Scarim A L, Heitmeier M R, Corbett J A
The Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Missouri 63104, USA.
Endocrinology. 1997 Dec;138(12):5301-7. doi: 10.1210/endo.138.12.5583.
The purpose of this study was to identify the duration of exposure of islets to interleukin 1beta (IL-1beta) that results in irreversible damage. Treatment of rat islets for 18 h with IL-1beta results in an inhibition of glucose-stimulated insulin secretion, mitochondrial aconitase activity, and total protein synthesis. The addition of N(G)-monomethyl-L-arginine (NMMA) or aminoguanidine to islets preincubated for 18 h with IL-1beta, followed by continued culture for 8 h (with both NMMA and IL-1beta), results in the recovery of islet secretory function, aconitase activity, and protein synthesis. However, islet metabolic function is irreversibly inhibited after a 36-h incubation with IL-1beta, as an additional 8-h incubation with NMMA or aminoguanidine does not stimulate the recovery of insulin secretion, aconitase activity, or protein synthesis. The irreversible inhibition of metabolic function correlates with the commitment of islets to destruction. Treatment of islets for 96 h with IL-1beta results in islet degeneration. NMMA, added to islets 24 h after the addition of IL-1beta, followed by continued culture for 72 h (with NMMA and IL-1beta), prevents islet degeneration. However, NMMA added to islets 36 h or 48 h after the addition of IL-1beta, followed by continued culture for a total of 96 h, does not prevent islet degeneration. New messenger RNA expression appears to be required for islet recovery from IL-1beta-induced damage as actinomycin D prevents the recovery of islet aconitase activity. Lastly, treatment of human islets with a combination of IL-1beta and interferon-gamma (IFNgamma) results in a potent inhibition of mitochondrial aconitase activity. NMMA, when cocultured with IL-1beta + IFNgamma, completely prevents cytokine-induced inhibition of human islet aconitase activity. NMMA, when added to human islets pretreated for 18 h with IL-1beta + IFNgamma, stimulates the recovery of mitochondrial aconitase activity after an additional 8 h incubation. These findings indicate that nitric oxide-induced islet damage is reversible; however, prolonged production of nitric oxide (after a 36-h exposure to IL-1beta) results in the irreversible inhibition of islet metabolic and secretory function.
本研究的目的是确定胰岛暴露于白细胞介素1β（IL-1β）导致不可逆损伤的持续时间。用IL-1β处理大鼠胰岛18小时会导致葡萄糖刺激的胰岛素分泌、线粒体乌头酸酶活性和总蛋白质合成受到抑制。在与IL-1β预孵育18小时的胰岛中添加N（G）-单甲基-L-精氨酸（NMMA）或氨基胍，然后继续培养8小时（同时添加NMMA和IL-1β），会导致胰岛分泌功能、乌头酸酶活性和蛋白质合成恢复。然而，与IL-1β孵育36小时后，胰岛代谢功能会受到不可逆抑制，因为再用NMMA或氨基胍孵育8小时并不能刺激胰岛素分泌、乌头酸酶活性或蛋白质合成的恢复。代谢功能的不可逆抑制与胰岛走向破坏有关。用IL-1β处理胰岛96小时会导致胰岛退化。在添加IL-1β 24小时后向胰岛中添加NMMA，然后继续培养72小时（同时添加NMMA和IL-1β），可防止胰岛退化。然而，在添加IL-1β 36小时或48小时后向胰岛中添加NMMA，然后继续培养总共96小时，不能防止胰岛退化。胰岛从IL-1β诱导的损伤中恢复似乎需要新的信使核糖核酸表达，因为放线菌素D会阻止胰岛乌头酸酶活性的恢复。最后，用IL-1β和干扰素-γ（IFNγ）联合处理人胰岛会导致线粒体乌头酸酶活性受到有效抑制。当与IL-1β + IFNγ共培养时，NMMA完全可防止细胞因子诱导的人胰岛乌头酸酶活性抑制。当添加到用IL-1β + IFNγ预处理18小时的人胰岛中时，NMMA在再孵育8小时后可刺激线粒体乌头酸酶活性恢复。这些发现表明一氧化氮诱导的胰岛损伤是可逆的；然而，一氧化氮的长期产生（在暴露于IL-1β 36小时后）会导致胰岛代谢和分泌功能的不可逆抑制。
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