Prevention of hypoglycemia associated autonomic failure by enhancing melanocortin 4 receptor function

通过增强黑皮质素 4 受体功能预防低血糖相关的自主神经衰竭

• 批准号: 9807544
• 负责人: Kavaljit H Chhabra
• 金额: $ 11.55万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-16 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9807544
• 关键词: Adrenal Glands; Agonist; Applications Grants; Blood Glucose; Cessation of life; Clinical Trials; Collaborations; Data; Diabetes Mellitus; Diabetic mouse; Epinephrine; Exhibits; Failure; Functional disorder; Funding; Gene Expression; Generations; Genetic; Glucagon; Goals; Health; Hormones; Hypoglycemia; Hypothalamic structure; Impairment; Inbred NOD Mice; Incidence; Insulin; Insulin-Dependent Diabetes Mellitus; K-Series Research Career Programs; Kidney; Lead; Life; Measures; Mediating; Melanocortin 4 Receptor; Mentored Research Scientist Development Award; Mus; Nerve; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Norepinephrine; Obesity; Outcome; Pathway interactions; Patients; Pharmacology; Plasma; Prevention; Pro-Opiomelanocortin; Receptor Signaling; Recurrence; Resources; Risk; Role; Streptozocin; Structure of nucleus infundibularis hypothalami; Sympathetic Nervous System; System; Testing; Time; Tyrosine 3-Monooxygenase; Universities; base; blood glucose regulation; cost; counterregulation; diabetes management; experience; fight against; mouse model; paraventricular nucleus; prevent; programs; receptor; receptor function; response; skills

Risk of fatal hypoglycemia due to insulin or its secretagogues is a major limiting factor for optimal glucose control in management of diabetes. Hypoglycemia causes about 6 to 10% of deaths in diabetes patients and costs nearly $1.4 billion annually in the US. Moreover, repeated hypoglycemia leads to hypoglycemia associated autonomic failure (HAAF), which is a phenomenon of progressive decline in counterregulatory response to subsequent episodes of hypoglycemia. To effectively prevent or counteract HAAF, it is imperative that we first understand the mechanisms underlying this potentially fatal condition. We have observed that melanocortin 4 receptor (MC4R) deficiency in the paraventricular nucleus of the hypothalamus (PVH) impairs the stimulation of the release of counterregulatory hormones such as glucagon and epinephrine in response to hypoglycemia in mice (findings from my K01-funded project). Moreover, administration of MC4R agonist in the PVH of diabetic mice restored their counterregulatory response to hypoglycemia. Collectively, these data indicate that normal MC4R signaling is critical to counteract hypoglycemia. Therefore, weakening of the MC4R function can lead to defective hypoglycemia counterregulation. Based on our preliminary data and the role of MC4R in stimulating the sympathetic nervous system activity, it is likely that recurrent hypoglycemia causes autonomic failure by diminishing the function of MC4R in the PVH. Hence, we hypothesize that HAAF is a consequence of dysfunctional MC4R in the PVH and that enhancement of the MC4R function will prevent HAAF in health and diabetes. To test our hypothesis, in Aim 1, we will determine if recurrent hypoglycemia impairs the stimulation of release of counterregulatory hormones by reducing the function of MC4R, which in turn decreases adrenal sympathetic nerve activity to mediate HAAF. Moreover, in Aim 2, we will evaluate the efficacy of genetic and pharmacological enhancement of MC4R function in the PVH to prevent HAAF in health and diabetes. Through my career development award - K01, I have acquired necessary skills and experience to accomplish the goals of this project. Moreover, the University of Rochester has outstanding resources and facilities to support the project. In summary, we will establish whether or not recurrent hypoglycemia diminishes the function of MC4R in the PVH to mediate HAAF. Enhancing MC4R function may emerge as a strategy to prevent HAAF in diabetes. Importantly, this R03 funding program will augment the progress of my K award and facilitate the generation of sufficient preliminary data for my subsequent R01 grant application focusing on further unraveling the MC4R downstream pathways that are responsible for stimulating the counterregulatory response to hypoglycemia and mitigating HAAF.

胰岛素或其促分泌剂引起的致命低血糖风险是最佳血糖的主要限制因素。 糖尿病管理中的控制。糖尿病患者中约6%至10%的死亡是由低血糖引起的 在美国，每年花费近14亿美元。此外，反复低血糖会导致低血糖。 相关自主神经衰竭(HAAF)，这是一种逆调节进行性下降的现象 对随后的低血糖发作的反应。要有效地预防或对抗赤潮，势在必行。 我们首先要了解这种潜在致命疾病背后的机制。我们观察到， 下丘脑室旁核黑素皮质素4受体(MC4R)缺乏损害 刺激胰升糖素和肾上腺素等逆调节激素的释放 小鼠的低血糖(来自我的K01资助项目的发现)。此外，MC4R激动剂在脑内的应用 糖尿病小鼠的PVH恢复了对低血糖的反调节反应。总的来说，这些数据 提示正常的MC4R信号在对抗低血糖中起关键作用。因此，MC4R的弱化 功能障碍可导致有缺陷的低血糖反调节。根据我们的初步数据和 MC4R在刺激交感神经系统活动时，很可能是反复低血糖引起的 PVH中MC4R功能减弱所致的自主神经功能衰竭。因此，我们假设haaf是一个 MC4R功能障碍在PVH中的后果和MC4R功能的增强将防止 健康和糖尿病方面的问题。为了验证我们的假设，在目标1中，我们将确定复发性低血糖 通过降低MC4R的功能来削弱对反调节激素释放的刺激，在 TURN降低了肾上腺交感神经的活性，以调节HAAF。此外，在目标2中，我们将评估 遗传和药物增强PVH患者MC4R功能对预防健康人群房颤的疗效 还有糖尿病。通过我的职业发展奖-K01，我获得了必要的技能和经验 来完成这个项目的目标。此外，罗切斯特大学拥有出色的资源和 支持该项目的设施。总而言之，我们将确定复发性低血糖是否减少。 MC4R在PVH中的作用增强MC4R功能可能会成为一种战略 预防糖尿病的HAAF。重要的是，这个R03资助计划将增加我的K奖的进展，并 促进为我随后的R01拨款申请生成足够的初步数据，重点是 进一步解开负责刺激反调控的MC4R下游通路 对低血糖和缓解HAAF的反应。