Moriyama Hiroaki, Nagata Masao, Arai Takashi, Okumachi Yasuyo, Yamada Katsumi, Kotani Reiko, Yasuda Hisafumi, Hara Kenta, Yokono Koich
Department of Internal and Geriatric Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
Diabetes Res Clin Pract. 2007 Sep;77 Suppl 1:S155-60. doi: 10.1016/j.diabres.2007.01.050. Epub 2007 Apr 24.
Rodents have two functional preproinsulin genes named insulin 1 and insulin 2 on different chromosome and have two amino acid differences in insulin B chain. We have established insulin 1 or insulin 2 knockout (KO) non-obese diabetic (NOD) colonies in the animal institute of Kobe University and evaluated anti-insulin autoimmunity. Similar to the previous report, insulin 1-KO provides strong protection from insulitis (islet-infiltration of mononuclear cells) and diabetes, whereas the insulin 2-KO markedly accelerated insulitis and development of diabetes even at further backcross breeding with NOD/Shi/Kbe mice (P<0.0001). Expression of serum anti-insulin autoantibodies (IAA) was enhanced in insulin 2-KO mice at a time between 10 and 15 weeks of age (P<0.005) while the expression of insulin 1-KO NOD mice was rather reduced. Furthermore, T cell reactivity in splenocytes of insulin 2-KO NOD mice to insulin 1 B:9-23 peptide was increased (P<0.05), suggesting that expanding insulin-reactive T cells may contribute to the acceleration of diabetes in insulin 2-KO mice. Based on those observations, we hypothesize that insulin 1 is a crucial T cell antigen in murine autoimmune diabetes and modification of anti-insulin autoimmunity can be applicable to antigen-based therapy for human type 1 diabetic patients.
啮齿动物在不同染色体上有两个功能性胰岛素原基因，分别命名为胰岛素1和胰岛素2，其胰岛素B链存在两个氨基酸差异。我们在神户大学动物研究所建立了胰岛素1或胰岛素2基因敲除（KO）的非肥胖糖尿病（NOD）小鼠品系，并评估了抗胰岛素自身免疫性。与之前的报道相似，胰岛素1基因敲除能为胰岛炎（单核细胞浸润胰岛）和糖尿病提供强大的保护作用，而胰岛素2基因敲除即使在与NOD/Shi/Kbe小鼠进一步回交繁殖时，也会显著加速胰岛炎和糖尿病的发展（P<0.0001）。在10至15周龄之间，胰岛素2基因敲除小鼠血清抗胰岛素自身抗体（IAA）的表达增强（P<0.005），而胰岛素1基因敲除的NOD小鼠的IAA表达则有所降低。此外，胰岛素2基因敲除的NOD小鼠脾细胞对胰岛素1 B:9 - 23肽的T细胞反应性增加（P<0.05），这表明胰岛素反应性T细胞的扩增可能导致胰岛素2基因敲除小鼠糖尿病的加速发展。基于这些观察结果，我们推测胰岛素1是小鼠自身免疫性糖尿病中的关键T细胞抗原，对抗胰岛素自身免疫性的调节可能适用于人类1型糖尿病患者的基于抗原的治疗。
