obesity (Silver Spring). 2014;22(2):426–34.

    Article  CAS  Google Scholar 

  164. Boyle KE, Zheng D, Anderson EJ, Neufer PD, Houmard JA. Mitochondrial lipid oxidation is impaired in cultured myotubes from obese humans. Int J Obes. 2012;36(8):1025–31.

    Article  CAS  Google Scholar 

  165. Boyle KE, Patinkin ZW, Shapiro AL, Baker PR 2nd, Dabelea D, Friedman JE. Mesenchymal stem cells from infants born to obese mothers exhibit greater potential for adipogenesis: the healthy start babybump project. Diabetes. 2016;65(3):647–59.

    Article  CAS  PubMed  Google Scholar 

  166. Teh AL, Pan H, Chen L, Ong ML, Dogra S, Wong J, et al. The effect of genotype and in utero environment on interindividual variation in neonate DNA methylomes. Genome Res. 2014;24(7):1064–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Ollikainen M, Smith KR, Joo EJ, Ng HK, Andronikos R, Novakovic B, et al. DNA methylation analysis of multiple tissues from newborn twins reveals both genetic and intrauterine components to variation in the human neonatal epigenome. Hum Mol Genet. 2010;19(21):4176–88.

    Article  CAS  PubMed  Google Scholar 

  168. Cooper WN, Khulan B, Owens S, Elks CE, Seidel V, Prentice AM, et al. DNA methylation profiling at imprinted loci after periconceptional micronutrient supplementation in humans: results of a pilot randomized controlled trial. FASEB J. 2012;26(5):1782–90.

    Article  CAS  PubMed  Google Scholar 

  169. Guenard F, Deshaies Y, Cianflone K, Kral JG, Marceau P, Vohl MC. Differential methylation in glucoregulatory genes of offspring born before vs. after maternal gastrointestinal bypass surgery. Proc Natl Acad Sci U S A. 2013;110(28):11439–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Khulan B, Cooper WN, Skinner BM, Bauer J, Owens S, Prentice AM, et al. Periconceptional maternal micronutrient supplementation is associated with widespread gender related changes in the epigenome: a study of a unique resource in the gambia. Hum Mol Genet. 2012;21(9):2086–101.

    Article  CAS  PubMed  Google Scholar 

  171. Dominguez-Salas P, Moore SE, Baker MS, Bergen AW, Cox SE, Dyer RA, et al. Maternal nutrition at conception modulates DNA methylation of human metastable epialleles. Nat Commun. 2014;5:3746.

    Article  CAS  PubMed  Google Scholar 

  172. Waterland RA, Kellermayer R, Laritsky E, Rayco-Solon P, Harris RA, Travisano M, et al. Season of conception in rural Gambia affects DNA methylation at putative human metastable epialleles. PLoS Genet. 2010;6(12):E1001252.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Ganu RS, Harris RA, Collins K, Aagaard KM. Maternal diet: a modulator for epigenomic regulation during development in nonhuman primates and humans. Int J Obes Suppl. 2012;2(Suppl 2):S14–S8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Fu Q, Yu X, Callaway CW, Lane RH, Mcknight RA. Epigenetics: intrauterine growth retardation (IUGR) modifies the histone code along the rat hepatic IGF-1 gene. FASEB J. 2009;23(8):2438–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Bhutta ZA, Das JK, Rizvi A, Gaffey MF, Walker N, Horton S, et al. Evidence-based interventions for improvement of maternal and child nutrition: what can be done and at what cost? Lancet. 2013;382(9890):452–77.

    Article  PubMed  Google Scholar 

  176. Godfrey KM, Sheppard A, Gluckman PD, Lillycrop KA, Burdge GC, Mclean C, et al. Epigenetic gene promoter methylation at birth is associated with child’s later adiposity. Diabetes. 2011;60(5):1528–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Radaelli T, Lepercq J, Varastehpour A, Basu S, Catalano PM, Hauguel-De MS. Differential regulation of genes for fetoplacental lipid pathways in pregnancy with gestational and type 1 diabetes mellitus. Am J Obstet Gynecol. 2009;201(2):209.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  178. Pantham P, Aye IL, Powell TL. Inflammation in maternal obesity and gestational diabetes mellitus. Placenta. 2015;36(7):709–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Frias AE, Morgan TK, Evans AE, Rasanen J, Oh KY, Thornburg KL, et al. Maternal high-fat diet disturbs uteroplacental hemodynamics and increases the frequency of stillbirth in a nonhuman primate model of excess nutrition. Endocrinology. 2011;152(6):2456–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Acharya G, Albrecht C, Benton SJ, Cotechini T, Dechend R, Dilworth MR, et al. IFPA meeting 2011 workshop report I: placenta: predicting future health; roles of lipids in the growth and development of feto-placental unit; placental nutrient sensing; placental research to solve clinical problems–a translational approach. Placenta. 2012;33(Suppl):S4–8.

    Article  PubMed  Google Scholar 

  181. Lager S, Gaccioli F, Ramirez VI, Jones HN, Jansson T, Powell TL. Oleic acid stimulates system a amino acid transport in primary human trophoblast cells mediated by toll-like receptor 4. J Lipid Res. 2013;54(3):725–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Ategbo JM, Grissa O, Yessoufou A, Hichami A, Dramane KL, Moutairou K, et al. Modulation of adipokines and cytokines in gestational diabetes and macrosomia. J Clin Endocrinol Metab. 2006;91(10):4137–43.

    Article  CAS  PubMed  Google Scholar 

  183. Jones HN, Jansson T, Powell TL. Full-length adiponectin attenuates insulin signaling and inhibits insulin-stimulated amino acid transport in human primary trophoblast cells. Diabetes. 2010;59(5):1161–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Aye IL, Waddell BJ, Mark PJ, Keelan JA. Oxysterols exert proinflammatory effects in placental trophoblasts via TLR4-dependent, cholesterol-sensitive activation of NF-kappab. Mol Hum Reprod. 2012;18(7):341–53.

    Article  CAS  PubMed  Google Scholar 

  185. Jansson N, Greenwood SL, Johansson BR, Powell TL, Jansson T. Leptin stimulates the activity of the system a amino acid transporter in human placental villous fragments. J Clin Endocrinol Metab. 2003;88(3):1205–11.

    Article  CAS  PubMed  Google Scholar 

  186. Jansson T, Ekstrand Y, Bjorn C, Wennergren M, Powell TL. Alterations in the activity of placental amino acid transporters in pregnancies complicated by diabetes. Diabetes. 2002;51(7):2214–9.

    Article  CAS  PubMed  Google Scholar 

  187. Jansson N, Rosario FJ, Gaccioli F, Lager S, Jones HN, Roos S, et al. Activation of placental mTOR signaling and amino acid transporters in obese women giving birth to large babies. J Clin Endocrinol Metab. 2013;98(1):105–13.

    Article  CAS  PubMed  Google Scholar 

  188. Perazzolo S, Hirschmugl B, Wadsack C, Desoye G, Lewis RM, Sengers BG. The influence of placental metabolism on fatty acid transfer to the fetus. J Lipid Res. 2017;58(2):443–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Calabuig-Navarro V, Haghiac M, Minium J, Glazebrook P, Ranasinghe GC, Hoppel C, et al. Effect of maternal obesity on placental lipid metabolism. Endocrinology. 2017;158(8):2543–55.

    Article  PubMed  PubMed Central  Google Scholar 

  190. Radaelli T, Varastehpour A, Catalano P, Hauguel-De Mouzon S. Gestational diabetes induces placental genes for chronic stress and inflammatory pathways. Diabetes. 2003;52(12):2951–8.

    Article  CAS  PubMed  Google Scholar 

  191. Perichart-Perera O, Munoz-Manrique C, Reyes-Lopez A, Tolentino-Dolores M, Espino YSS, Ramirez-Gonzalez MC. Metabolic markers during pregnancy and their association with maternal and newborn weight status. PLoS One. 2017;12(7):E0180874.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  192. Desoye G, Hauguel-De MS. The human placenta in gestational diabetes mellitus. The insulin and cytokine network. Diabetes Care. 2007;30(Suppl 2):S120–S6.

    Article  CAS  PubMed  Google Scholar 

  193. Ingvorsen C, Brix S, Ozanne SE, Hellgren LI. The effect of maternal inflammation on foetal programming of metabolic disease. Acta Physiol (Oxf). 2015;214(4):440–9.

    Article  CAS  Google Scholar 

  194. Brumbaugh DE, Friedman JE. Developmental origins of nonalcoholic fatty liver disease. Pediatr Res. 2014;75(1–2):140–7.

    Article  CAS  PubMed  Google Scholar 

  195. Isganaitis E, Rifas-Shiman SL, Oken E, Dreyfuss JM, Gall W, Gillman MW, et al. Associations of cord blood metabolites with early childhood obesity risk. Int J Obes. 2015;39(7):1041–8.

    Article  CAS  Google Scholar 

  196. Sandler V, Reisetter AC, Bain JR, Muehlbauer MJ, Nodzenski M, Stevens RD, et al. Associations of maternal BMI and insulin resistance with the maternal metabolome and newborn outcomes. Diabetologia. 2017;60(3):518–30.

    Article  CAS  PubMed  Google Scholar 

  197. Baker PR 2nd, Patinkin ZW, Shapiro S, De La Houssaye B, Boyle K, Vanderlinden L, et al. Maternal obesity and increased neonatal adiposity are associated with compromised infant mesenchymal stem cell metabolism and energy sensing. JCI Insight. 2017;2(21). pii: 94200. https://doi.org/10.1172/jci.insight.94200.

  198. Simmons D. Prevention of gestational diabetes mellitus: where are we now? Diabetes Obes Metab. 2015;17(9):824–34.

    Article  CAS  PubMed  Google Scholar 

  199. Luoto R, Laitinen K, Nermes M, Isolauri E. Impact of maternal probiotic-supplemented dietary counselling on pregnancy outcome and prenatal and postnatal growth: a double-blind, placebo-controlled study. Br J Nutr. 2010;103(12):1792–9.

    Article  CAS  PubMed  Google Scholar 

  200. Wickens KL, Barthow CA, Murphy R, Abels PR, Maude RM, Stone PR, et al. Early pregnancy probiotic supplementation with Lactobacillus rhamnosus HN001 may reduce the prevalence of gestational diabetes mellitus: a randomised controlled trial. Br J Nutr. 2017;117(6):804–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Nitert MD, Barrett HL, Foxcroft K, Tremellen A, Wilkinson S, Lingwood B, et al. Spring: an RCT study of probiotics in the prevention of gestational diabetes mellitus in overweight and obese women. BMC Pregnancy Childbirth. 2013;13:50.

    Article  PubMed  PubMed Central  Google Scholar 

  202. Callaway LK, Mcintyre HD, Barrett HL, Foxcroft K, Tremellen A, Lingwood BE, et al. Probiotics for the prevention of gestational diabetes mellitus in overweight and obese women: findings from the spring double-blind randomized controlled trial. Diabetes Care. 2019;42(3):364–71.

    CAS  PubMed  Google Scholar 

  203. D’Anna R, Scilipoti A, Giordano D, Caruso C, Cannata ML, Interdonato ML, et al. myo-Inositol supplementation and onset of gestational diabetes mellitus in pregnant women with a family history of type 2 diabetes: a prospective, randomized, placebo-controlled study. Diabetes Care. 2013;36(4):854–7.

    Article  PubMed  PubMed Central  Google Scholar 

  204. Farren M, Daly N, Mckeating A, Kinsley B, Turner MJ, Daly S. The prevention of gestational diabetes mellitus with antenatal oral inositol supplementation: a randomized controlled trial. Diabetes Care. 2017;40(6):759–63.

    Article  CAS  PubMed  Google Scholar 

  205. Saccone G, Saccone I, Berghella V. Omega-3 long-chain polyunsaturated fatty acids and fish oil supplementation during pregnancy: which evidence? J Matern Fetal Neonatal Med. 2016;29(15):2389–97.

    CAS  PubMed  Google Scholar 

  206. Haghiac M, Yang X, Presley L, Smith S, Dettelback S, Minium J, et al. Dietary omega-3 fatty acid supplementation reduces inflammation in obese pregnant women: a randomized double-blind controlled clinical trial. PLoS One. 2015;10(9):E0137309.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  207. Vanky E, Stridsklev S, Heimstad R, Romundstad P, Skogoy K, Kleggetveit O, et al. Metformin versus placebo from first trimester to delivery in polycystic ovary syndrome: a randomized, controlled multicenter study. J Clin Endocrinol Metab. 2010;95(12):E448–55.

    Article  CAS  PubMed  Google Scholar 

  208. Zhuo Z, Wang A, Yu H. Effect of metformin intervention during pregnancy on the gestational diabetes mellitus in women with polycystic ovary syndrome: a systematic review and meta-analysis. J Diabetes Res. 2014;2014:381231.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  209. Syngelaki A, Nicolaides KH, Balani J, Hyer S, Akolekar R, Kotecha R, et al. Metformin versus placebo in obese pregnant women without diabetes mellitus. N Engl J Med. 2016;374(5):434–43.

    Article  CAS  PubMed  Google Scholar 

  210. Balsells M, Garcia-Patterson A, Sola I, Roque M, Gich I, Corcoy R. Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis. BMJ. 2015;350:H102.

    Article  PubMed  PubMed Central  Google Scholar 

  211. Barbour LA, Scifres C, Valent AM, Friedman JE, Buchanan TA, Coustan D, et al. A cautionary response to SMFM statement: pharmacological treatment of gestational diabetes. Am J Obstet Gynecol. 2018;219(4):367 E1–7.

    Article  Google Scholar 

  212. Barbour LA. Unresolved controversies in gestational diabetes: implications on maternal and infant health. Curr Opin Endocrinol Diabetes Obes. 2014;21(4):264–70.

    Article  CAS  PubMed  Google Scholar 

  213. Sacco F, Calderone A, Castagnoli L, Cesareni G. The cell-autonomous mechanisms underlying the activity of metformin as an anticancer drug. Br J Cancer. 2016;115(12):1451–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Griss T, Vincent EE, Egnatchik R, Chen J, Ma EH, Faubert B, et al. Metformin antagonizes cancer cell proliferation by suppressing mitochondrial-dependent biosynthesis. PLoS Biol. 2015;13(12):E1002309.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  215. Rowan JA, Hague WM, Gao W, Battin MR, Moore MP, Mi GTI. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008;358(19):2003–15.

    Article  CAS  PubMed  Google Scholar 

  216. Barrett HL, Dekker NM, Jones L, O’Rourke P, Lust K, Gatford KL, et al. Determinants of maternal triglycerides in women with gestational diabetes mellitus in the Metformin in Gestational Diabetes (MiG) study. Diabetes Care. 2013;36(7):1941–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Rowan JA, Rush EC, Obolonkin V, Battin M, Wouldes T, Hague WM. Metformin in Gestational diabetes: The Offspring Follow-Up (MiG TOFU): body composition at 2 years of age. Diabetes Care. 2011;34(10):2279–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Barbour LA, Van Pelt RE, Brumbaugh DE, Hernandez TL, Friedman JE. Comment on: Rowan et al. Metformin in Gestational diabetes: The Offspring Follow-Up (MiG TOFU): body composition at 2 years of age. Diabetes Care. 2011;34:2279–2284. Diabetes Care. 2012;35(3):E28.

    Article  PubMed  PubMed Central  Google Scholar 

  219. Carlsen SM, Martinussen MP, Vanky E. Metformin’s effect on first-year weight gain: a follow-up study. Pediatrics. 2012;130(5):E1222–6.

    Article  PubMed  Google Scholar 

  220. Eriksson JG, Kajantie E, Osmond C, Thornburg K, Barker DJ. Boys live dangerously in the womb. Am J Hum Biol. 2010;22(3):330–5.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine and Nursing, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado, Children’s Hospital Colorado, Aurora, CO, USA

    Teri L. Hernandez

  2. Department of Pediatrics, Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado, Aurora, CO, USA

    Jacob E. Friedman

  3. Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of Colorado, Aurora, CO, USA

    Linda A. Barbour

Authors
  1. Teri L. Hernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jacob E. Friedman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Linda A. Barbour
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Teri L. Hernandez .

Editor information

Editors and Affiliations

  1. Section of Pediatric Endocrinology, Children’s Hospital Colorado, Aurora, CO, USA

    Philip S. Zeitler

  2. Department of Pediatrics, Children’s Hospital Colorado, Aurora, CO, USA

    Kristen J. Nadeau

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Hernandez, T.L., Friedman, J.E., Barbour, L.A. (2020). Insulin Resistance in Pregnancy: Implications for Mother and Offspring. In: Zeitler, P., Nadeau, K. (eds) Insulin Resistance. Contemporary Endocrinology. Humana, Cham. https://doi.org/10.1007/978-3-030-25057-7_5

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-25057-7_5

  • Published:

  • Publisher Name: Humana, Cham

  • Print ISBN: 978-3-030-25055-3

  • Online ISBN: 978-3-030-25057-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation