CHUM Research Center and Faculty of Medicine, University of Montréal, Montréal, QC, Canada.
Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK.
Nat Metab. 2024 Nov;6(11):2039-2053. doi: 10.1038/s42255-024-01097-6. Epub 2024 Aug 8.
Functional pancreatic islet beta cells are essential to ensure glucose homeostasis across species from zebrafish to humans. These cells show significant heterogeneity, and emerging studies have revealed that connectivity across a hierarchical network is required for normal insulin release. Here, we discuss current thinking and areas of debate around intra-islet connectivity, cellular hierarchies and potential "controlling" beta-cell populations. We focus on methodologies, including comparisons of different cell preparations as well as in vitro and in vivo approaches to imaging and controlling the activity of human and rodent islet preparations. We also discuss the analytical approaches that can be applied to live-cell data to identify and study critical subgroups of cells with a disproportionate role in control Ca dynamics and thus insulin secretion (such as "first responders", "leaders" and "hubs", as defined by Ca responses to glucose stimulation). Possible mechanisms by which this hierarchy is achieved, its physiological relevance and how its loss may contribute to islet failure in diabetes mellitus are also considered. A glossary of terms and links to computational resources are provided.
功能性胰岛β细胞对于确保从斑马鱼到人等各种物种的葡萄糖内环境稳定至关重要。这些细胞表现出明显的异质性，新出现的研究表明，正常胰岛素释放需要分层网络之间的连通性。在这里，我们讨论了围绕胰岛内连通性、细胞层次结构和潜在的“控制”β细胞群体的当前思维和争议领域。我们重点介绍了方法学，包括比较不同细胞制剂以及体外和体内成像和控制人类和啮齿动物胰岛制剂活性的方法。我们还讨论了可应用于活细胞数据的分析方法，以识别和研究在控制 Ca 动力学和胰岛素分泌中具有不成比例作用的关键细胞亚群（例如，根据葡萄糖刺激的 Ca 反应定义的“第一反应者”、“领导者”和“枢纽”）。还考虑了实现这种层次结构的可能机制、其生理相关性以及其丧失如何导致糖尿病中胰岛衰竭。提供了术语表和计算资源链接。
