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 Ca²⁺ dynamics and thus insulin secretion (such as “first responders”, “leaders” and “hubs”, as defined by Ca²⁺ 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类等物种的葡萄糖稳态至关重要。这些细胞表现出显着的异质性，新兴研究表明，正常的胰岛素释放需要跨层次网络的连接。在这里，我们讨论当前关于胰岛内连接、细胞层次结构和潜在“控制”β细胞群的想法和争论领域。我们专注于方法学，包括不同细胞制剂的比较以及对人类和啮齿动物胰岛制剂的活性进行成像和控制的体外和体内方法。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 ²⁺动力学和胰岛素分泌方面发挥不成比例作用的关键细胞亚群（例如“第一响应者”、“领导者”和“ Hubs”，由 Ca ²⁺对葡萄糖刺激的反应定义）。还考虑了实现该等级的可能机制、其生理相关性以及其损失如何导致糖尿病中的胰岛衰竭。提供了术语表和计算资源链接。