修回日期: 2015-06-12
接受日期: 2015-06-24
在线出版日期: 2015-11-18
非酒精性脂肪肝病(nonalcoholic fatty liver disease, NAFLD)在2型糖尿病(type 2 diabetes mellitus, T2DM)人群中广泛流行. 胰岛素抵抗架起了T2DM和NAFLD间相互联系的病生理桥梁. 两者合并发病, 预示着病情的加重和死亡风险的增加, 有效防治T2DM患者NAFLD刻不容缓. 胰高糖素样多肽-1(glucagon like peptide-1, GLP-1)受体激动剂、二肽基肽酶-4(dipeptidyl peptidase-4, DPP-4)抑制剂等药物的问世给T2DM合并NAFLD的防治带来的新希望; 外科减肥手术的成功开展为肥胖的T2DM合并NAFLD的治疗提供强有力的手段; 脂联素、成纤维细胞生长因子21(fibroblast growth factor 21, FGF21)等脂肪因子的发现为研发防治T2DM合并NAFLD的药物提供新的方向. 本文结合T2DM合并NAFLD的流行病学、二者的病生理联系等特点, 系统阐述了T2DM患者NAFLD治疗手段以及研究现状.
核心提示: 胰岛素抵抗(insulin resistance, IR)是非酒精性脂肪肝病(nonalcoholic fatty liver disease, NAFLD)与2型糖尿病(type 2 diabetes mellitus, T2DM)相互联系的生理机制. 既可安全降糖, 又可改善IR、控制体质量, 改善肝脏的病理转归的防治手段在T2DM患者NALFD的防治中具有良好的应用前景.
引文著录: 周赛君, 于德民, 于珮. 糖尿病非酒精性脂肪肝防治新进展. 世界华人消化杂志 2015; 23(32): 5113-5122
Revised: June 12, 2015
Accepted: June 24, 2015
Published online: November 18, 2015
Nonalcoholic fatty liver disease (NAFLD) is frequently seen in the type 2 diabetes mellitus (T2DM) population. Insulin resistance is the pathophysiologic bridge which links T2DM and NAFLD. Coexistence of both diseases indicates more severe diseases and higher risk of death. As a result, it is urgent to effectively control NAFLD in patients with T2DM. The advent of glucagon like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors brings new hope for effectively managing NAFLD in T2DM patients. Bariatric surgery provides obese T2DM patients with a powerful means to treat NAFLD. The discovery of adipokines such as adiponectin and fibroblast growth factor 21 (FGF21) may point to a new research direction for NAFLD. In this paper, we present therapeutic options currently available for NAFLD in T2DM patients as well as the present research progress in NAFLD with T2DM, with regards to epidemiology and pathophysiologic links between them.
- Citation: Zhou SJ, Yu DM, Yu P. Prevention and treatment of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus. Shijie Huaren Xiaohua Zazhi 2015; 23(32): 5113-5122
- URL: https://www.wjgnet.com/1009-3079/full/v23/i32/5113.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v23.i32.5113
非酒精性脂肪肝病(nonalcoholic fatty liver disease, NAFLD)是一种与2型糖尿病(type 2 diabetes mellitus, T2DM)、肥胖、高胰岛素血症等密切相关, 无过量饮酒史、以肝细胞脂肪变性和脂质储积为特征的临床病理综合征, 亦被认为是代谢综合征的肝脏表现[1]. 根据NAFLD病理进展情况可分为: 单纯性脂肪肝、脂肪性肝炎(nonalcoholic steatohepatitis, NASH)、脂肪性肝纤维化/肝硬化、肝癌[2]. 随着肥胖和T2DM患病率的急速上升, NAFLD的在世界范围内, 尤其在T2DM人群中广泛流行, 已成为导致肝损害的主要肝脏疾患, 也是导致患者发生心血管死亡风险增加的重要危险因素[3-5]. 因此有效防治NAFLD对降低糖尿病NAFLD患者肝病相关死亡和心血管死亡具有极其重要的意义. 本文就NAFLD在糖尿病患者中的流行病学、二者相互联系的病生理机制以及目前NAFLD治疗手段及研究现状等进行了系统阐述.
随着人们生活水平的提高、生活方式的改变, T2DM与NAFLD患病率急速上升, 已成为严重影响人类健康的两大公共卫生问题, 二者间的密切关系也得到了越来越多的关注[1]. 西方国家的流行病学数据显示, NAFLD在普通成人中的发病率为20%-30%[3,6], 而在糖尿病人群中则高达43%-60%[7,8]. 我国的研究数据亦表明, NAFLD在T2DM患者当中广泛流行: 朱方超等[9]研究数据显示, 我国大中城市普通成人中NAFLD的患病率为20%; 糖尿病患者中的NAFLD的发病率为54.73%[10]; 而住院的T2DM患者NAFLD的患病率高达61%-70%[11,12]. 因此, NAFLD在T2DM人群中具有高患病率的特点.
NAFLD的发病机制尚未完全阐明, 但是胰岛素抵抗(insulin resistance, IR)依然是目前公认的NAFLD发病的核心环节[13]. 而肥胖则是导致IR最常见原因. IR导致高胰岛素血症和胰岛素受体后信号通路异常, 进而导致脂肪合成增加, 游离脂肪酸(free fatty acid, FFA)产生增多. 而FFA水平的升高, 可抑制胰岛素的促脂解作用, 从而导致肝脏脂质输出减少和甘油三酯(triglycerides, TG)的合成增多, 导致肝脏内TG大量积聚和脂肪样变[14]. 因此, 肝脏内脂肪沉积是IR的结果. 而肝脏内脂肪的蓄积进而导致FFA在线粒体内被过量氧化, 产生过多的活性氧自由基(reactive oxygen species, ROS), 进而激活氧化应激[15]和一系列相关的炎症通路, 从而导致大量炎性因子如肿瘤坏死因子(tumor necrosis factor, TNF)-α的产生和释放, 进一步加剧线粒体损伤. 氧化应激、炎性细胞因子的释放及线粒体功能异常等, 进而使脂肪变性的肝脏进一步发生炎症、坏死和纤维化[1].
IR亦是T2DM重要的致病机制. 糖尿病甚至糖尿病前期时, 升高的血糖为TG的合成提供了大量的底物, 进一步促进肝脏内TG的合成和蓄积[16]. 此外, NAFLD亦是IR、T2DM独立的危险因素[17].
因此, T2DM和NAFLD间具有密切的病生理联系, 而IR架起了二者相互联系的病生理桥梁; 氧化应激和炎性损伤则是二者重要的损伤机制.
T2DM对NAFLD病情的进展起着重要的作用. 研究[18]显示, T2DM可导致NAFLD患者发生肝硬化的风险增加1.8-2.8倍, 发生肝癌的风险增加1.86-4.00倍. 并且T2DM亦是NAFLD患者肝病相关死亡的独立危险因素[16]. 因此, 上述研究结果提示T2DM是导致NAFLD病情进展和恶化的因素. NAFLD患者同时并发T2DM, 则预示着NAFLD发展为肝硬化、肝癌等终末期肝病甚至死亡等风险明显增加.
T2DM可促进NAFLD的发生和发展, 而NAFLD的出现又可提高了T2MD的风险, 并且使血糖更难控制. 研究[19]显示: NAFLD患者IR、脂代谢紊乱程度显著高于非NAFLD, 并且NAFLD可升高糖尿病患者空腹血糖的水平达10%-20%[16]. NAFLD还可加重T2DM患者糖尿病肾病和糖尿病视网膜病变等微血管并发症[20], 同时也明显增加T2DM发生心脑血管疾病和外周血管疾病等大血管并发症的风险[21]. 更重要的是, NAFLD可显著增加T2DM患者的死亡风险. 研究[22]显示T2DM合并NAFLD较同年龄、同性别的糖尿病患者发生全因死亡的风险增加达70%, 其中主要的死亡原因为缺血性心脏病、恶性肿瘤以及肝病相关死亡.
因此, T2DM和NAFLD间有着密切的关系, 二者在病情上相互促进, 可形成恶性循环. 二者的合并发病预示着患者病情的加重和死亡风险的明显增加, 有效防治T2DM患者NAFLD刻不容缓.
生活方式干预是T2DM防治的基础, 亦是目前唯一被公认的NAFLD有效防治方法[16]. 生活方式干预主要包括减轻体质量、加强锻炼、行为方式的改变等. 肥胖是T2DM合并NAFLD的重要致病因素, 减轻体质量是T2DM合并NAFLD的一线治疗方案[1]. 研究[23]显示, T2DM合并NAFLD患者, 平均体质量减轻4%-14%, 可显著改善患者的IR、降低血转氨酶的水平; T2DM合并NASH患者体质量减轻5%-10%, 可获得明显肝脏组织形态学的改善[24]. 因此, 减轻体质量对T2DM合并NAFLD的防治具有重要的意义.
研究[25]亦证实, NAFLD患者通过足量的运动同样能够获得降低转氨酶的水平和减轻肝脏脂肪样变的疗效, 并且这种获益独立于患者的体质量减轻之外. 但是目前学术界对于运动的强度对糖尿病NAFLD的防治作用尚存在争议. 有研究[26]认为有氧运动和耐力训练对T2DM合并NAFLD均具有重要的防治作用. Bacchi等[27]的研究比较了T2DM患者分别进行有氧运动和耐力训练肝脏脂肪含量的影响, 研究结果显示, 4 mo后两组患者肝脏脂肪含量降低均达25%. 然而亦有研究[28]证实, 增加高强度运动的时间可显著减轻肝硬化的进展, 而增加中等运动的强度并未获得同样的益处. 因此, 运动强度对T2DM合并NAFLD防治作用及其远期疗效的差异尚待进一步研究加以证实.
尽管生活方式的干预在NAFLD患者中取得了明显的疗效, 但是患者的依从性不佳的问题是亟待解决的难题. 有研究[29]调查了坚持有氧运动方案治疗的NAFLD患者的长期依从性, 研究结果显示, 能坚持2年的比例不到20%. 因此, 进行生活方式的干预, 关键可能还是需要建立患者健康生活行为方式. 但是探讨患者行为方式的改变对患者糖尿病NAFLD的防治作用的研究费时、费力, 研究成本很高, 难以在大规模的人群中实现. 但是一项小样本的人群研究[30]取得令人欣喜的结果, 该研究中入选患者每周均接受饮食和行为指导, 每个月接受运动指导, 肝脏磁共振显像结果显示: 4 mo后64%的患者肝脏脂肪含量减少了5%. 因此建立患者的健康的生活行为习惯是T2DM合并NAFLD基础治疗的关键.
IR是联系T2DM和NAFLD关键的病生理机制, 因此治疗T2DM合并NAFLD肝患者, 最佳的药物应该不仅是一种安全有效的降血糖药物, 还应是一种改善IR, 减轻氧化应激损伤, 从而改善脂肪肝转归的药物, 同时应该避免体质量增加和肝肾毒性.
4.2.1 改善IR类降糖药物: IR是T2DM和NAFLD有共同的病理生理基础, 改善IR在T2DM合并NAFLD的防治具有重要的意义. 二甲双胍是T2DM患者首选降糖药物. 二甲双胍可通过激活腺苷酸活化蛋白激酶(ATP-activated protein kinase, AMPK)信号通路, 促进外周组织对葡萄糖的摄取, 促进肝糖原和脂肪的合成, 加速FFA的β-氧化, 具有潜在的改善NAFLD的药理作用[31,32]. 然而临床研究[33]关于二甲双胍对NAFLD的治疗作用尚存在争议, 目前也尚无证据证实该药物可改善单纯NASH患者肝脏组织病理改变[34]. 因此目前学术界对于二甲双胍是否推荐用于NAFLD甚至T2DM合并NAFLD的防治中尚持保守意见[35].
经典的胰岛素增敏剂噻唑烷二酮类如吡咯列酮、罗格列酮等均被证实不仅可改善糖尿病合并NAFLD或单纯NAFLD患者肝脏脂肪样变以及生化指标[36,37]. 然而该类药物是否同样能改善肝纤维化的发生, 尚待进一步研究加以证实[38]. FLIRT研究[39]纳入了63例NASH患者, 该研究结果显示, T2DM的存在则是患者对该类药物反应性不佳的预测指标. 并且该类药物的潜在的不良反应如体质量的增加以及心血管病风险的增加, 以及停药以后肝酶的反弹等问题, 该类药物对于糖尿病合并NAFLD长期用药的安全性和有效性均有待于进一步研究.
4.2.2 降脂药物: 脂代谢紊乱是IR的重要原因, 降脂药物可降低患者血脂水平, 改善糖尿病患者IR. 他汀类药物不仅可降低患者血胆固醇的水平, 还可降低糖尿病患者心血管死亡的风险, 对糖尿病NAFLD具有潜在的治疗作用, 然而一项荟萃分析[40]结果显示, 辛伐他汀和阿托伐他汀均不能改善NAFLD患者肝脏生化指标以及肝脏脂肪样变, 但是亦未观察到明显的不良反应. 因此目前认为NAFLD不是他汀类药物的禁忌证. 贝特类药物是改善患者血TG水平主要的降脂药物, 研究[41]证实依替米贝抑制胆固醇在小肠吸收, 降低低密度脂蛋白, 改善患者IR, 在NAFLD干预研究中取得了阳性结果. 亦研究[42]比较了非诺贝特与易善复对NAFLD的治疗作用, 研究结果显示非诺贝特治疗脂肪肝疗效明显优于易善复, 并无明显不良反应.
4.2.3 抗氧化剂: 氧化应激在糖尿病NAFLD导致肝损伤的重要机制, 抗氧化治疗可能是糖尿病NAFLD防治的手段之一. Vitamin E和vitamin C是临床常用的抗氧化剂. 然而目前临床研究[43]数据显示, NAFLD患者给予vitamin E或vitamin C的干预, 并未获得血谷丙转氨酶(alanine transaminase, ALT)水平的明显降低以及机体抗氧化物质水平的提高. 临床荟萃分析结果提示: vitamin E仅仅适合无糖尿病、肝硬化以及肝脏活动性病变的成人NAFLD患者[16,44]. 因此, 目前糖尿病合并NAFLD患者是否加用vitamin E或vitamin C等抗氧化剂治疗, 学术界尚无定论.
然而绿茶[45]、生姜[46]、大蒜[47]等具有抗氧化作用成分食物可显著改善NAFLD小鼠内脏脂肪的含量、改善IR、降低炎症因子的水平以及肝脏的脂肪样变. 因此糖尿病患者NAFLD增加上述天然的抗氧化作用的食物可能对NAFLD防治具有一定的作用, 但是该结论尚待大样本的临床随机对照研究数据加以证实.
4.2.4 GLP-1受体激动剂和DPP-4抑制剂: 胰高糖素样多肽-1(glucagon like peptide-1, GLP-1)主要是由肠黏膜的L细胞分泌, 可通过与其受体相互作用, 不仅能够以葡萄糖浓度依赖性的方式促进胰岛素的分泌, 抑制胰高糖素的分泌, 促进肝脏、脂肪组织以及骨骼肌对葡萄糖的摄取, 发挥降糖作用; 还可通过延缓胃排空、抑制食欲, 从而减轻体质量, 增加胰岛素敏感性等生理活性[48], 但是GLP-1可被二肽基肽酶-4(dipeptidyl peptidase-4, DPP-4)快速降解, 其在体内的半衰期仅有1-2 min, 若能抑制DPP-4的活性则可以增加的GLP-1的循环半衰期, 更好的发挥GLP-1的生理功能[49]. GLP-1受体激动剂如利拉鲁肽、埃噻那肽等集成了GLP-1生理活性、克服其的半衰期短的缺点, 因此目前GLP-1受体激动剂在T2DM中得到了广泛应用[50]. GLP-1受体激动剂通过抑制肝脂肪生成的作用, 通过激活AMPK信号通路, 降低肝脂肪蓄积和营养物诱发的肝脏炎症反应, 从而对NAFLD发挥治疗作用. 此外, GLP-1激动剂还可通过显著地改善患者体质量, 从而改善NAFLD[51-53]. 并且研究证实GLP-1激动剂在减轻患者体质量的作用明显优于饮食控制和运动控制. 而DPP-4抑制剂因其可抑制GLP-1的降解, 延长GLP-1的作用时间, 发挥与GLP-1受体激动剂相似的作用. 此外DPP-4抑制剂还可通过减少硬酯酰辅酶A去饱和脂肪酶1(stearoyl-CoA desaturase 1, SCD-1)和增加肝脏过氧化物酶体增殖物激活受体-α(peroxisome proliferators-activated receptor-α, PPAR-α)的表达, 从而减轻脂肪肝. 研究[54]证实沙格列汀治疗后, 患者体内葡萄糖氧化增加, 减少了脂肪酸的释放, 并且降低了TG水平, 减轻了脂肪酸氧化代谢的脂毒性. 研究[55]证实DPP-4抑制剂还可以改善糖尿病合并NAFLD患者肝功能以及肝纤维化程度.
上述研究都显示GLP-1受体激动剂和DPP-4抑制剂均具有改善T2DM合并NAFLD患者的体质量、减轻IR、良好的降糖等作用以及对肝脏的病理学转归. 该类药物是目前治疗T2DM合并NAFLD的一个新的切点, 值得引起临床关注, 但是其长期疗效和安全性尚待更多循证医学证据加以评估.
此外, 胃泌素调节素(oxyntomodulin, OXM)除调节壁细胞的胃酸分泌外, 还是一个生理性的双受体(GLP-1R/GCGR)激动剂, 可改善糖代谢、减少能量摄入、降低体质量, 对糖尿病NAFLD的防治具有潜在的药理作用[56]. 其类似物Aib2 C24 40k与Aib2 C24 lactam 40k均为以GLP-1R选择性为主的双受体激动剂. 动物实验研究结果显示, 肥胖小鼠皮下注射Aib2 C24 40k或Aib2 C24 lactam 40k, 1 mo后发现两组均具有减轻体质量、内脏脂肪减少、能量消耗增加、胰岛素敏感性、血糖水平、血脂水平均得到改善, 并且小鼠肝脏组织病理学证实肝脏脂肪样变明显改善[57]. DualAG则为以GCGR选择性为主的双受体激动剂. 对肥胖小鼠皮下注射2 wk后发现, DualAG同样具有降低体质量、减少摄食、减少脂肪、改善糖耐量的作用, 并降低血脂和瘦素水平, 改善肝脏脂肪变性[56,58]. 因此, OXM的生理作用为研发双受体(GLP-1R/GCGR)激动剂提供了理论依据. 目前啮齿类动物研究中双受体(GLP-1R/GCGR)激动剂展示出良好的预期效果, 对糖尿病NAFLD防治具有应用前景, 但未来走进临床还需要大量的工作.
4.2.5 保肝抗炎药物: 保肝抗炎药物具备修复肝脏生物膜, 拮抗氧化应激和/或脂质过氧化, 以及抗凋亡、抗炎及抗纤维化等药理作用, 从而阻止肝病进展, 减少肝硬化和肝功能衰竭的发生. 因而, 理论上保肝抗炎药物是NAFLD的有效方法. 一项荟萃分析[59]显示, 多烯磷脂酰胆碱治疗酒精性肝病和脂肪肝是安全的, 可提高治疗有效率, 改善患者的临床症状和体征; 同时具有降低早期死亡率和防止肝组织学恶化的趋势. 研究[60]发现水飞蓟素不仅能降低NASH患者ALT和谷草转氨酶(aspartate transaminase, AST)水平, 改善血脂水平, 而且能显著降低血浆丙二醛(malonaldehyde, MDA)含量, 升高超氧化物歧化酶(superoxide dismutase, SOD)和谷胱甘肽过氧化物酶(glutathione peroxidase, GSH-Px)活性, 表明水飞蓟素能改善NASH患者的脂质过氧化状态, 从而减轻或阻止NASH的进展. 但是目前对于保肝抗炎药物用于NAFLD的研究, 样本量较小, 因此其疗效尚待大规模随机对照临床研究加以进一步明确.
4.2.6 中药: 临床和基础研究证实许多具备降血脂作用的中草药如何首乌、丹参、泽泻、川芍、决明子、山植, 一些中药方剂如小柴胡汤、四逆散、六味地黄丸以及中成药物血脂康和脂必妥对糖尿病NAFLD治疗脂肪肝和高脂血症均有一定的疗效[61].
4.2.7 脂肪因子: 新近研究[62]证实脂肪组织可分泌系列激素类因子如瘦素、脂联素、内肥素等, 具有参与代谢的调控等作用, 具备改善糖尿病NAFLD的潜在的药理作用. 瘦素是由脂肪组织分泌的细胞因子, 具有调节能量代谢、组织修复以及神经内分泌等功能. 研究证实瘦素对NAFLD具有双重作用: 一方面瘦素可作用于肝细胞, 抑制脂肪的从头合成, 并且促进FFA的β氧化, 从而减少肝脏TG的含量, 减轻脂毒性; 还可抑制肝细胞的糖原分解, 减轻糖毒性, 可显著改善动物肝脏脂肪样变; 另一方面, 瘦素可激活Kupffer, 上调CD14的表达, 从而加剧氧化应激、促进转化生长因子(transforming growth factor, TGF)-β1等炎性因子的分泌, 从而导致肝脏的损伤和纤维化的进展[63].
脂联素是血浆浓度最高的脂肪因子. 研究[64]证实脂联素具有促进能量消耗、调节脂肪代谢、抗炎症反应以及改善IR等生理作用. 动物实验证实脂联素可经AMPK信号途径显著改善NAFLD大鼠肝脏脂肪变性, 促进肝细胞损伤的修复[65]. 临床相关分析数据显示脂联素是NAFLD患者的保护因子[66]. 因此脂联素可能对糖尿病NAFLD具有潜在的治疗作用, 但未来走进临床还需要大量的工作.
成纤维细胞生长因子(fibroblast growth factors, FGFs)家族成员FGF19和FGF21被认为是新的脂肪因子. FGF19作用于肝脏提高能量代谢率, 对血糖水平和胰岛素敏感性起着重要的调节作用[67]. 其机制为FGF19通过与FGFR4结合, 调节脂肪和胆固醇的代谢, 提高肝脏内脂肪酸的β氧化. 但是其潜在的促增殖作用可能导致其临床应用前景受到限制[68]. 而FGF21不仅可以显著降空腹血糖, 果糖胺、TG、胰岛素及高血糖, 可显著改善脂代谢, 包括降低密度脂蛋白胆固醇, 增高高密度脂蛋白胆固醇. 其机制为FGF21可通过抑制胆固醇调控元件结合蛋白-1来降低与脂肪酸及TG合成相关的基因表达、并可激活解偶联蛋白1与2表达, 增加能量消耗、促进脂肪利用和脂类排泄以降低TG水平[69,70]. 并且FGF21无潜在的促细胞增殖作用, 因此, FGF21可能对糖尿病NAFLD的防治具备良好的研究价值和应用前景.
目前研究认为减轻体质量是糖尿病合并NAFLD有效的防治方法. 而减肥手术不仅可使患者获得满意的体质量控制, 还可显著降低患者肥胖相关并发症如T2DM、脂代谢紊乱、高血压以及呼吸睡眠暂停等. 新近研究[71]证实, 减肥手术可显著改善NAFLD患者肝脏形态学变化. Mummadi等[72]的研究, 纳入了15项接受减肥术的患者766例, 分别于手术前后进行肝脏活检, 研究结果显示患者手术前后肝脏脂肪样变、NASH以及肝硬化病变改善或逆转率分别为: 91.6%、81.3%和65.5%. 上述研究均为患者手术前后自身的比较, 目前尚缺乏对减肥术的临床随机对照研究以严格评价手术对NAFLD患者的获益和风险[73]. 亦有大量研究[74,75]报道了Roux-en-Y胃旁路术(RYGB)可显著改善T2DM合并NAFLD患者肝脏脂肪样变、肝脏的炎性反应甚至肝硬化, 且其效果优于胃结扎术. 外科减肥术后患者可显著改善体质量、降低肝脏脂肪含量以及提高IR等, 患者的这些获益可能与手术后患者胃肠道激素GLP-1或内分泌调节肽(peptide tyrosine tyrosine, PYY)分泌得到了明显改善有关[76-79].
因此, 外科减肥术, 对于明显肥胖的糖尿病NAFLD患者提供了一种减肥效果显著、作用持久的强有力手段, 并且患者通过减肥手术可能获得明显减轻体质量、改善IR甚至恢复胰岛功能、提高患者的生活质量, 降低肥胖相关的合并症、提高患者的预期寿命等益处, 但是手术的长期疗效、术后的慢性并发症等潜在风险尚待进一步的研究加以评价.
T2DM合并NAFLD的有效防治刻不容缓, 虽然基础治疗在NAFLD患者中取得了良好的疗效, 而患者的长期的依从性不佳的问题尚待解决; GLP-1受体激动剂、DPP-4抑制剂等可通过改善IR, 增加胰岛素分泌及抑制胰高糖素的分泌, 既可安全有效降糖, 肝肾毒性小, 又可显著改善体质量, 给T2DM合并NAFLD患者的防治带来了新希望, 但是该类药物上市时间尚短, 其远期的疗效和安全性以及对脂肪肝组织学的改善等问题尚待更多的询证医学证据加以阐明. GLP-1R/GCGR等双受体激动剂以及FGF21等脂肪因子改善糖脂代谢的生理作用显示其对T2DM合并NAFLD的防治中具有良好的研究价值和应用前景. 外科减肥手术在明显肥胖的糖尿病NAFLD患者的防治中显示出其优越性, 但手术的长期疗效、术后的慢性并发症等潜在风险尚待进一步的研究加以评价.
2型糖尿病(type 2 diabetes mellitus, T2DM)和非酒精性脂肪肝病(nonalcoholic fatty liver disease, NAFLD)是目前亟待解决的两大公共卫生问题, 且NALFD在T2DM人群中广泛流行. 二者合并发病, 可显著增加患者肝脏相关死亡和心血管死亡风险. 因此有效防治T2DM患者NALFD刻不容缓.
郭永红, 副主任医师, 西安交通大学医学院第二附属医院感染科; 刘长征, 副教授, 中国医学科学院基础医学研究所
目前GLP-1R/GCGR双受体激动剂, 在动物实验中, 展示出良好的改善糖代谢、减少能量摄入、降低体质量等作用; 脂联素、成纤维细胞生长因子21(fibroblast growth factor 21)等脂肪因子在动物试验中也表现出良好的改善能量代谢和肝脏病理组织学变化, 但脂肪因子类走进临床还需要大量的研究.
Tai等系统介绍了NAFLD的流行情况、发病机制、诊断方法. 详细阐述了生活方式干预对糖尿病NAFLD的防治作用, 并概述了临床常用的药物.
本文非常系统、全面地介绍了目前国内外T2DM合并NAFLD的防治手段、疗效、应用的局限性, 对T2DM合并NAFLD临床防治以及认识该领域目前的研究动向具有一定的意义.
胰岛素抵抗: 是指靶组织(如肝脏、肌肉和脂肪组织等)对胰岛素的反应不敏感, 使得胰岛素促进葡萄糖的摄取和利用的生物学效应低于预计正常水平. 胰岛细胞代偿性超量分泌胰岛素的情况, 表现为高胰岛素血症伴代谢应激综合征.
本文从致病机制和临床治疗两个方面出发阐述了目前国内外T2DM合并NAFLD的防治方法. 同时展示了该领域的研究动向, 基础研究的成果可以很好地为临床治疗提供服务, 使临床治疗更为精准有效, 为防治T2DM合并NAFLD的药物研究提供新的方向.
编辑: 韦元涛 电编: 闫晋利
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