Is there a role for locally produced interleukin-1 in the deleterious effects of high glucose or the type 2 diabetes milieu to human pancreatic islets?
Is there a role for locally produced interleukin-1 in the deleterious effects of high glucose or the type 2 diabetes milieu to human pancreatic islets?
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DOI：
10.2337/diabetes.54.11.3238
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发表时间：
2005-11-01
期刊：
影响因子：
7.7
通讯作者：
Eizirik, DL
中科院分区：
文献类型：
--
作者：
Welsh, N;Cnop, M;Eizirik, DL
I型和2型糖尿病中存在不同程度的P细胞衰竭和凋亡。最近有人提出，2 型糖尿病中高葡萄糖诱导的 β 细胞凋亡与 1 型糖尿病具有最终的共同途径，包括 β 细胞产生白细胞介素 1 β (IL-1 β)、核因子 κ B (NF-κ B) 激活以及通过 Fas-FasL 死亡。本研究的目的是测试人类胰岛在体外暴露于高葡萄糖或体内 2 型糖尿病环境是否会诱导 IL-1 β 表达并随后激活 NF-κ B 依赖性基因。从五名血糖正常的器官捐献者中分离出人类胰岛。将胰岛在 5.6、11 或 28 mmol/l 葡萄糖下培养 48 小时至 7 天。出于比较目的，胰岛也暴露于 IL-1 β。通过实时 RT-PCR 以盲法评估基因 mRNA 表达水平。与 5.6 mmol/l 葡萄糖相比，在 11 mmol/l 和 28 mmol/l 葡萄糖下培养人胰岛可诱导中度胰岛素增加 4 至 5 倍，但 IL-1 β 和 IL-1 受体拮抗剂 (IL-1ra) 的表达均未发生变化。 IL-1β 和 IL-1ra 蛋白向培养基的释放也没有变化。平行研究的刺激人类单核细胞释放的 IL-1 β 比胰岛多 50 倍以上。也没有葡萄糖诱导的胰岛 Fas 表达。 IL-1β 可诱导人胰岛中 NF-κ B 依赖性基因 Iκ B-α 和单核细胞趋化蛋白 (MCP)-1 的表达，但高葡萄糖则不会诱导表达。在第二组实验中，从 7 名 2 型糖尿病患者和 8 名对照受试者中分离出人类胰岛。 mRNA水平的结果与体外实验基本相同，即体内糖尿病状态不会诱导人胰岛中IL-1β、Fas或MCP-1的表达，也不会改变IL-1ra的表达。目前的研究结果表明，体外高葡萄糖或体内糖尿病环境不会诱导人胰岛产生 IL-1β 或 NF-κB 激活。这使得本地产生的IL-1β不太可能是人类胰岛糖毒性的重要介质，并且反对IL-1β-NF-κB-Fas途径作为1型和2型糖尿病中P细胞死亡的常见介质。
Different degrees of P-cell failure and apoptosis are present in type I and type 2 diabetes. It has been recently suggested that high glucose-induced beta-cell apoptosis in type 2 diabetes shares a final common pathway with type I diabetes, involving interleukin-1 beta (IL-1 beta) production by beta-cells, nuclear factor-kappa B (NF-kappa B) activation, and death via Fas-FasL. The aim of this study was to test whether human islet exposure to high glucose in vitro, or to the type 2 diabetes environment in vivo, induces IL-1 beta expression and consequent activation of NF-kappa B-dependent genes. Human islets were isolated from five normoglycemic organ donors. The islets were cultured for 48 h to 7 days at 5.6, 11, or 28 mmol/l glucose. For comparative purposes, islets were also exposed to IL-1 beta. Gene mRNA expression levels were assessed by real-time RT-PCR in a blinded fashion. Culture of the human islets at 11 and 28 mmol/l glucose induced a four- to fivefold increase in medium insulin as compared with 5.6 mmol/l glucose, but neither IL-1 beta nor IL-1 receptor antagonist (IL-1ra) expression changed. IL-1 beta and IL-1ra protein release to the medium was also unchanged. Stimulated human monocytes, studied in parallel, released > 50-fold more IL-1 beta than the islets. There was also no glucose-induced islet Fas expression. Expression of the NF-kappa B-dependent genes I kappa B-alpha and monocyte chemoattractant protein (MCP)-1 was induced in human islets by IL-1 beta but not by high glucose. In a second set of experiments, human islets were isolated from seven type 2 diabetic patients and eight control subjects. The findings on mRNA levels were essentially the same as in the in vitro experiments, namely the in vivo diabetic state did not induce IL-1 beta, Fas, or MCP-1 expression in human islets, and also did not modify IL-1ra expression. The present findings suggest that high glucose in vitro, or the diabetic milieu in vivo, does not induce IL-1 beta production or NF-kappa B activation in human islets. This makes it unlikely that locally produced IL-1 beta is an important mediator of glucotoxicity to human islets and argues against the IL-1 beta-NF-kappa B-Fas pathway as a common mediator for P-cell death in type 1 and type 2 diabetes.