Abstract
Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease characterized by beta cell destruction, insulin deficiency and hyperglycemia. Activated macrophages and autoimmune T cells play a crucial role in the pathogenesis of hyperglycemia in NOD murine diabetes models, but the molecular mechanisms of macrophage activation are unknown. We recently identified pigment epithelium-derived factor (PEDF) as an adipocyte-derived factor that activates macrophages and mediates insulin resistance. Reasoning that PEDF might participate as a proinflammatory mediator in murine diabetes, we measured PEDF levels in NOD mice. PEDF levels are significantly elevated in pancreas, in correlation with pancreatic TNF levels in NOD mice. To identify experimental therapeutics, we screened 2,327 compounds in two chemical libraries (the NIH Clinical Collection and Pharmakon-1600a) for leads that inhibit PEDF mediated TNF release in macrophage cultures. The lead molecule selected, "emetine" is a widely used emetic. It inhibited PEDF-mediated macrophage activation with an EC50 or 146 nM. Administration of emetine to NOD mice and to C57Bl6 mice subjected to streptozotocin significantly attenuated hyperglycemia, reduced TNF levels in pancreas, and attenuated insulitis. Together, these results suggest that targeting PEDF with emetine may attenuate TNF release and hyperglycemia in murine diabetes models. This suggests that further investigation of PEDF and emetine in the pathogenesis of human diabetes is warranted.
Highlights
Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease characterized by β cell destruction resulting in insulin deficiency and hyperglycemia
Pancreatic pigment epithelium-derived factor (PEDF) levels increased in time-dependent manner following streptozotocin administration (Figure 1B)
We observed that tumor necrosis factor (TNF) levels in the pancreas were significantly increased (Figure 1D), and were strongly correlated with pancreatic PEDF levels (Figure 1E)
Summary
Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease characterized by β cell destruction resulting in insulin deficiency and hyperglycemia. Experimental models of T1D include the non-obese diabetic (NOD) mice, and streptozotocin (STZ)-induced diabetes in C57Bl6 mice. Macrophages and dendritic cells are the first to infiltrate the pancreas during the development of experimental T1D in NOD mice [8, 9]. Non-invasive cytofluorometric analysis shows progressive infiltration of the pancreas by CD11b + /CD11c- macrophages in the BDC2.5_NOD T cell receptor transgenic murine model of T1D [10]. Inhibition of complement receptor 3 (CR3 or CD11b/ CD18) prevents macrophage and T cell infiltration of pancreatic islets and EMETINE TREATMENT IN MURINE TYPE 1 DIABETES
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