Metabolic and Functional Heterogeneity in Pancreatic β Cells

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.