Type 1 diabetes mellitus (T1 DM) 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 LIP to 145 days after treatment withdrawal. The therapeutic effect of this regimen was associated with improved beta-cell metabolism and insulin secretion. while reducing P-cell apoptosis. It is possible that such combined therapy Could become a new strategy to defeat T1DM in humans. (c) 2006 Elsevier Inc. All rights reserved.