CENTRAL GLP-1 SYSTEMS IN COUNTER REGULATORY RESPONSES

强化治疗是优化胰岛素依赖型糖尿病（IDDM）血糖控制的必要条件。然而，避免低血糖是IDDM管理的主要挑战。在低血糖期间，中枢神经系统监测血糖水平并协调反调节反应。然而，反调控反应背后的机制和主要途径尚不清楚。我们的初步研究结果表明，中枢胰高血糖素样肽1 （GLP-1）系统调节交感神经流出，并参与调节中枢神经系统对胰岛素诱导的低血糖的反应。我们假设GLP-1系统的作用在低血糖期间协调内分泌和自主反调节反应中是基础的。在本提案中，我们概述了旨在表征瘦素和血清素系统相互作用以调节食物摄入的神经解剖学机制的实验。首先，我们将确定外周和中枢注射GLP-1R激动剂和拮抗剂对激活交感肾上腺和血压反应的影响。接下来，使用逆行示迹和原位杂交，我们将确定下丘脑和脑干的GLP-1敏感神经元亚群是否支配脊髓内外侧细胞柱的交感神经节前神经元。第三，在选定的大脑区域进行微注射，我们将确定大脑中对GLP-1有反应的部位，导致血压升高和肾上腺儿茶酚胺分泌的激活。第四，通过中枢注射GLP-1受体拮抗剂，我们将确定GLP-1Rs中枢拮抗剂对低血糖反调节反应的影响。最后，使用GLP-1R-/-小鼠和过表达GLP-1受体激动剂的小鼠，我们将确定GLP-1R敲除小鼠和过表达EXN-4转基因小鼠在胰岛素诱导的低血糖后对协调反调节反应的影响。

Intensive therapy is essential to optimize glucose control in insulin- dependent diabetes mellitus (IDDM). However, avoiding hypolglycemia is a major challenge for the management of IDDM. The central nervous system monitors glucose levels and coordinates a counter regulatory response during periods of hypoglycemia. However, the mechanism(s) and central pathways that underlie the counter regulatory response are not understood. Our preliminary findings suggest central glucagon-like peptide 1 (GLP-1) systems regulate sympathetic outflow and are involved in regulating CNS responses to insulin-induced hypoglycemia. We hypothesis that the action of GLP-1 systems are fundamental in the coordinated endocrine and autonomic counter regulatory responses during hypoglycemia. In this proposal, we outline experiments designed to characterize the neuroanatomic mechanisms by which leptin and serotonin systems interact to regulate food intake. First, we will determine the effect of peripheral and central injections of GLP-1R agonists and antagonists on activating the sympathoadrenal and blood pressure responses. Next, using retrograde tracing and in situ hybridization, we will determine if subpopulations of GLP-1 sensitive neurons in hypothalamus and brainstem innervate sympathetic preganglionic neurons in the interomedial lateral cell column in the (IML) spinal cord. Third, using micro injections into selected brain regions, we will determine the sites in the brain that respond to GLP-1 resulting in increased blood pressure and activation of adrenal catecholamine secretion. Fourth, using central injections of GLP-1 receptor antagonists we will determine the effect of central antagonism of GLP-1Rs on the counter regulatory responses to hypoglycemia. Finally, using GLP-1R-/- mice and mine over expressing GLP-1 receptor agonists, we will determine the effects on the coordinated counter regulatory responses following insulin-induced hypoglycemia in GLP-1R knockout mice and EXN-4 over expressing transgenic mice.