Insulin Receptor Substrate-2 in β-Cells Decreases Diabetes in Nonobese Diabetic Mice

• Published in: Endocrinology (Philadelphia) 2009-10, Vol.150 (10), p.4531-4540
• Main Authors: Norquay, Lisa D, D'Aquino, Katharine E, Opare-Addo, Lynn M, Kuznetsova, Alexandra, Haas, Michael, Bluestone, Jeffrey A, White, Morris F
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Beta cells; CD3 antigen; CD3 Complex - immunology; Cell growth; Cell survival; Destruction; Diabetes; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 1 - therapy; Glucose; Glucose - metabolism; Glucose tolerance; Health risks; Homeostasis; Immunological tolerance; Immunotherapy; Insulin; Insulin Receptor Substrate Proteins - metabolism; Insulin receptors; Insulin-Secreting Cells - physiology; Insulitis; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Transgenic; Mitosis; Receptors; Remission
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2009-0395

Insulin receptor substrate-2 (Irs2) integrates insulin-like signals with glucose and cAMP agonists to regulate β-cell growth, function, and survival. This study investigated whether increased Irs2 concentration in β-cells could reduce β-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 β-cells to create NODIrs2 mice. After backcrossing NODIrs2 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 NODIrs2 mice. Moreover, the risk of diabetes decreased 50% in NODIrs2 mice until the experiment was terminated at 40 wk of age. Nondiabetic NODIrs2 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 NODIrs2 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 NODIrs2 mice; however, anti-CD3-treated NODIrs2 mice were less likely than NOD mice to relapse during the experimental period because they displayed 10-fold greater β-cell mass and mitogenesis. In conclusion, increased Irs2 attenuated the progression of β-cell destruction, promoted β-cell mitogenesis, and reduced diabetes incidence in NODIrs2 mice. Increasing expression of Irs2 in the pancreas attenuates the progression of β-celdestruction, promotes β-cell mitogenesis, and reduces diabetes incidence in NODIrs2-mice.