FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3084416578> ?p ?o ?g. }

• W3084416578 abstract "Abstract Aims/hypothesis Pancreatic beta cells are highly metabolic secretory cells that are subjected to exogenous damaging factors such as proinflammatory cytokines or excess glucose that can cause accumulation of damage-inducing reactive oxygen species (ROS) during the pathogenesis of diabetes. We and others have shown that beta cell autophagy can reduce ROS to protect against apoptosis both in vitro and in vivo. 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 hypothesized that beta cell autophagy is dysfunctional in type 1 diabetes, and that there is a progressive loss during early diabetes development. Methods Mouse pancreata were collected from chloroquine injected and non-injected NOR, nondiabetic NOD, and 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). To assess autophagic flux, we injected the mice with chloroquine to inhibit the final stages of autophagy. We analyzed tissues for markers of autophagy via immunofluorescence analysis. Tissue sections were stained with antibodies against proinsulin or insulin (beta cell markers), LC3A/B (autophagosome marker), Lamp1 (lysosome marker), and p62 (autophagy adaptor protein and marker for autophagic flux). Images were collected on a scanning laser confocal microscope then analyzed with CellProfiler and ImageJ. Secondary lysosomes and telolysosomes (formerly called lipofuscin bodies, residual bodies or tertiary lysosomes) were analyzed in electron micrographs of pancreatic tissue sections from human organ donors (nPOD; n=12) deposited in www.nanotomy.org/OA/nPOD . Energy Dispersive X-ray (EDX) analysis was also performed on these tissues to analyze distribution of elements such as nitrogen, phosphorus, and osmium in secondary lysosomes and telolysosomes of nondiabetic and autoantibody positive donor tissues (n=5). Results We observed increased autophagosome numbers in islets of diabetic NOD mice (p=0.0077) and increased p62 in islets of both nondiabetic and diabetic NOD mice (p<0.0001 in both cases) when compared to NOR mice. There was also a significant reduction in autophagosome:lysosome colocalization in islets of diabetic NOD mice compared to both nondiabetic NOD mice (p=0.0004) and NOR mice (p=0.0003). Chloroquine infusions elicited accumulation of autophagosomes in the islets of NOR (p=0.0029) and nondiabetic NOD mice (p<0.0001), but not in the islets of diabetic NOD mice. Chloroquine also stimulated an accumulation of the autophagy adaptor protein p62 in the islets of NOR mice (p<0.001), however this was not observed in NOD mice (regardless of diabetes status). In the human pancreata, we observed significantly reduced autophagosome:lysosome colocalization (p=0.0002) in the residual beta cells of donors with type 1 diabetes compared to nondiabetic controls. We also observed reduced colocalization of proinsulin with lysosomes in the residual beta cells of donors with type 1 diabetes compared to both nondiabetic (p<0.0001) and autoantibody positive donors (p<0.0001). Electron microscopy based analysis of human pancreas sections also revealed accumulation of telolysosomes in beta cells of autoantibody positive donors (p=0.0084), the majority of which had an nitrogen dense ring outside a phospholipid core. Conclusions/interpretation Collectively, we provide evidence of impairment in the final degradation stages of islet macroautophagy and crinophagy in human type 1 diabetes. We also document an accumulation of telolysosomes with nitrogen accumulation at their periphery in the beta cells of autoantibody positive donors. This demonstrates clear differences in the lysosome contents of autoantibody positive donors that may be associated with lysosome dysfunction prior to clinical hyperglycemia. We observe similar impairments in macroautophagy in the diabetic NOD mouse, a model of type 1 diabetes, suggesting that this mouse model can be appropriately used to study the pathogenesis of autophagy/crinophagy loss and how it relates to disease initiation and progression. Considering these data in the context of what is known regarding the cell-protective effects of islet autophagy, we suggest targeting beta cell autophagy pathways as an approach to reduce apoptosis in individuals at risk for type 1 diabetes development. Research in context What is already known about this subject? Autophagy confers a cytoprotective role in the beta cell. Autophagy is reduced in type 2 diabetes. Autophagy in the context of type 1 diabetes is unexplored. What is the key question? Is autophagy reduced during the pathogenesis of human type 1 diabetes? What are the new findings? We provide evidence of reduced autophagy and crinophagy in human type 1 diabetes. These data are supported by observations of reduced autophagy in a mouse model of autoimmune diabetes. How might this impact on clinical practice in the foreseeable future? This study provides evidence that autophagy is impaired in human type 1 diabetes. Prior studies have shown that loss of autophagy in the islet is associated with increased beta cell apoptosis, therefore we propose that therapeutic targeting of autophagy pathways may reduce beta cell death in type 1 diabetes development." @default.
• W3084416578 created "2020-09-14" @default.
• W3084416578 creator A5007457713 @default.
• W3084416578 creator A5015077140 @default.
• W3084416578 creator A5017000770 @default.
• W3084416578 creator A5027614554 @default.
• W3084416578 creator A5044120923 @default.
• W3084416578 creator A5051876965 @default.
• W3084416578 creator A5059287883 @default.
• W3084416578 creator A5086769682 @default.
• W3084416578 date "2020-09-10" @default.
• W3084416578 modified "2023-09-26" @default.
• W3084416578 title "Pancreatic Beta Cell Autophagy is Impaired in Type 1 Diabetes" @default.
• W3084416578 cites W1976706061 @default.
• W3084416578 cites W1979566598 @default.
• W3084416578 cites W2014506057 @default.
• W3084416578 cites W2015897559 @default.
• W3084416578 cites W2024670158 @default.
• W3084416578 cites W2038977244 @default.
• W3084416578 cites W2039035664 @default.
• W3084416578 cites W2044102028 @default.
• W3084416578 cites W2060216777 @default.
• W3084416578 cites W2067097574 @default.
• W3084416578 cites W2109069544 @default.
• W3084416578 cites W2121165599 @default.
• W3084416578 cites W2138806334 @default.
• W3084416578 cites W2138846538 @default.
• W3084416578 cites W2139442812 @default.
• W3084416578 cites W2146237406 @default.
• W3084416578 cites W2154494644 @default.
• W3084416578 cites W2156356581 @default.
• W3084416578 cites W2160887986 @default.
• W3084416578 cites W2322556561 @default.
• W3084416578 cites W2525933295 @default.
• W3084416578 cites W2529697284 @default.
• W3084416578 cites W2586691160 @default.
• W3084416578 cites W2604670820 @default.
• W3084416578 cites W2611234466 @default.
• W3084416578 cites W2752326209 @default.
• W3084416578 cites W2766185488 @default.
• W3084416578 cites W2782121779 @default.
• W3084416578 cites W2791307726 @default.
• W3084416578 cites W2794931111 @default.
• W3084416578 cites W2803781307 @default.
• W3084416578 cites W2810037075 @default.
• W3084416578 cites W2900517523 @default.
• W3084416578 cites W2906401896 @default.
• W3084416578 cites W2914789585 @default.
• W3084416578 cites W2915324993 @default.
• W3084416578 cites W2972302022 @default.
• W3084416578 cites W3024276528 @default.
• W3084416578 cites W4231756003 @default.
• W3084416578 cites W587296895 @default.
• W3084416578 doi "https://doi.org/10.1101/2020.09.10.291443" @default.
• W3084416578 hasPublicationYear "2020" @default.
• W3084416578 type Work @default.
• W3084416578 sameAs 3084416578 @default.
• W3084416578 citedByCount "1" @default.
• W3084416578 countsByYear W30844165782020 @default.
• W3084416578 crossrefType "posted-content" @default.
• W3084416578 hasAuthorship W3084416578A5007457713 @default.
• W3084416578 hasAuthorship W3084416578A5015077140 @default.
• W3084416578 hasAuthorship W3084416578A5017000770 @default.
• W3084416578 hasAuthorship W3084416578A5027614554 @default.
• W3084416578 hasAuthorship W3084416578A5044120923 @default.
• W3084416578 hasAuthorship W3084416578A5051876965 @default.
• W3084416578 hasAuthorship W3084416578A5059287883 @default.
• W3084416578 hasAuthorship W3084416578A5086769682 @default.
• W3084416578 hasBestOaLocation W30844165781 @default.
• W3084416578 hasConcept C126322002 @default.
• W3084416578 hasConcept C134018914 @default.
• W3084416578 hasConcept C142724271 @default.
• W3084416578 hasConcept C165220095 @default.
• W3084416578 hasConcept C181199279 @default.
• W3084416578 hasConcept C190283241 @default.
• W3084416578 hasConcept C203522944 @default.
• W3084416578 hasConcept C2776828364 @default.
• W3084416578 hasConcept C2778013207 @default.
• W3084416578 hasConcept C2778764654 @default.
• W3084416578 hasConcept C2780216420 @default.
• W3084416578 hasConcept C55493867 @default.
• W3084416578 hasConcept C555293320 @default.
• W3084416578 hasConcept C55851684 @default.
• W3084416578 hasConcept C71924100 @default.
• W3084416578 hasConcept C86803240 @default.
• W3084416578 hasConcept C95444343 @default.
• W3084416578 hasConceptScore W3084416578C126322002 @default.
• W3084416578 hasConceptScore W3084416578C134018914 @default.
• W3084416578 hasConceptScore W3084416578C142724271 @default.
• W3084416578 hasConceptScore W3084416578C165220095 @default.
• W3084416578 hasConceptScore W3084416578C181199279 @default.
• W3084416578 hasConceptScore W3084416578C190283241 @default.
• W3084416578 hasConceptScore W3084416578C203522944 @default.
• W3084416578 hasConceptScore W3084416578C2776828364 @default.
• W3084416578 hasConceptScore W3084416578C2778013207 @default.
• W3084416578 hasConceptScore W3084416578C2778764654 @default.
• W3084416578 hasConceptScore W3084416578C2780216420 @default.
• W3084416578 hasConceptScore W3084416578C55493867 @default.
• W3084416578 hasConceptScore W3084416578C555293320 @default.
• W3084416578 hasConceptScore W3084416578C55851684 @default.

• next