Lysosomal degradation of newly formed insulin granules contributes to \u03b2 cell failure in diabetes

Adrien Pasquier,François Pattou,M Pinget ,Meryem Senkara,Coralie Spiegelhalter,Axel J Ganzhorn ,Yannick Schwab,Julie Kerr–Conte ,Zengzhen Liu,Élisa Maillard ,Victor Aubert,Gilbert Marciniak,Paul Säftig ,Zhi Rong Zhang ,Nicole L Schieber,Paolo Ronchi,Eric Erbs,Alexander Goginashvili,Kevin Vivot,Roméo Ricci

doi:10.1038/s41467-019-11170-4

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.

Highlights

Compromised function of insulin-secreting pancreatic β cells is central to the development and progression of Type 2 Diabetes (T2D)
Both enhanced[5,7,15,17] and reduced macroautophagy[13,16,18] have been reported in metabolically challenged β cells. These seemingly controversial observations can be explained by the fact that macroautophagy levels are high and protective in compensated β cells in pre-diabetes, while they decrease at later stages, which contributes to β cell failure
We have demonstrated that nutrient-deprived β cells deliver newly synthesized secretory granules (SGs) to lysosomes in the Golgi area, where degradation of their cargo provides necessary nutrients leading to mechanistic Target of Rapamycin (mTOR)-mediated suppression of macroautophagy

Summary

Introduction

Compromised function of insulin-secreting pancreatic β cells is central to the development and progression of Type 2 Diabetes (T2D). Macroautophagy is a major mechanism used by the cells to remove damaged organelles and unused or aggregated proteins It helps maintaining cellular homeostasis and is activated in response to nutrient shortage[1,2,3]. Evidence for the protective role of macroautophagy has been provided in high-fat diet-induced obesity[5,6], in Endoplasmic Reticulum (ER) stressinduced diabetes[7,8], in human islet amyloid polypeptideinduced diabetes[9,10,11,12] as well as in lipo- and glucotoxicity models[13,14,15,16] Both enhanced[5,7,15,17] and reduced macroautophagy[13,16,18] have been reported in metabolically challenged β cells. Consistent with perturbed autophagic flux, accumulation of autophagosomes has been observed in β cells of islets isolated from T2D patients[20,21]

Methods

Results

Conclusion