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

胰岛素或其促分泌素引起的致死性低血糖风险是最佳血糖的主要限制因素 控制糖尿病的管理。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。而且，反复低血糖导致低血糖 相关的自主神经功能衰竭（HAAF），这是一种反调节功能进行性下降的现象， 对后续低血糖发作的反应。为了有效地预防或对抗HAAF， 我们首先要了解这种潜在致命疾病的机制。我们观察到 下丘脑室旁核（PVH）中黑素皮质素4受体（MC 4 R）缺乏损害 刺激反调节激素如胰高血糖素和肾上腺素的释放， 小鼠低血糖（来自我的K 01资助项目的发现）。此外，MC 4 R激动剂在小鼠中的给药， 糖尿病小鼠PVH恢复了对低血糖的反调节反应。这些数据共同 表明正常的MC 4 R信号传导对于对抗低血糖是至关重要的。因此，MC 4 R的弱化 功能可能导致有缺陷的低血糖反调节。根据我们的初步数据和 MC 4 R在刺激交感神经系统活动时，很可能是反复发生低血糖的原因 通过降低PVH中MC 4 R的功能来降低自主神经功能衰竭。因此，我们假设HAAF是一种 这是PVH中MC 4 R功能失调的后果，并且MC 4 R功能的增强将防止PVH中MC 4 R功能失调。 HAAF在健康和糖尿病中的作用为了检验我们的假设，在目标1中，我们将确定复发性低血糖是否 通过降低MC 4 R的功能来削弱对反调节激素释放的刺激， turn降低肾上腺交感神经活性介导HAAF。此外，在目标2中，我们将评估 PVH中MC 4 R功能的遗传和药理学增强对健康人预防HAAF的功效 和糖尿病通过我的职业发展奖-K 01，我获得了必要的技能和经验 来实现这个项目的目标。此外，罗切斯特大学拥有卓越的资源， 设施，以支持该项目。总之，我们将确定复发性低血糖是否减少 PVH中MC 4 R介导HAAF的功能。增强MC 4 R功能可能成为一种策略， 预防糖尿病HAAF。重要的是，这个R 03资助计划将增加我的K奖的进展， 为我随后的R 01赠款申请提供足够的初步数据，重点是 进一步阐明负责刺激反调节的MC 4 R下游通路， 缓解低血糖和HAAF。

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.