The present invention provides methods of preventing, treating or ameliorating diabetes by administering to a subject in need thereof a therapeutically effective amount of Dll4 antagonists that block Dll4-Notch signal pathways. As observed in a mouse model of diabetes, Dll4 antagonists exhibit protective effects on pancreatic islets, lower blood glucose levels, and block the production of auto-antibodies, including those against insulin and glutamic acid decarboxylase 65 (GAD65), via the expansion of regulatory T cells (Tregs). Thus, the present invention further provides methods of lowering the levels of blood glucose, and/or reducing or blocking the production of auto-antibodies, by administering to a subject in need thereof a therapeutically effective amount of Dll4 antagonists. Suitable Dll4 antagonists for the invention include antibodies or antibody fragments that specifically bind Dll4 and block Dll4-Notch interactions, the extracellular domain of Dll4, and the like.
