Abstract
Diabetes during pregnancy is thought to contribute to metabolic changes in the fetus, which predispose the offspring of diabetic mothers to obesity, insulin resistance, diabetes and cardiovascular disease. Altered maternal fuels, including but not limited to glucose, may affect the development of the endocrine pancreas in the fetus, resulting in increased adiposity and decreased beta cell mass and/or function.
Prospective studies in the Pima Indians and at Northwestern University in Chicago have demonstrated increased adiposity among children exposed to diabetes in utero, although not all studies have replicated this relationship. Impaired glucose tolerance (IGT), which can result from either reduced insulin secretion or increased insulin resistance, has also been associated with exposure to diabetes in utero. Type 2 diabetes is more common in offspring of mothers with diabetes than in offspring of nondiabetic and prediabetic women among the Pima Indians. Further, a diabetic intrauterine environment has been shown to induce biochemical alterations in the cardiovascular system, and children born to diabetic mothers have increased cardiovascular risk factors compared with children not exposed to diabetes in utero.
Type 2 diabetes has a known genetic component and tends to cluster in families. As a result, obesity, IGT and type 2 diabetes may be more common in offspring of diabetic mothers due to maternal genes rather than metabolic imprinting during fetal development. In order to disentangle genetic vs. environmental causes of type 2 diabetes, several methods were employed. The offspring of mothers with early onset type 2 diabetes have been compared by exposure to intrauterine diabetes, with a higher prevalence of type 2 diabetes demonstrated in exposed Pima Indian children compared with unexposed children. Adjustment for maternal obesity, which is a marker for genetic predisposition to type 2 diabetes, does not explain the increased risk of obesity in the offspring of diabetic mothers, further supporting an environmental contribution of excess maternal fuel. A comparison of offspring with maternal vs. paternal type 2 diabetes also allows for the disentangling of genetic and environmental causes, since fathers would transmit the same genetic risk of type 2 diabetes as mothers. However, the strongest evidence for the role of intrauterine diabetes in the development of type 2 diabetes in the offspring of diabetic mothers has come from the comparison of siblings born before and after the development of maternal diabetes.
Animal studies have allowed for the investigation of experimentally manipulated intrauterine environment on metabolism and glucose homeostasis in the offspring. Hyperglycemia can be induced either to a mild degree late in pregnancy to mimic gestational diabetes or to a severe degree early in pregnancy to mimic type 1 diabetes. An additional genetic model of diabetes has been examined using rats selectively bred for IGT. These animal models have allowed for insight into the effects of maternal hyperglycemia on beta cell mass and pancreatic development.
Diabetes prevalence is increasing worldwide, and it is one of the most pressing public health issues due to the increased costs, comorbidity and mortality associated with diabetes. The exposure to diabetes in utero may create a vicious cycle where the offspring of diabetic mothers are more likely to develop obesity and glucose intolerance, leading to an increased risk of developing gestational diabetes or type 2 diabetes during pregnancy themselves, and therefore perpetuate a destructive cycle of metabolic dysfunction. Reducing obesity and type 2 diabetes must be a primary goal of public health organizations and clinicians.
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Hussain A, Claussen B, Ramachandran A, Williams R. Prevention of type 2 diabetes: a review. Diabetes Res Clin Pract 2007; 76:317–26
Dabelea D, Pettitt DJ, Jones KL, Arslanian SA. Type 2 diabetes mellitus in minority children and adolescents. An emerging problem. Endocrinol Metab Clin North Am 1999; 28:709–29, viii
Dabelea D, Snell-Bergeon JK, Hartsfield CL, Bischoff KJ, Hamman RF, McDuffie RS; Kaiser Permanente of Colorado GDM Screening Program. Increasing prevalence of gestational diabetes mellitus (GDM) over time and by birth cohort: Kaiser Permanente of Colorado GDM Screening Program. Diabetes Care 2005; 28:579–84
Ferrara A, Kahn HS, Quesenberry CP, Riley C, Hedderson MM. An increase in the incidence of gestational diabetes mellitus: Northern California, 1991–2000. Obstet Gynecol 2004; 103:526–33
Meigs JB, Cupples LA, Wilson PW. Parental transmission of type 2 diabetes: the Framingham Offspring Study. Diabetes 2000; 49:2201–7
Plagemann A. ‘Fetal programming’ and ‘functional teratogenesis’: on epigenetic mechanisms and prevention of perinatally acquired lasting health risks. J Perinat Med 2004; 32:297–305
Freinkel N. Banting Lecture 1980. Of pregnancy and progeny. Diabetes 1980; 29:1023–35
Dorner G, Mohnike A, Steindel E. On possible genetic and epigenetic modes of diabetes transmission. Endokrinologie 1975; 66:225–7
Martin AO, Simpson JL, Ober C, Freinkel N. Frequency of diabetes mellitus in mothers of probands with gestational diabetes: possible maternal influence on the predisposition to gestational diabetes. Am J Obstet Gynecol 1985; 151:471–5
Aerts L, Van Assche FA. Animal evidence for the transgenerational development of diabetes mellitus. Int J Biochem Cell Biol 2006; 38:894–903
Gauguier D, Nelson I, Bernard C, Parent V, Marsac C, Cohen D, et al. Higher maternal than paternal inheritance of diabetes in GK rats. Diabetes 1994; 43:220–4
Gill-Randall RJ, Adams D, Ollerton RL, Alcolado JC. Is human Type 2 diabetes maternally inherited? Insights from an animal model. Diabet Med 2004; 21:759–62
Lampl M, Jeanty P. Exposure to maternal diabetes is associated with altered fetal growth patterns: a hypothesis regarding metabolic allocation to growth under hyperglycemic-hypoxemic conditions. Am J Hum Biol 2004; 16:237–63
Jansson T, Cetin I, Powell TL, Desoye G, Radaelli T, Ericsson A, et al. Placental transport and metabolism in fetal overgrowth – a workshop report. Placenta 2006; 27(Suppl A):S109–13
Ericsson A, Saljo K, Sjostrand E, Jansson N, Prasad PD, Powell TL, et al. Brief hyperglycaemia in the early pregnant rat increases fetal weight at term by stimulating placental growth and affecting placental nutrient transport. J Physiol 2007; 581(3):1323–1332
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; 189:1698–704
Pettitt DJ, Nelson RG, Saad MF, Bennett PH, Knowler WC. Diabetes and obesity in the offspring of Pima Indian women with diabetes during pregnancy. Diabetes Care 1993; 16:310–4
Pettitt DJ, Bennett PH, Saad MF, Charles MA, Nelson RG, Knowler WC. Abnormal glucose tolerance during pregnancy in Pima Indian women. Long-term effects on offspring. Diabetes 1991; 40(Suppl 2):126–30
Pettitt DJ, Baird HR, Aleck KA, Bennett PH, Knowler WC. Excessive obesity in offspring of Pima Indian women with diabetes during pregnancy. N Engl J Med 1983; 308:242–5
Pettitt DJ, Knowler WC, Bennett PH, Aleck KA, Baird HR. Obesity in offspring of diabetic Pima Indian women despite normal birth weight. Diabetes Care 1987; 10:76–80
Silverman BL, Rizzo T, Green OC, Cho NH, Winter RJ, Ogata ES, et al. Long-term prospective evaluation of offspring of diabetic mothers. Diabetes 1991; 40(Suppl 2):121–5
Gillman MW, Rifas-Shiman S, Berkey CS, Field AE, Colditz GA. Maternal gestational diabetes, birth weight, and adolescent obesity. Pediatrics 2003; 111:e221–6
Whitaker RC, Pepe MS, Seidel KD, Wright JA, Knopp RH. Gestational diabetes and the risk of offspring obesity. Pediatrics 1998; 101:E9
Petersen JL, McGuire DK. Impaired glucose tolerance and impaired fasting glucose--a review of diagnosis, clinical implications and management. Diab Vasc Dis Res 2005; 2:9–15
Plagemann A, Harder T, Kohlhoff R, Rohde W, Dorner G. Glucose tolerance and insulin secretion in children of mothers with pregestational IDDM or gestational diabetes. Diabetologia 1997; 40:1094–100
Silverman BL, Metzger BE, Cho NH, Loeb CA. Impaired glucose tolerance in adolescent offspring of diabetic mothers. Relationship to fetal hyperinsulinism. Diabetes Care 1995; 18:611–7
Malcolm JC, Lawson ML, Gaboury I, Lough G, Keely E. Glucose tolerance of offspring of mother with gestational diabetes mellitus in a low-risk population. Diabet Med 2006; 23:565–70
Hunter WA, Cundy T, Rabone D, Hofman PL, Harris M, Regan F, et al. Insulin sensitivity in the offspring of women with type 1 and type 2 diabetes. Diabetes Care 2004; 27:1148–52
Gautier JF, Wilson C, Weyer C, Mott D, Knowler WC, Cavaghan M, et al. Low acute insulin secretory responses in adult offspring of people with early onset type 2 diabetes. Diabetes 2001; 50:1828–33
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; 49:2208–11
Dabelea D, Pettitt DJ. Intrauterine diabetic environment confers risks for type 2 diabetes mellitus and obesity in the offspring, in addition to genetic susceptibility. J Pediatr Endocrinol Metab 2001; 14:1085–91
Holemans K, Gerber RT, Meurrens K, De Clerck F, Poston L, Van Assche FA. Streptozotocin diabetes in the pregnant rat induces cardiovascular dysfunction in adult offspring. Diabetologia 1999; 42:81–9
Rasanen J, Kirkinen P. Growth and function of human fetal heart in normal, hypertensive and diabetic pregnancy. Acta Obstet Gynecol Scand 1987; 66:349–53
Bunt JC, Tataranni PA, Salbe AD. Intrauterine exposure to diabetes is a determinant of hemoglobin A(1)c and systolic blood pressure in pima Indian children. J Clin Endocrinol Metab 2005; 90:3225–9
Manderson JG, Mullan B, Patterson CC, Hadden DR, Traub AI, McCance DR. Cardiovascular and metabolic abnormalities in the offspring of diabetic pregnancy. Diabetologia 2002; 45:991–6
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; 9:83–8
Harder T, Franke K, Kohlhoff R, Plagemann A. Maternal and paternal family history of diabetes in women with gestational diabetes or insulin-dependent diabetes mellitus type I. Gynecol Obstet Invest 2001; 51:160–4
Pettitt DJ, Knowler WC. Long-term effects of the intrauterine environment, birth weight, and breast-feeding in Pima Indians. Diabetes Care 1998; 21(Suppl 2):B138–41
McLean M, Chipps D, Cheung NW. Mother to child transmission of diabetes mellitus: does gestational diabetes program Type 2 diabetes in the next generation? Diabet Med 2006; 23:1213–5
Perucca-Lostanlen D, Narbonne H, Hernandez JB, Staccini P, Saunieres A, Paquis-Flucklinger V, et al. Mitochondrial DNA variations in patients with maternally inherited diabetes and deafness syndrome. Biochem Biophys Res Commun 2000; 277:771–5
Stride A, Shepherd M, Frayling TM, Bulman MP, Ellard S, Hattersley AT. Intrauterine hyperglycemia is associated with an earlier diagnosis of diabetes in HNF-1alpha gene mutation carriers. Diabetes Care 2002; 25:2287–91
Weiss PA, Scholz HS, Haas J, Tamussino KF, Seissler J, Borkenstein MH. Long-term follow-up of infants of mothers with type 1 diabetes: evidence for hereditary and nonhereditary transmission of diabetes and precursors. Diabetes Care 2000; 23:905–11
Sobngwi E, Boudou P, Mauvais-Jarvis F, Leblanc H, Velho G, Vexiau P, et al. Effect of a diabetic environment in utero on predisposition to type 2 diabetes. Lancet 2003; 361:1861–5
Franks PW, Looker HC, Kobes S, Touger L, Tataranni PA, Hanson RL, et al. Gestational glucose tolerance and risk of type 2 diabetes in young Pima Indian offspring. Diabetes 2006; 55:460–5
Bihoreau MT, Ktorza A, Kervran A, Picon L. Effect of gestational hyperglycemia on insulin secretion in vivo and in vitro by fetal rat pancreas. Am J Physiol 1986; 251:E86–91
Kervran A, Guillaume M, Jost A. The endocrine pancreas of the fetus from diabetic pregnant rat. Diabetologia 1978; 15:387–93
Bihoreau MT, Ktorza A, Kinebanyan MF, Picon L. Impaired glucose homeostasis in adult rats from hyperglycemic mothers. Diabetes 1986; 35:979–84
Aerts L, Sodoyez-Goffaux F, Sodoyez JC, Malaisse WJ, Van Assche FA. The diabetic intrauterine milieu has a long-lasting effect on insulin secretion by β cells and on insulin uptake by target tissues. Am J Obstet Gynecol 1988; 159:1287–92
Aerts L, Holemans K, Van Assche FA. Maternal diabetes during pregnancy: consequences for the offspring. Diabetes Metab Rev 1990; 6:147–67
Aerts L, Vercruysse L, Van Assche FA. The endocrine pancreas in virgin and pregnant offspring of diabetic pregnant rats. Diabetes Res Clin Pract 1997; 38:9–19
Holemans K, Aerts L, Van Assche FA. Evidence for an insulin resistance in the adult offspring of pregnant streptozotocin-diabetic rats. Diabetologia 1991; 34:81–5
Holemans K, Van Bree R, Verhaeghe J, Aerts L, Van Assche FA. In vivo glucose utilization by individual tissues in virgin and pregnant offspring of severely diabetic rats. Diabetes 1993; 42:530–6
Portha B. Programmed disorders of beta-cell development and function as one cause for type 2 diabetes? The GK rat paradigm. Diabetes Metab Res Rev 2005; 21:495–504
Serradas P, Gangnerau MN, Giroix MH, Saulnier C, Portha B. Impaired pancreatic beta cell function in the fetal GK rat. Impact of diabetic inheritance. J Clin Invest 1998; 101:899–904
Portha B, Lacraz G, Kergoat M, Homo-Delarche F, Giroix MH, Bailbe D, et al. The GK rat beta-cell: a prototype for the diseased human beta-cell in type 2 diabetes? Mol Cell Endocrinol 2009; 297(1–2):73–85
Calderari S, Gangnerau MN, Meile MJ, Portha B, Serradas P. Is defective pancreatic beta-cell mass environmentally programmed in Goto-Kakizaki rat model of type 2 diabetes?: insights from crossbreeding studies during suckling period. Pancreas 2006; 33:412–7
Pedersen J. Weight and length at birth of infants of diabetic mothers. Acta Endocrinol (Copenh) 1954; 16:330–42
Manderson JG, Patterson CC, Hadden DR, Traub AI, Leslie H, McCance DR. Leptin concentrations in maternal serum and cord blood in diabetic and nondiabetic pregnancy. Am J Obstet Gynecol 2003; 188:1326–32
Tapanainen P, Leinonen E, Ruokonen A, Knip M. Leptin concentrations are elevated in newborn infants of diabetic mothers. Horm Res 2001; 55:185–90
Harder T, Aerts L, Franke K, Van Bree R, Van Assche FA, Plagemann A. Pancreatic islet transplantation in diabetic pregnant rats prevents acquired malformation of the ventromedial hypothalamic nucleus in their offspring. Neurosci Lett 2001; 299:85–8
Susa JB, Boylan JM, Sehgal P, Schwartz R. Impaired insulin secretion after intravenous glucose in neonatal rhesus monkeys that had been chronically hyperinsulinemic in utero. Proc Soc Exp Biol Med 1992; 199:327–31
Susa JB, Boylan JM, Sehgal P, Schwartz R. Impaired insulin secretion in the neonatal rhesus monkey after chronic hyperinsulinemia in utero. Proc Soc Exp Biol Med 1990; 194:209–15
Susa JB, Boylan JM, Sehgal P, Schwartz R. Persistence of impaired insulin secretion in infant rhesus monkeys that had been hyperinsulinemic in utero. J Clin Endocrinol Metab 1992; 75:265–9
Odeleye OE, de Courten M, Pettitt DJ, Ravussin E. Fasting hyperinsulinemia is a predictor of increased body weight gain and obesity in Pima Indian children. Diabetes 1997; 46:1341–5
Koistinen HA, Koivisto VA, Andersson S, Karonen SL, Kontula K, Oksanen L, et al. Leptin concentration in cord blood correlates with intrauterine growth. J Clin Endocrinol Metab 1997; 82:3328–30
Persson B, Westgren M, Celsi G, Nord E, Ortqvist E. Leptin concentrations in cord blood in normal newborn infants and offspring of diabetic mothers. Horm Metab Res 1999; 31:467–71
Christou H, Connors JM, Ziotopoulou M, Hatzidakis V, Papathanassoglou E, Ringer SA, et al. Cord blood leptin and insulin-like growth factor levels are independent predictors of fetal growth. J Clin Endocrinol Metab 2001; 86:935–8
Simmons D, Breier BH. Fetal overnutrition in Polynesian pregnancies and in gestational diabetes may lead to dysregulation of the adipoinsular axis in offspring. Diabetes Care 2002; 25:1539–44
Gauguier D, Bihoreau MT, Picon L, Ktorza A. Insulin secretion in adult rats after intrauterine exposure to mild hyperglycemia during late gestation. Diabetes 1991; 40(Suppl 2):109–14
Dabelea D, Hanson RL, Bennett PH, Roumain J, Knowler WC, Pettitt DJ. Increasing prevalence of Type II diabetes in American Indian children. Diabetologia 1998; 41:904–10
Polak M, Bouchareb-Banaei L, Scharfmann R, Czernichow P. Early pattern of differentiation in the human pancreas. Diabetes 2000; 49:225–32
Fowden AL, Hill DJ. Intra-uterine programming of the endocrine pancreas. Br Med Bull 2001; 60:123–42
Pinter E, Haigh J, Nagy A, Madri JA. Hyperglycemia-induced vasculopathy in the murine conceptus is mediated via reductions of VEGF-A expression and VEGF receptor activation. Am J Pathol 2001; 158:1199–206
Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS; Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) Trial Group. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med 2005; 352:2477–86
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Snell-Bergeon, J.K., Dabelea, D. (2009). The Infant of the Diabetic Mother: Metabolic Imprinting. In: Tsatsoulis, A., Wyckoff, J., Brown, F. (eds) Diabetes in Women. Contemporary Diabetes. Humana Press. https://doi.org/10.1007/978-1-60327-250-6_20
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DOI: https://doi.org/10.1007/978-1-60327-250-6_20
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