Tacrolimus impairment of insulin secretion in isolated rat islets occurs at multiple distal sites in stimulus-secretion coupling
Tacrolimus impairment of insulin secretion in isolated rat islets occurs at multiple distal sites in stimulus-secretion coupling
复制标题
DOI：
10.1210/en.2003-1152
复制
发表时间：
2004-05-01
期刊：
影响因子：
4.8
通讯作者：
Iida, M
中科院分区：
文献类型：
--
作者：
Uchizono, Y;Iwase, M;Iida, M
其发病机制仍存在争议。我们利用大鼠胰岛模型研究了他克莫司抑制胰岛素分泌的机制。他克莫司在7-d培养过程中导致每个胰岛的DNA和胰岛素含量减少。他克莫司呈时间依赖性抑制葡萄糖刺激的胰岛素分泌，治疗浓度为0.01mumol/L时，7d后抑制葡萄糖刺激的胰岛素分泌为对照组的32+/-5%。他克莫司不改变胰岛细胞对葡萄糖的利用和氧化、三磷酸腺苷的产生、胰岛素mRNA的表达或高糖对细胞内钙离子的升高能力，但改变了细胞内钙离子浓度的快速振荡。他克莫司抑制线粒体燃料(L-亮氨酸、L-谷氨酰胺和α-酮基异己酸的混合物)和格列本脲刺激的胰岛素分泌，但不抑制L-精氨酸刺激的胰岛素分泌。在细胞外钙离子存在或不存在的情况下，他克莫司抑制卡巴胆碱和蛋白激酶C激动剂诱导的胰岛素分泌。在严格的无钙条件下，他克莫司不影响马斯托卡兰诱导的胰岛素分泌，但抑制其血糖升高。我们的结果提示，他克莫司可抑制胰岛素胞吐时细胞内钙离子升高的下游葡萄糖刺激的胰岛素分泌，蛋白激酶C介导的(钙依赖和非钙依赖的)GTP信号通路可能参与了这一过程。然而，他克莫司引起的胰岛素分泌障碍在停药3d后被逆转。我们的研究表明，他克莫司在刺激-分泌耦合的多个步骤中损害胰岛素的分泌。
the pathogenetic mechanisms remain controversial. We studied the mechanism of tacrolimus-induced impairment of insulin secretion using isolated rat pancreatic islets. Tacrolimus caused reductions in DNA and insulin contents per islet during 7-d culture. Tacrolimus time-dependently suppressed glucose-stimulated insulin secretion, and at a therapeutic concentration of 0.01 mumol/liter, it suppressed glucose-stimulated insulin secretion to 32 +/- 5% of the control value after 7-d incubation. Tacrolimus did not change islet glucose utilization and oxidation, ATP production, insulin mRNA expression, or the capacity for high glucose to increase intracellular Ca2+, but altered the rapid frequency oscillations of Ca2+ concentration. Tacrolimus suppressed insulin secretion stimulated by mitochondrial fuel ( combination of L-leucine and L-glutamine, and alpha-ketoisocaproate) and glibenclamide, but not by L-arginine. Tacrolimus suppressed insulin secretion induced by carbachol and by a protein kinase C agonist in the presence or absence of extracellular Ca2+. Under stringent Ca2+-free conditions, tacrolimus did not affect mastoparan-induced insulin secretion, but suppressed its glucose augmentation. Our results suggest that tacrolimus impairs glucose-stimulated insulin secretion downstream of the rise in intracellular Ca2+ at insulin exocytosis, and that protein kinase C-mediated (Ca2+-dependent and independent) and Ca2+-independent GTP signaling pathways may be involved. However, tacrolimus-induced impaired insulin secretion was reversed 3 d after removal of the drug. Our study demonstrated that tacrolimus impairs insulin secretion at multiple steps in stimulus-secretion coupling.