To appraise the effects and involved mechanism of Dendropanax morbifera leaves extract (DLE) on diabetes and retinal degeneration, in this study, male C57BLKS/J-m+/db and five groups of db/db mice were treated with 0.5% CMC or metformin or three doses of DLE for 6 weeks. Administration of DLE stimulated AMP-activated protein kinase in the liver, skeletal muscle and adipose tissue, leading to the improvement of gene and protein expression related with insulin resistance and glucose homeostasis in db/db mice. Morphological changes and insulin depletion of pancreatic islets were also attenuated by treatment of DLE. Moreover, DLE treatment prevented the deterioration of retina by regulating not only the gene expression related with apoptosis and neovascularization, but also the level of activator protein-1 in retina. Therefore, DLE improves diabetic phenotype and retinal degeneration, suggesting that DLE could be a prospective agent for preventing diabetes and related eye complication. [ABSTRACT FROM AUTHOR]