Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Edgbaston, United Kingdom.
Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, United Kingdom; Lee Kong Chian School of Medicine, Nan Yang Technological University, Singapore.
J Mol Biol. 2020 Mar 6;432(5):1395-1406. doi: 10.1016/j.jmb.2019.08.005. Epub 2019 Aug 13.
Metabolic and secretory heterogeneity are fundamental properties of pancreatic islet β cells. Emerging data suggest that stable differences in the transcriptome and proteome of individual cells may create cellular hierarchies, which, in turn, establish coordinated functional networks. These networks appear to govern the secretory activity of the whole islet and be affected in some forms of diabetes mellitus. Functional imaging, for example, of intracellular calcium dynamics, has led to the demonstration of "small worlds" behavior, and the identification of highly connected "hub" (or "leader") cells and of follower populations subservient to them. Subsequent inactivation of members of either population, for example, using optogenetic approaches or photoablation, has confirmed the importance of hub cells as possible pacemakers. Hub cells appear to be enriched for the glucose phosphorylating enzyme glucokinase and for genes encoding other enzymes involved in glucose metabolism compared to follower cells. Recent findings have shown the relevance of cellular hierarchy in islets from multiple species including human, mouse and fish, and shown that it is preserved in vivo in the context of the fully vascularized and innervated islet. Importantly, connectivity is impaired by insults, which mimic the diabetic milieu, including high glucose and/or fatty levels, and by the ablation of genes associated with type 2 diabetes risk in genome-wide association studies. We discuss here the evidence for the existence of these networks and their failure in disease settings. We also briefly survey the challenges in understanding their properties.
代谢和分泌异质性是胰岛β细胞的基本特性。新出现的数据表明，单个细胞的转录组和蛋白质组的稳定差异可能会产生细胞层次结构，进而建立协调的功能网络。这些网络似乎控制着整个胰岛的分泌活动，并在某些形式的糖尿病中受到影响。例如，对细胞内钙动力学的功能成像导致了“小世界”行为的证明，并确定了高度连接的“枢纽”（或“领导者”）细胞和服从它们的跟随者群体。随后，使用光遗传学方法或光消融等方法对任何群体的成员进行失活，证实了枢纽细胞作为可能的起搏器的重要性。与跟随细胞相比，枢纽细胞似乎富含葡萄糖磷酸化酶葡萄糖激酶和编码其他参与葡萄糖代谢的酶的基因。最近的发现表明，细胞层次结构在包括人类、小鼠和鱼类在内的多种物种的胰岛中具有相关性，并表明它在完全血管化和神经支配的胰岛的体内环境中得以保留。重要的是，连接性受到损伤的影响，这些损伤模拟了糖尿病环境，包括高葡萄糖和/或脂肪水平，以及与全基因组关联研究中 2 型糖尿病风险相关的基因的消融。在这里，我们讨论了存在这些网络及其在疾病状态下失效的证据。我们还简要调查了理解它们特性的挑战。
