1. Investigación

I. During the first two thirds of gestation, coinciding with a minimal accretion by the conceptus, the mother is in an anabolic state which is supported by her hyperphagia and the more efficient conservation of exogenous nutrients when she eats. During this phase maternal fat deposits are accumulated thanks to the enhancement in adipose tissue lipogenic and glycerolgenic activity. In contrast, in the latter part of gestation, the rapid fetal growth is sustained by the intense transfer of nutrients from maternal circulation. 2. Glucose is quantitatively the most abundant of the several substrates that cross the placenta and despite increased maternal gluconeogenesis this transfer is responsible for the maternal tendency to hypoglycemia. This causes a switch to a net catabolic state which is especially evident in the net breakdown of fat depots. 3. Enhanced release of adipose tissue Iipolytic products, free fatty acids (FFA) and glycerol, facilitates the liver synthesis of triglycerides and their later release into circulation associated to very low-density lipoprotein (VLDL). Glycerol is also used as an important gluconeogenic substrate and FF As are broken down through 13-oxidation for ketone body synthesis. Flow through these pathways becomes increased when food is withheld and this actively contributes to the availability of fuels to the fetus which becomes partially preserved from maternal metabolic insult. Increased liver production of VLDL-triglycerides and decreased extrahepatic lipoprotein lipase contribute to exaggerated maternal hypertriglyceridemia which, besides being a floating metabolic reserve for emergency conditions such as starvation, constitutes an essential substrate for milk synthesis around parturition in preparation for lactation. 4. While the maternal anabolic tendencies found during the first two-thirds of gestation seem to be facilitated by hyperinsulinemia in the presence of a normal responsiveness to the hormone, it is proposed that most of the metabolic changes taking place during the last third of gestation seem to be caused by the insulin-resistant state which is consistently present at this stage, since its reversion caused by sustained exaggerated hyperinsulinemia also reverts several of these metabolic adaptations.

Pregnant rats at 12 and 21 days of gestation and their virgin controls were injected intravenously with U-14C-glycerol and decapitated 1, 3, or 10 min later. The conversion of labelled glycerol to 14 C-glucose was augmented in the 21-day pregnant rats. The disappearance of the newly formed 14C-glucose from blood was faster in both 12- and 21-day pregnant rats than in their controls, being partially retained as liver 14C-glycogen. The greatest amount of radioactivity in all tissues appeared in the carcass hydrosoluble fraction. This amount was smaller in the pregnant rats. The reduced utilization of glycerol by extrahepatic tissues allowed the 21-day pregnant rats to dispose a greater amount of this substrate for gluconeogenesis.

Female rats were treated with two daily equihypoglycemic doses (as observed in acute treatment) of tolbutamide, glibenclamide or glipentide . by stomach tube, and were compared with control ammals treated with the suspending medium alone. On day 29 the rats were subjected to a 48 h fast and then were injected intraperitoneally with 100 .μMoles of C' -alanine. Blood samples were collected before and 5, 15 and 30 minutes after the alanine injection, at which time the animals were killed. Blood glucose levels increased after the injection of alanine in all groups, but at the different times stll:died, both the glibenclamide and glipentide treated_ anu_n~ls showed hypoglycemia versus controls. The rad10act1:"1ty found in blood glucose and liver glycogen and glycendeglycerol decreased in the glibenclamide treated anima~s compared with controls while in the other groups 1t was similar. The increase in liver glycogen after the injection of alanine was also diminished in the_ glibenclamide treated animals. Alanine produced an mcrease in the plasma levels of gluconeogenic, basic, aromatic and sulphur-containing amino acids in the controls, while in the animals treated with glipentide the alanine effect was less pronounced. The results show an impairment of gluconeogenic function in glibenclamide treated animals. The effects of both tolbutamide and glipentide were less dramatic. Nevertheless, the findings hinted at an effect of both drugs upon glycogen metabolism in liver.