Oral Metformin Treatment Prevents Enhanced Insulin Demand and Placental Dysfunction in the Pregnant Rat Fed a Fructose-Rich Diet

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 [1], 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 [9]. 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