Dextran sulfate protects pancreatic β-cells, reduces autoimmunity, and ameliorates type 1 diabetes

Abstract

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 auto-immunity, and ameliorate T1D is unknown. In this study, 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 humanisletsinaproinflammatory environment. Interestingly, daily treatment with DS significantly reduces diabetes in-cidence in prediabetic NOD mice and, most importantly, reverses diabetes in early-onset diabetic NOD mice. DS decreases β-cell death, enhances islet heparan sulfate (HS)/HS proteoglycan expression, and preserves β-cell mass and plasma insulin in these mice. DS administration also increases the expression of the inhibitory costimulatory 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 immu-nomodulation can reverse diabetes in NOD mice, high-lighting its therapeutic potential for the treatment of T1D.