CENTRAL GLP-1 SYSTEMS IN COUNTER REGULATORY RESPONSES

强化治疗对于胰岛素依赖型糖尿病（IDDM）的血糖控制至关重要.然而，避免低血糖是对IDDM管理的主要挑战。中枢神经系统监测血糖水平，并在低血糖期间协调反调节反应。然而，反调节反应的机制和中枢通路尚不清楚。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反应。我们假设GLP-1系统的作用是低血糖时协调内分泌和自主神经反调节反应的基础。在这个建议中，我们概述了旨在表征瘦素和5-羟色胺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-1 R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，使用逆行追踪和原位杂交，我们将确定下丘脑和脑干中GLP-1敏感神经元的亚群是否支配（IML）脊髓中中间外侧细胞柱中的交感节前神经元。第三，使用微注射到选定的大脑区域，我们将确定大脑中对GLP-1产生反应的部位，导致血压升高和肾上腺儿茶酚胺分泌激活。第四，使用GLP-1受体拮抗剂的中枢注射，我们将确定GLP-1 R的中枢拮抗作用对低血糖的反调节反应的影响。最后，使用GLP-1 R-/-小鼠和我的过表达GLP-1受体激动剂，我们将确定GLP-1 R敲除小鼠和EXN-4过表达转基因小鼠中胰岛素诱导低血糖后对协调的反调节反应的影响。

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.