VA Nebraska-Western Iowa Health Care System, University of Nebraska Medical Center, Omaha, Neb; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Neb.
VA Nebraska-Western Iowa Health Care System, University of Nebraska Medical Center, Omaha, Neb; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Neb; Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Neb.
Transl Res. 2014 Mar;163(3):221-31. doi: 10.1016/j.trsl.2013.12.002. Epub 2013 Dec 4.
Although the contribution of the immunosuppressants tacrolimus (TAC) and sirolimus (SIR) to the development of posttransplant diabetes mellitus (PTDM) are being increasingly recognized, the mechanisms of immunosuppressant-induced hyperglycemia are unclear. SIR induces insulin resistance predominantly, but is associated with β-cell dysfunction in rodents. TAC affects islet function but is associated with worsening insulin sensitivity in a few, and improvement in some, clinical studies. We sought to clarify the contributions of TAC and SIR to insulin resistance and islet function. Four groups of male and female Sprague-Dawley rats received TAC, SIR, TAC and SIR, or control for 2 weeks. All rats were administered an oral glucose challenge at the end of treatment. Half the groups were sacrificed 10 minutes after administration of regular insulin whereas the other half did not receive insulin before sacrifice. Liver, pancreas, fat, and muscle were harvested subsequently. Quantification of Western blots revealed that SIR and TAC plus SIR suppressed the phospho-Akt (pAkt)-to-Akt ratios in liver, muscle, and fat compared with control, regardless of sex. TAC alone did not impair the pAkt-to-Akt ratios in any of the tissues in male and female rats. β-Cell mass was reduced significantly after TAC treatment in male rats. SIR did not affect β-cell mass, regardless of sex. Our study demonstrated very clearly that SIR impairs insulin signaling, without any effect on β-cell mass, and TAC does not impair insulin signaling but reduces β-cell mass. Our efforts are key to understanding the mechanisms of immunosuppressant-induced hyperglycemia and to tailoring treatments for PTDM.
虽然免疫抑制剂他克莫司（TAC）和西罗莫司（SIR）在移植后糖尿病（PTDM）发展中的作用越来越受到关注，但免疫抑制剂引起高血糖的机制尚不清楚。SIR 主要引起胰岛素抵抗，但在啮齿动物中与β细胞功能障碍有关。TAC 影响胰岛功能，但在少数临床研究中与胰岛素敏感性恶化有关，而在一些研究中与胰岛素敏感性改善有关。我们试图阐明 TAC 和 SIR 对胰岛素抵抗和胰岛功能的影响。四组雄性和雌性 Sprague-Dawley 大鼠分别接受 TAC、SIR、TAC 和 SIR 或对照治疗 2 周。所有大鼠在治疗结束时接受口服葡萄糖挑战。一半的大鼠在给予常规胰岛素 10 分钟后被处死，而另一半在处死前没有接受胰岛素。随后采集肝脏、胰腺、脂肪和肌肉。Western blot 定量显示，SIR 和 TAC 加 SIR 与对照组相比，抑制了肝、肌肉和脂肪中的磷酸化 Akt（pAkt）-Akt 比值，而与性别无关。TAC 单独治疗在雄性和雌性大鼠的任何组织中均未损害 pAkt-Akt 比值。TAC 治疗后雄性大鼠的β细胞质量显著减少。SIR 无论性别如何，均不影响β细胞质量。我们的研究非常清楚地表明，SIR 损害胰岛素信号传递，而不影响β细胞质量，而 TAC 不损害胰岛素信号传递，但会减少β细胞质量。我们的努力是理解免疫抑制剂引起高血糖的机制和为 PTDM 定制治疗的关键。
