Insulin receptor substrate-2 (Irs2) integrates insulin-like signals with glucose and cAMP agonists to regulate -cell growth, function and survival. This study investigated whether increased Irs2 concentration in -cells could reduce -cell destruction and the incidence of type 1 diabetes in non-obese diabetic (NOD) mice. NOD-mice were intercrossed with C57Bl/6 mice overexpressing Irs2 specifically in -cells to create NOD^Irs2-mice. After backcrossing NOD^Irs2-mice for 12 generations, glucose homeostasis and diabetes incidence were compared against NOD littermates. Compared to 12-week old NOD-mice, the progression of severe insulitis was reduced and islet mass was increased in NOD^Irs2-mice. Moreover, the risk of diabetes decreased 50% in NOD^Irs2-mice until the experiment was terminated at 40 weeks of age. Nondiabetic NOD^Irs2-mice displayed better glucose tolerance than nondiabetic NOD-mice throughout the duration of the study and up to the age of 18 months. The effect of Irs2 to increase islet mass and improve glucose tolerance raised the possibility that NOD^Irs2-mice might have an increased capacity to respond to anti-CD3 antibody, which can induce remission of overt diabetes in some NOD mice. Anti-CD3 antibody injections restored glucose tolerance in newly diabetic NOD- and NOD^Irs2-mice; however, anti-CD3-treated NOD^Irs2-mice were less likely than NOD-mice to relapse during the experimental period, as they displayed 10-fold greater -cell mass and mitogenesis. In conclusion, increased Irs2 attenuated the progression of -cell destruction, promoted -cell mitogenesis, and reduced diabetes incidence in NOD^Irs2-mice.