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.

提案摘要 葡萄糖稳态受到血浆葡萄糖水平保持在狭窄范围的动物的严格控制。 胰岛素（由β细胞分泌）通过促进有效的葡萄糖处置和抑制来调节 当葡萄糖水平升高时，葡萄糖从肝脏释放，胰高血糖素，由α细胞分泌，反调节 通过在水平下降时通过糖原分解和糖异生从肝脏释放的葡萄糖释放。 肾上腺素，皮质醇和生长激素在葡萄糖反调节中起支持作用。受损 反调节反应会导致低血糖，这是一种潜在的致命状况。低血糖经常是 按1型和后期2型糖尿病患者体验，这限制了疾病中侵略性疗法的使用 管理。这种受损的反调节的病因尚未得到充分理解。另一方面，阿尔法 细胞功能障碍（葡萄糖对胰高血糖素分泌的抑制受损）导致空腹葡萄糖水平升高 并减少了葡萄糖挑战后胰高血糖素的早期抑制。这种障碍形式加剧了类型 2种糖尿病，可能有助于其发展和进展。我建议研究两种形式的损害。 在口服葡萄糖耐量测试中，早期抑制胰高血糖素，然后降低了胰高血糖素 在2型糖尿病患者中观察到抑制作用。这导致高血糖恶化，随后血糖症。 如果完全阐明了持续的胰高血糖素抑制和延迟恢复背后的机制，那将是 可以防止降血糖事件。我建议探索生长抑素的不同机制 GLP-1通过扩展葡萄糖 - 胰岛素的良性模型来介导的胰高血糖素分泌的调节 我开发的胰高血糖素动力学。反应性低血糖（RHG）摄入几个小时后发生 碳水化合物富餐。血浆葡萄糖水平降至55 mg/dL以下，患者显示神经胶质细胞减少症 摄入葡萄糖可以缓解的症状。目前对这种行为没有明确的解释。 我将延长我开发的葡萄糖 - 胰岛素 - 葡萄糖素模型，以包括其他激素并验证 来自OGTT研究患者的数据的模型。我还将研究胰岛素在 增强RHG。 2型糖尿病病理生理学中的总体问题是疾病的性质 从正常到糖尿病前期到明显的糖尿病状态的进展。 α细胞功能障碍的关键作用在 尚未研究疾病的发展和进展。我将连接葡萄糖 - 胰岛素 - 葡萄糖葡萄糖 我使用现有疾病进展模型开发的模型。这将确定α细胞功能障碍的作用 以及胰高血糖素在2型糖尿病的发育和加速中的作用。我将研究低血糖的病因 在目标1和2中以及α细胞功能障碍在2型糖尿病中的影响通过纵向建模 目标3中的疾病进展。