Regulation of hepatic-mediated glucose release following hypoglycemic stress.

自主神经系统（ANS）在葡萄糖反调节反应中起着关键作用，以降低血液葡萄糖的循环水平（低血糖）。通过ANS的交感神经（SNS）、副交感神经（PNS）和交感-肾上腺（SNS-肾上腺）分支的激活，胰腺-胰高血糖素和肾上腺-肾上腺素的刺激释放导致肝葡萄糖的释放增加，随后恢复到正常葡萄糖水平。有证据表明，必须存在额外的神经调节系统，其中，对肝组织的直接SNS神经支配是最有可能的候选者。ANS通过这种多方面的调节系统协调肝葡萄糖释放的神经机制还不清楚。此外，还没有建立每种神经激素因子与肝脏中导致葡萄糖产生和释放的代谢信号通路活化之间的分子联系。阐明这些控制葡萄糖稳态的神经控制机制，将证明是至关重要的理解如何在ANS活动的扰动，如在高血糖症的状态，可以阻碍正常的葡萄糖反调节低血糖症的反应，否则健康的个人。 本研究的目的是：1）建立低血糖时肝介导的葡萄糖释放的神经调控因子。2)提供这些神经调节因子与刺激肝组织中葡萄糖产生和释放的代谢信号传导途径之间的分子联系，以及3）确定在ANS活动中的高血糖相关紊乱后，控制葡萄糖稳态的神经募集模式是否改变。 所提出的实验将利用分离的胰腺-肝脏制备物通过胰岛素输注诱导低血糖。通过在去除SNS、PNS和SNS-肾上腺神经支配至肝脏后输注可追踪的葡萄糖，计算每种神经激素因子在刺激肝脏葡萄糖释放中的重要性。同样，输注选择性抑制肝组织中关键代谢信号传导途径的药理学试剂将阐明肝脏在低血糖期间激活葡萄糖产生和释放的分子方式。在这些发现的基础上，将完成研究，以了解这些神经控制模式，管理葡萄糖稳态的变化后，在ANS活动的急性和慢性状态升高引起的变化。 总之，这些拟议的实验将采用多器官研究模型，该模型将提供器官系统与控制其功能的神经因子之间的分子联系，一直到介导其参与的基因、细胞和分子。

The Autonomic Nervous System (ANS) plays a key role in the glucose counter-regulatory response to lowered circulating levels of blood glucose (hypoglycemia). Through the activation of the sympathetic (SNS), parasympathetic (PNS), and sympatho-adrenal (SNS-adrenal) branches of the ANS, the stimulated release of pancreatic-glucagon and adrenal-epinephrine leads to the increased release of hepatic glucose and a subsequent return to normal glucose levels. Evidence would suggest that additional neural regulatory systems must exist, of which, the direct SNS innervation to hepatic tissues is the most likely candidate. The neural mechanisms by which the ANS coordinates the release of hepatic glucose via this multi-faceted regulatory system are not well understood. Further, the molecular linkages between each neurohormonal factor and the activation of metabolic signalling pathways in the liver that lead to the production and release of glucose has not been made. The elucidation of these neural control mechanisms governing glucose homeostasis will prove paramount to the understanding of how perturbations in ANS activity, such as during states of hyperglycemia, can impede the normal glucose counter-regulatory response to hypoglycemia in otherwise healthy individuals. The objectives of the proposed research program are 1) to establish the neural factors governing hepatic-mediated glucose release during hypoglycemia. 2) To provide a molecular link between these neural regulatory factors and the metabolic signalling pathways that stimulate glucose production and release in hepatic tissues and 3) to determine whether the neural recruitment patterns governing glucose homeostasis are altered following hyperglycemic-related disturbances in ANS activity. The proposed experiments will utilize an isolated pancreas-liver preparation to induce hypoglycemia via insulin infusion. The importance of each neurohormonal factor in stimulating hepatic glucose release will be calculated by the infusion of traceable glucose following the removal of SNS, PNS, and SNS-adrenal innervation to the liver. Similarly, the infusion of pharmacological agents that selectively inhibit key metabolic signalling pathways in hepatic tissues will elucidate the molecular means by which the liver activates glucose production and release during hypoglycemia. Building on these findings, studies will be completed to understand how these neural control patterns that govern glucose homeostasis change following alterations in ANS activity resulting from elevated acute and chronic states of glycemia. In summary, these proposed experiments will employ a multi-organ investigation model that will provide molecular linkages between organ systems and the neural factors that govern their function, right down to the genes, cells, and molecules that mediate their involvement.