THE PRESENT INVENTION PROVIDES METHODS OF PREVENTING, TREATING OR AMELIORATING DIABETES BY ADMINISTERING TO A SUBJECT IN NEED THEREOF A THERAPEUTICALLY EFFECTIVE AMOUNT OF DII4 ANTAGONISTS THAT BLOCK DII4-NOTCH SIGNAL PATHWAYS. AS OBSERVED IN A MOUSE MODEL OF DIABETES, DII4 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 DII4 ANTAGONISTS.； SUITABLE DII4 ANTAGONISTS FOR THE INVENTION INCLUDE ANTIBODIES OR ANTIBODY FRAGMENTS THAT SPECIFICALLY BIND DII4 AND BLOCK DII4-NOTCH INTERACTIONS, THE EXTRACELLULAR DOMAIN OF DII4, AND THE LIKE.
