Functional Heterogeneity Among Pancreatic Alpha Cells

项目摘要 胰岛的阿尔法细胞是体内胰高血糖素的主要来源，它起着 β细胞来源的胰岛素的主要逆调节激素。胰高血糖素动员肝脏葡萄糖产生 提高血糖和防止低血糖，但除了对血糖状态做出反应外，阿尔法 细胞分泌受多种其他信号的调节。在其他阿尔法细胞效应器中，有肾上腺素， 精氨酸加压素、催产素和来自胰岛外的氨基酸。影响阿尔法细胞的许多输入和 到目前为止，它们在胰岛中其他细胞类型中的不均匀分布阻止了研究人员产生 全面了解它们是如何运作的。这种复杂性并不比糖尿病更明显， 在胰岛素受损的情况下，尽管有近50人，但胰升糖素功能障碍仍未解决 多年来对这个问题的研究。更好地理解阿尔法细胞的机制对发展是至关重要的 有效的治疗方法来解决糖尿病的缺陷。 在惠兴实验室，我开创了一种实时成像完整胰岛中阿尔法细胞活动的方法， 通过这样做，极大地增加了可测量的阿尔法细胞行为的吞吐量。我观察到 阿尔法细胞对不同刺激的异质性反应先前假设统一激活ALL 胰岛内的阿尔法细胞。这些观察导致了我的假设，即阿尔法细胞作为一个池存在 对不同刺激做出反应的功能不同的亚群。它们的相对分布 在糖尿病的背景下，亚型会发生变化，导致疾病中出现的胰升糖素分泌的变化。 在这项提议中，我的目标是量化健康和糖尿病小鼠中阿尔法细胞的异质性反应 和人类的胰岛，以及这如何反映了总的胰高血糖素分泌。通过成功地利用我的快感 完整胰岛钙和cAMP的吞吐量实时成像以确定α细胞的功能异质性 激活I将建立一种新的范式，通过该范式，场可能需要考虑的不仅仅是阿尔法细胞， 但总的来说，胰岛细胞。在以下背景下成功证明了阿尔法细胞异质性的变化 糖尿病有可能提供更有效的方法，使疾病中的胰高血糖素释放正常化。

Project Summary The alpha cells of the pancreatic islet are the primary source of glucagon in the body, which serves as the main counterregulatory hormone to beta cell-derived insulin. Glucagon mobilizes hepatic glucose production to increase blood glucose and protect from hypoglycemia, but in addition to reacting to glycemic status, alpha cell secretion is mediated by a multitude of other signals. Among the other alpha cell effectors are epinephrine, arginine vasopressin, oxytocin, and amino acids from outside the islet. The many inputs affecting alpha cells and their uneven distribution amongst other cell types in the islet has so far precluded researchers from generating a comprehensive understanding of how they function. This complexity is no more apparent than in diabetes, where, in conjunction with insulin impairment, glucagon dysfunction remains unaddressed despite nearly 50 years of research on the issue. A better mechanistic understanding of alpha cells is paramount to developing effective therapeutics to address the defects in diabetes. In the Huising Lab, I have pioneered a method of imaging alpha cell activity in intact islets in real time, and in doing so vastly increased the throughput of measurable alpha cell behavior. I have observed heterogeneous responsiveness of alpha cells to different stimuli previously assumed to uniformly activate all alpha cells within an islet. These observations have led to my hypothesis that alpha cells exist as a pool of functionally heterogeneous subpopulations that respond to different stimuli. The relative distribution of these subtypes is altered in the context of diabetes, contributing to the changes in glucagon secretion seen in disease. In this proposal, I aim to quantify heterogeneous responses by alpha cells in healthy and diabetic mouse and human islets and how this reflects on the total glucagon secretion. By successfully leveraging my high throughput live imaging of both calcium and cAMP in intact islets to define functional heterogeneity in alpha cell activation I will have established a new paradigm by which the field may need to think about not just alpha cells, but the islet cells in general. Successful demonstration of changes in alpha cell heterogeneity in the context of diabetes has the potential to inform on more effective methods by which to normalize glucagon release in disease.