Regulation of hepatic-mediated glucose release following hypoglycemic stress.

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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.