药学学报, 2022, 57(3): 568-575
梁眉黛, 杨秀颖*, 杜冠华*. 2型糖尿病诱导骨骼肌萎缩机制及常用降糖药影响研究进展[J]. 药学学报, 2022, 57(3): 568-575.
LIANG Mei-dai, YANG Xiu-ying*, DU Guan-hua*. The mechanisms of type 2 diabetic skeletal muscle atrophy and the effects of commonly used hypoglycemic drugs: a review[J]. Acta Pharmaceutica Sinica, 2022, 57(3): 568-575.

梁眉黛, 杨秀颖*, 杜冠华*
中国医学科学院、北京协和医学院药物研究所, 药物靶点研究与新药筛选北京市重点实验室, 北京 100050
2型糖尿病是一种以糖脂代谢紊乱和胰岛素绝对或相对缺乏为特征的高消耗代谢性疾病,可诱导产生骨骼肌萎缩。高血糖、高血脂、胰岛素抵抗及炎症因子异常释放可引发骨骼肌组织信号转导异常,使蛋白质合成及降解失衡而引起肌萎缩。正常情况下,胰岛素样生长因子1 (IGF-1)/胰岛素可激活磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B (AKT),AKT既可以通过哺乳动物雷帕霉素靶蛋白(mTOR)增加蛋白质的合成,也可以使叉头框蛋白O转录因子(FoxO)磷酸化从而抑制某些泛素连接酶(如MAFbx/atrogin-1和MuRF1)或自噬相关基因的转录。2型糖尿病状态下的IGF-1/PI3K/AKT通路减弱是导致骨骼肌萎缩的重要因素。有研究表明,现有常用抗糖尿病药物在调控骨骼肌蛋白的合成与降解方面存在差异。文献报道,具有抗2型糖尿病肌萎缩作用的药物包括噻唑烷二酮类、胰高血糖素样肽类似物、葡萄糖钠协同转运蛋白2抑制剂等;仍旧存在争议或者对骨骼肌萎缩具有促进作用的药物包括二甲双胍和部分磺酰脲类及非磺酰脲类胰岛素促分泌剂。本文通过对目前常用的抗2型糖尿病药物进行梳理分析,及所涉及的相关机制进行总结,为抗糖尿病药物在2型糖尿病中的合理应用提供参考。
关键词:    2型糖尿病      抗糖尿病药物      骨骼肌萎缩      哺乳动物雷帕霉素靶蛋白      泛素连接酶     
The mechanisms of type 2 diabetic skeletal muscle atrophy and the effects of commonly used hypoglycemic drugs: a review
LIANG Mei-dai, YANG Xiu-ying*, DU Guan-hua*
Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Type 2 diabetes is a hypermetabolic disease characterized with disorders of glucose/lipid metabolism, absolute or relative lack of insulin, and can induce skeletal muscle atrophy. Hyperglycemia, hyperlipidemia, insulin resistance, and abnormal release of inflammatory factors can lead to abnormal signal transduction in skeletal muscle, thus make protein synthesis and degradation imbalance and eventually causing muscle atrophy. Under normal conditions, insulin-like growth factor 1 (IGF-1)/insulin can activate phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT). AKT not only increases protein synthesis through mammalian target protein of rapamycin (mTOR), but also phosphorylates forkhead box O (FoxO) transcription factor and then inhibits the transcription of several ubiquitin ligases (such as MAFbx/atrogin-1 and MuRF1), or autophagy related genes. The weakened IGF-1/PI3K/AKT pathway in type 2 diabetes is an important factor leading to skeletal muscle atrophy. Studies have shown that the commonly used anti-type 2 diabetic drugs have different effects in regulating the synthesis and degradation of skeletal muscle protein. Studies reported that drugs with effect of anti-diabetic muscle atrophy include thiazolidinediones, glucagon-like peptide analogs, glucose-sodium cotransporter 2 inhibitors, etc.; drugs that are still in controversial or even promote skeletal muscle atrophy include metformin, and some sulfonylurea or non-sulfonylurea insulin secretagogues. This article overviewed and analyzed the currently commonly used drugs for type 2 diabetes and summarized the related mechanisms, with the aim to provide references for the rational applications of drugs for type 2 diabetes.
Key words:    type 2 diabetes    antidiabetic drug    skeletal muscle atrophy    mTOR    ubiquitin ligase   
收稿日期: 2021-08-23
DOI: 10.16438/j.0513-4870.2021-1217
基金项目: 国家科技重大专项(2018ZX09711001-012,2018ZX09711001-003-005,2017YFG0112900);国家自然科学基金资助项目(81470159,81770847);中国医学科学院创新工程医科院创新工程(CAMS-I2M,2016-I2M-3-007,2017-I2M-1-010)。
通讯作者: 杨秀颖,Tel:86-10-63165313,E-mail:lucia@imm.ac.cn;杜冠华,Tel:86-10-63165184,E-mail:dugh@imm.ac.cn
Email: lucia@imm.ac.cn;dugh@imm.ac.cn
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