title: Combined treatment with lisofylline and exendin-4 reverses autoimmune diabetes.
abstract: Type 1 diabetes mellitus (T1DM) is an autoimmune disease leading to near complete pancreatic beta-cell destruction. New evidence suggests that beta-cell regeneration is possible, but ongoing autoimmune damage prevents restoration of beta-cell mass. We tested the hypothesis that simultaneously blocking autoimmune cytokine damage and supplying a growth-promoting stimulus for beta-cells would provide a novel approach to reverse T1DM. Therefore, in this study we combined lisofylline to suppress autoimmunity and exendin-4 to enhance beta-cell proliferation for treating autoimmune-mediated diabetes in the non-obese diabetic (NOD) mouse model. We found that this combined therapy effectively reversed new-onset diabetes within a week of therapy, and even maintained euglycemia up to 145 days after treatment withdrawal. The therapeutic effect of this regimen was associated with improved beta-cell metabolism and insulin secretion, while reducing beta-cell apoptosis. It is possible that such combined therapy could become a new strategy to defeat T1DM in humans.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia, Charlottesville, VA, USA. zandong_yang@merck.com
authors.forename: Zandong
authors.initials: Z
authors.lastname: Yang
authors.forename: Meng
authors.initials: M
authors.lastname: Chen
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Carter
authors.forename: Craig S
authors.initials: CS
authors.lastname: Nunemaker
authors.forename: James C
authors.initials: JC
authors.lastname: Garmey
authors.forename: Sarah D
authors.initials: SD
authors.lastname: Kimble
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Nadler
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D004338:Drug Combinations; D000077270:Exenatide; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010431:Pentoxifylline / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010455:Peptides / Q000008:administration & dosage*; D016896:Treatment Outcome; D014688:Venoms / Q000008:administration & dosage*
chemical_list: D004338:Drug Combinations; D010455:Peptides; D014688:Venoms; D000077270:Exenatide; C025189:lisofylline; D010431:Pentoxifylline