INSERM, U986, DeAR Lab Avenir, Cochin/Saint Vincent de Paul Hospital, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Eur J Immunol. 2012 Jun;42(6):1553-61. doi: 10.1002/eji.201242394.
Despite encouraging results in the NOD mouse, type 1 diabetes prevention trials using subcutaneous insulin have been unsuccessful. To explain these discrepancies, 3-week-old NOD mice were treated for 7 weeks with subcutaneous insulin at two different doses: a high dose (0.5 U/mouse) used in previous mouse studies; and a low dose (0.005 U/mouse) equivalent to that used in human trials. Effects on insulitis and diabetes were monitored along with immune and metabolic modifications. Low-dose insulin did not have any effect on disease incidence. High-dose treatment delayed but did not prevent diabetes, with reduced insulitis reappearing once insulin discontinued. This effect was not associated with significant immune changes in islet infiltrates, either in terms of cell composition or frequency and IFN-γ secretion of islet-reactive CD8(+) T cells recognizing the immunodominant epitopes insulin B(15-23) and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)(206-214). Delayed diabetes and insulitis were associated with lower blood glucose and endogenous C-peptide levels, which rapidly returned to normal upon treatment discontinuation. In conclusion, high- but not low-dose prophylactic insulin treatment delays diabetes onset and is associated with metabolic changes suggestive of β-cell "rest" which do not persist beyond treatment. These findings have important implications for designing insulin-based prevention trials.
尽管在 NOD 小鼠中取得了令人鼓舞的结果，但使用皮下胰岛素进行的 1 型糖尿病预防试验并未成功。为了解释这些差异，将 3 周龄的 NOD 小鼠用两种不同剂量的皮下胰岛素治疗 7 周：高剂量（0.5 U/只），用于以前的小鼠研究；低剂量（0.005 U/只），相当于人类试验中使用的剂量。监测胰岛炎和糖尿病的影响，同时监测免疫和代谢改变。低剂量胰岛素对疾病发生率没有任何影响。高剂量治疗虽然延迟但不能预防糖尿病，一旦停止胰岛素治疗，炎症反应就会再次出现。这种效果与胰岛浸润中胰岛反应性 CD8(+)T 细胞识别免疫优势表位胰岛素 B(15-23)和胰岛特异性葡萄糖-6-磷酸酶催化亚基相关蛋白（IGRP）(206-214)的细胞组成、频率和 IFN-γ分泌的显著免疫变化无关。延迟的糖尿病和胰岛炎与较低的血糖和内源性 C 肽水平相关，一旦停止治疗，这些水平迅速恢复正常。总之，高剂量而非低剂量的预防性胰岛素治疗延迟了糖尿病的发病，并与代谢变化相关，这些变化提示β细胞“休息”，但在治疗结束后不会持续存在。这些发现对设计基于胰岛素的预防试验具有重要意义。
