背景：西罗莫司对于胰岛素分泌的作用依然广受争议。我们的目的在于研究西罗莫司对胰岛素分泌的作用，通过两方面：（1）健康的小型猪体内；（2）体外对于人胰岛细胞。方法：对10头小型猪的三个阶段进行评估：（a）基线；（b）在服用西罗莫司4周时；（c）西罗莫司停用4周后。我们采用急性胰岛素反应（AIR）来测定胰岛素分泌，采用外周葡萄糖移去率(GDR)来测定葡萄糖耐量。（2）检测体外人胰岛细胞采用西罗莫司处理前后的胰岛素含量、刺激指数、三磷酸腺苷（ATP）和凋亡情况。结果：（1）基础和刺激后胰岛素水平和GDR在西罗莫司处理后上升，停用后下降回基线；（2）除外培养阶段，西罗莫司减少胰岛细胞凋亡和胰岛素含量，且有剂量依赖性。刺激指数和ATP也明显增强，但仅仅在西罗莫司处理阶段。结论：该研究提示西罗莫司在临床实践的血药浓度水平时（1）能够在体内提高基础和刺激后胰岛素水平，而在体外能提高除外培养阶段的胰岛素含量；（2）能够减少凋亡。该研究可能成为提高胰岛细胞移植效果的基础。

BACKGROUND: The effects of sirolimus on insulin secretion are still debated. Our aim was to investigate the effects of sirolimus, both (1) in vivo in healthy minipigs; and (2) in vitro on human islets. METHODS: (1) Ten minipigs were evaluated during three successive stages: (a) basal; (b) at the end of a 4-week period of treatment with sirolimus; and (c) after a 4-week period of wash-out. We evaluated insulin secretion with the acute insulin response (AIR), and glucose tolerance with the glucose disposal  rate (GDR). (2) Insulin content, stimulation index, adenosine triphosphate (ATP), and apoptosis were measured in human islets treated in vitro with sirolimus at therapeutic and supratherapeutic concentrations. RESULTS: (1) Basal and stimulated insulin levels and GDR increased during sirolimus administration and returned to baseline after a wash-out period; (2) regardless of culture duration, sirolimus dose-dependently decreased apoptosis and increased insulin content. Stimulation indexes and ATP were also significantly enhanced but only at therapeutic concentrations. CONCLUSIONS: This study suggests that sirolimus, at plasma-drug concentrations usually targeted in clinical practice, (1) increases basal and stimulated insulin levels in vivo and insulin content in vitro regardless of culture duration; (2) is able to reduce apoptosis. These findings may partly underlie the improved results of islet transplantation.

[责任编辑:tang]