@article{d6b40d51e89647608753cae4668763a8,
title = "Mechanism and effects of pulsatile GABA secretion from cytosolic pools in the human beta cell",
abstract = "Pancreatic beta cells synthesize and secrete the neurotransmitter GABA (γ-aminobutyric acid) as a paracrine and autocrine signal to help regulate hormone secretion and islet homeostasis. Islet GABA release has classically been described as a secretory-vesicle-mediated event. Yet, a limitation of the hypothesized vesicular GABA release from islets is the lack of expression of a vesicular GABA transporter in beta cells. Consequentially, GABA accumulates in the cytosol. Here, we provide evidence that the human beta cell effluxes GABA from a cytosolic pool in a pulsatile manner, imposing a synchronizing rhythm on pulsatile insulin secretion. The volume regulatory anion channel, functionally encoded by LRRC8A or Swell1, is critical for pulsatile GABA secretion. GABA content in beta cells is depleted and secretion is disrupted in islets from patients with type 1 and type 2 diabetes, suggesting that loss of GABA as a synchronizing signal for hormone output may correlate with diabetes pathogenesis.",
author = "Danusa Menegaz and Hagan, {D. Walker} and Joana Alma{\c c}a and Chiara Cianciaruso and Rayner Rodriguez-Diaz and Judith Molina and Dolan, {Robert M.} and Becker, {Matthew W.} and Schwalie, {Petra C.} and Rita Nano and Fanny Lebreton and Chen Kang and Rajan Sah and Gaisano, {Herbert Y.} and Berggren, {Per Olof} and Steinunn Baekkeskov and Alejandro Caicedo and Phelps, {Edward A.}",
note = "Funding Information: Human pancreas tissues. Human pancreatic sections from tissue donors of both sexes were obtained via the Network for Pancreatic Organ Donors with Diabetes (nPOD) tissue bank, University of Florida. Human pancreata were harvested from cadaveric organ donors by certified organ procurement organizations partnering with nPOD in accordance with organ donation laws and regulations and classified as {\textquoteleft}Non-Human Subjects{\textquoteright} by the University of Florida Institutional Review Board (IRB) (IRB no. 392-2008), waiving the need for consent98,99. nPOD tissues specifically used for this project were approved as nonhuman by the University of Florida IRB (IRB no. 201701113). Human pancreatic islets were obtained from deceased nondiabetic donors and from donors with type 2 diabetes from the Human Islet Cell Processing Facility at the Diabetes Research Institute at the University of Miami Miller School of Medicine, from the National Institute of Diabetes and Digestive and Kidney Diseases-funded Integrated Islet Distribution Program at City of Hope, from the European Consortium on Islet Transplantation Islets for Basic Research Program and from Prodo Laboratories. Human pancreatic islets from deceased donors with type 1 diabetes were isolated by the nPOD Islet Isolation Program. Human islets received from the University Hospital of Geneva and San Raffaele Scientific Institute, Milan, through the European Consortium on Islet Transplantation Islets for Basic Research Program were approved by the IRB of the University Hospital of Geneva and Commission Cantonale d{\textquoteright}Ethique de la Recherche (CCER no. 05-028) and by the Ethics Committee of the San Raffaele Scientific Institute of Milan (IPF002-2014). The University of Geneva and the San Raffaele Institute Ethics Committees waived the need for consent from the donors because islets were used for experimental research only when not suitable for clinical purposes and would otherwise have been destined for destruction. In such cases, obtaining informed consent is not mandatory in Switzerland and Italy. Cadaveric human islets for research were approved as nonhuman by the University of Florida IRB (IRB no. 201702860). Funding Information: This work was funded by the Intramural Research Program of UF{\textquoteright}s Wertheim College of Engineering and J. Crayton Pruitt Family Department of Biomedical Engineering (E.A.P.), the Intramural Research Program of EPFL{\textquoteright}s School of Life Sciences (S.B.), the Diabetes Research Institute Foundation, NIH grant nos. R56DK084321 (A.C.), R01DK084321 (A.C.) and R01DK106009 (R.S.), the NIDDK-supported Human Islet Research Network (HIRN, RRID:SCR_014393; https://hirnetwork.org; grant no. UC4DK104208 (E.A.P)), a JDRF award (grant no. 31-2008-416) to the European Consortium for Islet Transplantation (ECIT) Islets for Basic Research Program, a JDRF Faculty Transition Award (grant no. 1-FAC-2017-367-A-N) (E.A.P.), a JDRF Advanced Postdoctoral Fellowship (grant no. 3-APF-2014-208-A-N) (E.A.P.), a Whitaker International Program Postdoctoral Scholarship (E.A.P.), The Shepard Broad Foundation (E.A.P.), the Swedish Research Council (P.-O.B.), the Novo Nordisk Foundation (P.-O.B.), the Family Erling-Persson Foundation (P.-O.B.), the Stichting af Jochnick Foundation (P.-O.B.), the American Diabetes Association (grant no. 1-18-IBS-229) (R.S.) and the Canadian Institutes for Health Research (grant nos. PJT-159741 and PJT-148652) (H.Y.G.). Human pancreatic islets were provided by the NIDDK-funded Integrated Islet Distribution Program (IIDP) at City of Hope, NIH grant no. 2UC4DK098085, and the JDRF-funded IIDP Islet Award Initiative (E.A.P.). This research was performed with the support of the Network for Pancreatic Organ donors with Diabetes (nPOD; RRID:SCR_014641), a collaborative type 1 diabetes research project sponsored by JDRF (grant no. 5-SRA-2018-557-Q-R) and The Leona M. & Harry B. Helmsley Charitable Trust (grant no. 2018PG-T1D053). The content and views expressed are the responsibility of the authors and do not necessarily reflect the official view of nPOD. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2019",
month = nov,
day = "1",
doi = "10.1038/s42255-019-0135-7",
language = "English",
volume = "1",
pages = "1110--1126",
journal = "Nature Metabolism",
issn = "2522-5812",
number = "11",
}