Mechanisms of Hypoglycemia Associated Autonomic Failure

低血糖相关自主神经衰竭的机制

• 批准号: 8018093
• 负责人: ILAN GABRIELY
• 金额: $ 36.61万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8018093
• 关键词: Achievement; Acute; Animals; Arousal; Attenuated; Award; Beta Cell; Biochemical; Blood Glucose; Brain; Catecholamines; Clinical Investigator; Clinical Research; Complication; Complications of Diabetes Mellitus; Data; Dental caries; Deterioration; Development; Diabetes Mellitus; Disease; Dose; Effectiveness; Endorphins; Enzymes; Exercise; Failure; Fasting; Fructose; Glucagon; Glucokinase; Gluconeogenesis; Glucose; Glucose Plasma Concentration; Glucose-6-Phosphate; Glycogen; Grant; Hepatic; Homeostasis; Hormonal; Hormones; Human; Hydrocortisone; Hypoglycemia; Individual; Infusion procedures; Injection of therapeutic agent; Insulin; Insulin-Dependent Diabetes Mellitus; Intravenous infusion procedures; Laboratories; Laboratory Research; Lead; Liver Glycogen; Memory; Mentored Patient-Oriented Research Career Development Award; Mentorship; Metabolic; Methodology; Methods; Naloxone; Names; Neurologic; Neurosecretory Systems; Opioid Receptor; Pathway interactions; Patients; Persons; Plasma; Play; Predisposition; Principal Investigator; Recovery; Recurrence; Regulation; Research; Research Methodology; Research Training; Risk; Role; Somatotropin; Source; Stress; Syndrome; System; Time; Tissues; Tracer; beta-Endorphin; counterregulation; diabetes control; endogenous opioids; glucose production; glucose uptake; glycemic control; glycogen metabolism; glycogenolysis; hypoglycemia unawareness; improved; insight; new therapeutic target; non-diabetic; novel strategies; prevent; programs; response; tool

DESCRIPTION (provided by applicant): Severe hypoglycemia (SH) is the major limitation of intensive insulin treatment in type 1 diabetes (T1DM), and the near-term prospects for perfected insulin therapy without this risk are dim. Intensively treated T1DM patients suffer from impaired counterregulation of hypoglycemia (HYPO) ie, HYPO-Associated Autonomic Failure (HAAF) and HYPO unawareness (HU) which enhance their susceptibility to SH. The precise mechanisms of HAAF and HU, however, have not been clarified, though multiple redundant control systems are implicated. Experimental HYPO and exercise in normal and T1DM subjects reproduce HAAF and HU, providing a robust experimental paradigm of these disorders. We have shown that fructose, infused in a catalytic dose for modulating glucokinase activity, results in augmentation of the counterregulatory responses to HYPO in nondiabetic and in T1DM individuals. We hypothesize that an equivalent infusion of fructose will prevent HAAF in nondiabetic and in T1DM persons. Furthermore, since both HYPO and exercise are associated with endogenous opioid (EO) release, and blocking EO improves HYPO counterregulation, we hypothesize that repeated HYPO episodes induce alterations in the modulatory effects of EO on hormonal and glucose counterregulation, ultimately leading to HAAF. We also propose that HYPO autoregulation, and hepatic glycogen metabolism play important roles in the development of HAAF and HU. The specific aims are: 1) to determine the effects of previous modulation of glucokinase activity on the counterregulatory hormonal and glucose recovery responses to subsequent HYPO in nondiabetic and T1DM subjects, 2) to examine the effects of blocking the inhibitory action of endorphins on the central neuroendocrine response system (with naloxone), during recurrent HYPO or exercise, on subsequent HYPO counterregulatory responses in nondiabetic and T1DM subjects, 3) to analyze the effects of recurrent mild HYPO (autoregulation), on subsequent HYPO counterregulation in nondiabetic and in T1DM subjects, and 4) to determine the effects of recurrent HYPO on hepatic glycogen content in nondiabetic and T1DM subjects, and the effects of normalization of liver glycogen content, by means of insulin and glucose administration, on experimental HAAF in T1DM subjects.Type 1 diabetes mellitus is a disease characterized by elevated blood sugar due to lack of insulin. Adequate treatment with insulin injections results in amelioration of blood sugar, but caries a risk of low blood sugar, which may be a fatal complication of this treatment. This proposal will analyze the mechanisms involved in the induction of low blood sugar and will develop methods to improve this risk.

描述（由申请人提供）：严重低血糖（SH）是 1 型糖尿病（T1DM）强化胰岛素治疗的主要限制，没有这种风险的完善胰岛素治疗的近期前景很暗淡。接受强化治疗的T1DM患者患有低血糖反调节(HYPO)受损，即低血糖相关自主神经衰竭(HAAF)和低血糖无意识(HU)，这增加了他们对SH的易感性。然而，HAAF 和 HU 的确切机制尚未阐明，尽管涉及多个冗余控制系统。正常和 T1DM 受试者的实验性 HYPO 和运动再现了 HAAF 和 HU，为这些疾病提供了强有力的实验范例。我们已经证明，以催化剂量注入果糖以调节葡萄糖激酶活性，可增强非糖尿病和 T1DM 个体对 HYPO 的反调节反应。我们假设，同等量的果糖输注将预防非糖尿病患者和 T1DM 患者发生 HAAF。 此外，由于 HYPO 和运动都与内源性阿片类药物 (EO) 释放相关，并且阻断 EO 会改善 HYPO 反调节，因此我们假设重复的 HYPO 发作会​​导致 EO 对激素和葡萄糖反调节的调节作用发生改变，最终导致 HAAF。我们还提出 HYPO 自身调节和肝糖原代谢在 HAAF 和 HU 的发展中发挥重要作用。具体目标是：1) 确定先前调节葡萄糖激酶活性对非糖尿病和 T1DM 受试者随后 HYPO 的反调节激素和葡萄糖恢复反应的影响，2) 检查阻断内啡肽对中枢神经系统的抑制作用的影响。神经内分泌反应系统（纳洛酮），在反复 HYPO 或运动期间，对非糖尿病和 T1DM 受试者随后的 HYPO 反调节反应， 3) 分析复发性轻度 HYPO（自动调节）对非糖尿病和 T1DM 受试者随后 HYPO 反调节的影响，以及 4) 确定复发性 HYPO 对非糖尿病和 T1DM 受试者肝糖原含量的影响以及正常化的影响通过注射胰岛素和葡萄糖，对 T1DM 受试者的实验性 HAAF 进行肝糖原含量的测定。1 型糖尿病是一种以血糖升高为特征的疾病由于缺乏胰岛素。充分的胰岛素注射治疗可以改善血糖，但会带来低血糖的风险，这可能是这种治疗的致命并发症。该提案将分析引起低血糖的机制，并开发改善这种风险的方法。