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

糖尿病自主神经病变的动物模型：机制和治疗研究

基本信息

批准号：
7911877
负责人：
Jonas Bernard Galper
金额：
$ 58.37万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7911877
关键词：
Acetylcholine Adenylate Cyclase Adrenergic Agents Animal Model Animals Anti-Arrhythmia Agents Arrhythmia Binding Binding Proteins Blood Vessels Carbamoylcholine Catalytic Domain Cholesterol Homeostasis Cholinergic Receptors Clinical Coupled Cyclic AMP Data Development Diabetes Mellitus Diabetic Autonomic Neuropathy Diabetic mouse Dissociation Exhibits Family Fatty Acids Functional disorder GIRK1 subunit, G protein-coupled inwardly-rectifying potassium channel GTP-Binding Proteins Glucose Goals Heart Heart Atrium Heart Rate Heterotrimeric GTP-Binding Proteins Hydroxymethylglutaryl-CoA Reductase Inhibitors Impairment Incidence Insulin Insulin-Dependent Diabetes Mellitus Laboratories Life Measures Mediating Modeling Molecular Mus Muscarinic Agonists Muscarinic M2 Receptor Muscle Cells Myocardial Infarction Patients Phenotype Play Population Potassium Channel Predisposition Process Production Protein Family Reflex action Regulatory Element Research Design Research Personnel Response Elements Role Signal Transduction Sterols Structure of parasympathetic ganglion Sudden Death Testing Therapeutic Therapeutic Intervention Time Ventricular Ventricular Arrhythmia adenylate adrenergic age related animal model development atrioventricular node base cardiogenesis cholesterol control chronotropic diabetic diabetic patient follow-up glucose metabolism heart rate variability insight member mortality new therapeutic target non-diabetic outcome forecast programs protein expression response sudden cardiac death transcription factor type I diabetic

项目摘要

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.

描述（由申请人提供）：糖尿病与严重的衰弱并发症有关，其中包括糖尿病自主神经病（DAN），其特征是心脏自主反应降低。大约50％的糖尿病患者10年或更长时间证明了DAN。 I型糖尿病患者的证据表明，与没有DAN患者相比，5年死亡率高5年，猝死发病率增加。副交感神经刺激已被证明可以保护心脏免受心律不齐的发展，尤其是在心肌梗塞的情况下。因此，在副交感神经功能障碍存在下，糖尿病人群中猝死的发生率增加可能反映了致命性心律不齐的倾向。心脏的副交感神经反应涉及M2毒蕈碱受体，GAI2和内向整流K通道的相互作用，（GIRK1）2/（GIRK4）2刺激IKACH，刺激IKACH和BEAT速率和GAI2和GAI2和腺酸循环酶的降低，从而降低了降低人群的作用力。胰岛素调节固醇反应元件结合蛋白（SREBPS）的水平，这些蛋白在控制胆固醇，脂肪酸和葡萄糖代谢中发挥作用。初步数据表明，与非糖尿病性WT相比，I型糖尿病性秋田小鼠表现出对副交感神经信号传导的反应减少，并在心肌梗塞后会发展出威胁性心律失常，而毒蕈碱激动剂激动剂氨基甲胆碱反转。将使用此鼠标4假设进行测试：1）Akita小鼠是DAN的模型；证明副交感神经功能障碍，IKACH降低了抑制3-肾上腺素能刺激的抑制作用2）糖尿病中的低胰岛素血症导致M2，GAI2和GIRK1的表达降低，因为SREBP 3）响应于I型糖尿病型的动物模型而响应于SREBP的降低而导致的动物模型的降低。 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.该模型为DAN机制和治疗及其与心律不齐和猝死的关系提供了新的机会。