Regulation of hepatic-mediated glucose release following hypoglycemic stress.

自主神经系统（ANS）在降低循环血糖水平（低血糖）的葡萄糖反调节反应中起关键作用。通过激活ANS的交感神经（SNS）、副交感神经（PNS）和交感-肾上腺神经（SNS-肾上腺）分支，胰高血糖素和肾上腺肾上腺素的刺激释放导致肝葡萄糖释放增加，随后血糖水平恢复正常。有证据表明，一定存在其他的神经调节系统，其中直接支配肝组织的SNS神经是最有可能的候选。ANS通过这个多方面的调节系统协调肝脏葡萄糖释放的神经机制尚不清楚。此外，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的激活之间的分子联系尚未确定。阐明这些控制葡萄糖稳态的神经控制机制，将证明对理解ANS活动的扰动（如高血糖状态）如何阻碍健康个体对低血糖的正常葡萄糖反调节反应至关重要。****本研究计划的目标是：1)建立低血糖时控制肝脏介导的葡萄糖释放的神经因子。2)提供这些神经调节因子与刺激肝组织葡萄糖产生和释放的代谢信号通路之间的分子联系；3)确定控制葡萄糖稳态的神经募集模式是否在高血糖相关的ANS活性紊乱后发生改变。***拟议的实验将利用分离胰肝制剂通过胰岛素输注诱导低血糖。在去除SNS、PNS和SNS-肾上腺神经支配到肝脏后，通过输注可追踪的葡萄糖来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关键代谢信号通路的药理学药物，将阐明低血糖期间肝脏激活葡萄糖产生和释放的分子途径。在这些发现的基础上，研究将完成，以了解这些控制葡萄糖稳态的神经控制模式是如何在急性和慢性血糖升高引起的ANS活性改变后发生变化的。总之，这些拟议的实验将采用一个多器官研究模型，该模型将提供器官系统和控制其功能的神经因子之间的分子联系，直至介导其参与的基因、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.