Gender Specific Complications of Diabetic Autonomic Neuropathy: A New Mouse Model

描述（由申请人提供）：糖尿病自主神经病变（DAN）的特征是心脏自主反应性受损。DAN与糖尿病患者心律失常和猝死的发生率增加有关。虽然女性猝死的总体发生率低于男性，但女性与糖尿病相关的猝死风险高于男性。对绝经后妇女的研究表明，联合雌激素/孕激素治疗可降低糖尿病的发病率。心率变异性的比较表明，心脏的副交感神经反应的增加，年轻女性与男性相比，这种差异在绝经后减弱，但保持在女性激素替代治疗（HRT）。提示绝经期妇女更易发生DAN，HRT可保护心脏，减少心律失常和猝死的发生。秋田小鼠在糖尿病的发展中表现出性别差异：雄性小鼠出现严重的高血糖症和糖尿病的继发性影响，而雌性小鼠仅表现出轻度高血糖症。使用雄性秋田小鼠，我们以前已经开发了一种动物模型的DAN，其特征是出现自发性室性心律失常后，心肌梗死（MI）。在这里，我们建议测试的假设，雌性秋田小鼠可能作为动物模型的性别特异性并发症的研究。具体而言，我们将检验以下假设：1）雌性秋田小鼠的卵巢切除导致糖尿病表型的发展和糖尿病的继发性效应，如通过高血糖症、蛋白尿和异丙肾上腺素刺激的L型Ca 2+电流的副交感神经抑制降低的发展所证明的，而雌激素可以逆转这种效应2）雌激素替代可保护卵巢切除的雌性秋田小鼠免受MI后自发性室性心律失常的发展; 3）基因阵列研究将建立一个在卵巢切除小鼠中差异表达的基因子集，这些小鼠在MI后发生心律失常，这可能作为治疗和预防女性糖尿病影响的候选基因。本申请的研究提出建立一种独特的动物模型，这可能为糖尿病和DAN并发症提供一种新的性别特异性治疗方法。公共卫生相关性：糖尿病自主神经病变（DAN）的特征是心脏自主反应性受损，心律失常和猝死的发生率增加。数据表明，绝经期妇女可能更容易发展DAN，激素替代治疗可能会保护心脏免受DAN的发展，降低心律失常和猝死的发生率。在这里，我们建议测试的假设，雌性秋田小鼠可能作为一种动物模型的研究性别特异性并发症的DAN和雌激素的保护作用，对发展的糖尿病及其继发性并发症的心脏。

DESCRIPTION (provided by applicant): Diabetic Autonomic Neuropathy (DAN) is characterized by impairment of autonomic responsiveness of the heart. DAN has been associated with an increased incidence of arrhythmia and sudden death in diabetics. Although the overall incidence of sudden death is lower in women than in men, the risk of sudden death associated with diabetes in women is greater than in men. Studies in postmenopausal women demonstrated that combined estrogen/progestin therapy reduced the incidence of diabetes. Comparison of heart rate variability showed that the parasympathetic response of the heart was increased in young women compared with men; this difference was attenuated after menopause, but maintained in women on hormone replacement therapy (HRT). These data suggested the hypothesis that menopausal women might be more likely to develop DAN and that HRT might protect the heart from development of DAN and decrease the incidence of arrhythmia and sudden death. The Akita mouse manifests a gender difference in the development of diabetes: males develop severe hyperglycemia and secondary effects of diabetes, while females exhibit only a mild hyperglycemia. Using male Akita mice, we have previously developed an animal model for DAN that is characterized by the appearance of spontaneous ventricular arrhythmias following myocardial infarction (MI). Here we propose to test the hypothesis that the female Akita mouse might serve as an animal model for the study of Gender Specific Complications of DAN. Specifically, we will test the hypotheses 1) that ovariectomy of female Akita mice results in the development of the diabetic phenotype and secondary effects of diabetes as demonstrated by the development of hyperglycemia, proteinuria and a decreased parasympathetic inhibition of Isoproterenol-stimulated L-type Ca2+ currents, and that estrogen reverses this effect 2) that estrogen replacement protects ovariectomized female Akita mice against the development of spontaneous ventricular arrhythmias following MI and 3) that gene array studies will establish a subset of genes that are differentially expressed in ovariectomized mice who develop arrhythmias following MI, which might serve as candidate genes for the treatment and prevention of this effect of diabetes in women. Studies in this application propose to establish a unique animal model, which might offer a new gender specific therapeutic approach to diabetes and the complications of DAN. PUBLIC HEALTH RELEVANCE: Diabetic Autonomic Neuropathy (DAN) is characterized by impairment of autonomic responsiveness of the heart and an increased incidence of arrhythmia and sudden death. Data suggest the hypothesis that menopausal women might be more likely to develop DAN and that hormone replacement therapy might protect the heart from development of DAN and decrease the incidence of arrhythmia and sudden death. Here we propose to test the hypothesis that the female Akita mouse might serve as an animal model for the study of Gender Specific Complications of DAN and the protective effects of estrogens against the development of diabetes and its secondary complications in the heart.