Loss of intra-islet heparan sulfate is a highly sensitive marker of type 1 diabetes progression in humans
| العنوان: | Loss of intra-islet heparan sulfate is a highly sensitive marker of type 1 diabetes progression in humans |
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| المؤلفون: | Christopher R. Parish, J. Dennis Wilson, Helen E. Thomas, Fui Jiun Choong, Barbara Ludwig, Andrew F. Ziolkowski, Charmaine J. Simeonovic, Sarah K. Popp, Stefan R. Bornstein, Thomas W.H. Kay, Lora Starrs, Craig Freeman, Thomas Loudovaris, Debra J. Brown, Alberto Pugliese |
| المساهمون: | University of Zurich, Simeonovic, Charmaine J |
| المصدر: | PLoS ONE, Vol 13, Iss 2, p e0191360 (2018) PLoS ONE |
| بيانات النشر: | Public Library of Science (PLoS), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, endocrine system diseases, medicine.medical_treatment, 10265 Clinic for Endocrinology and Diabetology, lcsh:Medicine, Biochemistry, White Blood Cells, chemistry.chemical_compound, Endocrinology, Spectrum Analysis Techniques, 0302 clinical medicine, Animal Cells, Medicine and Health Sciences, Insulin, Child, lcsh:Science, Cells, Cultured, Staining, Multidisciplinary, geography.geographical_feature_category, Chemistry, Cell Staining, Drugs, Heparan sulfate, Flow Cytometry, Islet, 3. Good health, medicine.anatomical_structure, Spectrophotometry, Child, Preschool, Disease Progression, Female, Cytophotometry, Anatomy, Cellular Types, medicine.symptom, Beta cell, Biliary Disorders, Research Article, Adult, medicine.medical_specialty, endocrine system, Adolescent, Endocrine Disorders, Immune Cells, Immunology, Endocrine System, 030209 endocrinology & metabolism, Inflammation, 610 Medicine & health, Gastroenterology and Hepatology, 1100 General Agricultural and Biological Sciences, Research and Analysis Methods, Sensitivity and Specificity, Islets of Langerhans, Young Adult, 03 medical and health sciences, Exocrine Glands, 1300 General Biochemistry, Genetics and Molecular Biology, Internal medicine, Diabetes Mellitus, medicine, Humans, Heparanase, Pancreas, Pharmacology, Diabetic Endocrinology, geography, 1000 Multidisciplinary, Blood Cells, Heparin, Pancreatic islets, lcsh:R, Biology and Life Sciences, Infant, Cell Biology, medicine.disease, Hormones, Diabetes Mellitus, Type 1, 030104 developmental biology, Specimen Preparation and Treatment, Metabolic Disorders, Case-Control Studies, lcsh:Q, Heparitin Sulfate, Insulitis, Biomarkers |
| الوصف: | Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing beta cells in pancreatic islets are progressively destroyed. Clinical trials of immunotherapies in recently diagnosed T1D patients have only transiently and partially impacted the disease course, suggesting that other approaches are required. Our previous studies have demonstrated that heparan sulfate (HS), a glycosaminoglycan conventionally expressed in extracellular matrix, is present at high levels inside normal mouse beta cells. Intracellular HS was shown to be critical for beta cell survival and protection from oxidative damage. T1D development in Non-Obese Diabetic (NOD) mice correlated with loss of islet HS and was prevented by inhibiting HS degradation by the endoglycosidase, heparanase. In this study we investigated the distribution of HS and heparan sulfate proteoglycan (HSPG) core proteins in normal human islets, a role for HS in human beta cell viability and the clinical relevance of intra-islet HS and HSPG levels, compared to insulin, in human T1D. In normal human islets, HS (identified by 10E4 mAb) co-localized with insulin but not glucagon and correlated with the HSPG core proteins for collagen type XVIII (Col18) and syndecan-1 (Sdc1). Insulin-positive islets of T1D pancreases showed significant loss of HS, Col18 and Sdc1 and heparanase was strongly expressed by islet-infiltrating leukocytes. Human beta cells cultured with HS mimetics showed significantly improved survival and protection against hydrogen peroxide-induced death, suggesting that loss of HS could contribute to beta cell death in T1D. We conclude that HS depletion in beta cells, possibly due to heparanase produced by insulitis leukocytes, may function as an important mechanism in the pathogenesis of human T1D. Our findings raise the possibility that intervention therapy with dual activity HS replacers/heparanase inhibitors could help to protect the residual beta cell mass in patients recently diagnosed with T1D. |
| وصف الملف: | pone.0191360.pdf - application/pdf |
| اللغة: | English |
| تدمد: | 1932-6203 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b710034fc5ae324ee64bd93770d4b09fTest http://europepmc.org/articles/PMC5802856?pdf=renderTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b710034fc5ae324ee64bd93770d4b09f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
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