A wealth of epidemiological, clinical, and experimental studies have been linked to poor intrauterine conditions as well as metabolic and associated cardiovascular changes postnatal. These are novel perspectives connecting the altered intrauterine milieu to a rising number of metabolic diseases, such as diabetes, obesity, and hypercholesterolemia as well as the Metabolic Syndrome (Met S). Moreover, metabolic associated atherosclerotic diseases are connected to perigestational maternal health. The “Thrifty Phenotype Hypothesis” introduced cross-generational links between poor conditions during gestation and metabolic as well as cardiovascular alterations postnatal. Still, mechanisms altering the intrauterine milieu causing metabolic and associated atherosclerotic diseases are currently poorly understood. This paper will give novel insights in fundamental concepts connected to specific molecular mechanisms “programming” diabetes and associated metabolic as well as cardiovascular diseases. 1. Introduction Type 2 diabetes, obesity, and associated metabolic as well as cardiovascular diseases run an epidemic wave worldwide. Regarding to the World Health Organization (WHO) there are 347 millions people diagnosed with diabetes worldwide [1]. Furthermore, based on WHO fact sheets more than 1.4 billion adults were diagnosed overweight, in 2008, and of these more than 200 million men and approximately 300 million women were documented being obese [1]. Hence, over 40 million children under the age of 5 years were diagnosed overweight in the year 2010 [1]. Causes are seen in life style factors, such as high carbohydrate, respectively, high fat diets, and lack of exercise leading to obesity causing insulin resistance, type 2 diabetes and beta cell dysfunction, as well as associated metabolic and cardiovascular diseases. But, there is more and more evidence, that maternal peri-gestational genomic and environmental conditions may “imprint” metabolic and cardiovascular conditions in their offspring. Furthermore, novel insights underline important molecular and epigenetic changes in dysmetabolic pregnancies altering the intrauterine environment featuring evident programming concepts of metabolic and cardiovascular diseases in these offspring. Fundamental concepts of molecular and epigenetic mechanisms as well as key functions of the uteroplacental unit are starting to emerge quickly. Based on highlighted literature, especially Fernandez-Twinn et al. [2], this paper will give novel and future-directed insights in essential concepts linked to molecular mechanisms of
References
[1]
World Health Organization (WHO), http://www.who.int/mediacentre/factsheets/.
[2]
D. S. Fernandez-Twinn and S. E. Ozanne, “Mechanisms by which poor early growth programs type-2 diabetes, obesity and the metabolic syndrome,” Physiology & Behavior, vol. 88, no. 3, pp. 234–243, 2006.
[3]
D. J. P. Barker, “The developmental origins of chronic adult disease,” Acta Paediatrica, vol. 93, no. 446, pp. 26–33, 2004.
[4]
C. N. Hales, D. J. P. Barker, P. M. S. Clark et al., “Fetal and infant growth and impaired glucose tolerance at age 64,” British Medical Journal, vol. 303, no. 6809, pp. 1019–1022, 1991.
[5]
D. J. P. Barker, “Fetal programming of coronary heart disease,” Trends in Endocrinology and Metabolism, vol. 13, no. 9, pp. 364–368, 2002.
[6]
P. D. Gluckman and M. A. Hanson, “Maternal constraint of fetal growth and its consequences,” Seminars in Fetal & Neonatal Medicine, vol. 9, no. 5, pp. 419–425, 2004.
[7]
A. C. J. Ravelli, J. H. P. van der Meulen, R. P. J. Michels et al., “Glucose tolerance in adults after prenatal exposure to famine,” The Lancet, vol. 351, no. 9097, pp. 173–177, 1998.
[8]
S. Bo, P. Cavallo-Perin, L. Scaglione, G. Ciccone, and G. Pagano, “Low birthweight and metabolic abnormalities in twins with increased susceptibility to type 2 diabetes mellitus,” Diabetic Medicine, vol. 17, no. 5, pp. 365–370, 2000.
[9]
P. Poulsen, K. O. Kyvik, A. Vaag, and H. Beck-Nielsen, “Heritability of type II (non-insulin-dependent) diabetes mellitus and abnormal glucose tolerance—a population-based twin study,” Diabetologia, vol. 42, no. 2, pp. 139–145, 1999.
[10]
K. Christensen, A. Wienke, A. Skytthe, N. V. Holm, J. W. Vaupel, and A. I. Yashin, “Cardiovascular mortality in twins and the fetal origins hypothesis,” Twin Research, vol. 4, no. 5, pp. 344–349, 2001.
[11]
T. Harder, E. Rodekamp, K. Schellong, J. W. Dudenhausen, and A. Plagemann, “Birth weight and subsequent risk of type 2 diabetes: a meta-analysis,” American Journal of Epidemiology, vol. 165, no. 8, pp. 849–857, 2007.
[12]
C. A. Newsome, A. W. Shiell, C. H. D. Fall, D. I. W. Phillips, R. Shier, and C. M. Law, “Is birth weight related to later glucose and insulin metabolism?—A systematic review,” Diabetic Medicine, vol. 20, no. 5, pp. 339–348, 2003.
[13]
E. Oken and M. W. Gillman, “Fetal origins of obesity,” Obesity Research, vol. 11, no. 4, pp. 496–506, 2003.
[14]
R. S. Lindsay, R. M. Lindsay, B. J. Waddell, and J. R. Seckl, “Prenatal glucocorticoid exposure leads to offspring hyperglycaemia in the rat: studies with the 11 β-hydroxysteroid dehydrogenase inhibitor carbenoxolone,” Diabetologia, vol. 39, no. 11, pp. 1299–1305, 1996.
[15]
R. A. Simmons, “Developmental origins of diabetes: the role of oxidative stress,” Free Radical Biology and Medicine, vol. 40, no. 6, pp. 917–922, 2006.
[16]
C. J. Petry, M. W. Dorling, D. B. Pawlak, S. E. Ozanne, and C. N. Hales, “Diabetes in old male offspring of rat dams fed a reduced protein diet,” International Journal of Experimental Diabetes Research, vol. 2, no. 2, pp. 139–143, 2001.
[17]
J. M. Reinisch, N. G. Simon, W. G. Karow, and R. Gandelman, “Prenatal exposure to prednisone in humans and animals retards intrauterine growth,” Science, vol. 202, no. 4366, pp. 436–438, 1978.
[18]
B. Reusens and C. Remacle, “Programming of the endocrine pancreas by the early nutritional environment,” International Journal of Biochemistry and Cell Biology, vol. 38, no. 5-6, pp. 913–922, 2006.
[19]
B. Reusens, S. E. Ozanne, and C. Remacle, “Fetal determinants of type 2 diabetes,” Current Drug Targets, vol. 8, no. 8, pp. 935–941, 2007.
[20]
J. Boloker, S. J. Gertz, and R. A. Simmons, “Gestational diabetes leads to the development of diabetes in adulthood in the rat,” Diabetes, vol. 51, no. 5, pp. 1499–1506, 2002.
[21]
C. Nilsson, B. M. Larsson, E. Jennische et al., “Maternal endotoxemia results in obesity and insulin resistance in adult male offspring,” Endocrinology, vol. 142, no. 6, pp. 2622–2630, 2001.
[22]
S. E. Ozanne, M. W. Dorling, C. L. Wang, and B. T. Nave, “Impaired PI 3-kinase activation in adipocytes from early growth-restricted male rats,” American Journal of Physiology, vol. 280, no. 3, pp. E534–E539, 2001.
[23]
J. Han, J. Xu, P. N. Epstein, and Y. Qui Liu, “Long-term effect of maternal obesity on pancreatic beta cells of offspring: reduced beta cell adaptation to high glucose and high-fat diet challenges in adult female mouse offspring,” Diabetologia, vol. 48, no. 9, pp. 1810–1818, 2005.
[24]
K. Holemans, L. Aerts, and F. A. van Assche, “Evidence for an insulin resistance in the adult offspring of pregnant streptozotocin-diabetic rats,” Diabetologia, vol. 34, no. 2, pp. 81–85, 1991.
[25]
J. A. Armitage, P. D. Taylor, and L. Poston, “Experimental models of developmental programming: consequences of exposure to an energy rich diet during development,” The Journal of Physiology, vol. 565, part 1, pp. 3–8, 2005.
[26]
K. Shankar, A. Harrell, X. Liu, J. M. Gilchrist, M. J. J. Ronis, and T. M. Badger, “Maternal obesity at conception programs obesity in the offspring,” American Journal of Physiology, vol. 294, no. 2, pp. R528–R538, 2008.
[27]
M. H. Vickers, P. D. Gluckman, A. H. Coveny et al., “The effect of neonatal leptin treatment on postnatal weight gain in male rats is dependent on maternal nutritional status during pregnancy,” Endocrinology, vol. 149, no. 4, pp. 1906–1913, 2008.
[28]
D. Dabelea and D. J. Pettitt, “Intrauterine diabetic environment confers risks for type 2 diabetes mellitus and obesity in the offspring, in addition to genetic susceptibility,” Journal of Pediatric Endocrinology and Metabolism, vol. 14, no. 8, pp. 1085–1091, 2001.
[29]
T. Lertbunnaphong, P. Talungjit, and V. Titapant, “Does gestational weight gain in normal pre-pregnancy BMI pregnant women reflect fetal weight gain?” Journal of the Medical Association of Thailand, vol. 95, no. 7, pp. 853–858, 2012.
[30]
I. C. McMillen, L. J. Edwards, J. Duffield, and B. S. Muhlhausler, “Regulation of leptin synthesis and secretion before birth: implications for the early programming of adult obesity,” Reproduction, vol. 131, no. 3, pp. 415–427, 2006.
[31]
A. Beyerlein, I. Nehring, P. Rzehak et al., “Gestational weight gain and body mass index in children: results from three German cohort studies,” PLoS One, vol. 7, no. 3, Article ID e33205, 2012.
[32]
W. Palinski, F. P. D'Armiento, J. L. Witztum et al., “Maternal hypercholesterolemia and treatment during pregnancy influence the long-term progression of atherosclerosis in offspring of rabbits,” Circulation Research, vol. 89, no. 11, pp. 991–996, 2001.
[33]
T. Yamashita, S. Freigang, C. Eberle et al., “Maternal immunization programs postnatal immune responses and reduces atherosclerosis in offspring,” Circulation Research, vol. 99, no. 7, pp. E51–E64, 2006.
[34]
C. L. Librach, S. L. Feigenbaum, K. E. Bass et al., “Interleukin-1β regulates human cytotrophoblast metalloproteinase activity and invasion in vitro,” The Journal of Biological Chemistry, vol. 269, no. 25, pp. 17125–17131, 1994.
[35]
C. Napoli, C. K. Glass, J. L. Witztum, R. Deutsch, F. P. D'Armiento, and W. Palinski, “Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: Fate of Early Lesions in Children (FELIC) study,” The Lancet, vol. 354, no. 9186, pp. 1234–1241, 1999.
[36]
C. Napoli, F. P. D'Armiento, F. P. Mancini et al., “Fatty streak formation occurs in human fetal aortas and is greatly enhanced maternal, hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atheroeclerotic lesions,” The Journal of Clinical Investigation, vol. 100, no. 11, pp. 2680–2690, 1997.
[37]
A. Garofano, P. Czernichow, and B. Bréant, “In utero undernutrition impairs rat beta-cell development,” Diabetologia, vol. 40, no. 10, pp. 1231–1234, 1997.
[38]
M. H. Vickers, B. A. Ikenasio, and B. H. Breier, “IGF-I treatment reduces hyperphagia, obesity, and hypertension in metabolic disorders induced by fetal programming,” Endocrinology, vol. 142, no. 9, pp. 3964–3973, 2001.
[39]
A. Snoeck, C. Remacle, B. Reusens, and J. J. Hoet, “Effect of a low protein diet during pregnancy on the fetal rat endocrine pancreas,” Biology of the Neonate, vol. 57, no. 2, pp. 107–118, 1990.
[40]
S. E. Ozanne, G. S. Olsen, L. L. Hansen et al., “Early growth restriction leads to down regulation of protein kinase C zeta and insulin resistance in skeletal muscle,” Journal of Endocrinology, vol. 177, no. 2, pp. 235–241, 2003.
[41]
S. Zamudio, S. K. Palmer, T. Droma, E. Stamm, C. Coffin, and L. G. Moore, “Effect of altitude on uterine artery blood flow during normal pregnancy,” Journal of Applied Physiology, vol. 79, no. 1, pp. 7–14, 1995.
[42]
N. O. Lunell, L. E. Nylund, R. Lewander, and B. Sarby, “Uteroplacental blood flow in pre-eclampsia measurements with indium-113m and a computer-linked gamma camera,” Clinical and Experimental Hypertension B, vol. 1, no. 1, pp. 105–117, 1982.
[43]
L. Myatt, “Placental adaptive responses and fetal programming,” The Journal of Physiology, vol. 572, part 1, pp. 25–30, 2006.
[44]
G. Li, Y. Xiao, J. L. Estrella, C. A. Ducsay, R. D. Gilbert, and L. Zhang, “Effect of fetal hypoxia on heart susceptibility to ischemia and reperfusion injury in the adult rat,” Journal of the Society for Gynecologic Investigation, vol. 10, no. 5, pp. 265–274, 2003.
[45]
J. Peyronnet, Y. Dalmaz, M. Ehrstr？m et al., “Long-lasting adverse effects of prenatal hypoxia on developing autonomic nervous system and cardiovascular parameters in rats,” Pflügers Archiv, vol. 443, no. 5-6, pp. 858–865, 2002.
[46]
D. O'Regan, C. J. Kenyon, J. R. Seckl, and M. C. Holmes, “Glucocorticoid exposure in late gestation in the rat permanently programs gender-specific differences in adult cardiovascular and metabolic physiology,” American Journal of Physiology, vol. 287, no. 5, pp. E863–E870, 2004.
[47]
V. E. Murphy, R. Smith, W. B. Giles, and V. L. Clifton, “Endocrine regulation of human fetal growth: the role of the mother, placenta, and fetus,” Endocrine Reviews, vol. 27, no. 2, pp. 141–169, 2006.
[48]
D. E. Challis, C. D. Pfarrer, J. W. K. Ritchie, G. Koren, and S. L. Adamson, “Glucose metabolism is elevated and vascular resistance and maternofetal transfer is normal in perfused placental cotyledons from severely growth-restricted fetuses,” Pediatric Research, vol. 47, no. 3, pp. 309–315, 2000.
[49]
T. Jansson, V. Scholtbach, and T. L. Powell, “Placental transport of leucine and lysine is reduced in intrauterine growth restriction,” Pediatric Research, vol. 44, no. 4, pp. 532–537, 1998.
[50]
G. Pardi, A. M. Marconi, and I. Cetin, “Placental-fetal interrelationship in IUGR fetuses—a review,” Placenta, vol. 23, pp. S136–S141, 2002.
[51]
A. K. Karabulut, R. Layfield, and M. K. Pratten, “Growth promoting effects of human placental lactogen during early organogenesis: a link to insulin-like growth factors,” Journal of Anatomy, vol. 198, no. 6, pp. 651–662, 2001.
[52]
L. A. Mucci, P. Lagiou, R. M. Tamimi, C. C. Hsieh, H. O. Adami, and D. Trichopoulos, “Pregnancy estriol, estradiol, progesterone and prolactin in relation to birth weight and other birth size variables (United States),” Cancer Causes and Control, vol. 14, no. 4, pp. 311–318, 2003.
[53]
L. A. Mucci, P. Lagiou, C. C. Hsieh et al., “A prospective study of pregravid oral contraceptive use in relation to fetal growth,” BJOG: An International Journal of Obstetrics & Gynaecology, vol. 111, no. 9, pp. 989–995, 2004.
[54]
A. Plagemann, I. Heidrich, F. G？tz, W. Rohde, and G. D？rner, “Obesity and enhanced diabetes and cardiovascular risk in adult rats due to early postnatal overfeeding,” Experimental and Clinical Endocrinology, vol. 99, no. 3, pp. 154–158, 1992.
[55]
A. Plagemann, T. Harder, A. Rake et al., “Observations on the orexigenic hypothalamic neuropeptide Y-system in neonatally overfed weanling rats,” Journal of Neuroendocrinology, vol. 11, no. 7, pp. 541–546, 1999.
[56]
A. Plagemann, H. Davidowa, T. Harder, and J. W. Dudenhausen, “Developmental programming of the hypothalamus: a matter of insulin. A comment on: Horvath, T. L., Bruning, J. C.: Developmental programming of the hypothalamus: a matter of fat. Nat. Med. (2006) 12: 52-53,” Neuroendocrinology Letters, vol. 27, no. 1-2, pp. 70–72, 2006.
[57]
A. Plagemann, “A matter of insulin: developmental programming of body weight regulation,” Journal of Maternal-Fetal and Neonatal Medicine, vol. 21, no. 3, pp. 143–148, 2008.
[58]
I. Bogdarina, H. C. Murphy, S. P. Burns, and A. J. L. Clark, “Investigation of the role of epigenetic modification of the rat glucokinase gene in fetal programming,” Life Sciences, vol. 74, no. 11, pp. 1407–1415, 2004.
[59]
A. J. Bennett, U. Sovio, A. Ruokonen, et al., “Variation at the insulin gene VNTR (variable number tandem repeat) polymorphism and early growth: studies in a large Finnish birth cohort,” Diabetes, vol. 53, no. 8, pp. 2126–2131, 2004.
[60]
S. Hauguel-de Mouzon and M. Guerre-Millo, “The placenta cytokine network and inflammatory signals,” Placenta, vol. 27, no. 8, pp. 794–798, 2006.
[61]
I. Juhan-Vague, M. C. Alessi, A. Mavri, and P. E. Morange, “Plasminogen activator inhibitor-1, inflammation, obesity, insulin resistance and vascular risk,” Journal of Thrombosis and Haemostasis, vol. 1, no. 7, pp. 1575–1579, 2003.
[62]
J. Barzilay and E. Freedland, “Inflammation and its association with glucose disorders and cardiovascular disease,” Treatments in Endocrinology, vol. 2, no. 2, pp. 85–94, 2003.
[63]
J. Spranger, A. Kroke, M. M？hlig et al., “Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study,” Diabetes, vol. 52, no. 3, pp. 812–817, 2003.
[64]
H. Xu, G. T. Barnes, Q. Yang et al., “Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance,” The Journal of Clinical Investigation, vol. 112, no. 12, pp. 1821–1830, 2003.
[65]
P. J. Barnes and M. Karin, “Nuclear factor-κB—a pivotal transcription factor in chronic inflammatory diseases,” The New England Journal of Medicine, vol. 336, no. 15, pp. 1066–1071, 1997.
[66]
H. P. Glauert, “Vitamin E and NF-kappaB activation: a review,” Vitamins & Hormones, vol. 76, pp. 135–153, 2007.
[67]
A. Zhou, S. Scoggin, R. B. Gaynor, and N. S. Williams, “Identification of NF-κB-regulated genes induced by TNFα utilizing expression profiling and RNA interference,” Oncogene, vol. 22, no. 13, pp. 2034–2044, 2003.
[68]
M. Lappas, M. Permezel, H. M. Georgiou, and G. E. Rice, “Nuclear factor Kappa B regulation of proinflammatory cytokines in human gestational tissues in vitro,” Biology of Reproduction, vol. 67, no. 2, pp. 668–673, 2002.
[69]
J. P. Kirwan, S. Hauguel-de Mouzon, J. Lepercq et al., “TNF-α is a predictor of insulin resistance in human pregnancy,” Diabetes, vol. 51, no. 7, pp. 2207–2213, 2002.
[70]
T. Cindrova-Davies, O. Spasic-Boskovic, E. Jauniaux, D. S. Charnock-Jones, and G. J. Burton, “Nuclear factor-κB, p38, and stress-activated protein kinase mitogen-activated protein kinase signaling pathways regulate proinflammatory cytokines and apoptosis in human placental explants in response to oxidative stress: effects of antioxidant vitamins,” The American Journal of Pathology, vol. 170, no. 5, pp. 1511–1520, 2007.
[71]
J. Lepercq, M. Caüzac, N. Lahlou et al., “Overexpression of placental leptin in diabetic pregnancy: a critical role for insulin,” Diabetes, vol. 47, no. 5, pp. 847–850, 1998.
[72]
E. Casanueva and F. E. Viteri, “Iron and oxidative stress in pregnancy,” The Journal of Nutrition, vol. 133, no. 5, pp. 1700S–1708S, 2003.
[73]
K. R. Page, The Physiology of Human Placenta, UCL Press, London, UK, 1993.
[74]
H. Sies, Oxidative Stress II. Oxidants and Antioxidants, Academic Press, London, UK, 1991.
[75]
A. K. Poranen, U. Ekblad, P. Uotila, and M. Ahotupa, “The effect of vitamin C and E on placental lipid peroxidation and antioxidative enzymes in perfused placenta,” Acta Obstetricia et Gynecologica Scandinavica, vol. 77, no. 4, pp. 372–376, 1998.
[76]
Y. P. Wang, S. W. Walsh, J. D. Guo, and J. Y. Zhang, “Maternal levels of prostacyclin, thromboxane, vitamin E, and lipid peroxides throughout normal pregnancy,” American Journal of Obstetrics and Gynecology, vol. 165, no. 6, part 1, pp. 1690–1694, 1991.
[77]
Y. Wang and S. W. Walsh, “Antioxidant activities and mRNA expression of superoxide dismutase, catalase, and glutathione peroxidase in normal and preeclamptic placentas,” Journal of the Society for Gynecologic Investigation, vol. 3, no. 4, pp. 179–184, 1996.
[78]
T. Yoshioka, M. Ando, K. Taniguchi, F. Yamasaki, and H. Motoyama, “Lipoperoxidation and antioxidant substances in the human placenta during gestation,” Nippon Sanka Fujinka Gakkai Zasshi, vol. 42, no. 12, pp. 1634–1640, 1990.
[79]
R. Z. Fardoun, “The use of vitamin E in type 2 diabetes mellitus,” Clinical and Experimental Hypertension, vol. 29, no. 3, pp. 135–148, 2007.
[80]
W. Kossenjans, A. Eis, R. Sahay, D. Brockman, and L. Myatt, “Role of peroxynitrite in altered fetal-placental vascular reactivity in diabetes or preeclampsia,” American Journal of Physiology, vol. 278, no. 4, pp. H1311–H1319, 2000.
[81]
R. Li, M. Chase, S. K. Jung, P. J. S. Smith, and M. R. Loeken, “Hypoxic stress in diabetic pregnancy contributes to impaired embryo gene expression and defective development by inducing oxidative stress,” American Journal of Physiology, vol. 289, no. 4, pp. E591–E599, 2005.
[82]
J. M. Fernández-Real, A. López-Bermejo, and W. Ricart, “Cross-talk between iron metabolism and diabetes,” Diabetes, vol. 51, no. 8, pp. 2348–2354, 2002.
[83]
T. T. Lao, K. F. Tam, and L. Y. Chan, “Third trimester iron status and pregnancy outcome in non-anaemic women; pregnancy unfavourably affected by maternal iron excess,” Human Reproduction, vol. 15, no. 8, pp. 1843–1848, 2000.
[84]
E. Sivan, E. A. Reece, Y. K. Wu, C. J. Homko, M. Polansky, and M. Borenstein, “Dietary vitamin E prophylaxis and diabetic embryopathy: morphologic and biochemical analysis,” American Journal of Obstetrics & Gynecology, vol. 175, no. 4, part 1, pp. 793–799, 1996.
[85]
J. A. Simoneau, S. R. Colberg, F. L. Thaete, and D. E. Kelley, “Skeletal muscle glycolitic and oxidative enzyme capacities are determinants of insulin sensitivity and muscle composition in obese women,” The FASEB Journal, vol. 9, no. 2, pp. 273–278, 1995.
[86]
S. Shah, M. Iqbal, J. Karam, M. Salifu, and S. I. McFarlane, “Oxidative stress, glucose metabolism, and the prevention of type 2 diabetes: pathophysiological insights,” Antioxidants and Redox Signaling, vol. 9, no. 7, pp. 911–929, 2007.
[87]
M. A. Selak, B. T. Storey, I. Peterside, and R. A. Simmons, “Impaired oxidative phosphorylation in skeletal muscle of intrauterine growth-retarded rats,” American Journal of Physiology, vol. 285, no. 1, pp. E130–E137, 2003.
[88]
K. Morino, K. F. Petersen, and G. I. Shulman, “Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction,” Diabetes, vol. 55, no. 2, pp. S9–S15, 2006.
[89]
U. J. Eriksson, “The pathogenesis of congenital malformations in diabetic pregnancy,” Diabetes/Metabolism Reviews, vol. 11, no. 1, pp. 63–82, 1995.
[90]
E. A. Reece, C. J. Homko, and Y. K. Wu, “Multifactorial basis of the syndrome of diabetic embryopathy,” Teratology, vol. 54, no. 4, pp. 171–182, 1996.
[91]
M. Horal, Z. Zhang, R. Stanton, A. Virkam？ki, and M. R. Loeken, “Activation of the hexosamine pathway causes oxidative stress and abnormal embryo gene expression: involvement in diabetic teratogenesis,” Birth Defects Research A, vol. 70, no. 8, pp. 519–527, 2004.
[92]
M. Kiely, P. A. Morrissey, P. F. Cogan, and P. J. Kearney, “Low molecular weight plasma antioxidants and lipid peroxidation in maternal and cord blood,” European Journal of Clinical Nutrition, vol. 53, no. 11, pp. 861–864, 1999.
[93]
R. Robles, N. Palomino, and A. Robles, “Oxidative stress in the neonate,” Early Human Development, vol. 65, supplement 2, pp. S75–S81, 2001.
[94]
C. Gicquel, A. El-Osta, and Y. Le Bouc, “Epigenetic regulation and fetal programming,” Best Practice and Research in Clinical Endocrinology and Metabolism, vol. 22, no. 1, pp. 1–16, 2008.
[95]
R. A. Simmons, “Developmental origins of diabetes: the role of epigenetic mechanisms,” Current Opinion in Endocrinology, Diabetes and Obesity, vol. 14, no. 1, pp. 13–16, 2007.
[96]
C. A. Cooney, A. A. Dave, and G. L. Wolff, “Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring,” The Journal of Nutrition, vol. 132, no. 8, supplement, pp. 2393S–2400S, 2002.
[97]
J. F. Costello, M. C. Fruhwald, D. J. Smiragtia, et al., “Aberrant CpG-island methylation has nonrandom and tumour-type-specific patterns,” Nature Genetics, vol. 24, no. 2, pp. 132–138, 2000.
[98]
O. Galm, H. Yoshikawa, M. Esteller, R. Osieka, and J. G. Herman, “SOCS-1, a negative regulator of cytokine signaling, is frequently silenced by methylation in multiple myeloma,” Blood, vol. 101, no. 7, pp. 2784–2788, 2003.
