Lysosomal degradation of newly formed ...
Document type :
Article dans une revue scientifique: Article original
PMID :
Permalink :
Title :
Lysosomal degradation of newly formed insulin granules contributes to β cell failure in diabetes
Author(s) :
Pasquier, Adrien [Auteur]
Vivot, Kevin [Auteur]
Erbs, Eric [Auteur]
Spiegelhalter, Coralie [Auteur]
Zhang, Zhirong [Auteur]
Aubert, Victor [Auteur]
Liu, Zengzhen [Auteur]
Senkara, Meryem [Auteur]
Maillard, Elisa [Auteur]
Pinget, Michel [Auteur]
Pattou Kerr-Conte, Julie [Auteur]
Recherche translationnelle sur le diabète (RTD) - U1190
Pattou, Francois [Auteur]
Recherche translationnelle sur le diabète (RTD) - U1190
Marciniak, Gilbert [Auteur]
Ganzhorn, Axel [Auteur]
Ronchi, Paolo [Auteur]
Schieber, Nicole L. [Auteur]
Schwab, Yannick [Auteur]
Saftig, Paul [Auteur]
Goginashvili, Alexander [Auteur]
Ricci, Romeo [Auteur]
Vivot, Kevin [Auteur]
Erbs, Eric [Auteur]
Spiegelhalter, Coralie [Auteur]
Zhang, Zhirong [Auteur]
Aubert, Victor [Auteur]
Liu, Zengzhen [Auteur]
Senkara, Meryem [Auteur]
Maillard, Elisa [Auteur]
Pinget, Michel [Auteur]
Pattou Kerr-Conte, Julie [Auteur]

Recherche translationnelle sur le diabète (RTD) - U1190
Pattou, Francois [Auteur]

Recherche translationnelle sur le diabète (RTD) - U1190
Marciniak, Gilbert [Auteur]
Ganzhorn, Axel [Auteur]
Ronchi, Paolo [Auteur]
Schieber, Nicole L. [Auteur]
Schwab, Yannick [Auteur]
Saftig, Paul [Auteur]
Goginashvili, Alexander [Auteur]
Ricci, Romeo [Auteur]
Journal title :
Nature Communications
Abbreviated title :
Nat Commun
Volume number :
10
Pages :
3312
Publisher :
Nature Publishing Group
Publication date :
2019-07-25
ISSN :
2041-1723
English keyword(s) :
Diabetes
Golgi
Lysosomes
Macroautophagy
Golgi
Lysosomes
Macroautophagy
HAL domain(s) :
Sciences du Vivant [q-bio]
English abstract : [en]
Compromised function of insulin-secreting pancreatic β cells is central to the development and progression of Type 2 Diabetes (T2D). However, the mechanisms underlying β cell failure remain incompletely understood. Here, ...
Show more >Compromised function of insulin-secreting pancreatic β cells is central to the development and progression of Type 2 Diabetes (T2D). However, the mechanisms underlying β cell failure remain incompletely understood. Here, we report that metabolic stress markedly enhances macroautophagy-independent lysosomal degradation of nascent insulin granules. In different model systems of diabetes including of human origin, stress-induced nascent granule degradation (SINGD) contributes to loss of insulin along with mammalian/mechanistic Target of Rapamycin (mTOR)-dependent suppression of macroautophagy. Expression of Protein Kinase D (PKD), a negative regulator of SINGD, is reduced in diabetic β cells. Pharmacological activation of PKD counters SINGD and delays the onset of T2D. Conversely, inhibition of PKD exacerbates SINGD, mitigates insulin secretion and accelerates diabetes. Finally, reduced levels of lysosomal tetraspanin CD63 prevent SINGD, leading to increased insulin secretion. Overall, our findings implicate aberrant SINGD in the pathogenesis of diabetes and suggest new therapeutic strategies to prevent β cell failure.Show less >
Show more >Compromised function of insulin-secreting pancreatic β cells is central to the development and progression of Type 2 Diabetes (T2D). However, the mechanisms underlying β cell failure remain incompletely understood. Here, we report that metabolic stress markedly enhances macroautophagy-independent lysosomal degradation of nascent insulin granules. In different model systems of diabetes including of human origin, stress-induced nascent granule degradation (SINGD) contributes to loss of insulin along with mammalian/mechanistic Target of Rapamycin (mTOR)-dependent suppression of macroautophagy. Expression of Protein Kinase D (PKD), a negative regulator of SINGD, is reduced in diabetic β cells. Pharmacological activation of PKD counters SINGD and delays the onset of T2D. Conversely, inhibition of PKD exacerbates SINGD, mitigates insulin secretion and accelerates diabetes. Finally, reduced levels of lysosomal tetraspanin CD63 prevent SINGD, leading to increased insulin secretion. Overall, our findings implicate aberrant SINGD in the pathogenesis of diabetes and suggest new therapeutic strategies to prevent β cell failure.Show less >
Language :
Anglais
Peer reviewed article :
Oui
Audience :
Internationale
Popular science :
Non
ANR Project :
Administrative institution(s) :
Université de Lille
Inserm
CHU Lille
Inserm
CHU Lille
Collections :
Submission date :
2024-01-19T23:47:55Z
2024-10-04T12:51:06Z
2024-10-04T12:51:06Z
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