The impact of the mTOR inhibitor sirolimus on the proliferation and function of pancreatic islets and ductal cells
The impact of the mTOR inhibitor sirolimus on the proliferation and function of pancreatic islets and ductal cells
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DOI：
10.1007/s00125-006-0374-5
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发表时间：
2006-10-01
期刊：
影响因子：
8.2
通讯作者：
Korbutt, G. S.
中科院分区：
文献类型：
--
作者：
Bussiere, C. T.;Lakey, J. R. T.;Korbutt, G. S.
目的/假说用于胰岛移植的埃德蒙顿方案为1型糖尿病患者带来了希望。然而，该方案需要终生免疫抑制，特别是西罗莫司，一种细胞抗增殖药物。西罗莫司对人胰腺导管细胞(HDCs)的影响尚不清楚。这一点可能很重要，因为高密度脂蛋白被认为是胰岛前体。由于新生猪胰岛含有大量的导管前体细胞，可能是临床上潜在的胰岛来源，我们还检测了西罗莫司对这一组织的影响。方法将4例新生猪胰岛(n=4)、9例新生猪胰岛(n=9)和5例人胰岛(n=5)分别加入和不加入西罗莫司(20 ng/ml)培养6d。结果与对照组相比，加入西罗莫司培养的HDC和NPI细胞数量分别减少50%和28%(P<；0.05)。对照培养相对于时间0分别扩大了1.65倍和2.44倍。TUNEL染色结果显示，西罗莫司处理组的细胞数量减少不是由于细胞凋亡所致。在高糖静态孵育后，没有观察到对人胰岛或NPI的功能影响。西罗莫司治疗同基因移植和幼稚的Balc/c小鼠导致OGTT谱改变，高血糖和体重增加持续时间延长。治疗组之间移植物和器官胰岛素含量无差异。结论/解释我们的结果表明，西罗莫司减少了培养的导管细胞数量，并改变了体内葡萄糖刺激的胰岛素分泌。对胰岛移植受者使用西罗莫司可能会由于减少导管新生和诱导胰岛素抵抗而损害移植物功能。
Aims/hypothesis The Edmonton Protocol for islet transplantation has provided hope for type 1 diabetic patients. However, this protocol requires lifelong immunosuppression, specifically sirolimus, a cellular antiproliferate. The effect of sirolimus on human pancreatic ductal cells (HDCs) is not known. This may be important since HDCs are believed to be islet precursors. Since neonatal porcine islets (NPIs), which contain many ductal precursor cells, could be a potential clinical source of islets, we also tested the effects of sirolimus on this tissue.Methods HDCs (n=4), NPIs (n=9) and human islets (n=5) were cultured with and without sirolimus (20 ng/ml) for 6 days.Results HDCs and NPIs cultured with sirolimus showed a 50 and 28% decrease, respectively, in cell number relative to control (p < 0.05). Control cultures expanded 1.65- and 2.44-fold relative to time 0. Decreases in cell number of sirolimus-treated HDCs were not due to apoptosis as measured by TUNEL staining. No functional effects on human islets or NPIs were observed following static incubation with high glucose. Treatment of syngeneically transplanted and naive BALC/c mice with sirolimus resulted in altered OGTT profiles with prolonged elevation of hyperglycaemia and weight gain. There was no difference in graft and organ insulin content between treatment groups.Conclusions/interpretations Our results indicate that sirolimus decreases ductal cell numbers in culture and alters glucose-stimulated insulin secretion in vivo. The administration of sirolimus to islet transplant recipients is likely to impair graft function as a result of decreasing ductal neogenesis and induction of insulin resistance.