药学学报, 2022, 57(3): 568-575
引用本文:
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.

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
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
摘要:
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
Abstract:
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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参考文献:
[1] Malone JI, Hansen BC. Does obesity cause type 2 diabetes mellitus (T2DM)? Or is it the opposite?[J]. Pediatr Diabetes, 2019, 20:5-9.
[2] Saeedi P, Petersohn I, Salpea P, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045:results from the International Diabetes Federation Diabetes Atlas, 9th edition[J]. Diabetes Res Clin Pract, 2019, 157:107843.
[3] Fanzani A, Conraads VM, Penna F, et al. Molecular and cellular mechanisms of skeletal muscle atrophy:an update[J]. J Cachexia Sarcopenia Muscle, 2012, 3:163-179.
[4] Monaco CMF, Perry CGR, Hawke TJ. Diabetic myopathy:current molecular understanding of this novel neuromuscular disorder[J]. Curr Opin Neurol, 2017, 30:545-552.
[5] Park SW, Goodpaster BH, Strotmeyer ES, et al. Accelerated loss of skeletal muscle strength in older adults with type 2 diabetes:the health, aging, and body composition study[J]. Diabetes Care, 2007, 30:1507-1512.
[6] Zhang YX, Zhang R, Yang J, et al. Relationship between fatigue caused by type 2 diabetes mellitus and 5-HT degradation in skeletal muscle[J]. Acta Pharm Sin (药学学报), 2021, 56:190-200.
[7] Kalyani RR, Corriere M, Ferrucci L. Age-related and disease-related muscle loss:the effect of diabetes, obesity, and other diseases[J]. Lancet Diabetes Endocrinol, 2014, 2:819-829.
[8] Evans PL, McMillin SL, Weyrauch LA, et al. Regulation of skeletal muscle glucose transport and glucose metabolism by exercise training[J]. Nutrients, 2019, 11:2432.
[9] Fiorentino TV, Monroy A, Kamath S, et al. Pioglitazone corrects dysregulation of skeletal muscle mitochondrial proteins involved in ATP synthesis in type 2 diabetes[J]. Metabolism, 2021, 114:154416.
[10] Huang X, Liu G, Guo J, et al. The PI3K/AKT pathway in obesity and type 2 diabetes[J]. Int J Biol Sci, 2018, 14:1483-1496.
[11] Perry BD, Caldow MK, Brennan-Speranza TC, et al. Muscle atrophy in patients with type 2 diabetes mellitus:roles of inflammatory pathways, physical activity and exercise[J]. Exerc Immunol Rev, 2016, 22:94-109.
[12] Zhang L, Pan J, Dong Y, et al. Stat3 activation links a C/EBPδ to myostatin pathway to stimulate loss of muscle mass[J]. Cell Metab, 2013, 18:368-379.
[13] Sriwijitkamol A, Christ-Roberts C, Berria R, et al. Reduced skeletal muscle inhibitor of κBβ content is associated with insulin resistance in subjects with type 2 diabetes[J]. Diabetes, 2006, 55:760-767.
[14] Fruman DA, Meyers RE, Cantley LC. Phosphoinositide kinases[J]. Annu Rev Biochem, 1998, 67:481-507.
[15] Bodine SC, Stitt TN, Gonzalez M, et al. Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo[J]. Nat Cell Biol, 2001, 3:1014-1019.
[16] Krook A, Roth RA, Jiang XJ, et al. Insulin-stimulated Akt kinase activity is reduced in skeletal muscle from NIDDM subjects[J]. Diabetes, 1998, 47:1281-1286.
[17] Ato S, Kido K, Sato K, et al. Type 2 diabetes causes skeletal muscle atrophy but does not impair resistance training-mediated myonuclear accretion and muscle mass gain in rats[J]. Exp Physiol, 2019, 104:1518-1531.
[18] Sandri M, Sandri C, Gilbert A, et al. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy[J]. Cell, 2004, 117:399-412.
[19] Ho KK, Myatt SS, Lam EWF. Many forks in the path:cycling with FoxO[J]. Oncogene, 2008, 27:2300-2311.
[20] Stitt TN, Drujan D, Clarke BA, et al. The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors[J]. Mol Cell, 2004, 14:395-403.
[21] Okamura T, Hashimoto Y, Osaka T, et al. The sodium-glucose cotransporter 2 inhibitor luseogliflozin can suppress muscle atrophy in db/db mice by suppressing the expression of foxo1[J]. J Clin Biochem Nutr, 2019, 65:23-28.
[22] O'Neill BT, Lee KY, Klaus K, et al. Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis[J]. J Clin Invest, 2016, 126:3433-3446.
[23] Li H, Malhotra S, Kumar A. Nuclear factor-kappa B signaling in skeletal muscle atrophy[J]. J Mol Med (Berl), 2008, 86:1113-1126.
[24] Andreasen AS, Kelly M, Berg RMG, et al. Type 2 diabetes is associated with altered NF-κB DNA binding activity, JNK phosphorylation, and AMPK phosphorylation in skeletal muscle after LPS[J]. PLoS One, 2011, 6:e23999.
[25] Horvath CM. The Jak-STAT pathway stimulated by interleukin 6[J]. Sci STKE, 2004, 2004:tr9.
[26] Ramji DP, Foka P. CCAAT/enhancer-binding proteins:structure, function and regulation[J]. Biochem J, 2002, 365:561-575.
[27] Hajduch E, Rencurel F, Balendran A, et al. Serotonin (5-hydroxytryptamine), a novel regulator of glucose transport in rat skeletal muscle[J]. J Biol Chem, 1999, 274:13563-13568.
[28] Hasan MM, Shalaby SM, El-Gendy J, et al. Beneficial effects of metformin on muscle atrophy induced by obesity in rats[J]. J Cell Biochem, 2019, 120:5677-5686.
[29] Walton RG, Dungan CM, Long DE, et al. Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults:a randomized, double-blind, placebo-controlled, multicenter trial:the MASTERS trial[J]. Aging Cell, 2019, 18:e13039.
[30] Wang X, Hu Z, Hu J, et al. Insulin resistance accelerates muscle protein degradation:activation of the ubiquitin-proteasome pathway by defects in muscle cell signaling[J]. Endocrinology, 2006, 147:4160-4168.
[31] Iida M, Katsuno M, Nakatsuji H, et al. Pioglitazone suppresses neuronal and muscular degeneration caused by polyglutamine-expanded androgen receptors[J]. Hum Mol Genet, 2015, 24:314-329.
[32] Takada S, Masaki Y, Kinugawa S, et al. Dipeptidyl peptidase-4 inhibitor improved exercise capacity and mitochondrial biogenesis in mice with heart failure via activation of glucagon-like peptide-1 receptor signalling[J]. Cardiovasc Res, 2016, 111:338-347.
[33] Gurjar AA, Kushwaha S, Chattopadhyay S, et al. Long acting GLP-1 analog liraglutide ameliorates skeletal muscle atrophy in rodents[J]. Metabolism, 2020, 103:154044.
[34] Nguyen TTN, Choi H, Jun HS. Preventive effects of dulaglutide on disuse muscle atrophy through inhibition of inflammation and apoptosis by induction of Hsp72 expression[J]. Front Pharmacol, 2020, 11:90.
[35] Hong Y, Lee JH, Jeong KW, et al. Amelioration of muscle wasting by glucagon-like peptide-1 receptor agonist in muscle atrophy[J]. J Cachexia Sarcopenia Muscle, 2019, 10:903-918.
[36] Bamba RYP. Anti-skeletal muscle atrophy effect of luseogliflozin via lipidome modification in db/db mice[J]. Diabetes, 2020, 69:1137-P.
[37] Naznin F, Sakoda H, Okada T, et al. Canagliflozin, a sodium glucose cotransporter 2 inhibitor, attenuates obesity-induced inflammation in the nodose ganglion, hypothalamus, and skeletal muscle of mice[J]. Eur J Pharmacol, 2017, 794:37-44.
[38] Yamakage H, Tanaka M, Inoue T, et al. Effects of dapagliflozin on the serum levels of fibroblast growth factor 21 and myokines and muscle mass in Japanese patients with type 2 diabetes:a randomized, controlled trial[J]. J Diabetes Investig, 2020, 11:653-661.
[39] Mele A, Calzolaro S, Cannone G, et al. Database search of spontaneous reports and pharmacological investigations on the sulfonylureas and glinides-induced atrophy in skeletal muscle[J]. Pharmacol Res Perspect, 2014, 2:e00028.
[40] Lee CG, Boyko EJ, Barrett-Connor E, et al. Insulin sensitizers may attenuate lean mass loss in older men with diabetes[J]. Diabetes Care, 2011, 34:2381-2386.
[41] Krawiec BJ, Nystrom GJ, Frost RA, et al. AMP-activated protein kinase agonists increase mRNA content of the muscle-specific ubiquitin ligases MAFbx and MuRF1 in C2C12 cells[J]. Am J Physiol Endocrinol Metab, 2007, 292:E1555-E1567.
[42] Yi H, Jun P, Xuan P, et al. Updated research progress of selective PPARγ modulators[J]. Acta Pharm Sin (药学学报), 2021, 56:352-359.
[43] Zierath JR, Ryder JW, Doebber T, et al. Role of skeletal muscle in thiazolidinedione insulin sensitizer (PPARγ agonist) action[J]. Endocrinology, 1998, 139:5034-5041.
[44] Rabøl R, Boushel R, Almdal T, et al. Opposite effects of pioglitazone and rosiglitazone on mitochondrial respiration in skeletal muscle of patients with type 2 diabetes[J]. Diabetes Obes Metab, 2010, 12:806-814.
[45] Rendell M. The role of sulphonylureas in the management of type 2 diabetes mellitus[J]. Drugs, 2004, 64:1339-1358.
[46] Gilbert MP, Pratley RE. GLP-1 analogs and DPP-4 inhibitors in type 2 diabetes therapy:review of head-to-head clinical trials[J]. Front Endocrinol (Lausanne), 2020, 11:178.
[47] Bouchi R, Fukuda T, Takeuchi T, et al. Dipeptidyl peptidase 4 inhibitors attenuates the decline of skeletal muscle mass in patients with type 2 diabetes[J]. Diabetes Metab Res Rev, 2018, 34:e2957.
[48] Rizzo MR, Barbieri M, Fava I, et al. Sarcopenia in elderly diabetic patients:role of dipeptidyl peptidase 4 inhibitors[J]. J Am Med Dir Assoc, 2016, 17:896-901.
[49] Ishii S, Nagai Y, Kato H, et al. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin on muscle mass and the muscle/fat ratio in patients with type 2 diabetes[J]. J Clin Med Res, 2020, 12:122-126.
[50] Hasegawa Y, Hayashi K, Takemoto Y, et al. DPP-4 inhibition with linagliptin ameliorates the progression of premature aging in klotho-/- mice[J]. Cardiovasc Diabetol, 2017, 16:154.
[51] Chai W, Dong Z, Wang N, et al. Glucagon-like peptide 1 recruits microvasculature and increases glucose use in muscle via a nitric oxide-dependent mechanism[J]. Diabetes, 2012, 61:888-896.
[52] Drucker DJ. The biology of incretin hormones[J]. Cell Metab, 2006, 3:153-165.
[53] Perna S, Guido D, Bologna C, et al. Liraglutide and obesity in elderly:efficacy in fat loss and safety in order to prevent sarcopenia. A perspective case series study[J]. Aging Clin Exp Res, 2016, 28:1251-1257.
[54] Wu CN, Tien KJ. The impact of antidiabetic agents on sarcopenia in type 2 diabetes:a literature review[J]. J Diabetes Res, 2020, 2020:9368583.
[55] Yabe D, Nishikino R, Kaneko M, et al. Short-term impacts of sodium/glucose co-transporter 2 inhibitors in Japanese clinical practice:considerations for their appropriate use to avoid serious adverse events[J]. Expert Opin Drug Saf, 2015, 14:795-800.
[56] Gao F, Hall S, Bach LA. Myopathy secondary to empagliflozin therapy in type 2 diabetes[J]. Endocrinol Diabetes Metab Case Rep, 2020. DOI:10.1530/EDM-20-0017.
[57] Todd MK, Watt MJ, Le J, et al. Thiazolidinediones enhance skeletal muscle triacylglycerol synthesis while protecting against fatty acid-induced inflammation and insulin resistance[J]. Am J Physiol Endocrinol Metab, 2007, 292:E485-E493.
[58] Perry T, Holloway HW, Weerasuriya A, et al. Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathy[J]. Exp Neurol, 2007, 203:293-301.
[59] Yamamoto K, Amako M, Yamamoto Y, et al. Therapeutic effect of exendin-4, a long-acting analogue of glucagon-like peptide-1 receptor agonist, on nerve regeneration after the crush nerve injury[J]. Biomed Res Int, 2013, 2013:315848.