Lysosomal degradation of newly formed insulin granules contributes to β cell failure in diabetes.
Adrien PasquierKevin VivotEric ErbsCoralie SpiegelhalterZhirong ZhangVictor AubertZengzhen LiuMeryem SenkaraElisa MaillardMichel PingetJulie Kerr-ConteFrancois PattouGilbert MarciniakAxel GanzhornPaolo RonchiNicole L SchieberYannick SchwabPaul SaftigAlexander GoginashviliRomeo RicciPublished in: Nature communications (2019)
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.
Keyphrases
- type diabetes
- glycemic control
- stress induced
- cardiovascular disease
- induced apoptosis
- single cell
- cell therapy
- polycystic kidney disease
- insulin resistance
- poor prognosis
- stem cells
- weight loss
- cell proliferation
- oxidative stress
- metabolic syndrome
- radiation therapy
- endoplasmic reticulum stress
- transcription factor
- mesenchymal stem cells
- bone marrow
- radiation induced