胰岛α细胞胰岛素抵抗与炎症通路激活的关系及机制

目的探讨高脂饲养大鼠胰岛α细胞炎症通路分子基因的表达变化及吡格列酮干预的影响。方法 8周龄雄性 SD 大鼠随机分为3组(每组15只):正常饲养组(NC)、高脂饲养组(HF)、高脂+吡格列酮组(HP)。喂养20周后检测空腹血胰岛素(FIns)、胰高血糖素(Glc)、游离脂肪酸(FFA)、高敏 C 反应蛋白(hsCRP)水平;正常血糖高胰岛素钳夹试验评价外周胰岛素抵抗程度;离体胰岛细胞表面灌注检测高糖状态 Glc 分泌的动态变化,同时3组大鼠各随机入组8只给予大剂量链脲菌素去β细胞处理,分为正常去β细胞组(NC-B),高脂去β细胞组(HF-B),高脂+吡格列酮去β细胞组(HP-B),采用定量 PCR 方法比较3组去β细胞大鼠α细胞 NF-B、NF-B抑制蛋白α(IBα)mRNA 表达的情况。结果 (1)HF 组葡萄糖输注率(GIR)明显低于 NC 组,血 FIns、Glc、FFA及 hsCRP 水平均显著高于 NC 组;而 HP 组以上各项指标较 HF 组均明显改善。(2)胰岛细胞表面灌注,HF 组基础 Glc 的分泌高于 NC 组(P<0.01),16.7 mmol/L 葡萄糖灌注后 HF 组胰岛的 Glc 分泌未受抑制,HP 组与 NC 组比较差异无统计学意义。(3)与 NC-B 组相比,HF-B 组α细胞 NF-B mRNA的表达增高20.5%,IBα mRNA 表达降低24.3%(P 值均<0.01)。HP-B 组较 HF-B 组 NF-κB、IκBαmRNA 分别改善78.3%、58.8%。(4)HF 组血 FFA 水平与 GIR 呈负相关(r=-0.675,P<0.01);与NF-κB mRNA 表达呈正相关(r=0.775,P<0.05)。结论高脂饲养导致胰岛α细胞胰岛素抵抗,同时激活了α细胞炎症通路基因的表达且与 FFA 升高有关。吡格列酮干预能改善上述变化。

Inflammation-and stress-related signaling pathways in hepatocarcinogenesis

It has been established that cancer can be promoted and exacerbated by inflammation.Hepatocellular carcinoma(HCC) is the fifth most common cancer worldwide,and its long-term prognosis remains poor.Although HCC is a complex and heterogeneous tumor with several genomic mutations,it usually develops in the context of chronic liver damage and inflammation,suggesting that understanding the mechanism(s) of inflammation-mediated hepatocarcinogenesis is essential for the treatment and prevention of HCC.Chronic liver damage induces a persistent cycle of necroinflammation and hepatocyte regeneration,resulting in genetic mutations in hepatocytes and expansion of initiated cells,eventually leading to HCC development.Recently,several inflammation-and stress-related signaling pathways have been identified as key players in these processes,which include the nuclear factor B,signal transducer and activator of transcription,and stress-activated mitogen-activated protein kinase pathways.Although these pathways may suggest potential therapeutic targets,they have a wide range of functions and complex crosstalk occurs among them.This review focuses on recent advances in our understanding of the roles of these signaling pathways in hepatocarcinogenesis.