Targeting Ascending Catecholamine Pathways to Prevent Hypoglycemia

项目概要/摘要 糖尿病是导致死亡的主要原因之一，在美国影响超过3000万人，四分之一的 65岁以上的人患有其衰弱症状。从经济上讲，糖尿病是一种 由于相关的医疗保健成本和生产力损失而造成的巨大负担。胰岛素最有效 许多糖尿病患者使用的治疗方法。然而，实现正常血糖平衡可能是一个挑战，因为 治疗性胰岛素经常导致血糖水平意外急剧下降，引起严重的低血糖 如果不及时处理可能导致昏迷和死亡频繁的低血糖是最可靠的 预测糖尿病恶性疾病病程和死亡率。通常，低血糖是通过以下方式避免的： 大脑中的反调节反应通路，它协调一系列生理措施，沿着 饥饿，恢复血糖。然而，由于强化胰岛素治疗， 和日常活动，损害这些大脑通路，使糖尿病患者容易受到随后的 低血糖对中枢反调节通路的研究揭示了脑干在中枢神经系统中的重要作用。 儿茶酚胺神经元我们和其他人已经证明，这些神经元广泛投射到下丘脑， 这些预测对他们的反监管行动至关重要。然而，这些中的下丘脑靶点 神经元的损伤以及它们被反复低血糖损害的潜在机制尚未确定。 这项建议的总体目标是确定神经回路介导的反调节行动， 脑干儿茶酚胺神经元这项资助的目的是：1）确定直接的神经靶点， 下丘脑中的髓质儿茶酚胺神经元介导反调节，以及2）确定如何 反复的低血糖发作使该通路中的通信脱敏。为了实现这些目标，我们将 使用髓质的儿茶酚胺神经元的轴突作为下游回路的地图。这些研究将提供新的 对中央反调节通路的基本见解。此外，通过确定 受损的反调节，这些研究可能会导致新的治疗靶点，用于治疗 低血糖相关的自主神经衰竭和低血糖无意识。

PROJECT SUMMARY / ABSTRACT Diabetes is one of the leading causes of death, affecting more than 30 million people in the U.S., with one in four individuals over 65 years suffering from its debilitating symptoms. Economically, diabetes represents an enormous burden due to associated healthcare cost and loss of productivity. Insulin is the most effective treatment used by many diabetic patients. However, achieving euglycemic balance can be a challenge since therapeutic insulin often leads to unintended sharp drop in blood glucose level, causing severe hypoglycemia which, if not addressed, may result in coma and death. Frequent hypoglycemia is one of the most reliable predictor of malignant disease course and mortality in diabetes. Normally, hypoglycemia is averted by counterregulary response pathway in the brain, which coordinates a series of physiological measures, along with hunger, to restore blood glucose. However, recurrent hypoglycemic episodes, due to intensive insulin therapy and daily activities, impairs these brain pathways, leaving diabetic patients vulnerable to subsequent hypoglycemia. Efforts to identify the central counterregulatory pathways revealed essential role of brainstem catecholamine neurons. We and others have shown that these neurons project extensively to hypothalamus, and these projections are essential for their counterregulatory actions. However, hypothalamic target(s) of these neurons and the mechanism(s) underlying their impairment by repeated hypoglycemia has not been determined. The overall goal of this proposal is to identify the neural circuit(s) mediating counterregulatory actions of brainstem catecholamine neurons. The aims of this grant are to 1) determine the direct neuronal target(s) of medullary catecholamine neurons in the hypothalamus mediating counterregulation, and 2) determine how repeated hypoglycemic episodes desensitize communication in this pathway. To accomplish these aims, we will use axons of medullary catecholamine neurons as a map to downstream circuits. These studies will provide new fundamental insights into the central counterregulatory pathways. In addition, by identifying mechanism of impaired counterregulation, these studies may lead to novel therapeutic targets for the treatment of hypoglycemia associated autonomic failure and hypoglycemia unawareness.