Journal article

Atp6ap2 deletion causes extensive vacuolation that consumes the insulin content of pancreatic beta cells

Katrina J Binger, Martin Neukam, Sudhir Gopal Tattikota, Fatimunnisa Qadri, Dmytro Puchkov, Diana M Willmes, Sabrina Wurmsee, Sabrina Geisberger, Ralf Dechend, Klemens Raile, Thomas Kurth, Genevieve Nguyen, Matthew N Poy, Michele Solimena, Dominik N Muller, Andreas L Birkenfeld

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | NATL ACAD SCIENCES | Published : 2019

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 com..

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Grants

Awarded by Australian National Health Medical Research Council (NHMRC) fellowship


Awarded by German Research Foundation


Awarded by German Research Foundation (DFG)


Awarded by German-Israeli Foundation


Funding Acknowledgements

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).