An Animal Model of Diabetic Autonomic Neuropathy: Study of Mechanism and Therapy

描述（由申请人提供）：糖尿病与严重的衰弱性并发症相关，其中包括以心脏自主神经反应性降低为特征的糖尿病自主神经病变（DAN）。大约50%的10年以上糖尿病患者表现为DAN。有DAN证据的I型糖尿病患者的5年死亡率和猝死发生率比无DAN的患者高5倍。副交感神经刺激已被证明可以保护心脏免受心律失常的发展，特别是在心肌梗死的情况下。因此，糖尿病人群猝死发生率的增加可能反映了副交感神经功能障碍时致死性心律失常的易感性。心脏的副交感神经反应涉及M2毒毒碱受体Gai2和向内整流K通道（GIRK1）2/(Girk4)2的相互作用，后者刺激IKACh并降低心跳速率和Gai2和腺苷酸环化酶，后者降低收缩力。胰岛素调节甾醇反应元件结合蛋白（SREBPs）的水平，SREBPs在控制胆固醇、脂肪酸和葡萄糖代谢中发挥作用。初步数据表明，与非糖尿病型小白鼠相比，1型糖尿病秋田鼠对副交感神经信号的反应降低，并在心肌梗死后发生危及生命的心律失常，这种情况可通过毒蕈碱激动剂氨甲酰胆碱逆转。使用这只老鼠将测试4个假设：1)秋田老鼠是DAN的模型；显示副交感神经功能障碍，IKACh降低，心脏3-肾上腺素能刺激抑制降低2)糖尿病低胰岛素血症导致M2， Gai2，3) I型糖尿病秋田小鼠是Ml后自发性危及生命的心律失常发展的动物模型，DAN副交感神经功能障碍使心脏易发生心律失常，4)增加SREBP的治疗干预，如胰岛素治疗或HMG-CoA还原酶抑制剂，会增加M2、Gai2和GIRK1的表达。逆转副交感神经功能障碍并降低Ml后VT的发生率。该模型为DAN的机制和治疗及其与心律失常和猝死的关系提供了一个独特的机会。

DESCRIPTION (provided by applicant): Diabetes mellitus is associated with severe debilitating complications which include a Diabetic Autonomic Neuropathy (DAN) characterized by decreased autonomic responsiveness of the heart. Approximately 50% of patients with diabetes for 10 years or more demonstrate DAN. Type I diabetics with evidence of DAN demonstrate a fivefold higher 5 year mortality and increased incidence of sudden death than those without DAN. Parasympathetic stimulation has been shown to protect the heart from the development of arrhythmias especially in the setting of myocardial infarction. Thus the increased incidence of sudden death in the diabetic population might reflect a predisposition to fatal arrhythmias in the presence of parasympathetic dysfunction. Parasympathetic response of the heart involves the interaction of the M2 muscarinic receptor, Gai2, and the inward rectifying K channel, (GIRK1)2/(Girk4)2 which stimulates IKACh and a decrease in beat rate and Gai2 and adenlyate cyclase which decreases the force of contraction. Insulin regulates levels of sterol response element binding proteins (SREBPs), which play a role in the control of cholesterol, fatty acid, and glucose metabolism. Preliminary data suggest that compared to non-diabetic WT, the type I diabetic Akita mouse demonstrates a decreased response to parasympathetic signaling and develops life threatening arrhythmias following myocardial infarction which are reversed by the muscarinic agonist carbamylcholine. Using this mouse 4 hypotheses will be tested: 1)that the Akita mouse is a model for DAN; demonstrates parasympathetic dysfunction, decreased IKACh decreased inhibition of 3-adrenergic stimulation of the heart 2) that hypoinsulinemia in diabetes results in a decrease in the expression of M2, Gai2, and GIRK1 in response to a decrease in SREBP 3) that the Type I diabetic Akita mouse is an animal model for the development of spontaneous life threatening arrhythmias following Ml and that parasympathetic dysfunction of DAN predisposes the heart to the development of arrhythmias and 4) that therapeutic interventions that increase SREBP such as insulin therapy or HMG-CoA reductase inhibitors increase M2, Gai2, and GIRK1 expression, reverse parasympathetic dysfunction and decrease the incidence of post Ml VT. This model offers a unique opportunity for new insights into mechanism and therapy of DAN and its relationship to arrhythmia and sudden death.