Atp6ap2 deletion causes extensive vacuolation that consumes the insulin content of pancreatic β 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 Poy, Michele Solimena, Dominik N. Muller, Andreas L. Birkenfeld

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)19983-19988
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number40
DOIs
StatePublished - Jan 1 2019

Fingerprint

Insulin
Autophagy
Vacuoles
Lysosomes
Clustered Regularly Interspaced Short Palindromic Repeats
Vacuolar Proton-Translocating ATPases
Insulinoma
Exocytosis
Secretory Vesicles
Blood Glucose
Cytoplasm
Homeostasis
Glucose

Keywords

  • (pro)renin receptor
  • Autophagy
  • Diabetes
  • Vacuolar H ATPase

ASJC Scopus subject areas

  • General

Cite this

Atp6ap2 deletion causes extensive vacuolation that consumes the insulin content of pancreatic β cells. / Binger, Katrina J.; Neukam, Martin; Tattikota, Sudhir Gopal; Qadri, Fatimunnisa; Puchkov, Dmytro; Willmes, Diana M.; Wurmsee, Sabrina; Geisberger, Sabrina; Dechend, Ralf; Raile, Klemens; Kurth, Thomas; Nguyen, Genevieve; Poy, Matthew; Solimena, Michele; Muller, Dominik N.; Birkenfeld, Andreas L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 40, 01.01.2019, p. 19983-19988.

Research output: Contribution to journalArticle

Binger, KJ, Neukam, M, Tattikota, SG, Qadri, F, Puchkov, D, Willmes, DM, Wurmsee, S, Geisberger, S, Dechend, R, Raile, K, Kurth, T, Nguyen, G, Poy, M, Solimena, M, Muller, DN & Birkenfeld, AL 2019, 'Atp6ap2 deletion causes extensive vacuolation that consumes the insulin content of pancreatic β cells', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 40, pp. 19983-19988. https://doi.org/10.1073/pnas.1903678116
Binger, Katrina J. ; Neukam, Martin ; Tattikota, Sudhir Gopal ; Qadri, Fatimunnisa ; Puchkov, Dmytro ; Willmes, Diana M. ; Wurmsee, Sabrina ; Geisberger, Sabrina ; Dechend, Ralf ; Raile, Klemens ; Kurth, Thomas ; Nguyen, Genevieve ; Poy, Matthew ; Solimena, Michele ; Muller, Dominik N. ; Birkenfeld, Andreas L. / Atp6ap2 deletion causes extensive vacuolation that consumes the insulin content of pancreatic β cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 40. pp. 19983-19988.
@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 Matthew Poy and Michele Solimena and Muller, {Dominik N.} and Birkenfeld, {Andreas L.}",
year = "2019",
month = "1",
day = "1",
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",
number = "40",

}

TY - JOUR

T1 - Atp6ap2 deletion causes extensive vacuolation that consumes the insulin content of pancreatic β cells

AU - Binger, Katrina J.

AU - Neukam, Martin

AU - Tattikota, Sudhir Gopal

AU - Qadri, Fatimunnisa

AU - Puchkov, Dmytro

AU - Willmes, Diana M.

AU - Wurmsee, Sabrina

AU - Geisberger, Sabrina

AU - Dechend, Ralf

AU - Raile, Klemens

AU - Kurth, Thomas

AU - Nguyen, Genevieve

AU - Poy, Matthew

AU - Solimena, Michele

AU - Muller, Dominik N.

AU - Birkenfeld, Andreas L.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - (pro)renin receptor

KW - Autophagy

KW - Diabetes

KW - Vacuolar H ATPase

UR - http://www.scopus.com/inward/record.url?scp=85072758913&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072758913&partnerID=8YFLogxK

U2 - 10.1073/pnas.1903678116

DO - 10.1073/pnas.1903678116

M3 - Article

C2 - 31527264

AN - SCOPUS:85072758913

VL - 116

SP - 19983

EP - 19988

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 40

ER -