Beta Cell Hubs Dictate Pancreatic Islet Responses to Glucose

• Published in: Cell metabolism Vol. 24; no. 3; pp. 389 - 401
• Main Authors: Johnston, Natalie R., Mitchell, Ryan K., Haythorne, Elizabeth, Pessoa, Maria Paiva, Semplici, Francesca, Ferrer, Jorge, Piemonti, Lorenzo, Marchetti, Piero, Bugliani, Marco, Bosco, Domenico, Berishvili, Ekaterine, Duncanson, Philip, Watkinson, Michael, Broichhagen, Johannes, Trauner, Dirk, Rutter, Guy A., Hodson, David J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.09.2016; Cell Press
• Subjects: Animals; Calcium Signaling - drug effects; Calcium Signaling - radiation effects; Cell Differentiation - drug effects; Computer Systems; diabetes; Diabetes Mellitus - pathology; Glucose - pharmacology; Homeostasis - drug effects; Homeostasis - radiation effects; Humans; imaging; insulin; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; islets; Light; Lipids - toxicity; Metabolome - drug effects; Metabolomics; Mice; Optical Phenomena; optogenetics; Phenotype; Species Specificity; β cells; insulin; diabetes; imaging; islets; β cells; optogenetics
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2016.06.020

The arrangement of β cells within islets of Langerhans is critical for insulin release through the generation of rhythmic activity. A privileged role for individual β cells in orchestrating these responses has long been suspected, but not directly demonstrated. We show here that the β cell population in situ is operationally heterogeneous. Mapping of islet functional architecture revealed the presence of hub cells with pacemaker properties, which remain stable over recording periods of 2 to 3 hr. Using a dual optogenetic/photopharmacological strategy, silencing of hubs abolished coordinated islet responses to glucose, whereas specific stimulation restored communication patterns. Hubs were metabolically adapted and targeted by both pro-inflammatory and glucolipotoxic insults to induce widespread β cell dysfunction. Thus, the islet is wired by hubs, whose failure may contribute to type 2 diabetes mellitus. [Display omitted] •Optogenetic targeting reveals a pacemaker-like β cell subpopulation•These cells, termed hubs, are required for normal insulin release•Hubs are highly metabolic and transcriptionally immature•Hubs are targeted by a diabetic milieu to induce islet failure Combining optogenetics and photopharmacology, Johnston et al. show that a few (1%–10%) β cells exert disproportionate control over islet responses to glucose. These specialized cells, called hubs, are transcriptionally immature and highly metabolic. Their failure during type 2 diabetes mellitus may lead to reduced insulin secretion and impaired glucose homeostasis.