Abstract
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.
Highlights
Type 1 diabetes is an autoimmune disease which destroys the insulin-producing beta cells of pancreatic islets [1,2,3]
Our findings confirm the presence of high levels of intra-islet heparan sulfate (HS) and heparan sulfate proteoglycan (HSPG) core proteins in normal human islets and support a unique role for HS in human beta cell survival; we demonstrate that beta cell HS is lost before insulin in human Type 1 diabetes (T1D) and is a sensitive marker of disease progression
In T1D pancreases with Ins+ islets, staining for Col18, Sdc1 and HS correlated with residual insulin-containing beta cells (Fig 1F–1J), a finding which was observed in islets with insulitis (Fig 2)
Summary
Type 1 diabetes is an autoimmune disease which destroys the insulin-producing beta cells of pancreatic islets [1,2,3]. Recent clinical trials testing the blockade of T cell activation and function as well as cytokine-based strategies for immunomodulation in patients with new-onset type 1 diabetes have resulted in only limited therapeutic benefit, with a slower decline in insulin secretion and a modest impact on insulin requirement and disease progression [1, 7,8,9,10] These outcomes have stimulated other avenues of research to better understand the pathogenesis of the disease and to develop more effective intervention strategies. In this study we investigated a role for intracellular heparan sulfate (HS), a sulfated glycosaminoglycan, as a requirement for the survival of human beta cells and as a marker of beta cell damage in human T1D, identifying HS preservation as a possible novel therapeutic strategy for beta cell protection and preventing T1D progression
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