Lysosomal degradation of newly formed insulin granules contributes to β cell failure in diabetes

Adrien Pasquier, Kevin Vivot, Eric Erbs, Coralie Spiegelhalter, Zhirong Zhang, Victor Aubert, Zengzhen Liu, Meryem Senkara, Elisa Maillard, Michel Pinget, Julie Kerr-Conte, François Pattou, Gilbert Marciniak, Axel Ganzhorn, Paolo Ronchi, Nicole L. Schieber, Yannick Schwab, Paul Saftig, Alexander Goginashvili () and Romeo Ricci ()
Additional contact information
Adrien Pasquier: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Kevin Vivot: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Eric Erbs: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Coralie Spiegelhalter: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Zhirong Zhang: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Victor Aubert: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Zengzhen Liu: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Meryem Senkara: Biochemisches Institut, Christian-Albrechts Universität Kiel
Elisa Maillard: Université de Strasbourg
Michel Pinget: Université de Strasbourg
Julie Kerr-Conte: University of Lille
François Pattou: University of Lille
Gilbert Marciniak: Open Innovation Access Platform, Sanofi-Aventis R&D
Axel Ganzhorn: Open Innovation Access Platform, Sanofi-Aventis R&D
Paolo Ronchi: Electron Microscopy Core Facility
Nicole L. Schieber: Electron Microscopy Core Facility
Yannick Schwab: Electron Microscopy Core Facility
Paul Saftig: Biochemisches Institut, Christian-Albrechts Universität Kiel
Alexander Goginashvili: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Romeo Ricci: Institut de Génétique et de Biologie Moléculaire et Cellulaire

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-11170-4

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