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

提案摘要 在动物中，葡萄糖稳态受到严格控制，血浆葡萄糖水平维持在狭窄范围内。 而β细胞分泌的胰岛素通过促进有效的葡萄糖处理和抑制葡萄糖代谢来调节血糖， 当葡萄糖水平升高时，由α细胞分泌的胰高血糖素会反调节葡萄糖从肝脏释放 当水平下降时，通过糖原分解和糖原生成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反调节中起辅助作用。受损 反调节反应可导致低血糖症，这是一种潜在的致命疾病。低血糖症经常 1型和晚期2型糖尿病患者所经历的，这限制了在疾病中使用积极治疗 管理这种受损的反调节的病因还不清楚。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）导致空腹血糖水平升高 并且在葡萄糖激发后降低了胰高血糖素的早期抑制。这种形式的损害加剧了类型 2型糖尿病，并可能有助于其发展和进展。我建议研究这两种形式的损害。 在口服葡萄糖耐量试验中，胰高血糖素早期抑制作用减弱，随后胰高血糖素晚期抑制作用增强。 在2型糖尿病患者中观察到抑制。这导致高血糖恶化，随后是低血糖。 如果持续性胰高血糖素抑制和延迟恢复的机制得到充分阐明， 可以预防低血糖事件。我建议探索生长抑素的不同机制 和GLP-1介导的胰高血糖素分泌调节，通过扩展葡萄糖-胰岛素- 我开发的胰高血糖素动力学反应性低血糖（RHG）发生在服药后几小时。 富含碳水化合物的食物。血浆葡萄糖水平降至55 mg/dl以下，患者表现出神经性低血糖 通过摄入葡萄糖缓解的症状。目前对这种行为没有明确的解释。 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 该模型的数据来自RHG患者的OGTT研究。我还将研究胰岛素在 增强RHG。2型糖尿病病理生理学的首要问题是疾病的性质 从正常到糖尿病前期到明显的糖尿病状态的进展。α细胞功能障碍在 疾病的发展和进展尚未研究。我会把葡萄糖胰岛素胰高血糖素 我用现有的疾病进展模型开发的模型。这将确定阿尔法细胞功能障碍的作用 和胰高血糖素在2型糖尿病的发展和加速中的作用。我会研究低血糖的病因 在目标1和2中，通过纵向建模， 目标3中的疾病进展。

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.