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Pancreatic beta cell autophagy is impaired in type 1 diabetes
Pancreatic beta cell autophagy is impaired in type 1 diabetes
- Source :
- Diabetologia, 64(4), 865-877. SPRINGER, Diabetologia
- Publication Year :
- 2021
- Publisher :
- SPRINGER, 2021.
-
Abstract
- Aims/hypothesis Pancreatic beta cells are subjected to exogenous damaging factors such as proinflammatory cytokines or excess glucose that can cause accumulation of damage-inducing reactive oxygen species during the pathogenesis of diabetes. We and others have shown that beta cell autophagy can reduce reactive oxygen species to protect against apoptosis. While impaired islet autophagy has been demonstrated in human type 2 diabetes, it is unknown if islet autophagy is perturbed in the pathogenesis of type 1 diabetes. We hypothesised that beta cell autophagy is dysfunctional in type 1 diabetes, and that there is a progressive loss during early diabetes development. Methods Pancreases were collected from chloroquine-injected and non-injected non-obese diabetes-resistant (NOR) and non-obese diabetic (NOD) mice. Age- and BMI-matched pancreas tissue sections from human organ donors (N = 34) were obtained from the Network for Pancreatic Organ Donors with Diabetes (nPOD). Tissue sections were stained with antibodies against proinsulin or insulin (beta cell markers), microtubule-associated protein 1 light chain 3 A/B (LC3A/B; autophagosome marker), lysosomal-associated membrane protein 1 (LAMP1; lysosome marker) and p62 (autophagy adaptor). Images collected on a scanning laser confocal microscope were analysed with CellProfiler and ImageJ. Secondary lysosomes and telolysosomes were assessed in electron micrographs of human pancreatic tissue sections (n = 12), and energy dispersive x-ray analysis was performed to assess distribution of elements (n = 5). Results We observed increased autophagosome numbers in islets of diabetic NOD mice (p = 0.008) and increased p62 in islets of both non-diabetic and diabetic NOD mice (p p p p = 0.003) and non-diabetic NOD mice (p p p p p = 0.002). Conclusions/interpretation We provide evidence of islet macroautophagy/crinophagy impairment in human type 1 diabetes. We also document accumulation of telolysosomes with peripheral nitrogen in beta cells of autoantibody-positive donors, demonstrating altered lysosome content that may be associated with lysosome dysfunction before clinical hyperglycaemia. Similar macroautophagy impairments are present in the NOD mouse model of type 1 diabetes. Graphical abstract
- Subjects :
- Adult
Male
0301 basic medicine
Autophagosome
medicine.medical_specialty
Adolescent
Endocrinology, Diabetes and Metabolism
Autophagy-Related Proteins
Nod
Article
Young Adult
03 medical and health sciences
0302 clinical medicine
Mice, Inbred NOD
Insulin-Secreting Cells
Internal medicine
Diabetes mellitus
Macroautophagy
Internal Medicine
medicine
Autophagy
Animals
Humans
NOD mice
Proinsulin
Type 1 diabetes
business.industry
Autoantibody-positive
medicine.disease
Lysosome
Disease Models, Animal
Diabetes Mellitus, Type 1
030104 developmental biology
Endocrinology
Crinophagy
Case-Control Studies
Female
Beta cell
Lysosomes
business
030217 neurology & neurosurgery
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 14320428 and 0012186X
- Volume :
- 64
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Diabetologia
- Accession number :
- edsair.doi.dedup.....aca8a2e71e6e61e43eb7bea2f3d7a3e4
- Full Text :
- https://doi.org/10.1007/s00125-021-05387-6