Lysosomal degradation of newly formed insulin granules contributes to beta cell failure in diabetes
| العنوان: | Lysosomal degradation of newly formed insulin granules contributes to beta cell failure in diabetes |
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| المؤلفون: | 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 |
| المساهمون: | 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) |
| المصدر: | Nature Communications Nature Communications, 2019, 10 (1), ⟨10.1038/s41467-019-11170-4⟩ Nature Communications, Vol 10, Iss 1, Pp 1-14 (2019) |
| بيانات النشر: | HAL CCSD, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| اللغة: | English |
| تدمد: | 2041-1723 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0e6d7dd4c2ebd89d2394b0088c7a9973 https://doi.org/10.1038/s41467-019-11170-4 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....0e6d7dd4c2ebd89d2394b0088c7a9973 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
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