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Article Dans Une Revue Nature Communications Année : 2019

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

Axel Ganzhorn
  • Fonction : Auteur

Résumé

Compromised function of insulin-secreting pancreatic beta cells is central to the development and progression of Type 2 Diabetes (T2D). However, the mechanisms underlying beta 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 beta 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 beta cell failure.
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Origine : Publication financée par une institution

Dates et versions

hal-03679172 , version 1 (24-01-2024)

Identifiants

Citer

Adrien Pasquier, Kevin Vivot, Eric Erbs, Coralie Spiegelhalter, Zhirong Zhang, et al.. Lysosomal degradation of newly formed insulin granules contributes to beta cell failure in diabetes. Nature Communications, 2019, 10 (1), pp.3312. ⟨10.1038/s41467-019-11170-4⟩. ⟨hal-03679172⟩
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