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

项目总结/摘要 低血糖作为糖尿病治疗中的并发症， 1型糖尿病患者的死亡率糖尿病患者自主神经功能改变和反复低血糖可 增加心血管死亡率。假设发生低血糖诱导的死亡 通过两种不同的机制：1）急性低血糖介导的心律失常和2） 复发性低血糖引起的自主神经功能变化增加了主要 心血管事件，如心肌梗死（MI）。初步结果显示，1）大鼠 1型糖尿病患者的死亡率增加与副交感神经张力增加有关， 和2）复发性低血糖增加了MI的损害。目标1将利用体内研究， 大鼠和转基因小鼠来测试副交感神经系统和靶点的阻断 通过心脏兰尼碱受体的下游途径减少低血糖诱导的 心律失常此外，将使用离体心脏灌注来测试 副交感神经系统通过兰尼碱受体介导心律失常。目标2将 探讨复发性低血糖如何导致更差的结果的机制， 随后的MI通过使用体内大鼠和转基因小鼠。啮齿动物将经历一个 在反复低血糖3天后实验诱导的心肌梗死。的作用 副交感神经系统和ryanodine受体将通过药理学方法进行测试， 阻断和遗传破坏（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介导致命性心律失常 急性重度低血糖和复发性低血糖增加副交感神经张力，导致 再发生心肌梗死造成的损伤此外，机械研究将揭示， 兰尼碱受体是心律失常和心肌梗塞损伤的下游介质。 这两项研究的结果对改善靶向策略以预防 糖尿病患者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.