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Dextran Sulfate Protects Pancreatic β-Cells, Reduces Autoimmunity and Ameliorates Type 1 Diabetes

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posted on 07.05.2020 by Ada Admin, Geming Lu, Francisco Rausell-Palamos, Jiamin Zhang, Zihan Zheng, Tuo Zhang, Shelley Valle, Carolina Rosselot, Cecilia Berrouet, Patricia Conde, Matthew P. Spindler, John G. Graham, Dirk Homann, Adolfo Garcia-Ocaña
A failure in self-tolerance leads to autoimmune destruction of pancreatic β-cells and type 1 diabetes (T1D). Low molecular weight dextran sulfate (DS) is a sulfated semi-synthetic polysaccharide with demonstrated cytoprotective and immunomodulatory properties in vitro. However, whether DS can protect pancreatic β-cells, reduce autoimmunity and ameliorate T1D is unknown. Here we report that DS, but not dextran, protects human β-cells against cytokine-mediated cytotoxicity in vitro. DS also protects mitochondrial function and glucose-stimulated insulin secretion and reduces chemokine expression in human islets in a pro-inflammatory environment. Interestingly, daily treatment with DS significantly reduces diabetes incidence in pre-diabetic non-obese diabetic (NOD) mice, and most importantly, reverses diabetes in early-onset diabetic NOD mice. DS decreases β-cell death, enhances islet heparan sulfate (HS)/heparan sulfate proteoglycan (HSPG) expression and preserves β-cell mass and plasma insulin in these mice. DS administration also increases the expression of the inhibitory co-stimulatory molecule programmed death-1 (PD-1) in T-cells, reduces interferon-γ+ CD4+ and CD8+ T-cells and enhances the number of FoxP3+ cells. Collectively, these studies demonstrate that the action of one single molecule, DS, on β-cell protection, extracellular matrix preservation and immunomodulation can reverse diabetes in NOD mice highlighting its therapeutic potential for the treatment of T1D.

Funding

This work was supported in part by grants from the National Institutes of Health (DK-113079 and DK020541-38) and the Department of Defense (W81XWH-17-1-0363 and W81XWH-17-1-0364) to D.H. and A.G.-O; and the American Diabetes Association/F.M. Kirby Foundation 1-14-BS-069 to A.G.-O.

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