Carbohydrate Metabolism in Late Pregnancy

在妊娠后期，患有胰岛素依赖型糖尿病（IDDM）的妇女更容易发生更频繁和更严重的低血糖发作。其原因尚不清楚，但有人认为部分原因是为了尽量减少围产期发病率和死亡率而进行了必要的强化胰岛素治疗。然而，一些对孕妇和怀孕大鼠的研究表明，胰高血糖素对胰岛素引起的低血糖的反应，可能还有肾上腺素的反应，由于怀孕本身而减弱。我已经在怀孕的狗身上证明了循环去甲肾上腺素的增加也减弱了，这表明对低血糖反应的交感神经系统激活的减少也可能伴随着怀孕。在非怀孕状态下，反调节激素反应的强度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。这项提议的目的是研究怀孕改变了哪些反调节机制。潜在损伤的后续代谢后果也将被评估。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，一种新的犬类妊娠模型将被用来解决这些问题。贯穿胰腺的动静脉差异技术将用于评估α细胞对妊娠期血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的反应缺陷是否与胰腺神经驱动的减少相关。第三脑室插管技术将用于建立脑神经低血糖症，以评估怀孕是否会导致大脑对低血糖本身的敏感性发生变化。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，在未怀孕的母狗中，妊娠期的三种主要激素（雌激素、孕酮和催乳素）会长期升高，以确定重新创造部分妊娠期激素环境是否会减弱胰岛素诱导的低血糖反应中反调节激素的上升，类似于妊娠期的情况。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更频繁和更严重的低血糖发作。事实上，对怀孕犬模型的初步研究表明，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.