【原】特别关注｜乙型肝炎和丙型肝炎与2型糖尿病的关系

临床肝胆病杂志 2021-05-10

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病毒性肝炎和糖尿病均为全球性的主要公共卫生问题。据世界卫生组织的新近报告^[1]，2015年全球有134万人死于病毒性肝炎，其中96%为乙型肝炎和丙型肝炎所致。而根据国际糖尿病联合会的报告^[2]，2019年全球约4.63亿人患糖尿病，预计到2045年，糖尿病患者会达到7.002亿。糖尿病可分为胰岛β细胞破坏、胰岛素绝对缺乏的1型糖尿病和胰岛素抵抗(IR)为主伴胰岛素相对缺乏的2型糖尿病(T2DM)。其中T2DM占糖尿病患者90%以上。近年来，越来越多的研究指出，病毒性肝炎，主要是乙型肝炎和丙型肝炎增加T2DM发病风险^[3-4]，而T2DM患者则容易罹患乙型肝炎和丙型肝炎^[5-6]，表明乙型肝炎和丙型肝炎与T2DM有着密切的联系。因此，现就乙型肝炎、丙型肝炎与T2DM关系的新近研究作一综述。

1乙型肝炎与T2DM

乙型肝炎是否引起T2DM发病曾经是有争议的问题。近年的Meta分析^[7-8]指出，HBV感染可诱发T2DM或增加T2DM发病风险。新近的研究^[9-10]发现，HBV感染与妊娠糖尿病相关，可增加妊娠糖尿病的发病率。慢性HBV感染合并非酒精性脂肪性肝病患者普遍具有IR^[11]。实际上，HBV可通过对胰岛素敏感性的影响干扰机体糖稳态的调节。纪冬等^[12]报道，HBV前S2蛋白(pre-S2)可下调胰岛素受体(INSR)基因启动子活性，降低INSR的表达，导致胰岛素敏感性降低。Barthel等^[13]利用表达HBV的肝细胞发现，HBV诱导活化核因子E2相关因子2，引起INSR细胞内滞留，减少细胞表面功能性INSR，提示胰岛素结合被弱化，引起胰岛素信号传导抑制。值得注意的是，HBV反式调节蛋白可能在HBV感染促进T2DM发病上发挥重要作用。Kim等^[14]的研究发现，HBV X蛋白(HBx)诱导的胰岛素受体底物1(IRS-1)蛋白降解，损伤肝性胰岛素信号传导，而前列腺六次跨膜蛋白2能与HBx相互作用并降低其稳定性，阻止HBX诱导的IRS-1降解和IR。此外，近年来的研究^[15]还发现，HBX干扰宿主细胞PI3K/Akt胰岛素信号通路，不仅导致胰岛素信号转导受损，而且引起肝细胞糖原合成下降，升高血糖浓度。HBV作用的胰岛素信号途径相关因子见表 1。

尽管代谢综合征(MS)是导致T2DM的重要危险因素，但目前对乙型肝炎与MS关系的研究却得出不同的结果。Zhou等^[21]在上海的一项长达20年随访的回顾性队列研究结果表明，HBV感染与MS发病率呈正相关。但也有研究^[22-24]指出，HBV感染与MS发生呈负相关。有学者^[25]认为，不同研究人群的纳入标准、MS的诊断标准、纳入分析的危险因素不同以及较小的研究人群样本量可导致不同的研究结果。

乙型肝炎一方面促进T2DM发病，而另一方面T2DM患者易于感染HBV。国内研究^[26]发现，T2DM患者HBV感染风险显著增加。这可能与糖尿病导致多种器官功能的破坏，包括内分泌功能的抑制、细胞免疫受损和体液免疫亢进有关。

2丙型肝炎与T2DM

大量的研究表明，HCV感染与T2DM有密切的相关性。一方面，HCV感染增加T2DM发病率。Younossi等^[27]的研究发现，HCV感染增加肝移植后罹患糖尿病风险，提高T2DM发病率。Banks等^[28]报道，丙型肝炎患者糖尿病发病率为17.5%，远高于正常人群的3.3%。新近的研究^[24, 29]指出，HCV感染与MS和IR呈正相关，是发展为T2DM的重要危险因素。而另一方面，T2DM患者容易感染HCV。Guo等^[30]的随机效应模型分析结果显示，T2DM患者感染HCV的风险显著高于非T2DM患者，认为T2DM增加HCV感染的易感性。近年来，对T2DM患者血清HCV分析证实，T2DM患者HCV阳性率显著高于对照^[31]。

越来越多的研究指出，HCV感染导致T2DM的发生发展，一是抑制胰岛素信号通路导致IR。与HBV反式调节蛋白HBx和pre-S2作用于胰岛素信号通路的多个环节相似，HCV核心蛋白(HCV core)和HCV非结构蛋白5A(NS5A)作用于胰岛素信号通路的多个蛋白因子，干扰胰岛素信号转导(图 1)。

已有的研究资料表明，HCV感染对胰岛素信号通路的抑制主要通过HCV core发挥作用。Banerjee等^[32]报道，HCV core在肝细胞中增加IRS-1/IRS-2的丝氨酸氨基酸磷酸化，从而防止其与胰岛素受体缔合，并阻止AKT的下游活化。Kawaguchi等^[33]发现，HCV core还可以上调细胞因子信号传导抑制因子3(SOCS3)，导致IRS-1/IRS-2降解，阻止它与胰岛素受体相互作用并防止AKT磷酸化，其结果是胰岛素水平降低和肝IR的补偿性增强。此外，NS5A可增加肝细胞中IRS-1的丝氨酸磷酸化，从而导致其降解并损害下游Akt信号传导而导致IR^[34]。二是过度产生炎性细胞因子促进IR。研究^[35]表明，HCV感染者血液中IL-17和TNFα水平高于非糖尿病患者。Lemoine等^[36]对133例HCV感染者进行研究发现，血清TNFα水平与胰岛素抵抗指数(HOMA-IR)值呈正相关。Shintani等^[37]在转基因小鼠中发现HCV core的表达引起TNFα的分泌增加，导致胰岛素敏感性降低，而注射抗TNFα抗体可以使胰岛素敏感性恢复正常。三是下调GLUT2的细胞表达，从而抑制葡萄糖摄取^[38]。四是诱导氧化应激反应促进IR。Das等^[39]报道，T2DM患者氧化应激标志物丙二醛水平明显高于非糖尿病患者，丙二醛与HOMA-IR呈正相关。Deng等^[40]研究发现，HCV感染通过增加线粒体活性氧(ROS)生成诱导c-Jun氨基末端激酶(JNK)活化，导致FoxO1磷酸化，从而诱导IR发生。HCV的NS5A可刺激NADPH氧化酶1和4以及细胞色素P450的表达，增加ROS的生成^[41]。实际上，T2DM和丙型肝炎患者的ROS水平都较高^[42-43]。而高水平的ROS可促进IR。表 2概括了HCV作用于胰岛素信号途径相关因子。

3HBV/HCV合并感染与T2DM

Choi等^[45]使用队列方法研究HBV、HCV和HBV/HCV合并感染者的糖尿病发展与非感染参与者的关联性，用竞争风险回归模型估计糖尿病发展的累积发病率和风险比，发现合并感染组中糖尿病的累积发病率、发病率密度和风险比最高，其次是HCV、HBV和非感染组。Chen等^[46]的研究发现，HBV/HCV合并感染人群体脂百分比增加。鉴于肥胖诱导IR，这种HBV/HCV合并感染导致的体脂增加提示其与IR之间存在关联。新近的研究^[47]表明，HBV/HCV合并感染者血糖水平和T2DM的发病风险明显高于HBV和HCV单一感染者。

4结语

乙型肝炎和丙型肝炎与T2DM密切相关。HBV和HCV感染增加T2DM发病风险，实际上乙型肝炎和丙型肝炎患者人群T2DM发病率上升。而T2DM患者容易感染HBV和HCV。抑制胰岛素信号通路是HBV和HCV感染引发T2DM的主要发病机制。此外，HCV感染引起的炎性细胞因子过度生成和诱导氧化应激反应促进IR，也是发病的重要原因。近年来，大量的研究指出肝炎病毒可感染肝外组织^[48-49]，而HBV对胰腺的感染可影响胰岛β细胞的功能^[50]，这是否是肝炎病毒感染导致T2DM的一种发病机制有待进一步的研究证实。

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