CNS Mechanisms of Acute Hypoglycemia-Associate Autonomic Failure

急性低血糖相关自主神经衰竭的中枢神经系统机制

• 批准号: 7686674
• 负责人: DIANNE FIGLEWICZ LATTEMANN
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686674
• 关键词: Acute; Address; Adrenal Glands; Adrenal Medulla; Amygdaloid structure; Animal Model; Animals; Antidepressive Agents; Area; Biochemical; Blood Glucose; Brain; Brain Stem; Brain region; Cardiovascular system; Caregivers; Caring; Centers for Disease Control and Prevention (U.S.); Chronic; Clinical Research; Complications of Diabetes Mellitus; Country; Development; Diabetes Mellitus; Disease; Dorsal; Dose; Elements; Epinephrine; Failure; Glucagon; Glucocorticoids; Glucose; Goals; Hepatic; Hormonal; Hormones; Human; Hypoglycemia; Hypothalamic structure; Impairment; Incidence; Individual; Insulin; L-Glucose; Life; Link; Maps; Measurement; Measures; Medial; Mediation; Medical; Methodology; Middle Hypothalamus; Modeling; Neurons; Neurosecretory Systems; Pathway interactions; Patient Care; Patients; Pattern; Peripheral; Pituitary Gland; Plant Roots; Plasma; Play; Population; Prevalence; Prosencephalon; Publishing; Rattus; Recurrence; Reporting; Rodent Model; Role; Serotonin Agents; Sertraline; Services; Severities; Site; Spinal Cord; Stimulus; Streptozocin; Streptozocin Diabetes; Stress; Structure of alpha Cell of islet; Study Subject; Symptoms; Synapses; Syndrome; Testing; Therapeutic; Therapeutic Intervention; Thoracic spinal cord structure; Time; Treatment Protocols; Veterans; abstracting; base; cost; diabetic; diabetic rat; experience; falls; hypothalamic-pituitary-adrenal axis; men; mortality; neuronal cell body; non-diabetic; prevent; psychological distress; public health relevance; relating to nervous system; response; stressor

DESCRIPTION (provided by applicant): Abstract Hypoglycemia-associated autonomic failure, or HAAF, is a syndrome associated with type1 and type2 diabetes that results from the experience of multiple episodes of low blood sugar (hypoglycemia) within a short timeframe. It is characterized by impairment of both the sensing of symptoms of falling blood glucose and the neuroendocrine counterregulatory response (CRR), a hormonal and neural response that includes sympathoadrenal activation and epinephrine (EPI) release; activation of the hypothalamic/pituitary/adrenal (HPA) axis and release of adrenal glucocorticoids; and glucagon (GLU) release. Most critical of these responses are the GLU and EPI release, and consequent stimulation of hepatic glucose release within minutes. In the diabetic individual, the GLU response is lost early in the disease state, and thus diabetic individuals are critically dependent upon EPI release for the CRR to hypoglycemia. For the past ten years, we have been studying brain sites that play a critical role in the mediation of the CRR in a (non-diabetic) rodent model of HAAF. Our lab and others have identified neural cell groups in the brainstem, medial hypothalamus, and limbic forebrain that are linked to each other and contribute to the CRR. However, there is very little information available about the activation or response of the diabetic brain to a hypoglycemic challenge. We now propose to systematically evaluate the key neural elements of the CRR in a model of acute diabetes, with the long-term objective of determining the components of impaired responding as potential targets for therapeutic intervention. Using a streptozotocin (STZ)-diabetic rat model and hyperinsulinemic hypoglycemic clamp methodology, we will measure neural activation (cFos, pCREB, and pERK1/2 expression) in response to a single (SH) or a third (recurrent, RH) bout of hypoglycemia throughout the brain. We will also screen the spinal cord and adrenal gland, i.e., the pathway of activation of the adrenal gland from the brain. We will determine the responsivity of brain glucose-sensing sites to a localized neuroglucopenic stimulus. Finally, we will evaluate the effect of the serotonergic agent sertraline (SERT) on the hypoglycemia CRR in diabetic rats, as we have observed enhanced EPI responding in non-diabetic rats treated with this agent. The proposed studies will thus achieve the short-term overall objective of evaluating the sensing of, and response to, neuroglucopenia and hypoglycemia in an animal model of diabetes. PUBLIC HEALTH RELEVANCE: The prevalence and incidence of both type1 and type2 diabetes in the U.S., other "Westernized", and emerging countries is high, and has been increasing in the U.S. for the past decade, with current CDC estimates of 7.5 individuals per thousand in the population overall. Further, both type1 and type2 diabetes are prevalent at a high rate in the veteran population: Currently, it is estimated that 16% of men receiving medical care at the VA have diabetes. Diabetes is a costly disease from every perspective, including medical costs for complications, and psychological distress for both the patient and the care-givers in the patient's life. Care of patients in which poor blood sugar control has resulted in one or more of the chronic complications of diabetes is costly and time- intensive in terms of VA staff support and VA services. The goal of intensified insulin therapy to delay, prevent, or decrease the severity, of long-term complications is still, theoretically, the best treatment regimen available. However, the recent report of increased mortality, with no identified cardiovascular benefit, in a population of intensively-treated diabetic individuals highlights the need to address hypoglycemia as a diabetic complication. The response to hypoglycemia (and the failed response which occurs with frequent episodes of hypoglycemia) is clearly rooted in altered brain function, thus understanding the brain mechanisms underlying the response to hypoglycemia in diabetic animals or humans is critical. We have studied the activity of key brain regions in response to hypoglycemia in a non-diabetic animal model. We are now proposing to study brain activation in an animal model of diabetes, with the rationale that identifying brain regions that are vulnerable to hypoglycemia, as well as identification of their role in an impaired biochemical response to hypoglycemia, is the first critical step to ancillary therapies to prevent hypoglycemia in association with intensive insulin therapy in diabetes.

描述（由申请人提供）： 抽象降糖相关的自主神经失败或HAAF是一种与类型1和2型糖尿病相关的综合征，它是由于在短时间内低血糖（低血糖）的多个发作的经验而导致的。它的特征是降低了血糖降低的症状和神经内分泌反应反应（CRR）的症状，这是一种激素和神经反应，包括交感肾上腺激活和肾上腺素（EPI）释放；下丘脑/垂体/肾上腺（HPA）轴的激活和肾上腺糖皮质激素的释放；和胰高血糖素（GLU）释放。这些反应最关键的是GLU和EPI释放，因此在几分钟之内刺激了肝葡萄糖释放。在糖尿病患者中，GLU反应在疾病状态的早期失去，因此糖尿病患者严重依赖于CRR的EPI释放到低血糖。在过去的十年中，我们一直在研究在HAAF的（非糖尿病）啮齿动物模型中CRR中发挥关键作用的大脑部位。我们的实验室和其他实验室已经确定了脑干中的神经细胞组，内侧下丘脑和边缘前脑相互关联并有助于CRR。但是，关于糖尿病大脑对降血糖挑战的激活或反应的信息很少。现在，我们建议在急性糖尿病模型中系统地评估CRR的关​​键神经元素，其长期目的是确定受损的成分作为治疗干预的潜在目标。使用链蛋白酶（STZ） - 糖尿病大鼠模型和高胰岛素降血糖夹夹方法，我们将对整个大脑中低血糖的单个（SH）或第三（SH）或第三个（Recisurrent，rh）出发，以响应单个（SH）或第三个（SH）或第三个（SH）或第三个（RECRIRNERT，RH）来测量神经激活（CFOS，PCREB和PERK1/2表达）。我们还将筛选脊髓和肾上腺，即，肾上腺激活脑的途径。我们将确定脑葡萄糖传感位点对局部神经糖性刺激的反应性。最后，我们将评估血清素能药物舍曲林（SERT）对糖尿病大鼠低血糖CRR的影响，因为我们观察到的EPI在用该药物治疗的非糖尿病大鼠中的EPI反应增强。因此，拟议的研究将实现评估糖尿病动物模型中神经糖核和降血糖的感觉和反应的短期总体目标。 公共卫生相关性： 在美国，其他“西方化”和新兴国家的类型1和2型糖尿病的患病率和发病率很高，在过去的十年中，美国一直在增加，目前的CDC估计为总体人口总数为7.5个人。此外，在退伍军人人群中，Type1和Type2糖尿病都以高率的速度流行：目前，据估计，在VA接受医疗服务的男性中有16％的男性患有糖尿病。从各个角度来看，糖尿病是一种昂贵的疾病，包括并发症的医疗费用，以及患者生活中患者和护理人员的心理困扰。在VA员工的支持和VA服务方面，对血糖控制不佳的患者的护理导致糖尿病的一种或多种慢性并发症是昂贵且耗时的。从理论上讲，加强胰岛素疗法加强胰岛素疗法的延迟，预防或减轻长期并发症的严重程度仍然是最好的治疗方案。然而，最近有没有确定的心血管益处的死亡率增加的报告，在经过严格治疗的糖尿病患者中，这表明需要将低血糖作为糖尿病并发症。对低血糖的反应（以及频繁发作性低血糖症发生的失败反应）显然根植于脑功能的改变，因此了解糖尿病动物或人类中对低血糖反应的脑机制至关重要。我们已经研究了非糖尿病模型中关键大脑区域对低血糖的活性。我们现在建议在糖尿病的动物模型中研究大脑的激活，其理由是，鉴定容易受到低血糖症的大脑区域，并鉴定出它们在对低血糖的生化反应中的作用，这是预防辅助性胰岛素胰岛素治疗的辅助疗法的第一个关键步骤。