Bergerot I, Fabien N, Thivolet C
INSERM U. 448, Faculté de Médecine, RTH Laënnec, Lyon, France.
Diabetes Metab. 1996 Jul;22(4):235-9.
To compare the protective effects of IGF-1 and insulin on the autoimmune process of beta-cell destruction, permissive NOD recipients were adoptively transferred with 7 x 10(6) autoreactive T cells from diabetic NOD mice and then administered either 10 micrograms of rhIGF-1 or 0.5 unit of regular insulin subcutaneously twice daily for three weeks. The final incidence of successful transfers of diabetes observed at day 22 was significantly reduced in 1/12 mice (8.3%) treated with IGF-1, while diabetes was observed in 4/10 (40%) receiving insulin and 7/11 (63.4%) controls. A marked reduction of insulitis during histological analysis of the pancreatic glands of IGF-1 or insulin-treated mice was also observed. Non-diabetic mice treated with rhIGF-1 had a higher mean +/- SD percentage of intact islets (68.9 +/- 36% vs 10.7 +/- 13%, p < 0.01) and a lower percentage of severely infiltrated islets (5.7 +/- 9.8% vs 30.3 +/- 21%) than non-diabetic control mice. Insulin reduced islet-cell infiltration, though to a lesser extent, with a high percentage of normal islets (55.2 +/- 31%, p < 0.02). Some mice developed diabetes and severe islet-cell infiltration despite rhIGF-1 or insulin, thus indicating that some committed T cells were still able to invade islets and cause beta-cell destruction. To evaluate the effects of rhIGF-1 and insulin on cell trafficking in recipient mice, T cells from diabetic NOD Thy-1, 2 mice injected into congenic NOD-N Thy-1, 1 mice were monitored three weeks after adoptive cell transfer. The percentage of Thyq-1.2+ T cells was significantly reduced in the spleen (10.8 +/- 1.3% vs 17.2 +/- 3.9%, p = 0.004) of rhIGF-1 treated mice as compared to the thymus (68.4 +/- 7.9% vs 72.87 +/0 6.2, p = 0.306). Similar experiments performed in mice treated with insulin revealed no significant differences in the percentages of Thy-1,2+ T cells compared to controls in the spleen (l4.3 +/- 1.4%), thymus (84 +/- 2.5%) or pancreatic lymph nodes (21.5 +/- 1.6% vs 23.4 +/- 1.5%) of treated animals. These results suggest that rhIGF-1, as compared to insulin, could influence T-cell trafficking to the lymphoid organs in addition to affecting beta cells. These findings may have important implications for new preventive strategies in human Type 1 diabetes mellitus.
为比较胰岛素样生长因子-1（IGF-1）和胰岛素对β细胞破坏自身免疫过程的保护作用，将7×10⁶来自糖尿病NOD小鼠的自身反应性T细胞过继转移至免疫耐受的NOD受体小鼠，然后每天两次皮下注射10微克重组人IGF-1（rhIGF-1）或0.5单位普通胰岛素，持续三周。在第22天观察到，接受IGF-1治疗的1/12只小鼠（8.3%）成功转移糖尿病的最终发生率显著降低，而接受胰岛素治疗的4/10只小鼠（40%）以及7/11只对照小鼠（63.4%）出现了糖尿病。在对接受IGF-1或胰岛素治疗小鼠的胰腺进行组织学分析时，还观察到胰岛炎明显减轻。与非糖尿病对照小鼠相比，接受rhIGF-1治疗的非糖尿病小鼠完整胰岛的平均±标准差百分比更高（68.9±36%对10.7±13%，p<0.01），严重浸润胰岛的百分比更低（5.7±9.8%对30.3±21%）。胰岛素虽在较小程度上减少了胰岛细胞浸润，正常胰岛的百分比也较高（55.2±31%，p<0.02）。尽管使用了rhIGF-1或胰岛素，仍有一些小鼠发生了糖尿病并出现严重的胰岛细胞浸润，这表明一些已致敏的T细胞仍能够侵入胰岛并导致β细胞破坏。为评估rhIGF-1和胰岛素对受体小鼠细胞转运的影响，在过继细胞转移三周后，监测了注射到同基因NOD-N Thy-1,1小鼠体内的糖尿病NOD Thy-1,2小鼠的T细胞。与胸腺相比（68.4±7.9%对72.87±6.2，p = 0.306），rhIGF-1治疗小鼠脾脏中Thy-1.2⁺T细胞的百分比显著降低（10.8±1.3%对17.2±3.9%，p = 0.004）。在用胰岛素治疗的小鼠中进行的类似实验显示，与对照相比，治疗动物脾脏（14.3±1.4%）、胸腺（84±2.5%）或胰腺淋巴结（21.5±1.6%对23.4±1.5%）中Thy-1,2⁺T细胞的百分比无显著差异。这些结果表明，与胰岛素相比，rhIGF-可能除了影响β细胞外，还会影响T细胞向淋巴器官的转运。这些发现可能对人类1型糖尿病的新预防策略具有重要意义。
