Pancreatic beta cell autophagy is impaired in type 1 diabetes
| العنوان: | Pancreatic beta cell autophagy is impaired in type 1 diabetes |
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| المؤلفون: | Amelia K. Linnemann, Charanya Muralidharan, Abass M. Conteh, Pascal de Boer, Jeroen Kuipers, Michelle Marasco, Justin J. Crowder |
| المصدر: | Diabetologia, 64(4), 865-877. SPRINGER Diabetologia |
| بيانات النشر: | SPRINGER, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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 |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1432-0428 0012-186X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::aca8a2e71e6e61e43eb7bea2f3d7a3e4Test https://doi.org/10.1007/s00125-021-05387-6Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....aca8a2e71e6e61e43eb7bea2f3d7a3e4 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14320428 0012186X |
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