@article{fcff33b23c894c25b257353f01503cbd,
title = "Beta Cell Hubs Dictate Pancreatic Islet Responses to Glucose",
abstract = "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.",
keywords = "diabetes, imaging, insulin, islets, optogenetics, β cells",
author = "Johnston, {Natalie R.} and Mitchell, {Ryan K.} and Elizabeth Haythorne and Pessoa, {Maria Paiva} and Francesca Semplici and Jorge Ferrer and Lorenzo Piemonti and Piero Marchetti and Marco Bugliani and Domenico Bosco and Ekaterine Berishvili and Philip Duncanson and Michael Watkinson and Johannes Broichhagen and Dirk Trauner and Rutter, {Guy A.} and Hodson, {David J.}",
note = "Funding Information: N.R.J. was supported by a Diabetes UK RW and JM Collins Studentship (12/0004601). J.B. was supported by a European Foundation for the Study of Diabetes (EFSD) Albert Renold Young Scientist Fellowship and a Studienstiftung des deutschen Volkes PhD Studentship. D.T. was supported by an Advanced Grant from the European Research Commission (268795). G.A.R. was supported by Wellcome Trust Senior Investigator (WT098424AIA) and Royal Society Wolfson Research Merit Awards, and by MRC Programme (MR/J0003042/1), Biological and Biotechnology Research Council (BB/J015873/1), and Diabetes UK Project (11/0004210) grants. G.A.R. and M.W. acknowledge COST Action TD1304 Zinc-Net. D.J.H. was supported by Diabetes UK R.D. Lawrence (12/0004431), EFSD/Novo Nordisk Rising Star and Birmingham Fellowships, a Wellcome Trust Institutional Support Award, and an MRC Project Grant (MR/N00275X/1) with G.A.R. D.J.H and G.A.R. were supported by Imperial Confidence in Concept (ICiC) Grants. J.F. was supported by an MRC Programme grant (MR/L02036X/1). L.P. provided human islets through collaboration with the Diabetes Research Institute, IRCCS San Raffaele Scientific Institute (Milan), within the European islet distribution program for basic research supported by JDRF (1-RSC-2014-90-I-X). P.M. and M.B. were supported by the Innovative Medicine Initiative Joint Undertaking under grant agreement no. 155005 (IMIDIA), resources of which are composed of financial contribution from the European Union{\textquoteright}s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution, and by the Italian Ministry of University and Research (PRIN 2010-2012). D.B. and E.B. provided human islets through the European Consortium for Islet Transplantation sponsored by JDRF (1-RSC-2014-100-I-X). We are grateful to Drs. Richard K.P. Benninger (University of Colorado Denver), Francois Molino (Universit{\'e} Montpellier II), and Stephen Rothery (FILM Facility, Imperial College London) for useful discussion. The authors have no conflicts of interest to disclose. Publisher Copyright: {\textcopyright} 2016 The Author(s)",
year = "2016",
month = sep,
day = "13",
doi = "10.1016/j.cmet.2016.06.020",
language = "English (US)",
volume = "24",
pages = "389--401",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "3",
}