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 动物体内的血糖稳态受到严格控制，血浆葡萄糖水平维持在一个狭窄的范围内。 而由 β 细胞分泌的胰岛素则通过促进有效的葡萄糖处理和抑制 当葡萄糖水平升高时，肝脏释放葡萄糖，α细胞分泌的胰高血糖素会反向调节 当水平下降时，通过糖原分解和糖异生促进肝脏释放葡萄糖。 肾上腺素、皮质醇和生长激素在葡萄糖反调节中发挥支持作用。受损 反调节反应可能导致低血糖，这是一种潜在的致命疾病。低血糖很常见 1 型和晚期 2 型糖尿病患者会经历这种情况，这限制了积极治疗方法的使用 管理。这种反监管受损的原因尚不清楚。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作用受损）导致空腹血糖水平升高 并减少葡萄糖挑战后胰高血糖素的早期抑制。这种形式的损伤加剧了类型 2 型糖尿病，并可能促进其发生和进展。我建议研究这两种形式的障碍。 在口服葡萄糖耐量试验中，早期胰高血糖素抑制减弱，随后晚期胰高血糖素增强 在 2 型糖尿病患者中观察到抑制。这导致高血糖恶化，随后出现低血糖。 如果胰高血糖素持续抑制和延迟恢复背后的机制得到充分阐明，那么 可能预防低血糖事件。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-的简约模型介导胰高血糖素分泌调节 我开发的胰高血糖素动力学。反应性低血糖 (RHG) 发生在摄入 富含碳水化合物的膳食。血浆葡萄糖水平降至 55 mg/dl 以下，患者出现神经性低血糖 摄入葡萄糖可缓解症状。目前对于这种行为还没有明确的解释。 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 该模型采用 RHG 患者 OGTT 研究数据。我还将研究胰岛素的作用 增强 RHG。 2 型糖尿病病理生理学的一个首要问题是疾病的本质 从正常状态经过糖尿病前期到明显糖尿病状态的进展。 α细胞功能障碍的关键作用 疾病的发生和进展尚未被研究。我将连接葡萄糖-胰岛素-胰高血糖素 我用现有的疾病进展模型开发了模型。这将确定α细胞功能障碍的作用 和胰高血糖素在 2 型糖尿病发展和加速中的作用。我将研究低血糖的病因 通过纵向建模，研究目标 1 和 2 以及 α 细胞功能障碍对 2 型糖尿病的影响 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.