中国普外基础与临床杂志

中国普外基础与临床杂志

胃转流术治疗 2 型糖尿病与 JNK 信号通路的关系

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目的 探讨胃转流手术治疗肥胖合并 2 型糖尿病的机制及其与 c-Jun 氨基末端激酶(JNK)信号通路的关系。 方法 将小鼠胰岛素瘤(INS-1)细胞根据不同的处理方式分为 4 组:对照组(完全培养基)、高糖组(30 mmol/L 糖培养基)、高糖+100 nmol/L 胰高血糖素样肽-1 受体类似物艾塞那肽组(艾塞那肽组)及高糖+100 nmol/L 胰高血糖素样肽-1 受体类似物艾塞那肽+JNK 激动剂组(JNK 激动剂组)。各组细胞按培养条件培养至第 7 天时收集细胞,采用 MTT 法检测细胞活性,流式细胞仪检测细胞凋亡率,Western blot 法检测免疫球蛋白结合蛋白(Bip)、CCAAT 增强子结合蛋白同源蛋白(CHOP)、caspase-3 及 P-SAPK/JNK 蛋白的表达水平。 结果 与对照组比较,高糖组和 JNK 激动剂组的细胞活性明显下降(P<0.05),细胞凋亡率明显增加(P<0.01),P-SAPK/JNK 及 caspase-3 蛋白表达量明显上调,但 Bip 和 CHOP 蛋白表达量仅高糖组明显上升(P<0.01);与高糖组比较,艾塞那肽组的细胞活性明显升高(P<0.05),细胞凋亡率明显降低(P<0.05),Bip、CHOP、P-SAPK/JNK 及 caspase-3 蛋白表达量也明显下调(P<0.05),JNK 激动剂组的 BIP、CHOP 蛋白表达量也明显降低(P<0.05);与艾塞那肽组比较,JNK 激动剂的细胞活性明显下降(P<0.05),细胞凋亡率明显升高(P<0.05),P-SAPK/JNK 及 caspase-3 蛋白表达量明显上调(P<0.05)。 结论 胃转流手术可以通过调节 GLP-1 分泌增加来抑制胰岛 β 细胞内质网应激,进而抑制 JNK 信号通路,保护胰岛 β 细胞,抑制细胞凋亡,从而达到治疗 2 型糖尿病的效果。

Objective To explore mechanism of gastric bypass in treating obesity with type 2 diabetes mellitus (T2DM) and its relationship with c-Jun N-terminal kinase (JNK) signaling pathway. Methods The INS-1 cells were divided into 4 groups according to the different treatment: control group (complete medium), high glucose group (30 mmol/L glucose medium), high glucose+100 nmol/L exendin-4 group (exendin-4 group), and high glucose+100 nmol/L exendin-4+JNK agonist (JNK agonist group). When these cells were cultured on day 7, the cell activity was assessed by the MTT staining. The cell apoptosis was determined by the fluorescence microscopy analysis after Hoechst/PI staining and flow cytometric assay after Annexin V-FITC/PI staining. The expressions of the human immunoglobulin binding protein (Bip), CCAAT/enhancer-binding protein homologous protein (CHOP), P-SAPK/JNK, and caspase-3 protein were detected by the Western blot. Results Compared with the control group, the cell activities were significantly decreased (P<0.05), the cell apoptosis rates and the P-SAPK/JNK and caspase-3 protein expressions were significantly increased (P<0.01) of the high glucose group and the JNK agonist group, but the Bip and CHOP protein expressions were significantly increased (P<0.01) of the high glucose group. Compared with the high glucose group, the cell activity was significantly increased (P<0.05), the cell apoptosis rate and the Bip, CHOP, P-SAPK/JNK, and caspase-3 protein expressions were significantly decreased (P<0.01) of the exendin-4 group, the Bip and CHOP protein expressions were significantly decreased (P<0.01) of the exendin-4 group. Compared with the exendin-4 group, the cell activity was significantly decreased (P<0.05), the cell apoptosis rate and the P-SAPK/JNK and caspase-3 protein expressions were significantly increased (P<0.01) of the JNK agonist group. Conclusion Gastric bypass can inhibit endoplasmic reticulum stress in pancreatic β-cells by regulating secretion of GLP-1, thereby inhibiting JNK signaling pathway, protecting islet β-cells and inhibiting apoptosis, so as to achieve effect of treating T2DM.

关键词: 胃转流术; 2 型糖尿病; JNK 信号通路

Key words: gastric bypass; 2 diabetes mellitus; JNK signaling

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