Role of Ghrelin in the Counter-Regulatory Response to Insulin-Induced Hypoglycemia

生长素释放肽在胰岛素引起的低血糖的反调节反应中的作用

• 批准号: 10155479
• 负责人: Eric Berglund
• 金额: $ 53.95万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155479
• 关键词: Accidents; Address; Adherence; Animals; Applications Grants; Attenuated; Biology; Blood Glucose; Bolus Infusion; Caloric Restriction; Catecholamines; Cell physiology; Cells; Cessation of life; Closure by clamp; Collection; Development; Diabetes Mellitus; Drops; Exhibits; Exposure to; Failure; Famines; Glucose; Glucose Clamp; Goals; Hormones; Hypoglycemia; Hypothalamic structure; Impairment; Incidence; Infusion procedures; Insulin; Insulin Receptor; Insulin-Dependent Diabetes Mellitus; Internal Ribosome Entry Site; Knockout Mice; Measures; Mediating; Mediator of activation protein; Modality; Morbidity - disease rate; Mus; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Normal Range; Patients; Phlorhizin; Physiological; Play; Positioning Attribute; Predisposition; Productivity; Quality of life; Recombinants; Recommendation; Recurrence; Regimen; Role; SF1; Signal Transduction; Site; Source; Starvation; Sympathetic Nervous System; System; Technology; Testing; Transgenic Mice; Virus; Wild Type Mouse; Work; arm; base; blood glucose regulation; clinically significant; counterregulation; designer receptors exclusively activated by designer drugs; experience; experimental study; ghrelin; ghrelin receptor; glucose metabolism; hypoglycemia unawareness; improved; in vivo; insight; insulin tolerance; mortality; mouse model; novel; peptide hormone; prevent; response; stem

PROJECT SUMMARY/ABSTRACT Defense against hypoglycemia is critical for survival, and is of particular importance in the clinically-significant setting of insulin-induced hypoglycemia. Insulin-induced hypoglycemia is prevalent in Type 1 and advanced Type 2 diabetes mellitus, and is associated with a far-ranging negative impact, including reduced work productivity and quality of life, decreased adherence to or recommendations for intensive insulin regimens, increased incidence of accidents and other morbidities, and occasionally death. While the body has developed a highly integrated defense system with which to prevent or correct hypoglycemia, in diabetes patients experiencing recurrent hypoglycemia due to over-insulinization, these counter-regulatory defenses are compromised, contributing to what can become a vicious cycle of hypoglycemia and often hypoglycemia unawareness (hypoglycemia-associated autonomic failure; HAAF) stemming from an abrogated sympathoadrenal arm of the counter-regulatory response. Several facets of ghrelin biology suggest that ghrelin may participate in the counter-regulatory response to insulin-induced hypoglycemia: 1) ghrelin secretion is directly stimulated by low glucose and sympathoadrenal activation; 2) the ensuing raised ghrelin has at its disposal many potential downstream targets with which to influence glucose handling, including interactions with several traditional counter-regulatory response hormones. However, while ghrelin regulation of blood glucose and by blood glucose have been evaluated in contexts such as caloric restriction, the overall role of the ghrelin system in the counter-regulatory response to insulin-induced hypoglycemia has not been fully assessed experimentally, for instance by re-creating insulin-induced hypoglycemia or HAAF in mice without an intact ghrelin system. Here, we will test the concept that ghrelin plays a key, protective, counter-regulatory role in the body’s response to insulin-induced hypoglycemia. In particular, we will dissociate the direct effects of insulin versus hypoglycemia on ghrelin secretion by performing insulin bolus-induced hypoglycemia tests, hyperinsulinemic-hypoglycemic clamps, and ex vivo ghrelin secretion studies in mice lacking insulin receptors selectively in ghrelin cells and phloridzin-hypoglycemic clamps in ghrelin-KO mice. We will determine requirement and sufficiency for GHSRs in AgRP neurons or SF1 neurons on the counter-regulatory response using Cre-lox transgenic mice and chemogenetic technology. Also, we will determine if ghrelin deletion increases susceptibility to HAAF by assessing the ghrelin response to hypoglycemia in wild-type mice with HAAF and the overall counter-regulatory response following recurrent hypoglycemia in mice lacking ghrelin. Our one-of-a-kind toolbox of recombinant mouse models targeting the ghrelin system, our team’s expertise in studying both ghrelin action and secretion, and our expertise in glucose metabolism including performing glucose clamps in mice will allow us to gain important and novel insights into not only hypoglycemia counter- regulation and the development of HAAF, but also ghrelin cell physiology and ghrelin action.

项目摘要/摘要 防御低血糖症对于生存至关重要，并且在临床上特别重要 胰岛素诱导的低血糖的设置。胰岛素诱导的低血糖在1型中普遍存在，并且晚期 2型糖尿病，并与极范围的负面影响有关，包括减少工作 生产力和生活质量，对密集胰岛素方案的依从性或建议降低， 增加事故和其他病因的事件，偶尔死亡。当身体发展 糖尿病患者的高度集成防御系统可预防或纠正低血糖 由于过度胰岛素而导致的反复发作性低血糖，这些反调节性防御是 受到妥协，导致可能成为低血糖的恶性循环，通常是低血糖 不知情（低血糖相关的自主失败； HAAF）是由于废除的 反调节反应的交感神经臂。生生物学的几个方面表明ghrelin 可能参与对胰岛素诱导的低血糖症的反调节反应：1）生长素释放蛋白分泌是 直接被低葡萄糖和交感神经激活刺激； 2）随之而来的凸起的生长素有其 处理许多可能影响葡萄糖处理的潜在潜在目标，包括相互作用 具有几种传统的反调节反应激素。然而，何时血液调节血液 葡萄糖和血糖已在热量限制等情况下进行了评估， 对胰岛素诱导的低血糖的反调节反应中的生长素释放蛋白系统尚未完全 例如，通过重新创建胰岛素诱导的低血糖或HAAF在实验中评估的小鼠 完整的生长素系统。在这里，我们将测试生长素蛋白扮演关键，受保护的反调节角色的概念 在人体对胰岛素诱导的低血糖的反应中。特别是，我们将分离 胰岛素与低血糖对生长素素分泌的胰岛素分泌，通过进行胰岛素诱导的低血糖测试， 在缺乏胰岛素受体的小鼠中，高胰岛素血糖血糖夹和离体生长素素分泌研究 在生长素蛋白细胞中有选择地在生长素蛋白-KO小鼠中选择性地。我们将确定 AGRP神经元或SF1神经元中GHSR的需求和充分性 使用CRE-LOX转基因小鼠和化学发育技术。另外，我们将确定ghrelin是否删除 通过评估野生型小鼠降低血糖的反应来增加HAAF的易感性 HAAF和缺乏生长素蛋白的小鼠复发性低血糖后的总体反应反应。 我们的重组鼠标模型针对生长素系统的一种重组鼠标模型，我们的团队的专业知识 研究生长素释放的作用和分泌，以及我们在葡萄糖代谢方面的专业知识，包括执行 小鼠中的葡萄糖夹将使我们能够获得重要和新颖的见解 调节HAAF的调节和发育，以及生长素细胞生理学和生长素释放作用。