Functional Heterogeneity Among Pancreatic Alpha Cells

胰腺α细胞的功能异质性

基本信息

批准号：
10019320
负责人：
Glyn M Noguchi
金额：
$ 3.77万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-23 至 2021-09-22
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10019320
关键词：
Address Adrenal Medulla Affect Alpha Cell Amino Acids Argipressin Autonomic nervous system Behavior Beta Cell Biosensor Blood Glucose Calcium Catecholamines Cell Shape Cell secretion Cells Cues Cyclic AMP Data Set Defect Diabetes Mellitus Diabetic mouse Dimensions Disease Effector Cell Endocrine Ensure Epinephrine Exhibits Functional disorder Glucagon Glucose Hepatic Heterogeneity Hormones Human Hyperglycemia Hypoglycemia Image Impairment Insulin Islet Cell Islets of Langerhans Knowledge Measurable Mediating Meta-Analysis Methods Mus Organ Output Oxytocin Pacemakers Physiological Population Research Research Personnel Role Signal Pathway Signal Transduction Source Stimulus Structure of alpha Cell of islet Subgroup Testing Therapeutic Thinness Time Tissue-Specific Gene Expression Treatment Efficacy base blood glucose regulation cell behavior cell type diabetic experimental study glucose production imaging modality interest islet novel pancreatic juice paracrine receptor relating to nervous system release factor response single-cell RNA sequencing transcriptomics

项目摘要

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.

项目概要胰岛的α细胞是体内胰高血糖素的主要来源，胰高血糖素充当 β细胞源性胰岛素的主要反调节激素。胰高血糖素动员肝葡萄糖产生增加血糖并防止低血糖，但除了对血糖状态做出反应外，α 细胞分泌是由许多其他信号介导的。其他α细胞效应物包括肾上腺素、精氨酸加压素、催产素和来自胰岛外的氨基酸。许多输入影响阿尔法细胞和迄今为止，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的运作方式。这种复杂性并不比糖尿病更明显，尽管近 50 对这个问题进行了多年的研究。更好地理解α细胞的机制对于发育至关重要解决糖尿病缺陷的有效疗法。在Huising实验室，我首创了一种对完整胰岛中的α细胞活性进行实时成像的方法，这样做大大增加了可测量的α细胞行为的吞吐量。我观察到 α细胞对不同刺激的异质反应，以前假设统一激活所有胰岛内的α细胞。这些观察结果导致了我的假设：α 细胞作为一个池而存在。对不同刺激做出反应的功能异质亚群。这些的相对分布亚型在糖尿病的情况下发生改变，导致疾病中胰高血糖素分泌的变化。在这个提案中，我的目标是量化健康和糖尿病小鼠中α细胞的异质反应和人类胰岛以及这如何影响胰高血糖素的总分泌。通过成功地利用我的高对完整胰岛中的钙和 cAMP 进行实时成像，以定义 α 细胞的功能异质性我将建立一个新的范式，通过这个范式，该领域可能需要考虑的不仅仅是阿尔法细胞，但胰岛细胞一般。成功证明了α细胞异质性的变化糖尿病有可能提供更有效的方法来使疾病中的胰高血糖素释放正常化。