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

描述(申请人提供)：糖尿病与严重的衰弱并发症有关，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%的糖尿病患者在10年或更长时间内表现为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是没有DAN的患者的五倍。副交感神经刺激已经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，糖尿病人群中猝死发生率的增加可能反映了副交感神经功能障碍时易发生致命性心律失常。心脏的副交感反应涉及M2受体GAI2和内向整流钾通道(GIRK1)2/(Girk4)2的相互作用，后者刺激IKACh，并使心率和GAI2和腺苷环化酶减慢，从而降低收缩的力量。胰岛素调节固醇反应元件结合蛋白(SREBPs)的水平，而SREBPs在控制胆固醇、脂肪酸和葡萄糖代谢方面发挥作用。初步数据表明，与非糖尿病小鼠相比，I型糖尿病秋田小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，而这种心律失常可被毒扁豆碱激动剂氨基甲胆碱逆转。使用这只小鼠，将检验4个假设：1)秋田小鼠是丹的模型；3)证实副交感神经功能障碍，减少IKACh减少对心脏3-肾上腺素能刺激的抑制2)糖尿病低胰岛素血症导致M2、GAI2和GIRK1的表达减少，以回应SREBP的减少3)I型糖尿病秋田鼠是ML后自发性危及生命的心律失常的动物模型，DAN的副交感神经功能障碍使心脏易于发生心律失常；4)增加SREBP的治疗干预，如胰岛素治疗或HMG-CoA还原酶抑制剂，增加M2、GAI2和GIRK1的表达，逆转副交感神经功能障碍，降低ML后VT的发生率。该模型为深入了解DAN的发病机制和治疗方法及其与心律失常和猝死的关系提供了独特的机会。

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.