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）：严重的低血糖（SH）是1型糖尿病（T1DM）强化胰岛素治疗的主要局限性，并且没有这种风险的没有这种风险的完美胰岛素治疗的近期前景是暗淡的。经过多种治疗的T1DM患者患低血糖症（低血糖），IE，低血症相关的自主衰竭（HAAF）和低不认识（HU）受损，这增强了其对SH的易感性。然而，尽管涉及多个冗余控制系统，但尚未澄清HAAF和HU的确切机制。在正常和T1DM受试者中的实验性低下和运动繁殖HAAF和HU，提供了这些疾病的强大实验范式。我们已经表明，以催化剂量注入用于调节葡萄糖酶活性的果糖导致非糖尿病和T1DM个体中对低调的反应反应的增强。我们假设等效地输注果糖将阻止非糖尿病患者和T1DM人中的HAAF。 此外，由于低调和运动都与内源性阿片类药物（EO）释放相关，并且阻止EO改善了低调调节，因此我们假设反复发作会导致EO对激素和葡萄糖反调控的调节作用的改变，最终导致HAAF。我们还提出，低调自动调节和肝糖原代谢在HAAF和HU的发展中起着重要作用。 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在非糖尿病和T1DM受试者中，3）分析复发性轻度降低（自动调节），对随后的非糖尿病和T1DM受试者中随后的低调反调节的影响，以及4），以确定复发性低于Nondiabetic和T1DM的效果的肝糖原含量对肝糖原含量的影响，并通过nondin和T1DM的效果进行正常效应。在T1DM受试者中的实验性HAAF上给药。型1糖尿病是一种疾病，其特征是由于缺乏胰岛素而导致血糖​​升高。对胰岛素注射的适当治疗会导致血糖改善，但发生了低血糖的风险，这可能是这种治疗的致命并发症。该提案将分析诱导低血糖的机制，并将开发改善这种风险的方法。