@article{cd2f0f638d964c01b396dd28ab3fbc21,
title = "Pancreatic beta-Cell-Specific Deletion of VPS41 Causes Diabetes Due to Defects in Insulin Secretion",
abstract = "Insulin secretory granules (SGs) mediate the regulated secretion of insulin, which is essential for glucose homeostasis. The basic machinery responsible for this regulated exocytosis consists of specific proteins present both at the plasma membrane and on insulin SGs. The protein composition of insulin SGs thus dictates their release properties, yet the mechanisms controlling insulin SG formation, which determine this molecular composition, remain poorly understood. VPS41, a component of the endolysosomal tethering homotypic fusion and vacuole protein sorting (HOPS) complex, was recently identified as a cytosolic factor involved in the formation of neuroendocrine and neuronal granules. We now find that VPS41 is required for insulin SG biogenesis and regulated insulin secretion. Loss of VPS41 in pancreatic β-cells leads to a reduction in insulin SG number, changes in their transmembrane protein composition, and defects in granule-regulated exocytosis. Exploring a human point mutation, identified in patients with neurological but no endocrine defects, we show that the effect on SG formation is independent of HOPS complex formation. Finally, we report that mice with a deletion of VPS41 specifically in β-cells develop diabetes due to severe depletion of insulin SG content and a defect in insulin secretion. In sum, our data demonstrate that VPS41 contributes to glucose homeostasis and metabolism.",
author = "Burns, {Christian H} and Belinda Yau and Anjelica Rodriguez and Jenna Triplett and Drew Maslar and An, {You Sun} and {van der Welle}, {Reini E N} and Kossina, {Ross G} and Fisher, {Max R} and Strout, {Gregory W} and Bayguinov, {Peter O} and Tineke Veenendaal and David Chitayat and Fitzpatrick, {James A J} and Judith Klumperman and Kebede, {Melkam A} and Asensio, {Cedric S}",
note = "Funding Information: Acknowledgments. The authors thank Peter Arvan (University of Michigan, Ann Arbor, MI) for the INS-1 cell line and Yoh Wada (Osaka University, Osaka, Japan) for the VPS41fl/fl mice. PC1/3 antibody was a gift from Dick Mains (University of Connecticut, Farmington, CT) and Betty Eipper (University of Connecticut, Farmington, CT). Funding. The Washington University Center for Cellular Imaging was supported by Washington University School of Medicine, the Children{\textquoteright}s Discovery Institute of Washington University and St. Louis Children{\textquoteright}s Hospital (CDI-CORE-2015-505 and CDI-CORE-2019-813 to J.A.J.F.), the Foundation for Barnes-Jewish Hospital (3770 to J.A.J.F.), and the Washington University Diabetes Research Center (P30 DK020579). M.A.K. is supported by a Jennie Mackenzie Philanthropic Fellowship, The University of Sydney. Y.S.A. is a recipient of an Australian Postgraduate Scholarship. J.K. and R.E.N.v.d.W. are supported by the Deutsche Forschungsgemeinschaft FOR2625. This work was supported by American Diabetes Association grant 1-17-JDF-064 and National Institute of General Medical Sciences grants R01 GM124035 and R15 GM116096 to C.S.A. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. C.H.B. conducted in vitro experiments, acquired and analyzed data, and wrote the manuscript. B.Y. and Y.S.A. conducted in vivo experiments and acquired and analyzed data. A.R., J.T., D.M., R.E.N.v.d.W., and T.V. conducted in vitro experiments and acquired and analyzed data. R.G.K. and G.W.S. conducted the thin-section EM. M.R.F. and P.O.B. conducted the array tomography experiments. D.C. identified the S285P human mutation. J.A.J.F., J.K., and M.A.K. supervised the study and edited the manuscript. C.S.A. designed the study, analyzed data, supervised the study, and wrote the manuscript. C.S.A. is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. A non–peer-reviewed version of this article was submitted to the BioRxiv preprint server (https://www.biorxiv.org/content/10 .1101/2019.12.18.867333v1) on 20 December 2019. This work was presented at the 79th Scientific Sessions of the American Diabetes Association, San Francisco, CA, 7–11 June 2019 and at the Keystone Symposium on Diabetes: Glucose Control and Beyond, Santa Fe, NM, 27–31 January 2020. Publisher Copyright: {\textcopyright} 2020 by the American Diabetes Association.",
year = "2021",
month = feb,
day = "1",
doi = "10.2337/db20-0454",
language = "English",
volume = "70",
pages = "436--448",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "2",
}