Carbohydrate Metabolism in Late Pregnancy

在妊娠晚期，患有胰岛素依赖型糖尿病（IDDM）的妇女容易发生更频繁和更严重的低血糖发作。 其原因尚不清楚，但已被认为部分是由于强化胰岛素治疗，以尽量减少围产期发病率和死亡率。 然而，在妊娠女性和妊娠大鼠中的一些研究表明，胰高血糖素对胰岛素诱导的低血糖的反应，可能还有肾上腺素反应，因妊娠本身而减弱。 我已经在怀孕的狗身上证明，循环中去甲肾上腺素的增加也是迟钝的，这表明交感神经系统对低血糖反应的激活减少也可能伴随着怀孕。 在非妊娠状态下，反调节激素反应的大小似乎受到多种因素的调节，包括大脑对胰岛素的敏感性或低血糖的程度。 这项建议的目的是检查哪些反调节机制被怀孕改变。 还将评估潜在损伤的后续代谢后果。 回答所提出的问题所需的技术是侵入性的，实验条件对胎儿有潜在的危害。 因此，将采用一种新的犬妊娠模型来解决这些问题。跨胰腺的动静脉差异技术将用于评估α细胞对妊娠期葡萄糖下降的反应能力是否存在缺陷，以及胰高血糖素对胰岛素诱导的低血糖症的反应缺陷是否与胰腺神经驱动的减少相关。 将使用第三脑室插管技术建立脑神经性低血糖症，以评估妊娠是否会导致大脑对低血糖本身敏感性的变化。 最后，妊娠期内分泌环境的改变可能是反调节反应改变的原因，在非妊娠雌性犬中，三种主要的妊娠激素（雌激素、孕酮和催乳素）将长期升高，以确定重建妊娠期激素环境的一部分是否会减弱胰岛素诱导的低血糖反应中反调节激素的升高，与妊娠期观察到的情况相似。 本提案中的研究应有助于确定哪些反调节机制受到妊娠的影响，从而可能导致糖尿病孕妇发生更频繁和更严重的低血糖发作。事实上，在怀孕狗模型中的初步研究表明，怀孕改变了多种反调节机制。

During late pregnancy, women with insulin-dependent diabetes (IDDM) are vulnerable to more frequent and more severe hypoglycemic episodes. The cause of this is not known, but has been suggested to be due in part to the intensive insulin treatment necessary to minimize perinatal morbidity and mortality. However, a few studies in pregnant women and the pregnant rat have indicated that the glucagon response, and probably the epinephrine response, to insulin-induced hypoglycemia is blunted by pregnancy itself. I have demonstrated in the pregnant dog that the increment in circulating norepinephrine is blunted as well, suggesting that a reduction in activation of the sympathetic nervous system in response to hypoglycemia may also accompany pregnancy. In the nonpregnant state, the magnitude of the counterregulatory hormone response appears to be modulated by a variety of factors that include sensitivity of the brain to insulin or the degree of hypoglycemia. The aim of this proposal is to examine which counterregulatory mechanisms are altered by pregnancy. The ensuing metabolic consequences of potential impairments will also be assessed. The techniques required to answer the questions posed are invasive and the experimental conditions are potentially harmful to the fetus. Thus, a novel canine model of pregnancy will be employed to address these issues. Arteriovenous difference techniques across the pancreas will be used to assess whether there is a defect in the alpha cell's ability to respond to a fall in glucose in pregnancy, and whether the defective glucagon response to insulin-induced hypoglycemia correlates with a decrease in neural drive to the pancreas. A technique for cannulation of the third cerebroventricle will be used to establish brain neuroglycopenia to assess whether pregnancy causes changes in the brain's sensitivity to hypoglycemia per se. Finally, the altered endocrine environment of pregnancy is the likely cause of the altered counterregulatory response, and three of the major hormones of pregnancy (estrogen, progesterone and prolactin) will be chronically elevated in nonpregnant female dogs to determine whether re-creating part of the hormonal environment of pregnancy attenuates the rise in counterregulatory hormones in response to insulin-induced hypoglycemia, similar to that seen in pregnancy. The studies in this proposal should help to identify which counterregulatory mechanisms are affected by pregnancy, thereby potentially contributing to the more frequent and severe episodes of hypoglycemia experienced by pregnant women with diabetes. Preliminary studies in the pregnant dog model in fact suggest that multiple counterregulatory mechanisms are altered by pregnancy.