Etiology of Impaired Counterregulation in Glucose Homeostasis: Exploring the Roles of Glucagon, Somatostatin, Cortisol, and Epinephrine through Mathematical Modeling of Oral Glucose Tolerance Tests

葡萄糖稳态反调节受损的病因学：通过口服葡萄糖耐量测试的数学模型探索胰高血糖素、生长抑素、皮质醇和肾上腺素的作用

• 批准号: 10351245
• 负责人: Vijaya Subramanian
• 金额: $ 12.58万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-16 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10351245
• 关键词: Acceleration; Acute; Alpha Cell; Animals; Apoptosis; Behavior; Beta Cell; Carbohydrates; Chronic; Data; Development; Diabetes Mellitus; Disease; Disease Management; Disease Progression; Disease model; Drops; Epidemic; Epinephrine; Etiology; Event; Fasting; Functional disorder; Glucagon; Gluconeogenesis; Glucose; Goals; Healthcare Systems; Homeostasis; Hormones; Hour; Hydrocortisone; Hyperglycemia; Hypoglycemia; Impairment; Ingestion; Instruction; Insulin; Insulin Resistance; Investigation; Lead; Liver; Longitudinal Studies; Mediating; Modeling; Nature; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Pathology; Patients; Persons; Plasma; Play; Polycystic Ovary Syndrome; Prediabetes syndrome; Reactive hypoglycemia; Recovery; Regulation; Role; Signal Transduction; Somatostatin; Somatotropin; Symptoms; Type 2 diabetic; Validation; aggressive therapy; base; blood glucose regulation; cell regeneration; counterregulation; data modeling; diabetic; diabetic patient; endocrine pancreas development; experience; falls; fasting glucose; glucagon-like peptide 1; glucose disposal; glycogenolysis; inhibitor; insight; insulin secretion; mathematical model; response

PROPOSAL SUMMARY Glucose homeostasis is tightly controlled in animals with plasma glucose levels maintained in a narrow range. While insulin, secreted by the beta cell, regulates by promoting efficient glucose disposal and suppressing glucose release from the liver when glucose levels rise, glucagon, secreted by the alpha cells, counterregulates by facilitating glucose release from the liver through glycogenolysis and gluconeogenesis when levels fall. Epinephrine, cortisol and growth hormone play supporting roles in glucose counterregulation. Impaired counterregulatory responses can lead to hypoglycemia, a potentially fatal condition. Hypoglycemia is frequently experienced by type 1 and late-stage type 2 diabetics, which limits the use of aggressive therapies in disease management. The etiology of this impaired counterregulation is not well understood. On the other hand, alpha cell dysfunction (impaired inhibition of glucagon secretion by glucose) leads to elevated fasting glucose levels and diminished early suppression of glucagon after glucose challenge. This form of impairment exacerbates type 2 diabetes and may contribute to its development and progression. I propose to study both forms of impairment. In oral glucose tolerance tests, diminished early suppression of glucagon followed by greater late glucagon suppression is observed in type 2 diabetics. This leads to worsened hyperglycemia followed by hypoglycemia. If the mechanism behind persistent glucagon suppression and delayed recovery is fully elucidated, it would be possible to protect against hypoglycemic events. I propose to explore the different mechanisms of somatostatin and GLP-1 mediated regulation of glucagon secretion by extending the parsimonious model of glucose-insulin- glucagon dynamics I developed. Reactive Hypoglycemia (RHG) occurs a few hours after ingesting a carbohydrate rich meal. Plasma glucose levels drop below 55 mg/dl and the patient displays neuroglycopenic symptoms which are relieved by glucose ingestion. There is currently no definitive explanation for this behavior. I will extend the glucose-insulin-glucagon minimal model I developed to include the other hormones and validate the model with data from OGTT studies of patients with RHG. I will also investigate the role of insulin in potentiating RHG. An overarching question in type 2 diabetes pathophysiology is the nature of disease progression from normal through prediabetic to overt diabetic state. The critical role of alpha cell dysfunction in disease development and progression has not yet been studied. I will interface the glucose-insulin-glucagon model I developed with existing disease progression models. This will identify the role of alpha cell dysfunction and glucagon action in development and acceleration of type 2 diabetes. I will study the etiology of hypoglycemia in aims 1 and 2 and the impact of alpha cell dysfunction in type 2 diabetes through longitudinal modeling of disease progression in aim 3.

建议书摘要 血糖水平维持在一个狭窄的范围内的动物的血糖平衡受到严格控制。 而由β细胞分泌的胰岛素通过促进有效的葡萄糖处置和抑制 当葡萄糖水平升高时，由阿尔法细胞分泌的高血糖素对肝脏释放葡萄糖起反调节作用。 当水平下降时，通过糖原分解和糖异生促进葡萄糖从肝脏释放。 肾上腺素、皮质醇和生长激素在葡萄糖逆调节中起支持作用。受损的 反调节反应可能导致低血糖，这是一种潜在的致命疾病。低血糖常常是 1型和晚期2型糖尿病患者所经历的，这限制了疾病中积极治疗的使用 管理层。这种受损的反调节机制的病因尚不清楚。另一方面，阿尔法 细胞功能障碍(葡萄糖对胰升糖素分泌的抑制作用减弱)会导致空腹血糖水平升高 减少葡萄糖刺激后早期对胰高血糖素的抑制。这种形式的损害加剧了 2糖尿病，并可能促进其发展和进展。我建议研究这两种形式的损害。 在口服葡萄糖耐量试验中，早期对胰高血糖素的抑制减弱，随后较晚期的高血糖素 在2型糖尿病患者中观察到抑制。这会导致更严重的高血糖，随后是低血糖。 如果持续的高血糖素抑制和延迟恢复背后的机制被完全阐明，它将是 有可能预防低血糖事件。我建议探索生长抑素的不同作用机制 而GLP-1通过扩展葡萄糖-胰岛素-胰岛素的简约模型来调节胰升糖素的分泌。 我开发的胰高血糖素动力学。反应性低血糖(RHG)发生在摄入一种 碳水化合物丰富的一餐。血糖水平降至55毫克/分升以下，患者表现出神经性血糖减少 通过摄入葡萄糖而缓解的症状。目前还没有对这一行为的明确解释。 我将扩展我开发的葡萄糖-胰岛素-胰高血糖素最小模型，以包括其他激素并验证 该模型采用了对RHG患者进行OGTT研究的数据。我还将研究胰岛素在体内的作用 增强RHG。2型糖尿病病理生理学的一个首要问题是疾病的性质。 从正常到糖尿病前期再到明显的糖尿病状态的进展。阿尔法细胞功能障碍在脑损伤中的关键作用 疾病的发展和进展尚未被研究。我会把葡萄糖-胰岛素-胰高血糖素 模型I是利用现有的疾病进展模型开发的。这将确定阿尔法细胞功能障碍的作用 以及胰升糖素在2型糖尿病的发生和加速中的作用。我要研究低血糖的病因学 在AIMS 1和2中，通过纵向建模研究阿尔法细胞功能障碍对2型糖尿病的影响 AIM 3的疾病进展。