@article{329e56295b634eb6a7834f359e69d38d,
title = "Atp6ap2 deletion causes extensive vacuolation that consumes the insulin content of pancreatic β cells",
abstract = "Pancreatic β cells store insulin within secretory granules which undergo exocytosis upon elevation of blood glucose levels. Crinophagy and autophagy are instead responsible to deliver damaged or old granules to acidic lysosomes for intracellular degradation. However, excessive consumption of insulin granules can impair β cell function and cause diabetes. Atp6ap2 is an essential accessory component of the vacuolar ATPase required for lysosomal degradative functions and autophagy. Here, we show that Cre recombinase-mediated conditional deletion of Atp6ap2 in mouse β cells causes a dramatic accumulation of large, multigranular vacuoles in the cytoplasm, with reduction of insulin content and compromised glucose homeostasis. Loss of insulin stores and gigantic vacuoles were also observed in cultured insulinoma INS-1 cells upon CRISPR/Cas9-mediated removal of Atp6ap2. Remarkably, these phenotypic alterations could not be attributed to a deficiency in autophagy or acidification of lysosomes. Together, these data indicate that Atp6ap2 is critical for regulating the stored insulin pool and that a balanced regulation of granule turnover is key to maintaining β cell function and diabetes prevention.",
keywords = "(pro)renin receptor, Autophagy, Diabetes, Vacuolar H ATPase",
author = "Binger, {Katrina J.} and Martin Neukam and Tattikota, {Sudhir Gopal} and Fatimunnisa Qadri and Dmytro Puchkov and Willmes, {Diana M.} and Sabrina Wurmsee and Sabrina Geisberger and Ralf Dechend and Klemens Raile and Thomas Kurth and Genevieve Nguyen and Poy, {Matthew N.} and Michele Solimena and Muller, {Dominik N.} and Birkenfeld, {Andreas L.}",
note = "Funding Information: We thank Jana Czychi, Ilona Kamer, Francesca Spagnoli, and Thomas Rathjen (all MDC-Berlin), Prof. Gil Leibowitz (The Hebrew University of Jerusalem), Prof. Paul Gleeson (The University of Melbourne), and Anthony Rousselle for generously providing the Atp6ap2flox/+;R26YFPflox/flox mice (MDC-Berlin). K.J.B. was funded for this study by an Australian National Health Medical Research Council (NHMRC) fellowship (APP1037633). A.L.B. and D.M.W. were supported by the German Research Foundation (BI1292/4-2, BI1292/9-1, BI1292/10-1, BI1292/12-1, and IRTG2251). D.N.M. was supported by the German Research Foundation (DFG; 394046635 - SFB1365) and the German Center for Cardiovascular Research. M.N. was supported by a Dresden International Graduate School for Biomedicine and Bioengineering (DIGS-BB) PhD fellowship. M.S. was supported by the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research and by the German–Israeli Foundation (I-1429-201.2/2017). Funding Information: ACKNOWLEDGMENTS. We thank Jana Czychi, Ilona Kamer, Francesca Spagnoli, and Thomas Rathjen (all MDC-Berlin), Prof. Gil Leibowitz (The Hebrew University of Jerusalem), Prof. Paul Gleeson (The University of Melbourne), and Anthony Rousselle for generously providing the Atp6ap2flox/+;R26YFPflox/flox mice (MDC-Berlin). K.J.B. was funded for this study by an Australian National Health Medical Research Council (NHMRC) fellowship (APP1037633). A.L.B. and D.M.W. were supported by the German Research Foundation (BI1292/4-2, BI1292/9-1, BI1292/10-1, BI1292/12-1, and IRTG2251). D.N.M. was supported by the German Research Foundation (DFG; 394046635 - SFB1365) and the German Center for Cardiovascular Research. M.N. was supported by a Dresden International Graduate School for Biomedicine and Bioengineering (DIGS-BB) PhD fellowship. M.S. was supported by the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research and by the German–Israeli Foundation (I-1429-201.2/2017). Publisher Copyright: {\textcopyright} 2019 National Academy of Sciences. All rights reserved.",
year = "2019",
doi = "10.1073/pnas.1903678116",
language = "English (US)",
volume = "116",
pages = "19983--19988",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "40",
}