Preventing hypoglycemia-mediated arrhythmias and cardiac damage in type 1 diabetes

项目摘要/摘要 低血糖作为糖尿病治疗中的一种并发症，与高达10%的糖尿病相关 1型糖尿病的死亡人数。糖尿病患者自主神经功能改变和复发性低血糖可 增加心血管死亡率。假设会发生低血糖导致的死亡 通过两种不同的机制：1)急性低血糖导致心律失常；2) 复发性低血糖导致自主神经功能改变，增加了患重大糖尿病的风险 心血管事件，如心肌梗塞(MI)。初步结果显示：1)大鼠 1型糖尿病患者的死亡率随着副交感神经紧张程度的增加而增加， 2)反复低血糖会增加心肌梗死的损害。AIM 1将利用体内研究 大鼠和转基因小鼠测试对副交感神经系统和靶点的阻断 通过心脏Ryanodine受体的下游通路降低低血糖 心律失常。此外，体外心脏灌流将被用来测试参与 副交感神经系统通过兰尼定受体介导心律失常。目标2将 阐述复发性低血糖如何易导致较差的预后的机制 利用体内大鼠和转基因小鼠进行随后的心肌梗死。啮齿动物将经历一场 实验诱导心肌梗死后3天反复低血糖。的作用 副交感神经系统和兰尼定受体将通过药理学测试 阻断和基因破坏(转基因小鼠)。总体而言，预计 1型糖尿病患者副交感神经张力增加可导致致死性心律失常 急性重度低血糖，反复低血糖增加副交感神经张力 导致随后的心肌梗塞造成的伤害增加。此外，机械论研究将揭示 Ryanodine受体是心律失常和心肌梗死损伤的下游介质。 这两项研究的结果都对改进靶向策略以预防 糖尿病患者中与低血糖相关的心血管死亡率。

Project Summary/Abstract Hypoglycemia as a complication in the treatment of diabetes is associated with up to 10% of all deaths in type 1 diabetes. Altered autonomic function in diabetes and recurrent hypoglycemia can increase cardiovascular mortality. Hypoglycemia induced mortality is hypothesized to occur through two separate mechanisms: 1) acute hypoglycemia mediated cardiac arrhythmias and 2) recurrent hypoglycemia induced changes in autonomic function that increase risk of major cardiovascular events such as myocardial infarction (MI). Preliminary results revealed that 1) rats with type 1 diabetes have increased mortality associated with increased parasympathetic tone, and 2) recurrent hypoglycemia increases damage from an MI. Aim 1 will utilize in vivo studies in rats and transgenic mice to test blockade of the parasympathetic nervous system and target downstream pathways through the cardiac ryanodine receptor to reduce hypoglycemia-induced cardiac arrhythmias. Additionally, ex vivo heart perfusions will be used to test the involvement of parasympathetic nervous system mediated arrhythmias via the ryanodine receptor. Aim 2 will address the mechanisms of how recurrent hypoglycemia predisposes to worse outcome from a subsequent MI by utilizing in vivo rats and transgenic mice. Rodents will undergo an experimentally induced myocardial infarction after 3 days of recurrent hypoglycemia. The role of the parasympathetic nervous system and ryanodine receptors will be tested by pharmacological blockade and genetic disruption (transgenic mice), respectively. Overall, it is expected that the increased parasympathetic tone in type 1 diabetes mediates fatal cardiac arrhythmias during acute severe hypoglycemia, and recurrent hypoglycemia increases parasympathetic tone leading to increased damage from a subsequent MI. Additionally, mechanistic studies will reveal that ryanodine receptors are the downstream mediators of both arrhythmias and damage from an MI. Results from both studies have clinical implications for improving targeting strategies to prevent cardiovascular mortality associated with hypoglycemia in people with diabetes.