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

Abstract

Insulin receptor substrate-2 (Irs2) integrates insulin-like signals with glucose and cAMP agonists to regulate beta-cell growth, function, and survival. This study investigated whether increased Irs2 concentration in beta-cells could reduce beta-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 beta-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 NOD(Irs2) mice were less likely than NOD mice to relapse during the experimental period because they displayed 10-fold greater beta-cell mass and mitogenesis. In conclusion, increased Irs2 attenuated the progression of beta-cell destruction, promoted beta-cell mitogenesis, and reduced diabetes incidence in NOD(Irs2) mice.

ω-3 polyunsaturated fatty acids ameliorate type 1 diabetes and autoimmunity

“…No spontaneous reversal to less than 11.11 mmol/l was observed in any of the control groups (n = 15 per group). Consistent with results reported by others (26,27), we found that 80% of female NOD mice on a regular diet devel-IL-10 (21). The intervention of dysregulated Th cells is therefore critical to stopping autoimmune progression and the inflammatory attack against β cells.…”

“…injection of regular human insulin (0.8 U/kg; Novo Nordisk) diluted in sterile saline. Blood glucose levels were measured before insulin administration and then every 15 minutes afterwards, for 60 minutes (26). Histological studies and insulitis scoring.…”

Mulberry branch bark powder significantly improves hyperglycemia and regulates insulin secretion in type II diabetic mice

“…STZ can cause irreversible damage to pancreatic islet β-cells, inducing insulin secretion disorders, and resulting in the occurrence of diabetes [16]. The pictures in Figure 8 show that positive immunohistochemical staining was characterized by a deep tan in the pancreas; the positive parts mainly lying in the insulin-producing islet β-cells and the nuclei dyed blue.…”

Hes3 Is Expressed in the Adult Pancreatic Islet and Regulates Gene Expression, Cell Growth, and Insulin Release

“…Exendin-4 operates via Akt/Irs2 and mammalian target of rapamycin (31)(32)(33)(34), signaling components that in NSCs lead to Hes3 induction (10).…”