中华流行病学杂志  2022, Vol. 43 Issue (4): 598-602   PDF    
http://dx.doi.org/10.3760/cma.j.cn112338-20211112-00880
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文章信息

陈素庭, 许国章.
Chen Suting, Xu Guozhang
HIV感染及抗病毒治疗与糖尿病关系研究进展
Research progress on the relationship between HIV infection, antiretroviral therapy, and diabetes mellitus
中华流行病学杂志, 2022, 43(4): 598-602
Chinese Journal of Epidemiology, 2022, 43(4): 598-602
http://dx.doi.org/10.3760/cma.j.cn112338-20211112-00880

文章历史

收稿日期: 2021-11-12
HIV感染及抗病毒治疗与糖尿病关系研究进展
陈素庭1 , 许国章2     
1. 宁波大学医学院,宁波 315211;
2. 宁波市疾病预防控制中心,宁波 315010
摘要: 随着抗病毒治疗的广泛使用,HIV感染者的预期寿命、生活质量得到较大改善。与此同时,HIV相关的代谢性疾病,尤其是糖尿病的患病风险也有所增加。HIV感染者中糖尿病的风险增加与很多因素共同作用有关。近年来研究表明HIV感染及抗病毒治疗与糖尿病密切相关。本文综述了近年来HIV感染及抗病毒治疗在糖尿病发生发展中的作用机制。
关键词: 艾滋病病毒    感染    抗病毒治疗    糖尿病    机制    
Research progress on the relationship between HIV infection, antiretroviral therapy, and diabetes mellitus
Chen Suting1 , Xu Guozhang2     
1. School of Medicine, Ningbo University, Ningbo 315211, China;
2. Ningbo Municipal Center for Disease Control and Prevention, Ningbo 315010, China
Abstract: The expectancy and quality of life among people with HIV have improved remarkably with the widespread use of antiretroviral therapy (ART). In the meantime, the risks for HIV-related metabolic diseases have increased significantly, in particular diabetes mellitus. Multi-factors coeffect to increasing the risk of diabetes mellitus among HIV patients. Recently, growing of research has reported an association between HIV infections and ART and the development of diabetes mellitus. In this article, we summarize the recent studies investigating HIV infection and ART in diabetes mellitus to clarify their mechanism on the development of diabetes.
Key words: HIV    Infections    Antiretroviral therapy    Diabetes mellitus    Mechanism    

随着临床上抗病毒治疗的广泛应用,艾滋病的发病率和死亡率降低,HIV感染者的预期寿命和生活质量也有了较大改善和提高[1-2]。在HIV感染者存活率不断提高的同时,慢性非传染性疾病,特别是糖尿病的负担也日益加重[2-3]。多项研究发现,HIV感染及抗病毒治疗与糖尿病的发生发展存在一定的关联。但是国内外相关研究,尤其是HIV感染与糖尿病的关联研究尚缺乏高质量证据。现针对国内外HIV感染及抗病毒治疗与糖尿病的研究结果进行综述。

一、流行病学特征

糖尿病是一种复杂的多因素代谢性疾病,主要由胰岛素分泌缺陷和/或敏感性下降引起的高血糖导致。全球20~79岁年龄组糖尿病患病人数呈逐年递增趋势,据国际糖尿病联盟2019年的数据分析,2019年全球估计有4.63亿人患有糖尿病,而到2035年和2045年,全球糖尿病患病人数预计将分别达到5.78亿和7亿[4]。仅2016年我国因糖尿病死亡的人数就有22万,并且患病率已达到9.4%,对个人、家庭和国家产生了严重影响和经济负担[5]。基于传统危险因素,如缺乏锻炼和不健康饮食,不能单独解释当前糖尿病升高的趋势,这提示存在新的危险因素,如慢性感染/炎症的作用。截至2019年底,我国现存HIV感染者达96.3万例,死亡31.6万例[6]。有研究发现,HIV感染增加胰岛素抵抗的风险,而抗病毒治疗与2型糖尿病的发生也有一定关系[7]

在HIV感染者中,由于研究的样本量、抗病毒治疗药物种类、糖尿病的定义以及地域和种族的差异,糖尿病的患病率在1.7%~14.9%[8-10]。一些研究表明[3, 11-14],与HIV未感染者相比,HIV感染者的糖尿病患病率更高。一项意大利研究发现,在多因素分析中,HIV感染与糖尿病的风险增加相关(OR=1.70),HIV感染者糖尿病患病率约是健康人的2倍(4.1%比2.5%)[13]。其他的研究也表明,不论是在男性还是女性中,HIV感染者糖尿病的发生率都高于其他人群[3, 14]。国内也有研究发现,随访期间,HIV/AIDS的糖尿病发生率高于HIV阴性成年对照组[15]。但关于HIV感染和糖尿病的关系还存在一定的争议,也有一些研究得出了不同结论[8-9, 16-17]。有一项多中心的1 406例初治艾滋病患者研究发现,HIV感染与高血糖之间无相关性[8]。一项13 632例队列研究也发现,HIV未感染组糖尿病的发病率高于HIV感染组[13.60比11.35(/1 000人年)],多因素分析结果也证实了接受抗病毒治疗的HIV感染者发生糖尿病风险显著降低(aHR=0.55)[16]。由于这些研究数据大多是从当地的医疗机构数据库中提取出来的,且数据的收集是为了管理和计费,招募和数据收集都不在调查者的控制之下,因此存在着较大的信息偏倚,对研究结果造成影响。

二、HIV感染及抗病毒治疗在糖尿病发病机制中的作用

1. 慢性炎症:以往的研究表明[18-19],系统性炎症往往与HIV感染者的糖尿病发病机制有关。在校正基线标志物水平、年龄,抗病毒治疗1年后的BMI、CD4+T淋巴细胞(CD4)计数、茚地那韦(IDV)的使用情况后,抗病毒治疗1年时炎症标志物sTNFR1和sTNFR2越高,发生糖尿病的可能越大[18]。在HIV感染者中,肿瘤坏死因子(TNF)-α、白细胞介素(IL)-1β和其他介质释放的细胞因子被认为与抑制胰岛素信号传导、产生胰岛素抵抗有关[20-24]。TNF-α作用于胰岛素受体底物1(IRS-1)来减弱胰岛素受体信号,从而诱导胰岛素抵抗产生[21]。IL-1β是一种促炎细胞因子,在人体脂肪细胞中,部分介导了巨噬细胞诱导的胰岛素信号传导损伤[24]。研究表明,不论是接受抗病毒治疗的HIV感染者还是健康的中年妇女,IL-6和C反应蛋白(CRP)的升高与糖尿病风险增加密切相关[25-27]。在接受抗病毒治疗的HIV感染者中,IL-6和高敏C反应蛋白(hsCRP)水平每增加一倍的调整风险比(HR)分别为1.29和1.22[25]。最近关于CD163的研究发现,可溶性CD163(sCD163)与胰岛素稳态评估模型(HOMA-IR)评估的胰岛素抵抗有关联[28-30]。横断面研究显示,sCD163水平每增加50%会使HOMA-IR估计值增加36%左右[28]。一项2型糖尿病高危人群的研究显示,在调整性别和年龄后,sCD163与空腹胰岛素成正相关关系,且基线sCD163水平每增加1倍,胰岛素每年的变化约为0.971 pmol/L[29]。还有研究表明,巨噬细胞分泌或直接细胞接触介导的因子会对脂肪细胞的胰岛素敏感性产生影响[31-32]。巨噬细胞通过改变胰岛素信号传导和葡萄糖转运蛋白的表达来阻断脂肪细胞中的胰岛素作用[31]。一项小鼠实验发现,抗炎细胞因子IL-10在瘦小鼠脂肪组织的巨噬细胞中过度表达,可以保护脂肪细胞免受TNF-α诱导的胰岛素抵抗[32]。也有研究发现,CD8+T淋巴细胞(CD8)消耗可改善全身胰岛素抵抗,它依赖的脂肪炎症对全身代谢都有影响[33]。另有一些相关脂肪组织的研究发现,脂肪组织是HIV感染期间病毒持续存在和慢性免疫激活的关键辅助因子,脂肪细胞和固有脂肪因子共同促进CD4的激活和HIV的产生[34-35]

2. 抗病毒药物:在HIV感染者中,代谢性疾病不仅与传统风险因素(如肥胖、吸烟等)、慢性炎症相关,治疗过程中使用的抗病毒药物也有很大影响[3, 7, 36-37]。在一个小鼠模型中发现,抗病毒治疗能增强高脂饮食产生的炎症效应,从而导致胰岛素抵抗和代谢失调[7]。一项多中心的1 278例男性艾滋病队列研究发现,接受高效抗反转录病毒治疗(HAART)的HIV感染者的糖尿病风险,是HIV血清阴性的4倍以上[3]。在HIV感染者观察期间内累积暴露于HIV蛋白酶抑制剂(PIs)会增加患糖尿病风险[9, 17, 38-39]。伊朗一项退伍军人的研究发现,核苷类反转录酶抑制剂(NRTIs)和非核苷类反转录酶抑制剂(NNRTIs)与HIV感染退伍军人患糖尿病风险相关[9]。瑞士一项队列研究发现,目前使用含PIs治疗方案、含NRTIs治疗方案能增加2型糖尿病的患病风险[39]。国内关于HIV/AIDS研究也表明,NNRTIs中的依非韦伦(EFV)与发生糖尿病风险相关[10, 15]

(1)PIs:已经被证明与胰岛素抵抗增加、胰岛素分泌减少有关[40-44]。PIs通过2种机制损害HIV感染者的糖耐量:①PIs作为葡萄糖转运蛋白4(GLUT4)的非竞争性可逆抑制剂,可与GLUT4急性结合,抑制胰岛素刺激的葡萄糖摄取,从而导致外周胰岛素抵抗和糖耐量受损;②PIs会损伤胰腺β细胞的葡萄糖敏感性,导致分泌胰岛素能力受损[41-43]。也有其他研究发现,PIs会干扰细胞视黄酸结合蛋白1(CRABP1),这种对CRABP1的干扰可抑制过氧化物酶体增殖物激活受体(PPAR),从而促进胰岛素抵抗、脂肪细胞炎症和自由脂肪酸(FFAs)的释放[45]

不同种类PIs的血糖代谢作用存在差异[46-47]。IDV会诱导胰岛素抵抗但对脂质代谢没有影响,而利托那韦(RTV)和洛匹那韦(LPV)则会增加空腹TG和游离脂肪酸;RTV和IDV能阻断GLUT4,但安普那韦(APV)和阿扎那韦(ATV)则没有这种作用[45]。ATV对葡萄糖转运的体外影响明显小于其他PIs。一项30例健康研究对象的短期药效研究显示,口服ATV 5 d对胰岛素敏感性无影响,而RTV/LPV则会诱导胰岛素抵抗产生[46]。有研究发现,在HIV阴性志愿者中,单剂量800 mg RTV能急性恶化胰岛素敏感性,而2 000 mg APV则没有这种作用[47];在另一血清阴性志愿者研究中观察到200 mg的RTV没有恶化胰岛素抵抗,这表明RTV的药物效应是依赖于剂量的。不论是在动物还是健康人中,IDV可直接作用于GLUT4,从而抑制胰岛素刺激的葡萄糖进入脂肪细胞,导致胰岛素抵抗产生[48-50]

(2)NRTIs:可以作为线粒体DNA(mtDNA)聚合酶γ的底物,中断mtDNA的复制,从而产生线粒体毒性,而这种线粒体功能障碍与糖尿病和HOMA-IR测定的胰岛素抵抗相关[51-54]。研究发现累积暴露于NRTIs与HIV感染者的胰岛素抵抗及糖尿病发病率增加有关[55]。一项前瞻性研究发现[56],调整了糖尿病的危险因素和血脂后,司他夫定(D4T)(RR=1.19)和齐多夫定(AZT)与糖尿病显著相关;而进一步对脂质营养不良进行调整,关系仍保持不变,说明这两种药物可能通过线粒体毒性直接促进胰岛素抵抗产生。另一项研究发现,阿巴卡韦/拉米夫定(ABC/3TC)和替诺福韦/恩曲他滨(TDF/FTC)都能显著降低脂肪mtDNA含量,但只有TDF/FTC降低了复合物Ⅰ(氧化磷酸化烟酰胺腺嘌呤二核苷酸脱氢酶)和复合物Ⅳ(细胞色素c氧化酶)活性水平[57]。复合物Ⅰ和复合物Ⅳ含有mtDNA编码亚基的多肽,会受到mtDNA缺失的影响,因此能反映线粒体受损情况。还有一些研究发现,NRTIs产生的线粒体毒性还能改变脂肪形成和脂肪细胞分化,从而导致脂质营养不良[58-59]

(3)NNRTIs:目前相关研究较少,一些NNRTIs可能会对脂质细胞的葡萄糖代谢产生影响[60]。一项1 857例未抗病毒治疗的HIV感染者前瞻性研究中发现,相对于ATV/RTV组,接受EFV治疗组的葡萄糖水平显著提高(平均差4.4 mg/dl),但胰岛素或HOMA-IR结果无差异[61]。另一项研究发现,在调整了年龄、性别、BMI、基线CD4计数、病毒载量、主要NRTIs和其他致糖尿病药物后,EFV治疗增加了HIV感染者患糖尿病的风险(HR=1.27)[62]

(4)其他药物:新的抗病毒治疗药物包括FIs、INSTIs、CCR5拮抗剂等,但关于这一类药物的文献相对较少。一项INSTIs研究发现,在多变量和生存分析中,与NNRTIs或PIs相比,使用INSTIs作为进行联合抗病毒治疗感染者的第三种治疗药物,与新发糖尿病增加无统计学关联[63]

3. 遗传易感性:除了疾病相关的身体变化和药物治疗之间复杂的相互关系外,遗传易感性对葡萄糖稳态改变也起到了一定作用[64]。有研究显示,基因中抗药的单核苷酸多态性与包括胰岛素抵抗在内的代谢改变的风险增加有关[65]。另一研究表明,抵抗素的单核苷酸多态性与胰岛素抵抗有关[66]。在对2型糖尿病父母的胰岛素抵抗后代的研究中发现,后代的线粒体含量减少,线粒体功能下降,更易发生肌细胞内脂质堆积,从而导致胰岛素信号传导和肌肉活动的缺陷[67]。这说明在普通人群中,遗传相关的线粒体功能障碍与胰岛素抵抗、糖尿病相关。

4. HIV附属蛋白:一些HIV附属蛋白,如Tat蛋白和Vpr蛋白可能会直接导致胰岛素抵抗产生[60, 65]。Tat蛋白会激活核因子Kappa B,从而诱导TNF-α分泌,阻断脂肪细胞摄取游离脂肪酸的路径,抑制胰岛素受体的胰岛素信号,降低GLUT4易位,使IRS-1磷酸化。而Vpr蛋白则通过抑制过氧化物酶体增值物激活受体γ(PPAR-γ)的活性,从而影响胰岛素的转录活性[60]

5. 其他机制:一项生长激素的研究发现[68],在HIV脂质营养不良患者中,生长激素分泌异常与代谢异常(特别是内脏脂肪增加和游离脂肪酸升高)密切相关;而脂肪分布变化又与胰岛素抵抗增加有关,且在该人群中生长激素分泌减少。这说明,生长激素分泌异常可能是HIV感染者胰岛素抵抗的一个促进因素。

三、总结与展望

综上所述,HIV感染及抗病毒治疗广泛参与糖尿病的发病机制,包括炎症、各种抗病毒治疗药物、遗传易感性、HIV附属蛋白作用。通过对HIV感染及抗病毒治疗在糖尿病发病机制中的研究总结,在分子机制上提高了HIV感染及抗病毒治疗与糖尿病关系的认识,为进一步的研究方向提供了线索。

HIV感染及抗病毒治疗与糖尿病的研究尚处于起步阶段,还存在许多需要进一步探索的问题。首先,目前关于HIV感染及抗病毒治疗与糖尿病的队列研究相对较少,相互之间的关联还存在一定的争议。其次,HIV感染者中存在的炎症机制和一些抗病毒治疗药物的血糖代谢作用尚未完全阐明,仍有待于进一步研究和验证。因此需要样本量更大、随访时间更长的队列研究来探索HIV感染及抗病毒治疗和糖尿病的关联。

利益冲突  所有作者声明无利益冲突

志谢 感谢洪航老师对本文的指导和帮助

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