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dc.contributor.authorSimeonovic, CJ
dc.contributor.authorPopp, SK
dc.contributor.authorStarrs, LM
dc.contributor.authorBrown, DJ
dc.contributor.authorZiolkowski, AF
dc.contributor.authorLudwig, B
dc.contributor.authorBornstein, SR
dc.contributor.authorWilson, JD
dc.contributor.authorPugliese, A
dc.contributor.authorKay, TWH
dc.contributor.authorThomas, HE
dc.contributor.authorLoudovaris, T
dc.contributor.authorChoong, FJ
dc.contributor.authorFreeman, C
dc.contributor.authorParish, CR
dc.date.accessioned2020-12-09T23:22:21Z
dc.date.available2020-12-09T23:22:21Z
dc.date.issued2018-02-07
dc.identifierpii: PONE-D-17-31973
dc.identifier.citationSimeonovic, C. J., Popp, S. K., Starrs, L. M., Brown, D. J., Ziolkowski, A. F., Ludwig, B., Bornstein, S. R., Wilson, J. D., Pugliese, A., Kay, T. W. H., Thomas, H. E., Loudovaris, T., Choong, F. J., Freeman, C. & Parish, C. R. (2018). Loss of intra-islet heparan sulfate is a highly sensitive marker of type 1 diabetes progression in humans. PLOS ONE, 13 (2), https://doi.org/10.1371/journal.pone.0191360.
dc.identifier.issn1932-6203
dc.identifier.urihttp://hdl.handle.net/11343/253204
dc.description.abstractType 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.
dc.languageEnglish
dc.publisherPUBLIC LIBRARY SCIENCE
dc.titleLoss of intra-islet heparan sulfate is a highly sensitive marker of type 1 diabetes progression in humans
dc.typeJournal Article
dc.identifier.doi10.1371/journal.pone.0191360
melbourne.affiliation.departmentMedicine and Radiology
melbourne.source.titlePLoS One
melbourne.source.volume13
melbourne.source.issue2
dc.rights.licenseCC BY
melbourne.elementsid1307108
melbourne.contributor.authorKay, Thomas
melbourne.contributor.authorThomas, Helen
melbourne.contributor.authorLOUDOVARIS, THOMAS
dc.identifier.eissn1932-6203
melbourne.accessrightsOpen Access


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