1. Investigación

Fructose intake from added sugars correlates with the epidemic rise in obesity, metabolic syndrome and cardiovascular diseases. Fructose intake also causes features of metabolic syndrome in laboratory animals. Therefore, we have investigated whether fructose modifies lipidemia in pregnant rats and produces changes in their fetuses. Thus, fructose administration (10% wt/vol) in the drinking water of rats throughout gestation, leads to maternal hypertriglyceridemia. This change was not observed in glucose-fed rats, although both carbohydrates produced similar changes in liver triglycerides and in the expression of transcription factors and enzymes involved in lipogenesis. After fasting overnight, mothers fed carbohydrates were found to be hyperleptinemic. However, after a bolus of glucose, leptinemia in fructose-fed mothers showed no-response, whereas it increased in parallel in glucose-fed and control mothers. Fetuses from fructose-fed mothers showed hypotriglyceridemia and a higher hepatic triglyceride content than fetuses from control or glucose-fed mothers. A higher expression of genes related to lipogenesis and a lower expression of fatty acid catabolism genes were also found in fetuses from fructose-fed mothers. Moreover, although hyperleptinemic, these fetuses exhibited increased tyrosine phosphorylation of the signal transducer and activator of transcription-3 (STAT-3) protein, without a parallel increase in the serine phosphorylation of STAT-3 nor in the suppressor of cytokine signaling-3 (SOCS-3) protein levels whose expression is regulated by leptin through STAT-3 activation. Thus, fructose intake during gestation provoked a diminished maternal leptin-response to fasting and re-feeding, and an impairment in the transduction of the leptin signal in the fetuses which could be responsible for their hepatic steatosis.

Postnatal development of the glucose and insulin balance in offspring of ethanol-treated and control rats has been studied. Newborn rats were separated from their mothers and placed with normal lactating, nonethanol-treated dams. Prenatal exposure to ethanol led to hypoglycemia on the first day of extrauterine life and a general tendency to hyperinsulinemia during the entire postnatal period studied. The glucose-tolerance test in weaned rats (30 days old) gave a greater and faster increase than controls in levels of both glucose and plasma insulin. At adult age (90 days) the response of blood glucose to an oral glucose load in offspring from ethanol-treated mothers was not different from that in offspring from controls, but the insulin response was higher. This abnormal insulin response, such a long time after the end of ethanol exposure, suggests either a permanent alteration in the pancreatic response, or a peripheral insulin resistance and/or differences in the rate of insulin degradation in these animals.

In sham-operated rats, intravenous administration of 14C-very low density lipoprotein triglycerides (with labelled esterified fatty acids) caused an initial decrease and subsequent increase in plasma 14C-lipids of both very low density lipoproteins (VLDL) (density < 1.006) and lipoproteins of density > 1.019. There was a similar change in 14C-lipids in adipose tissue and heart whereas in kidney, spleen and liver, 14C-lipids increased initially and then decreased. Insulin treatment in sham-operated animals decreased circulating 14C-lipids in VLDL and in lipoproteins of density > 1.019, while intermediate density (1.006-1.019) lipoproteins increased. Insulin also enhanced the radioactivity retained in spleen. In functionally hepatectomized rats, 14C-lipids progressively increased in heart. Insulin treatment in these rats enhanced the disappearance from circulation of 14C-VLDL and of lipoproteins of density > 1.019, as well as the appearance of 14C-intermediate density lipoproteins. Toe appearance of 14C-lipids in white adipose tissue also was augmented, while it decreased in heart and lung. Thus, in sham-operated animals, insulin apparently stimulates the uptake of products of VLDL metabolism by cells in the reticuloendothelial system, while in functionally hepatectomized rats there is increased heart utilization of VLDL triglycerides, and insulin enhances the net extrahepatic catabolism of these lipoproteins.

To determine whether changes in uterine blood flow affect placental glucose transfer in the diabetic pregnant rat, on the 7th day of gestation rats were intravenously treated with either streptozotocin (45 mg/kg) (diabetics) or buffer (controls). On the 20th day of gestation, fetal body weight and uterine blood flow appeared reduced whereas fetal/maternal plasma glucose was enhanced and lactate ratios were unchanged in diabetics versus controls. After 20 min of (U- 14C)-D-glucose infusion through the maternal left uterine artery, plasma values of fetuses from left and right uterine horns were higher for 14C-glucose and lower for 14C-lactate in diabetics versus controls, and placental glucose transfer was greatly augmented in diabetics whether or not uterine blood flow was included in its calculation. Whereas a linear correlation existed between placental glucose transfer and maternal plasma glucose concentration, transferred glucose conversion into lactate remained stable even when the maternal glucose level was high. It was concluded that enhanced placental glucose transfer in the pregnant diabetic rat is not modified by reduced uterine blood flow. The limited capacity of the fetus to handle the great incoming flux of glucose through the placenta of a severely diabetic mother produces permanent hyperglycemia which may impair fetal growth.