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Autophagy is a major regulator of beta cell insulin homeostasis

Authors
 Yael Riahi  ;  Jakob D. Wikstrom  ;  Etty Bachar-Wikstrom  ;  Nava Polin  ;  Hava Zucker  ;  Myung-Shik Lee  ;  Wenying Quan  ;  Leena Haataja  ;  Ming Liu  ;  Peter Arvan  ;  Erol Cerasi  ;  Gil Leibowitz 
Citation
 DIABETOLOGIA, Vol.59(7) : 1480-1491, 2016 
Journal Title
DIABETOLOGIA
ISSN
 0012-186X 
Issue Date
2016
MeSH
Animals ; Autophagy/genetics ; Autophagy/physiology* ; Autophagy-Related Protein 7/genetics ; Autophagy-Related Protein 7/metabolism ; Blotting, Western ; Cell Line ; Homeostasis/genetics ; Homeostasis/physiology ; Humans ; Insulin/metabolism* ; Insulin-Secreting Cells/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microscopy, Electron ; Oxygen Consumption/genetics ; Oxygen Consumption/physiology ; RNA Interference/physiology
Keywords
Autophagy ; Beta cells ; Insulin secretion ; Lysosome ; Proinsulin ; Proteasome ; Protein degradation
Abstract
AIMS/HYPOTHESIS: We studied the role of protein degradation pathways in the regulation of insulin production and secretion and hypothesised that autophagy regulates proinsulin degradation, thereby modulating beta cell function. METHODS: Proinsulin localisation in autophagosomes was demonstrated by confocal and electron microscopy. Autophagy was inhibited by knockdown of autophagy-related (ATG) proteins and using the H(+)-ATPase inhibitor bafilomycin-A1. Proinsulin and insulin content and secretion were assessed in static incubations by ELISA and RIA. RESULTS: Confocal and electron microscopy showed proinsulin localised in autophagosomes and lysosomes. Beta-Atg7 (-/-) mice had proinsulin-containing sequestosome 1 (p62 [also known as SQSTM1])(+) aggregates in beta cells, indicating proinsulin is regulated by autophagy in vivo. Short-term bafilomycin-A1 treatment and ATG5/7 knockdown increased steady-state proinsulin and hormone precursor chromogranin A content. ATG5/7 knockdown also increased glucose- and non-fuel-stimulated insulin secretion. Finally, mutated forms of proinsulin that are irreparably misfolded and trapped in the endoplasmic reticulum are more resistant to degradation by autophagy. CONCLUSIONS/INTERPRETATION: In the beta cell, transport-competent secretory peptide precursors, including proinsulin, are regulated by autophagy, whereas efficient clearance of transport-incompetent mutated forms of proinsulin by alternative degradative pathways may be necessary to avoid beta cell proteotoxicity. Reduction of autophagic degradation of proinsulin increases its residency in the secretory pathway, followed by enhanced secretion in response to stimuli.
Full Text
https://link.springer.com/article/10.1007%2Fs00125-016-3868-9
DOI
10.1007/s00125-016-3868-9
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Lee, Myung Shik(이명식) ORCID logo https://orcid.org/0000-0003-3292-1720
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/151978
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