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.