title: Emetine Di-HCl Attenuates Type 1 Diabetes Mellitus in Mice.
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.
authors.affiliation: Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.|Hofstra North Shore-LIJ School of Medicine, Hempstead, New York, United States of America.
authors.forename: LaQueta K
authors.initials: LK
authors.lastname: Hudson
authors.affiliation: Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Meghan E
authors.initials: ME
authors.lastname: Dancho
authors.affiliation: Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Li
authors.affiliation: Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Johanna B
authors.initials: JB
authors.lastname: Bruchfeld
authors.affiliation: Center for Molecular Innovation, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Ragab
authors.affiliation: Center for Molecular Innovation, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Mingzhu M
authors.initials: MM
authors.lastname: He
authors.affiliation: Center for Comparative Physiology, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Meaghan
authors.initials: M
authors.lastname: Bragg
authors.affiliation: Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Delaney
authors.initials: D
authors.lastname: Lenaghan
authors.affiliation: Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Quinn
authors.affiliation: Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Fritz
authors.affiliation: Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Matthew V
authors.initials: MV
authors.lastname: Tanzi
authors.affiliation: Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Harold A
authors.initials: HA
authors.lastname: Silverman
authors.affiliation: Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: William M
authors.initials: WM
authors.lastname: Hanes
authors.affiliation: Department of Advanced Research, SetPoint Medical Corporation, Valencia, California, United States of America.
authors.forename: Yaakov A
authors.initials: YA
authors.lastname: Levine
authors.affiliation: Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Valentin A
authors.initials: VA
authors.lastname: Pavlov
authors.affiliation: Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Peder S
authors.initials: PS
authors.lastname: Olofsson
authors.affiliation: Laboratory for Diabetes and Diabetes-Related Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Jesse
authors.initials: J
authors.lastname: Roth
authors.affiliation: Center for Molecular Innovation, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Yousef
authors.initials: Y
authors.lastname: Al-Abed
authors.affiliation: Deptartment of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Andersson
authors.affiliation: Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.|Hofstra North Shore-LIJ School of Medicine, Hempstead, New York, United States of America.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tracey
authors.affiliation: Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Sangeeta S
authors.initials: SS
authors.lastname: Chavan
keywords: Emetine; PEDF; inflammation; insulitis; type 1 diabetes