Tacrolimus suppresses glucose-induced insulin release from pancreatic islets by reducing glucokinase activity
Tacrolimus suppresses glucose-induced insulin release from pancreatic islets by reducing glucokinase activity
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DOI：
10.1152/ajpendo.00390.2004
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发表时间：
2005-02-01
影响因子：
5.1
通讯作者：
Seino, Y
中科院分区：
文献类型：
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作者：
Radu, RG;Fujimoto, S;Seino, Y
他克莫司广泛用于免疫抑制剂治疗，包括各种器官移植。其主要副作用之一是由于胰岛素分泌减少而导致的高血糖症，但其机制仍不清楚。我们研究了他克莫司在不影响胰岛素含量的浓度下对胰岛素分泌的代谢作用。暴露于3 nM他克莫司24小时可减少高葡萄糖（16.7 mM）诱导的胰岛素分泌（对照组2.14 +/- 0.08 vs他克莫司1.75 +/- 0.02 ng）。胰岛（-1）。30 min（-1），P < 0.01），而不影响胰岛素含量。在动态实验中，他克莫司处理的胰岛在高糖暴露10分钟后的20分钟内胰岛素分泌和NAD（P）H荧光减少。在16.7 mM葡萄糖存在下，他克莫司处理的胰岛的ATP含量和葡萄糖利用率低于对照（ATP含量：对照9.69 +/- 0.99 vs.他克莫司6.52 +/- 0.40 pmol/胰岛，P < 0.01;葡萄糖利用率：对照103.8 +/- 6.9 vs.他克莫司74.4 +/- 5.1 pmol。胰岛（-1）。90 min（-1），P < 0.01）。然而，在16.7 mM α-酮异己酸（一种线粒体燃料）存在下，他克莫司处理的胰岛的胰岛素释放与对照胰岛的胰岛素释放相似。他克莫司治疗降低了决定糖酵解速度的葡萄糖激酶活性（对照组65.3 ± 3.4 pmol vs.他克莫司49.9 ± 2.8 pmol中心点胰岛（-1）中心点60 min（-1），P < 0.01），而己糖激酶活性不受影响。这些结果表明，长期暴露于他克莫司会降低葡萄糖刺激的胰岛素释放，这是由于ATP产生减少和葡萄糖激酶活性降低导致的糖酵解。
Tacrolimus is widely used for immunosuppressant therapy, including various organ transplantations. One of its main side effects is hyperglycemia due to reduced insulin secretion, but the mechanism remains unknown. We have investigated the metabolic effects of tacrolimus on insulin secretion at a concentration that does not influence insulin content. Twenty-four-hour exposure to 3 nM tacrolimus reduced high glucose (16.7 mM)-induced insulin secretion ( control 2.14 +/- 0.08 vs. tacrolimus 1.75 +/- 0.02 ng . islet(-1) . 30 min(-1), P < 0.01) without affecting insulin content. In dynamic experiments, insulin secretion and NAD(P) H fluorescence during a 20-min period after 10 min of high-glucose exposure were reduced in tacrolimus-treated islets. ATP content and glucose utilization of tacrolimus-treated islets in the presence of 16.7 mM glucose were less than in control ( ATP content: control 9.69 +/- 0.99 vs. tacrolimus 6.52 +/- 0.40 pmol/islet, P < 0.01; glucose utilization: control 103.8 +/- 6.9 vs. tacrolimus 74.4 +/- 5.1 pmol . islet(-1) . 90 min(-1), P < 0.01). However, insulin release from tacrolimus-treated islets was similar to that from control islets in the presence of 16.7 mM alpha-ketoisocaproate, a mitochondrial fuel. Glucokinase activity, which determines glycolytic velocity, was reduced by tacrolimus treatment (control 65.3 +/- 3.4 vs. tacrolimus 49.9 +/- 2.8 pmol center dot islet(-1) center dot 60 min(-1), P < 0.01), whereas hexokinase activity was not affected. These results indicate that glucose-stimulated insulin release is decreased by chronic exposure to tacrolimus due to reduced ATP production and glycolysis derived from reduced glucokinase activity.