Exendin-4 improves reversal of diabetes in NOD mice treated with Anti-CD3 monoclonal antibody by enhancing recovery of β-cells
Exendin-4 improves reversal of diabetes in NOD mice treated with Anti-CD3 monoclonal antibody by enhancing recovery of β-cells
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DOI：
10.1210/en.2007-0358
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发表时间：
2007-11-01
期刊：
影响因子：
4.8
通讯作者：
Herold, Kevan C.
中科院分区：
文献类型：
--
作者：
Sherry, Nicole A.;Chen, Wei;Herold, Kevan C.
免疫调节剂可以阻止1型糖尿病（T1 DM）中胰岛素分泌的丧失，但它们没有导致永久性疾病缓解或恢复正常的胰岛素分泌。我们测试了Exendin-4（胰高血糖素样肽-1受体激动剂）是否会增强用抗CD 3单克隆抗体（mAb）治疗的NOD小鼠中T1 DM的缓解，并研究了Exendin-4治疗对β细胞的细胞和代谢反应的影响。用抗CD 3单抗和exendin-4治疗的糖尿病NOD小鼠的缓解率（44%）高于单独用抗CD 3单抗（37%）或exendin-4（0%）或单独用胰岛素或IgG（0%）治疗的小鼠（P < 0.01）。在诊断时血糖水平低于350 mg/dl的小鼠中，exendin-4对抗CD 3 mAb后糖尿病逆转的作用最大（63%对39%，P < 0.05）。Exendin-4不影响β-细胞面积、复制或凋亡或降低致糖尿病或调节性T细胞的频率或调节胰岛细胞的抗原性。抗CD 3 mAb治疗T1 DM与诊断时确定的葡萄糖转运蛋白-2（+）/胰岛素（-）胰岛细胞中胰岛素的恢复相关。联合治疗的小鼠葡萄糖耐量和胰岛素反应得到改善，exendin-4增加了β细胞的胰岛素含量和胰岛素释放。我们得出结论，胰高血糖素样肽-1受体激动剂治疗通过增强残余胰岛的恢复来增强用抗CD 3 mAb治疗的T1 DMinNOD小鼠的缓解。这种组合方法可能有助于治疗新发T1 DM患者。
Immune modulators can arrest loss of insulin secretion in type 1 diabetes mellitus (T1DM), but they have not caused permanent disease remission or restored normal insulin secretion. We tested whether exendin-4, a glucagon-like peptide-1 receptor agonist, would enhance remission of T1DM in NOD mice treated with anti-CD3 monoclonal antibody (mAb) and studied the effects of exendin-4 treatment on cellular and metabolic responses of beta-cells. Diabetic NOD mice treated with anti-CD3 mAb and exendin-4 had a higher rate of remission (44%) than mice treated with anti-CD3 mAb alone (37%) or exendin-4 (0%) or insulin or IgG alone ( 0%) (P < 0.01). The effect of exendin-4 on reversal of diabetes after anti-CD3 mAb was greatest in mice with a glucose level of less than 350 mg/dl at diagnosis ( 63 vs. 39%, P < 0.05). Exendin-4 did not affect beta-cell area, replication, or apoptosis or reduce the frequency of diabetogenic or regulatory T cells or modulate the antigenicity of islet cells. Reversal of T1DM with anti-CD3 mAb was associated with recovery of insulin in glucose transporter-2(+)/insulin(-) islet cells that were identified at diagnosis. Glucose tolerance and insulin responses improved in mice treated with combination therapy, and exendin-4 increased insulin content and insulin release from beta-cells. We conclude that treatment with glucagon-like peptide-1 receptor agonist enhances remission of T1DMinNOD mice treated with anti-CD3mAb by enhancing the recovery of the residual islets. This combinatorial approach may be useful in treatment of patients with new-onset T1DM.