The intake of a fructose-rich diet (FRD) in the normal female rat induces features similar to those observed in the human metabolic syndrome phenotype. We studied the impact of FRD administration to mothers on pregnancy outcome. On gestational day (Gd) zero rats were assigned to either group: ad libitum drinking tap water alone (normal diet, ND) or containing fructose (10% w/vol; FRD) through pregnancy; all rats were fed a Purina chow diet ad libitum ND and FRD rats were daily cotreated or not with metformin (60？mg/Kg/day oral; ND + MF and FRD + MF) and submitted to a high glucose load test on Gd 14. Additionally, placentas from different groups were studied on Gd 20. Data indicated that: (1) although FRD rats well tolerated glucose overload, their circulating levels of insulin were significantly higher than in ND rats; (2) the mesometrial triangle blood vessel area was significantly lower in placentas from FRD than ND dams; (3) the detrimental effects of FRD administration to mothers were ameliorated by metformin cotreatment. Our study suggests that excessive intake of fructose during pregnancy enhanced the risk for developing gestational diabetes and subsequent preeclampsia, and that metformin prevented the poor pregnancy outcome induced by FRD. 1. Introduction The prevalence of gestational diabetes mellitus (GDM) has significantly increased during the last decades , and offspring born to mothers with GDM present a significantly increased risk of developing obesity and type 2 diabetes mellitus (T2DM) [2, 3]. Maternal anthropometric factors (e.g., prepregnancy body weight (BW), adiposity weight gain during pregnancy) account for the variance in offspring BW and adiposity at birth [1, 4], and on other risk factors as well [5, 6]. However, maternal nutrition is a highly important conditioning factor of fetal growth. GDM is characterized by impaired glucose tolerance/decreased insulin sensitivity, and mothers with GDM have an increased risk of developing preeclampsia (PE) [7, 8]. Although the pathogenesis of PE still remains unclear, it is accepted that PE is an endothelial cell disorder associated with marked maternal and neonatal morbidity . On the other hand, insulin effectiveness and angiogenesis [10–12] are key factors for the control of endothelial cell function. Consequently, the presence of decreased insulin sensitivity in the mother may enhance the defects in angiogenic function [13, 14], leading to an increased risk of PE. Maternal nutritional disturbances during critical developmental periods [15–17] are known to raise the offspring’s
P. M. Catalano, J. P. Kirwan, S. M. Haugel-De, and J. King, “Gestational diabetes and insulin resistance: role in short- and long-term implications for mother and fetus,” Journal of Nutrition, vol. 133, no. 5, pp. 1674S–1683S, 2003.
B. L. Silverman, T. A. Rizzo, N. H. Cho, and B. E. Metzger, “Long-term effects of the intrauterine environment: the northwestern university diabetes in pregnancy center,” Diabetes Care, vol. 21, no. 2, pp. B142–B149, 1998.
D. J. Pettitt, R. G. Nelson, M. F. Saad, P. H. Bennett, and W. C. Knowler, “Diabetes and obesity in the offspring of Pima Indian women with diabetes during pregnancy,” Diabetes Care, vol. 16, no. 1, pp. 310–314, 1993.
A. S. Kvehaugen, L. F. Andersen, and A. C. Staff, “Anthropometry and cardiovascular risk factors in women and offspring after pregnancies complicated by preeclampsia or diabetes mellitus,” Acta Obstetricia et Gynecologica Scandinavica, vol. 89, no. 11, pp. 1478–1485, 2010.
I. M. Bernstein and P. M. Catalano, “Examination of factors contributing to the risk of cesarean delivery in women with gestational diabetes,” Obstetrics and Gynecology, vol. 83, no. 3, pp. 462–465, 1994.
M. I. Schmidt, B. B. Duncan, A. J. Reichelt et al., “Gestational diabetes mellitus diagnosed with a 2-h 75-g oral glucose tolerance test and adverse pregnancy outcomes,” Diabetes Care, vol. 24, no. 7, pp. 1151–1155, 2001.
M. Wolf, L. Sandler, K. Mu？oz, K. Hsu, J. L. Ecker, and R. Thadhani, “First trimester insulin resistance and subsequent preeclampsia: a prospective study,” Journal of Clinical Endocrinology and Metabolism, vol. 87, no. 4, pp. 1563–1568, 2002.
E. Chou, I. Suzuma, K. J. Way et al., “Decreased cardiac expression of vascular endothelial growth factor and its receptors in insulin-resistant and diabetic states: a possible explanation for impaired collateral formation in cardiac tissue,” Circulation, vol. 105, no. 3, pp. 373–379, 2002.
M. Montagnani, L. V. Ravichandran, H. Chen, D. L. Esposito, and M. J. Quon, “Insulin receptor substrate-1 and phosphoinositide-dependent kinase-1 are required for insulin-stimulated production of nitric oxide in endothelial cells,” Molecular Endocrinology, vol. 16, no. 8, pp. 1931–1942, 2002.
D. Vicent, J. Ilany, T. Kondo et al., “The role of endothelial insulin signaling in the regulation of vascular tone and insulin resistance,” Journal of Clinical Investigation, vol. 111, no. 9, pp. 1373–1380, 2003.
J. K. Hamilton, E. Odrobina, J. Yin, A. J. Hanley, B. Zinman, and R. Retnakaran, “Maternal insulin sensitivity during pregnancy predicts infant weight gain and adiposity at 1 year of age,” Obesity, vol. 18, no. 2, pp. 340–346, 2010.
A. Alzamendi, D. Castrogiovanni, R. C. Gaillard, E. Spinedi, and A. Giovambattista, “Increased male offspring's risk of metabolic-neuroendocrine dysfunction and overweight after fructose-rich diet intake by the lactating mother,” Endocrinology, vol. 151, no. 9, pp. 4214–4223, 2010.
S. S. Elliott, N. L. Keim, J. S. Stern, K. Teff, and P. J. Havel, “Fructose, weight gain, and the insulin resistance syndrome,” American Journal of Clinical Nutrition, vol. 76, no. 5, pp. 911–922, 2002.
G. A. Bray, S. J. Nielsen, and B. M. Popkin, “Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity,” American Journal of Clinical Nutrition, vol. 79, no. 4, pp. 537–543, 2004.
O. R. Rebolledo, C. A. Marra, A. Raschia, S. Rodriguez, and J. J. Gagliardino, “Abdominal adipose tissue: early metabolic dysfunction associated to insulin resistance and oxidative stress induced by an unbalanced diet,” Hormone and Metabolic Research, vol. 40, no. 11, pp. 794–800, 2008.
A. Alzamendi, D. Castrogiovanni, H. H. Ortega, R. C. Gaillard, A. Giovambattista, and E. Spinedi, “Parametrial adipose tissue and metabolic dysfunctions induced by fructose-rich diet in normal and neonatal-androgenized adult female rats,” Obesity, vol. 18, no. 3, pp. 441–448, 2010.
K. G. Koski and M. A. Fergusson, “Amniotic fluid composition responds to changes in maternal dietary carbohydrate and is related to metabolic status in term fetal rats,” Journal of Nutrition, vol. 122, no. 2, pp. 385–392, 1992.
S. Rawana, K. Clark, S. Zhong, A. Buison, S. Chackunkal, and K. L. C. Jen, “Low dose fructose ingestion during gestation and lactation affects carbohydrate metabolism in rat dams and their offspring,” Journal of Nutrition, vol. 123, no. 12, pp. 2158–2165, 1993.
B. Yilmaz, A. Sucak, S. Kilic et al., “Metformin regresses endometriotic implants in rats by improving implant levels of superoxide dismutase, vascular endothelial growth factor, tissue inhibitor of metalloproteinase-2, and matrix metalloproteinase-9,” American Journal of Obstetrics and Gynecology, vol. 202, no. 4, pp. 368.e1–368.e8, 2010.
J. L. Bartha, F. González-Bugatto, R. Fernández-Macías, N. L. González-González, R. Comino-Delgado, and B. Hervías-Vivancos, “Metabolic syndrome in normal and complicated pregnancies,” European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 137, no. 2, pp. 178–184, 2008.
K. Holemans, S. Caluwaerts, L. Poston, and F. A. Van Assche, “Diet-induced obesity in the rat: a model for gestational diabetes mellitus,” American Journal of Obstetrics and Gynecology, vol. 190, no. 3, pp. 858–865, 2004.
J. C. Silva, D. R. Fachin, M. L. Coral, and A. M. Bertini, “. Perinatal impact of the use of metformin and glyburide for the treatment of gestational diabetes mellitus,” Journal of Perinatal Medicine, vol. 40, pp. 225–228, 2012.
U. Hiden, I. Lang, N. Ghaffari-Tabrizi, M. Gauster, U. Lang, and G. Desoye, “Insulin action on the human placental endothelium in normal and diabetic pregnancy,” Current Vascular Pharmacology, vol. 7, no. 4, pp. 460–466, 2009.
P. Nash, M. Olovsson, and U. J. Eriksson, “Placental dysfunction in Suramin-treated rats: impact of maternal diabetes and effects of antioxidative treatment,” Journal of the Society for Gynecologic Investigation, vol. 12, no. 3, pp. 174–184, 2005.
A. Lapolla, M. G. Dalfrà, E. Ragazzi, A. P. De Cata, and D. Fedele, “New international association of the diabetes and pregnancy study groups (IADPSG) recommendations for diagnosing gestational diabetes compared with former criteria: a retrospective study on pregnancy outcome,” Diabetic Medicine, vol. 28, pp. 1074–1077, 2011.
P. Gandhi, R. Bustani, P. Madhuvrata, and T. Farrell, “Introduction of metformin for gestational diabetes mellitus in clinical practice: has it had an impact?” European Journal of Obstetrics & Gynecology and Reproductive Biology, vol. 160, pp. 147–150, 2012.