Lysosomal degradation of newly formed insulin granules contributes to beta cell failure in diabetes
| Autor: | Meryem Senkara, Michel Pinget, Yannick Schwab, Paul Saftig, Paolo Ronchi, Axel Ganzhorn, Julie Kerr-Conte, Elisa Maillard, Nicole L. Schieber, François Pattou, Zengzhen Liu, Victor Aubert, Alexander Goginashvili, Romeo Ricci, Kevin Vivot, Adrien Pasquier, Coralie Spiegelhalter, Gilbert Marciniak, Eric Erbs, Zhirong Zhang |
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| Přispěvatelé: | univOAK, Archive ouverte, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Christian-Albrechts-Universität zu Kiel (CAU), Defymed : Centre Européen Étude du Diabète (CEED), Diabète et thérapies cellulaires (DIATHEC), Université de Strasbourg (UNISTRA), Recherche translationnelle sur le diabète - U 1190 (RTD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Lille, European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Sanofi-Aventis R&D, SANOFI Recherche, European Molecular Biology Laboratory [Heidelberg] (EMBL), Ludwig Institute for Cancer Research, University of California [San Diego] (UC San Diego), University of California (UC), Nouvel Hôpital Civil de Strasbourg, Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), ANR-17-CE14-0027,LYSODIABETES,Régulation de la fonction lysosomale par les nutriments dans le diabète de type 2(2017) |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male medicine.medical_treatment Science Cell General Physics and Astronomy 02 engineering and technology Type 2 diabetes [SDV.BC]Life Sciences [q-bio]/Cellular Biology General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Diabetes Insulin Lysosome Tetraspanin Diabetes mellitus Insulin-Secreting Cells Insulin Secretion Macroautophagy medicine Golgi Animals Humans Insulin lcsh:Science Mechanistic target of rapamycin [SDV.BC] Life Sciences [q-bio]/Cellular Biology PI3K/AKT/mTOR pathway Protein Kinase C Multidisciplinary biology Chemistry TOR Serine-Threonine Kinases Autophagy Diabetes General Chemistry 021001 nanoscience & nanotechnology medicine.disease 3. Good health Cell biology Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Diabetes Mellitus Type 2 biology.protein lcsh:Q 0210 nano-technology Lysosomes |
| Zdroj: | Nature Communications Nature Communications, 2019, 10 (1), ⟨10.1038/s41467-019-11170-4⟩ Nature Communications, Vol 10, Iss 1, Pp 1-14 (2019) |
| ISSN: | 2041-1723 |
| Popis: | 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. Impaired beta-cell insulin secretion is a key pathological feature of type 2 diabetes. Here, the authors describe metabolic stress induced lysosomal degradation of newly formed insulin granules, independent of macroautophagy, as a potential mechanism for beta-cell dysfunction. |
| Databáze: | OpenAIRE |
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