1. Investigación

El ejercicio incrementa el consumo de oxígeno y, consecuentemente, la producción de radicales libres y de MADO responsables del estrés oxidativo. A su vez, se conoce que el ejercicio aumenta la sensibilidad insulínica en c·ondiciones en que ésta se encuentra reducida, como sucede en la diabetes tipo II, no dependiente de insulina. Durante la gestación, la madre desarrolla una intensa hiperlipidemia y resistencia a la insulina (2), y en nuestro laboratorio hemos demostrado recientemente que el ejercicio en la rata gestante revierte la resistencia a la insulina.

Una dosis oral de glucosa (2 g/Kg de peso) produjo cambios similares en la glucosa sanguinea de ratas gestantes de 20 dias y virgenes mientras que el aumento en la insulina plasmatica fue mayor en los animales gestantes, indicando resistencia a la insulina. En el presente trabajo se estudia si un ejercicio moderado y aerobio durante la gestación modifica la respuesta a la insulina en la madre. Ratas virgenes y preñadas de 20 días corrieron en una cinta rodante inclinada 10° durante 5 dias/semana a 20 ml mine incremento progresivo hasta 75 min en el dia 20 de ejercicio y/o gestación en que fueron sometidas a un test de tolerancia intravenoso de insulina con 10 IU de insulina porcina/Kg peso. El efecto hipoglucemiante de la insulina intravenosa mostró una mayor respuesta a la insulina en las ratas preñadas ejercitadas con respecto a las no ejercitadas, mientras que no se observa efecto en las ratas virgenes.

To study insulin/glucose relationship during gestation, rats were studied on days 6, 12, 15, 18, 20 or 21 of presnancy and the results were compared to values in sex.matched virgin control rats. Blood glucose levels were decreased on days 20 and 21 of gestation whereas plasma insulin levels appeared decreased on days 6 and 12, unchanged on day 15 and enhanced on days 18. 20 and 2L of gestation. Total pancreas insulin content was already augmented on day 6 of gestation and continued to increase with gestational time. \Vith the exception of an increase in tbe 6-day.pregnant rats 22.5 min after an oral glucose toad, blood glucose levels did not differ between 6• or 12-day.pregnant rats and virgin controls although plasma insulin levels reached higher values on these days. However. in the 15-day-pregnam rats, glucose tolera!lce after the glucose load was enhanced while plasma insulin levels did not differ from those in virgin rats during the first 30 mjn. In the IS-day-pregnant rat blood glucose was more increased but plasma insulin did not differ after the glucose load when compared to virgin rats, whereas 20. or 21-day-pregnant rats showed a gJucose tolerance similar to that of virgin rats but their insulin levels shonly after the glucose load were higher. The hY'I.»" glycemic response lo a high intravenous dose of insulin was decreased in 12-, 18-. 20- and 21-day-pregnant rats. TI,erefore, whereas in both the 6- and 12-day-pregnant rats there is an enhanced 13-,celJ response to the glucose insulinotropic effect and insulin responsiveness is reduced in J 2. day-pregnant rats. the 15-day pregnam rat is in a transitory stage where both insulin sensitivity and the J},-ccll response return to non pregnant vaJ. ues. Ho\•.revcr. from 18 da)'S of gcslation on, there is an intense insulin• resistanl condition which is only partially compensated by an enormous accumulation of insuJin in the pancreas followed by a faster and larger insulin release after a glucose load.

La dieta rica en sacarosa (DRS) no modifica el peso corporal de la rata gestante ni de sus fetos. La práctica de un ejercicio aerobio moderado tampoco afecta a estos parámetros con independencia del tipo de dieta que ingieran o de su estado fisiológico. La respuesta metabólica a la DRS es diferente según el metabolito estudiado, así la hipertrigliceridemia es similar en ratas vírgenes y preñad3s, aunque en estas últimas el efecto de la DRS se suma al aumento de triglicéridos característico de la gestación. Los niveles de ácidos grasos libres no se modifican ni en vírgenes ni en preñadas como consecuencia de la DRS. En lo relativo a la glucemia e insulinemia existe una respuesta diferencial a la DRS dependiendo de que los animales estén o no preñados. Finalmente, la práctica de ejercicio reduce considerablemente la insulina en las ratas gestantes alimentadas con DRS o con la DC.

On the basis of the above findings it may be concluded that although placental transfer of lipids is small, sustained maternal hyperlipidemia during late gestation is of pivotal importance for the metabolism of the mother and her offspring. Besides aporting essential metabolites to the fetus in an indirect manner, such as glucose synthesized in maternal liver from glycerol released from adipose tissue, the active lipidic metabolism in the mother allows the availability of high amounts of circulating triglyceride-rich lipoproteins for milk synthesis in preparation for lactation. The induction of LPL activity in the mammary gland is important for this function, and warrants the availability of essential fatty acids from the diet to be present in the milk, as well as contributes to the disappearance of maternal hyperlipidemia around parturition. Besides, maternal hyperlipidemia constitutes a floating energetic store to be used under conditions of food deprivation to ensure the availability of alternative substrates for maternal tissues, such a ketone bodies, and to save essential metabolites for the fetus. Maternal hyperlipidemia is the result of numerous and dynamic metabolic adaptations that have to be controlled very finely. Any deviation from this control may alter maternal lipoprotein profile and even be responsible for an alteration in the milk composition, as it has been already reported in dyslipidemic mothers .

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.

Purpose and Methods: To determine whether pregnancy modifies the effect of aerobic exercise on insulin responsiveness, female rats were mated or kept nonpregnant and exercised or not on a treadmill (10° slope, 20 m·min-1) 5 d·wk-1 during a 20-min period that was increased progressively up to 70 min on the 19th d. On day 20, a hyperinsulinemic euglycemic clamp was performed with 0.8 IU insulin·h-1·kg-1 under conscious conditions. Results: Food intake and body weight, circulating lactic acid, glucose, and insulin as well as fetal body weight and number were unaffected by the exercise protocol. The rate of glucose infusion required to maintain basal glucose levels during the clamp was similar in exercised and nonexercised virgin rats and significantly lower in pregnant than in virgin nonexercised rats. However, in exercised pregnant rats the glucose infusion rate was almost as high as in the exercised virgin rats. Conclusions: The results show that although our aerobic exercise protocol does not affect insulin responsiveness in nonpregnant rats, it completely reverts the insulin resistance present in late pregnant rats.

The mechanism that induces maternal hypertriglyceridemia in late normal pregnancy, and its physiologic significance are reviewed as a model of the effects of sex steroids on lipoprotein metabolism. In the pregnant rat, maternal carcass fat content progressively increases up to day 19 of gestation, then declines at day 21. The decline may be explained by the augmented lipolytic activity in adipose tissue that is seen in late pregnancy in the rat. This change causes maternal circulating free fatty acids and glycerol levels to rise. Although the liver is the main receptor organ for these metabolites, liver triglyceride content is reduced. Circulating triglycerides and very-low-density lipoprotein (VLDL)-triglyceride levels are highly augmented in the pregnant rat, indicating that liver-synthesized triglycerides are rapidly released into the circulation. Similar increments in circulating VLDL-triglycerides are seen in pregnant women during the third trimester of gestation. This increase is coincident with a decrease in plasma postheparin lipoprotein lipase activity, indicating a reduced removal of circulating triglycerides by maternal tissues or a redistribution in their use among the different tissues. During late gestation in the rat, tissue lipoprotein lipase activity varies in different directions; it decreases in adipose tissue, the liver, and to a smaller extent the heart, but increases in placental and mammary gland tissue. These changes play an important role in the fate of circulating triglycerides, which are diverted from uptake by adipose tissue to uptake by the mammary gland for milk synthesis, and probably by the placenta for hydrolysis and transfer of released nonesterified fatty acids to the fetus. After 24 hours of starvation, lipoprotein lipase activity in the liver greatly increases in the rat in late pregnancy; this change is not seen in virgin animals. This alteration is similar to that seen in liver triglyceride content and plasma ketone body concentration in the fasted pregnant rat. In the fasting condition during late gestation, heightened lipoprotein lipase activity is the proposed mechanism through which the liver becomes an acceptor of circulating triglycerides, allowing their use as ketogenic substrates, so that both maternal and fetal tissues may indirectly benefit from maternal hypertriglyceridemia. Changes in the magnitude and direction of lipoprotein lipase activity in different tissues during gestation actively contribute both to the development of hypertriglyceridemia and to the metabolic fate of circulating triglycerides. Any deviation in these metabolic adaptations occurring in the human mother may have consequences that modify her lipoprotein profile, even postpartum. Hormone-induced changes in pregnancy mirror those seen with oral contraceptive steroids and provide a teleologic rationale for the lipoprotein changes induced by sex steroids.

The present study in rats was aimed at determining the specific day of pregnancy on which maternal body fat accumulation starts and which tissues are involved. Most of the body weight increase at day 12 of gestation corresponded to conceptus-free maternal weight which progressively increased until the 19th day of gestation after which maternal weight stabilized and the rate of conceptus weight gain became maximal. Maternal carcass fat content progressively increased until day 18 of gestation, increased very markedly on day 19, stabilized between day 19 and 20 and then decreased on day 21. These changes were the opposite of the course of the specific-gravity values. The fresh weight oflumbar fat-pads and mesenteric adipose tissue reflected the changes in carcass fat content throughout gestation. Periuterine adipose-tissue mass declined on day 12 of gestation to be recuperated later, subcutaneous adipose tissue increased on day 12 to decline progressively thereafter and interscapular brown adipose tissue remained stable until day 20 and increased on day 21. With only a few exceptions, the lipid concentration in all these adipose tissues remained stable throughout gestation. Mammary glands and liver weights increased intensely from day 12 and, whereas the lipid concentration in the former was stable, in the latter it decreased on day 12 and increased on days 18 and 19. These results show that in the rat (a) maternal carcass fat accumulation during gestation is not paralleled by the size of the different fatstoring tissues and (b) mammary-gland fat accumulation also contributes to maternal fat storage.

To determine whether aerobic training throughout gestation modifies glucose tolerance, female Wistar rats were mated or kept nonpregnant and run or not on a 10° slope treadmill for 5 days/week at 20 m/min, starting with a 20-min run, and with a progressive daily increase of 5 min, reaching a 75-min run on the 20th day of protocol or gestation. The exercise protocol did not modify food intake, maternal and fetal weights, litter size or blood lactic acid levels. The rise in blood glucose after an oral glucose load (2 g/kg bodyweight) did not differ between trained and untrained nonpregnant rats but was lower in trained than in untrained pregnant rats. In the untrained rats the rise in plasma insulin levels after the glucose load was much greater in pregnant than in non pregnant rats; in trained rats this difference between groups was attenuated by the greater effect of exercise decreasing the plasma insulin response to the glucose load in pregnant than in nonpregnant rats. Thus, an aerobic exercise protocol that does not modify the outcome of pregnancy does significantly reduce the altered oral glucose tolerance in pregnant rats and only has a minor effect in non pregnant rats.