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

糖尿病自主神经病变的性别特异性并发症：一种新的小鼠模型

• 批准号: 7923989
• 负责人: Jonas Bernard Galper
• 金额: $ 19.88万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7923989
• 关键词: Acetylcholine; Adrenergic Agents; Animal Model; Appearance; Arrhythmia; Attenuated; Autonomic Dysfunction; Binding; Candidate Disease Gene; Carbamoylcholine; Cardiac; Characteristics; Clinical Research; Complications of Diabetes Mellitus; Cyclic AMP; Data; Development; Diabetes Mellitus; Diabetic Autonomic Neuropathy; Dissociation; Estrogen Replacements; Estrogens; Event; Exhibits; Female; Functional disorder; Gender; Gene Expression; Genes; Heart; Hormone replacement therapy; Hyperglycemia; Impairment; Incidence; Isoproterenol; Life; Measures; Menopause; Mus; Muscarinic M2 Receptor; Muscle Cells; Myocardial Infarction; Ovariectomy; Patients; Phenotype; Placebos; Point Mutation; Postmenopause; Predisposition; Prevention; Production; Progestin Therapy; Proteinuria; Puberty; Recording of previous events; Risk; Sex Characteristics; Sexual Maturation; Signal Pathway; Signal Transduction; Sudden Death; Testing; Therapeutic; Ventricular; Ventricular Arrhythmia; Woman; adrenergic; cardiogenesis; diabetic; diabetic patient; heart rate variability; male; men; mouse model; non-diabetic; protective effect; public health relevance; response; therapeutic target

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.

描述（由申请人提供）：糖尿病自主神经病（DAN）的特征是心脏的自主反应性障碍。 Dan与糖尿病患者心律不齐和猝死的发生率增加有关。尽管女性猝死的总体死亡率低于男性，但与男性相关的外色死亡风险大于男性。对绝经后妇女的研究表明，雌激素/孕激素治疗的联合降低了糖尿病的发生率。心率变异性的比较表明，与男性相比，年轻女性的心脏副交感神经反应增加了。更年期后会减弱这种差异，但在女性中维持激素替代疗法（HRT）。这些数据表明，更年期妇女可能更有可能发展DAN，并且HRT可能会保护心脏免受DAN的发展并降低心律失常和猝死的发生。 Akita小鼠在糖尿病的发展中表现出性别差异：雄性会出现严重的高血糖和糖尿病的次要作用，而女性仅表现出轻度的高血糖症。使用雄性Akita小鼠，我们以前已经开发了DAN的动物模型，其特征是心肌梗塞（MI）后自发性心室心律不齐。在这里，我们建议测试以下假设：雌性Akita小鼠可能是研究DAN性别特定并发症的动物模型。具体而言，我们将测试假设1）雌性akita小鼠的卵巢切除术会导致糖尿病表型的发展和糖尿病的二次作用，这是由于高血糖症，蛋白尿，蛋白尿和降低的降低了同位素烯醇刺激的l-型ca2+ the Enter terres ca2+ ogen terregent and corter and corter and corter corter and corter corter corter corter corter and corter corter and corter corter corter corter contrent and cestreent and corter erter corter erter，并估计替代物可保护卵巢雌性akita小鼠免受MI和3）3）的自发性心室心律失常的发展。基因阵列研究将建立一个基因的子集，这些基因子集在卵巢切除术中差异表达的小鼠，这些小鼠在MI之后发展心动不下的心律失常，这可能会作为治疗和预防疾病的候选人的候选人的候选人，以此为治疗症状。该应用程序中的研究建议建立独特的动物模型，该模型可能为糖尿病和DAN的并发症提供新的特定性别治疗方法。公共卫生相关性：糖尿病自主神经病（DAN）的特征是心脏的自主反应障碍以及心律不齐和猝死的发病率增加。数据表明，更年期女性可能更可能发展DAN，而激素替代疗法可能会保护心脏免受DAN的发展，并降低心律不齐和猝死的发生。在这里，我们建议检验以下假设：雌性Akita小鼠可能是研究DAN性别特异性并发症的动物模型，以及雌激素对糖尿病及其心脏中二次并发症的保护作用。