Insulin Receptor Substrate-2 in (cid:1) -Cells Decreases Diabetes in Nonobese Diabetic Mice

Insulin receptor substrate-2 (Irs2) integrates insulin-like signals with glucose and cAMP agonists to regulate (cid:1) -cell growth, function, and survival. This study investigated whether increased Irs2 concentration in (cid:1) -cells could reduce (cid:1) -cell destruction and the incidence of type 1 diabetes in nonobese diabetic (NOD) mice. NOD mice were intercrossed with C57BL/6 mice overexpressing Irs2 specifically in (cid:1) -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 with 12-wk-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 wk 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

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