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中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志
中国生物工程杂志  2020, Vol. 40 Issue (11): 73-81    DOI: 10.13523/j.cb.2006040
综述     
基因技术在治疗2型糖尿病中的应用*
陈庆宇,王鲜忠,张姣姣()
西南大学动物医学院 重庆 400715
Application of Gene Technology in the Treatment of Type 2 Diabetes Mellitus
CHEN Qing-yu,WANG Xian-zhong,ZHANG Jiao-jiao()
College of Veterinary Medicine, Southwest University, Chongqing 400715, China
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摘要：

2型糖尿病(type 2 diabetes mellitus, T2DM)是一类由于胰岛β细胞损伤和机体对胰岛素耐受引发的慢性代谢性疾病,其快速增长的患病率和并发症所带来的高病死率已成为人类面临的医学难题。目前,T2DM主要是以降糖药物及胰岛素增敏剂等药物进行治疗,但是这类药物会产生严重的副作用,而且不能长期良好控制血糖和防止各种慢性并发症。因此,基因治疗是未来医疗发展的主要方向。基因治疗不仅可以靶向调控血糖水平进而提高降糖的效果,而且能够减少糖代谢异常引起的并发症,保护组织器官免受损伤。在认识传统药物治疗糖尿病的基础上,综述了基因技术在治疗T2DM中的应用,讨论了基因技术治疗T2DM的意义及存在的问题。基因技术的应用不仅有利于T2DM的预防和个体化治疗,同时也为糖尿病并发症提供了新的治疗途径。
关键词： 2型糖尿病;  药物治疗;  基因治疗;  病毒载体;  CRISPR    
Abstract:

Type 2 diabetes mellitus (T2DM) is a kind of chronic metabolic disease caused by β-cell damage and insulin tolerance. The rapid growth of its morbidity and high mortality caused by complications has become a medical problem. At present, T2DM is mainly treated with hypoglycemic drugs and insulin sensitizers, but these drugs will have serious side effects. And these drugs can’t control blood glucose and prevent various chronic complications for a long time. Therefore, gene therapy is the main direction of future medical development. Gene therapy can not only target to regulate blood glucose level and improve the effect of lowering blood glucose, but also reduce the complications caused by abnormal glucose metabolism and protect tissues and organs from damage. Based on the understanding of traditional medicine in the treatment of diabetes, the effect and advantages of gene technology in the treatment of T2DM are reviewed, which is not only conducive to the prevention and individualized treatment of T2DM, but also provides a new treatment for diabetic complications.
Key words: T2DM    Drug therapy    Gene therapy    Viral vectors    CRISPR
收稿日期: 2020-06-23 出版日期: 2020-12-11
ZTFLH:  Q78  
基金资助: * 重庆市自然科学基金面上项目(cstc2019jcyj-msxmX0056);中央高校基本科研业务费专项资金(SWU019002);重庆市高等教育教学改革研究项目(203259)
通讯作者: 张姣姣     E-mail: zhangjjff@126.com
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引用本文:

陈庆宇,王鲜忠,张姣姣. 基因技术在治疗2型糖尿病中的应用*[J]. 中国生物工程杂志, 2020, 40(11): 73-81.

CHEN Qing-yu,WANG Xian-zhong,ZHANG Jiao-jiao. Application of Gene Technology in the Treatment of Type 2 Diabetes Mellitus. China Biotechnology, 2020, 40(11): 73-81.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2006040    或    https://manu60.magtech.com.cn/biotech/CN/Y2020/V40/I11/73

类别 常用药物 适应证 用药方式 作用机制 优缺点
胰岛素及胰岛素类似物 诺和锐、诺和灵N、诺和平 T1DM、治疗效果不佳的T2DM 皮下注射、
口服		 与受体结合后促进葡萄糖的摄取和利用,并抑制糖原分解和异生 优点:用于日常基础控制血糖
缺点:治疗过程中需进行血糖监测避免不良反应
双胍类 盐酸二甲双胍 单纯饮食控制不满意的T2DM 口服 减少肝脏葡萄糖的输出,恢复胰岛素对腺苷环化酶的抑制,促进糖无氧酵解;改善外周胰岛素抵抗,抑制肠道对葡萄糖的吸收和肝糖输出;改善胰岛素敏感性而降低血糖 优点:可全程联合其他药物进行治疗,治疗首选药
缺点:会有胃肠道反应,需先从小剂量开始用药,形成耐受;长期使用者应注意维生素B12缺乏的可能性
磺脲类促泌药 格列喹酮、格列美脲 非肥胖
T2DM患者		 口服 作用于胰岛β细胞的K+-ATP通道,使K+外流受限,Ca2+内流刺激胰岛素释放,增加体内胰岛素水平进而降低血糖;直接刺激胰岛β细胞分泌胰岛素 优点:可作口服降糖药,对患者而言更加方便,与糖尿病微血管病变和大血管病变发生的风险下降有关
缺点:使用不当会导致低血糖,尤其是在老年患者和肝、肾功能不全者,会导致体重增加
非磺脲类促泌药 瑞格列奈、那格列奈 T2DM 口服 直接刺激胰岛β细胞分泌胰岛素;刺激胰岛素早时相分泌,降低餐后血糖水平,保护胰岛细胞 优点:导致低血糖的风险,但程度较磺脲类药物轻;肾功能不全的患者可使用
缺点:会导致低血糖和体重增加
α-葡糖苷酶抑制药 阿卡波糖 以碳水化合物为主食的糖尿病患者 口服 竞争性与小肠刷状缘α-葡糖苷酶结合,抑制α-葡糖苷酶活性;延缓肠道对葡萄糖的吸收 优点:使用剂量比达到同等疗效的二甲双胍少;单独服用不会发生低血糖
缺点:胃肠道反应
TZD 曲格列酮、罗格列酮、吡格列酮、环格列酮 T2DM 口服 增加靶细胞对胰岛素作用的敏感性而降低血糖;作用于细胞核的过氧化物酶体增殖体活化受体,减少胰岛素抵抗,增加脂肪细胞、肌肉和肝中胰岛素的敏感性,提高外周组织的糖利用度,抑制肝糖原生成 优点:可使糖化血红蛋白下降0.7%~1.0%
缺点:单独使用不导致低血糖,但与胰岛素联用可增加低血糖发生的风险;该药的使用与骨折和心力衰竭风险增加有关;会导致体重增加和水肿
GLP-1受体激动药 艾塞那肽、利拉鲁肽、贝那鲁肽、利司那肽、艾塞那肽周制剂 T2DM 皮下注射 与GLP-1受体结合后,一方面刺激胰岛素分泌,另一方面减少胰高血糖素的分泌,进而降低血糖浓度 优点:显著降低三酰甘油水平、血压和体重;单独使用不明显增加低血糖发生的风险;口服降糖药治疗失败后用GLP-1有效
缺点:患者对该药物的活性成分有过敏风险
DPP-4抑制药 西格列汀、沙格列汀、维格列汀、利格列汀、阿格列汀 T2DM 口服 减少体内GLP-1的分解,增加GLP-1浓度从而促进胰岛β细胞分泌胰岛素;改善胰岛β细胞敏感性,促进胰岛素分泌;抑制胰岛α细胞分泌胰高血糖素 优点:单独使用不增加低血糖和心血管病发生的风险,肝、肾功能不全的患者可以使用
缺点:该类药物价格较高,仅有少数患者能够承担
表1  治疗糖尿病的常用药物
基因技术方法 分类 优点 缺点
病毒载体技术 慢病毒载体 基因转染效率较高,可携带较大的T2DM相关基因片段,对细胞周期没有特别要求 生物安全性较差,携带较大基因片段时病毒滴度低
腺病毒载体 病毒滴度高,转染T2DM相关基因的能力较强,不整合到宿主基因组 引起动物机体发生强烈的免疫和炎症反应
腺相关病毒载体 低致命性、低免疫原性、宿主范围广、稳定表达,适用于长期T2DM相关基因矫正,生物安全性较高 引起动物机体轻微的免疫反应
非病毒载体技术 干细胞治疗 极强的自我更新能力,多向分化为胰岛β细胞,分泌多种T2DM治疗性细胞因子 免疫排斥反应,缺血缺氧等非免疫因素
再分化 祖细胞再分化为胰岛β细胞,从根源上治疗糖尿病 再分化诱导条件未明确,再分化效率较低,去分化过程中基因组易发生突变导致细胞内致癌风险增高
CRISPR/Cas9 对T2DM相关基因高精度修饰和调控,纠正糖尿病单一致病基因 难度较高,脱靶率高,转导效率低
表2  基因技术治疗糖尿病的优缺点
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