Beta Cell Hubs Dictate Pancreatic Islet Responses to Glucose

• DOI: 10.1016/j.cmet.2016.06.020
• Publication Date: 2016-07-21T22:52:34Z
• Authors: Natalie R. Johnston; Ryan K. Mitchell; Elizabeth Haythorne; Maria Paiva Pessoa; Francesca Semplici; Jorge Ferrer; Lorenzo Piemonti; Piero Marchetti; Marco Bugliani; Domenico Bosco; Ekaterine Berishvili; Philip Duncanson; Michael Watkinson; Johannes Broichhagen; Dirk Trauner; Guy A. Rutter; David J. Hodson
• Keywords: HOMEOSTASIS; Light; Optical Phenomena; Physiology; COMMUNICATION; 0601 Biochemistry and Cell Biology; ACTIVATION; CA2+; Mice; Insulin-Secreting Cells; Insulin Secretion; Homeostasis; Insulin; HETEROGENEITY; QD; glucose; islets; ddc:617; diabetes; RC660; imaging; Cell Differentiation; diabetes; imaging; insulin; islets; optogenetics; β cells; Physiology; Molecular Biology; Cell Biology; β cells; Glucose/pharmacology; Lipids; HALORHODOPSIN; Phenotype; 1101 Medical Biochemistry and Metabolomics; Calcium Signaling/drug effects/radiation effects; diabetes mellitus; Metabolome; light; Life Sciences & Biomedicine; insulin; mice; Insulin-Secreting Cells/drug effects/metabolism; Diabetes Mellitus/pathology; calcium signaling; INSULIN-SECRETION; Article; lipids; Endocrinology & Metabolism; diabetes; imaging; insulin; islets; optogenetics; Î2 cells; Animals; Calcium Signaling; Cell Differentiation; Computer Systems; Diabetes Mellitus; Glucose; Homeostasis; Humans; Insulin; Insulin-Secreting Cells; Light; Lipids; Metabolome; Metabolomics; Mice; Optical Phenomena; Phenotype; Species Specificity; Physiology; Molecular Biology; Cell Biology; Species Specificity; Computer Systems; 617; computer systems; Journal Article; OSCILLATIONS; Diabetes Mellitus; Animals; Humans; Metabolomics; Calcium Signaling; optogenetics; Molecular Biology; Insulin/secretion; Science & Technology; CHANNELS; Metabolome/drug effects; Cell Biology; Lipids/toxicity; DYSFUNCTION; SYNCHRONY; species specificity; Glucose; Cell Differentiation/drug effects; Homeostasis/drug effects/radiation effects

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.