Acceleration of autoimmune diabetes in Rheb-congenic NOD mice with β-cell-specific mTORC1 activation
Acceleration of autoimmune diabetes in Rheb-congenic NOD mice with β-cell-specific mTORC1 activation
复制标题
β细胞特异性 mTORC1 激活可加速 Rheb 同源 NOD 小鼠的自身免疫糖尿病
DOI：
10.1016/j.bbrc.2011.04.026
复制
发表时间：
2011
期刊：
影响因子：
--
通讯作者：
et al
中科院分区：
文献类型：
--
作者：
Sasaki;et al
脑中富含的RAS同源蛋白(Rheb)是一种类似RAS的小GTP酶，它激活雷帕霉素复合体1(MTORC1)的机制靶点，促进细胞生长。我们之前在β细胞(B6Rheb)中获得了高表达rheb的转基因C57BL/6小鼠，与野生型C57BL/6小鼠相比，该小鼠的β细胞体积增大，糖耐量提高，胰岛素分泌增加。这些小鼠还表现出对肥胖性高血糖(2型糖尿病模型)和多重低剂量链脲佐菌素(MLDS)诱导的高血糖(1型糖尿病模型(T1D))的抵抗力。为了研究Rheb对B6Rheb小鼠mTORC1mTORC 1激活的影响是否也在NOD小鼠中明显，NOD小鼠是一种自发的自身免疫性T1D模型，我们建立了两个在其β细胞中高表达Rheb的NOD小鼠品系(NODRheb；R3和R20)。我们验证了Rheb在β细胞中的过表达，mTORC1mRNA的相对激活和β细胞的扩大。到35周龄时，R3品系的糖尿病发病率显著高于NOD小鼠，R20品系的糖尿病发病率往往高于NOD小鼠。组织学分析显示，与NOD小鼠相比，12周龄R3NODRheb小鼠的胰岛素炎症明显加速。此外，血清胰岛素自身抗体(IAA)的表达显著高于NOD小鼠。我们还检查了完全弗氏佐剂(CFA)单独治疗或与胰高血糖素样肽-1(GLP-1)类似物一起治疗是否可以逆转NODRheb鼠的高血糖；出人意料的是，几乎没有一只小鼠达到正常血糖。总而言之，NODRheb鼠的糖尿病进展显著加速，而不是被预防。我们的结果提示，β细胞的增大可能只是增强了病理性T细胞对胰岛的自身免疫，导致自身免疫性糖尿病的加速。我们认为，自身免疫性T1D的理想治疗不仅需要β细胞的扩增，而且需要β细胞的再生，此外还需要防止T1D细胞的破坏。
The protein Ras homolog enriched in brain (Rheb) is a Ras-like small GTPase that activates the mechanistic target of rapamycin complex 1 (mTORC1), which promotes cell growth. We previously generated transgenic C57BL/6 mice overexpressing Rheb in β-cells (B6Rheb), which exhibited increased β-cell size and improved glucose tolerance with higher insulin secretion than wild type C57BL/6 mice. The mice also showed resistance to obesity-induced hyperglycemia, a model of type 2 diabetes, and to multiple low-dose-streptozotocin (MLDS)-induced hyperglycemia, a model of type 1 diabetes (T1D). To investigate whether the effects of mTORC1 activation by Rheb in B6Rhebmice would also be evident in NOD mice, a spontaneous autoimmune T1D model, we created two NOD mouse lines overexpressing Rheb in their β-cells (NODRheb; R3 and R20). We verified Rheb overexpression in β-cells, the relative activation of mTORC1 and β-cell enlargement. By 35 weeks of age, diabetes incidence was significantly greater in the R3 line and tended to be greater in the R20 line than in NOD mice. Histological analysis demonstrated that insulitis was significantly accelerated in 12-week-old R3 NODRhebmice compared with NOD mice. Furthermore, serum insulin autoantibody (IAA) expression was significantly higher than that of NOD mice. We also examined whether complete Freund’s adjuvant (CFA) treatment alone or with glucagon-like peptide-1 (GLP-1) analog would reverse the hyperglycemia of NODRhebmice; unexpectedly, almost none achieved normoglycemia. In summary, diabetes progression was significantly accelerated rather than prevented in NODRhebmice. Our results suggest that the β-cell enlargement might merely enhance the autoimmunity of pathogenic T-cells against islets, leading to acceleration of autoimmune diabetes. We conclude that not only enlargement but also regeneration of β-cells in addition to the prevention of β-cell destruction will be required for the ideal therapy of autoimmune T1D.