Research advance in correlations between fibroblast growth factor-21 and occurrence as well as development of vascular complications of type 2 diabetes mellitus
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摘要: 2型糖尿病(T2DM)是常见的慢性代谢性疾病,慢性并发症尤其是血管并发症是其主要危害。成纤维细胞生长因子-21(FGF-21)作为近年来新发现的代谢调节因子,被认为与T2DM的发生及糖尿病并发症的发生、发展密切相关。本文对FGF-21与糖尿病微血管并发症及大血管并发症相关研究进展进行综述。FGF-21作为糖尿病血管并发症的生物标志物或治疗靶点的作用值得进一步研究,对于T2DM血管并发症的预测具有重要价值。
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关键词:
- 2型糖尿病 /
- 成纤维细胞生长因子-21 /
- 糖尿病血管病变 /
- 并发症
Abstract: Type 2 diabetes(T2DM) is a common chronic metabolic disease, and its chronic complications, especially vascular complications, are the main damages of T2DM. Fibroblast growth factor-21(FGF-21) is a newly discovered metabolism regulator, which is considered to be closely linked to the development of T2DM and its complications. We summarized relevant studies about FGF-21 in vascular and macrovascular complications of T2DM. The role of FGF-21 as a biomarker or therapeutic target for vascular complications of T2DM requires further investigations, and its application in predicting vascular complications of T2DM has significant value. -
2型糖尿病(T2DM)发病率逐年增高,已成为全球面临的重大卫生问题。2020年由滕卫平教授牵头的关于中国糖尿病流行病学调查[1]发现,中国成人糖尿病患病率为11.2%, 糖尿病已成为继肿瘤、心脑血管疾病之后的第三大疾病。尽早发现糖尿病症状并对糖尿病及其并发症进行诊断及治疗对预后十分重要。近年来,成纤维细胞生长因子-21 (FGF-21)调节代谢的研究成为热点, FGF-21具有调节糖脂稳态、减轻体质量、维持能量平衡等作用。前瞻性研究[2]证实,无论是糖尿病发病前还是糖尿病发病中,患者血浆FGF-21水平均显著增高。FGF-21与糖尿病的发生、发展有关,是糖尿病的一个有效预测因子。多项动物试验及临床研究证实, FGF-21水平与动脉粥样硬化(AS)及糖尿病微血管并发症有关。因此, FGF-21为糖尿病及血管并发症的早期诊断及治疗提供了思路。本文对FGF-21与T2DM血管并发症的相关性进行综述,分析其生物学作用及临床意义,为防治T2DM血管并发症提供参考。
1. FGF-21概述
FGF-21是FGF家族的一个特殊成员,具有内分泌样激素作用。目前大量研究证实, FGF-21对血糖及血脂代谢的调节起重要作用。FGF-21与代谢性疾病关系十分密切[3], 尤其与T2DM的发生、发展相关。
1.1 FGF-21与糖代谢
动物试验证实, FGF-21可通过与肝脏FGF受体结合诱导过氧化物酶体增殖物激活受体γ辅激活因子1α(PGC-1α)基因表达从而激活过氧化物酶体增殖物激活受体α(PPARα)活性来调节糖异生[4]。FGF-21的降糖作用与胰岛素敏感性的特点密切相关。一方面, FGF-21通过激活PPARγ信号通路活性进而激活脂联素表达来增加胰岛素敏感性,另一方面通过抑制氧化应激及炎症反应来恢复胰岛素信号通路[5-6]。此外,学者[7]发现, FGF-21可通过葡萄糖转运蛋白1(GLUT-1)以不依赖胰岛素信号通路的方式增加葡萄糖的摄取从而降低血糖。
1.2 FGF-21与脂代谢
FGF-21调节脂质谱的重要作用目前已被广泛讨论,但尚无定论。研究[8]发现, FGF-21可通过激活三酰甘油水解酶及脂肪敏感性脂肪酶的活性促进脂肪分解。但有研究指出,短期内提高FGF-21水平会抑制脂肪分解, FGF-21还可增加肥胖小鼠脂肪生成,且FGF-21可以通过抑制胆固醇调节元件结合蛋白1(Srebp-1)降低甘油三酯水平,抑制Srebp-2减少胆固醇的合成[9-11]。此外, FGF-21是白色脂肪组织向棕色脂肪组织分化的关键调节因子,可促进脂肪细胞产热及能量消耗,从而减少机体脂肪含量[12]。因此, FGF-21可通过多种途径来维持脂质稳态。一项最新临床研究[13]证实, FGF-21类似物可改善非酒精性脂肪肝患者的血脂代谢紊乱。
2. FGF-21与糖尿病微血管并发症
2.1 FGF-21与糖尿病肾病(DKD)
DKD是最严重的DM微血管并发症之一,是导致终末期肾脏衰竭的常见原因。美国肾脏数据系统发布的2019年年度报告[14]显示,新增的接受透析的患者中糖尿病肾病约占46.9%。
研究[15]发现,所有受试者包括正常糖耐量(NGT)和糖耐量减低(IGT)患者及T2DM患者血清FGF-21水平均与尿白蛋白与肌酐的比值相关,提示FGF-21水平与肾功能相关。2013年的一项研究[16]首次证明,急慢性肾功能不全患者中循环FGF-21均明显增加,推测这一结果与肾功能不全、排泄FGF-21减少及FGF-21代偿性升高有关。近年来学者也发现,糖尿病肾病与FGF-21具有相关性。一项横断面研究[17]指出, T2DM患者血清FGF-21水平与尿白蛋白排泄率有独立相关性,提示血清FGF-21水平与糖尿病肾病发展有关。香港一项大型临床研究[18]表明,糖尿病肾病发生、发展过程中,尤其是在DKD早期,血清FGF-21水平升高可能预测T2DM患者肾脏疾病进展。动物试验研究[19]发现,在FGF21基因敲除小鼠中,脂质毒性和糖尿病引起的肾损伤会增强,而腹腔注射FGF21可明显预防这种损伤。这项研究结果发现, FGF21通过防止脂质积聚和抗炎、抗氧化应激、抗纤维化作用诱导肾脏对糖尿病早期肾细胞凋亡和晚期肾功能不全的保护作用。一项韩国试验[20]对糖尿病小鼠注射FGF-21结果发现, FGF-21通过改善胰岛素抵抗、血脂异常及抗炎作用达到保护肾脏的作用。最近一项动物试验[21]发现, FGF-21可激活Akt/MDM2/p53信号通路,从而负调节TGF-β/Smad2/3介导的上皮间质转化过程,起到预防肾纤维化的作用。这些研究得出的结论相似,证明FGF-21可以通过多种作用影响糖尿病肾病的发生、发展,并能防止DKD对机体的损伤,对日后治疗糖尿病肾病可能是一种新策略。
2.2 FGF-21与糖尿病视网膜病变(DR)
DR是糖尿病微血管并发症之一,是糖尿病患者致盲的常见原因。目前,关于FGF-21与DR的研究有限。2014年,一项病例对照研究发现, DR患者的血清FGF-21浓度高于非视网膜病变患者,表明FGF-21的升高与DR的发生有关,但FGF-21浓度在DR亚组间无显著差异,即与视网膜病变的严重程度无关,因此推测其可用于早期筛查视网膜病变,但无法作为评价其严重程度的指标[22]。2016年一项研究[23]发现,T2DM合并视网膜病变患者血清FGF-21浓度高于未合并视网膜病变的患者,且与DR的严重程度无关,但与有些研究提出的预测临界值相差较大,这可能与所使用的试剂盒不同有关。2015年,一项大样本及随访5年的队列研究[24]并未观察到基线血清FGF-21水平与新发的DR有任何显著相关性。研究结果不同可能与这些研究选择的患者特征差异等因素有关。最近一项研究[25]通过对227例T2DM患者统计分析发现,血清FGF-21水平与DR呈U形关系,血清FGF-21水平低可能与DR有关,而相对升高的血清FGF-21水平可能是一种代偿性增加。综合上述研究结果可知, FGF-21可能参与DR的发生、发展过程,且机制复杂,与FGF-21调节视网膜糖脂代谢、增加循环脂联素(APN)表达进而减少视网膜新生血管形成及抗感光细胞氧化应激作用有关[26-28]。但FGF-21在DR中的作用尚未完全清楚,未来还需要进行大量动物试验及临床研究进行进一步探索。
3. FGF-21与糖尿病大血管并发症
糖尿病大血管病变易导致DM患者伤残,甚至死亡。AS是糖尿病大血管并发症的重要基础过程, AS的发生与脂质沉积、炎症损伤、内皮功能损害等有关。
3.1 FGF-21与颈动脉粥样硬化(CAS)
颈动脉内膜中层厚度是评价早期动脉损伤的重要指标,临床上通过对颈动脉超声检查探索动脉硬化情况。研究[29]发现,血清FGF-21水平升高与人类CAS相关。一项研究[30]也发现,初发的T2DM患者血清FGF-21水平升高与亚临床AS患者的颈动脉病变呈正相关,提示FGF-21是CAS的独立影响因素,可能是AS潜在的治疗靶点,有助于早期诊断[31]。此外,一项动物试验发现, FGF21可以通过降低胆固醇对AS产生保护作用,是血脂异常及AS的重要保护因子[32]。可以推测, FGF-21在未来可能用于AS的早期预测及治疗。
3.2 FGF-21与冠心病(CHD)
CHD是糖尿病患者死亡的主要原因。一项临床研究[33]发现, T2DM合并CHD患者血清FGF-21水平明显高于单纯T2DM患者及单纯CHD患者,这提示FGF-21对于T2DM合并CHD的发病有一定联系。动物试验[34]指出, AS小鼠体内内源性的FGF-21及受体表达水平增高,而外源性注射FGF-21可以延缓AS斑块形成,最后得出FGF-21可能通过抑制内质网应激促凋亡反应来改善AS。一个相对短期的随访研究发现,长期T2DM患者群体中,血清FGF-21对心血管病发病率和死亡率的联合终点具有很强的预测价值,并且超过了传统的心血管病危险因素的预测价值[35]。2015年,一项对9697名T2DM患者的研究[36]发现,高血浆FGF-21水平与T2DM患者心血管事件风险增高相关。此后,中国的一项前瞻性研究确定了血清FGF-21水平对T2DM及无已知心血管疾病的受试者均有预测CHD的作用,进一步证实了T2DM患者进行CHD一级预防时, FGF-21可以作为一种血清生物标记物进行冠状动脉危险评估[37]。FGF-21一方面可以通过调节糖脂代谢来控制CHD的危险因素,并且促进脂联素的分泌间接作用于血管,减少内皮功能障碍,抑制平滑肌细胞增殖,阻止巨噬细胞向泡沫细胞转化[38]; 另一方面其在分子机制上可以发挥抑制细胞凋亡、抗氧化应激的作用[39-40]。研究[41]表明, FGF-21通过FGFR1/b-K1otho-PI3K-Akt1-BAD信号网络的介导,在心肌损伤中上调并从肝脏及脂肪组织释放,有助于对缺血心肌的保护。由此可见, FGF-21参与了T2DM合并CHD的发生、发展过程,并且对心脏血管及缺血心肌有保护作用,未来可能作为预测心血管疾病及推测预后的生物标志物。
3.3 FGF-21与周围动脉疾病(PAD)
PAD是T2DM的慢性并发症之一,常因动脉硬化、狭窄闭塞引起相应症状,表现为肢体缺血,严重时可导致患者截肢。一项对糖尿病合并下肢大血管病变的研究[42]指出, FGF-21为DM合并下肢大血管病变的独立危险因素,监测血清FGF-21水平对于早期防治DM患者下肢大血管病变意义重大。目前,对于糖尿病下肢大血管病变治疗方法有限,且一经发现多处于中晚期,因此早期通过简便方法进行筛查尤为重要。
4. FGF-21的应用前景
目前已有试验证实, FGF-21能够预防及改善糖尿病肾损伤及大血管病变,可作为治疗的候选药物。FGF-21类似物在人体内药理作用的研究显示,其可显著降低机体血脂水平,具有胰岛素增敏作用,虽空腹血糖无明显变化,但有降血糖的趋势[43]。一项对T2DM患者的临床研究[44]发现,进行FGF-21类似物(LY 2405319)治疗可迅速降低血脂,说明FGF-21在人体内具有生物活性,提示以FGF-21为基础的治疗方法可能对治疗代谢紊乱有效。动物实验表明,反复注射FGF-21可显著改善代谢异常小鼠的代谢水平[45]。另外, FGF-21不会促进细胞增殖。这些生理及药理特性对于其用于临床治疗提供了基础。目前,一些生长因子已经用于治疗多种糖尿病并发症,且能更好地修复坏死组织[46], 但长期疗效尚不明确,需要远期的临床研究来验证在人体内是否对糖脂代谢及血管损伤有改善作用,同时使用安全问题也需要进一步探索,尤其是FGF-21对骨转换的潜在不良影响[43]。因此, FGF-21类似物能否用于临床还需要未来大样本临床研究来证实。
中国T2DM患者基数大,发病率居高不下,血糖控制不佳。由于其并发症早期症状隐匿,发现及诊断时间较迟,治疗方法较局限,导致预后不佳。多项研究指出, FGF-21可能是评估T2DM大微血管并发症风险的潜在生物标志物, FGF-21在未来有可能成为一种可行且有前景的代谢性疾病的治疗方法,为预测及治疗DR提供了重要思路,但有待完善基础与临床研究进行证据支持。FGF-21作为糖尿病血管并发症的生物标志物或治疗靶点的作用需要进一步研究。
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[1] LI Y, TENG D, SHI X, et al. Prevalence of diabetes recorded in mainland China using 2018 diagnostic criteria from the American Diabetes Association: national cross sectional study[J]. Bmj, 2020, 369: 997.
[2] CHEN C, CHEUNG B M, TSO A W, et al. High plasma level of fibroblast growth factor 21 is an Independent predictor of type 2 diabetes: a 5. 4-year population-based prospective study in Chinese subjects[J]. Diabetes Care, 2011, 34(9): 2113-2115. doi: 10.2337/dc11-0294
[3] BABAKNEJAD N, NAYERI H, HEMMATI R, et al. An Overview of FGF19 and FGF21: The Therapeutic Role in the Treatment of the Metabolic Disorders and Obesity[J]. Horm Metab Res, 2018, 50(6): 441-452. doi: 10.1055/a-0623-2909
[4] XIAO F, GUO Y, DENG J, et al. Hepatic c-Jun regulates glucose metabolism via FGF21 and modulates body temperature through the neural signals[J]. Mol Metab, 2019, 20: 138-148. doi: 10.1016/j.molmet.2018.12.003
[5] CHO Y M, KIM D H, LEE K H, et al. The IRE1α-XBP1s pathway promotes insulin-stimulated glucose uptake in adipocytes by increasing PPARγ activity[J]. Exp Mol Med, 2018, 50(8): 1-15. http://www.ncbi.nlm.nih.gov/pubmed/30111834
[6] 周博, 郭秦乐, 李会霞, 等. 成纤维细胞生长因子21通过抑制肥胖小鼠肝脏氧化应激改善胰岛素抵抗[J]. 西安交通大学学报(医学版), 2017, 38(02): 161-165, 187. https://www.cnki.com.cn/Article/CJFDTOTAL-XAYX201702002.htm [7] HSU J W, YEH S C, TSAI F Y, et al. Fibroblast growth factor 21 secretion enhances glucose uptake in mono(2-ethylhexyl)phthalate-treated adipocytes[J]. Toxicol In Vitro, 2019, 59: 246-254. doi: 10.1016/j.tiv.2019.04.021
[8] MAIDA A, ZOTA A, VEGIOPOULOS A, et al. Dietary protein dilution limits dyslipidemia in obesity through FGF21-driven fatty acid clearance[J]. J Nutr Biochem, 2018, 57: 189-196. doi: 10.1016/j.jnutbio.2018.03.027
[9] LI X, GE H, WEISZMANN J, et al. Inhibition of lipolysis may contribute to the acute regulation of plasma FFA and glucose by FGF21 in ob/ob mice[J]. FEBS Lett, 2009, 583(19): 3230-3234. doi: 10.1016/j.febslet.2009.09.012
[10] ZHANG F, YU L, LIN X, et al. Minireview: Roles of Fibroblast Growth Factors 19 and 21 in Metabolic Regulation and Chronic Diseases[J]. Mol Endocrinol, 2015, 29(10): 1400-1413. doi: 10.1210/me.2015-1155
[11] HUANG Z, XU A, CHEUNG B M Y. The Potential Role of Fibroblast Growth Factor 21 in Lipid Metabolism and Hypertension[J]. CURR HYPERTENS REP, 2017, 19(4): 28. doi: 10.1007/s11906-017-0730-5
[12] CUEVAS-RAMOS D, MEHTA R, AGUILAR-SALINAS C A. Fibroblast Growth Factor 21 and Browning of White Adipose Tissue[J]. FRONT PHYSIOL, 2019, 10: 37. doi: 10.3389/fphys.2019.00037
[13] GENG L, LAM K S L, XU A. the therapeutic Potentlal of FGF21 in metabolic diseases: from bench to clinic[J]. Nat Rev Endocrinol, 2020, 16(11): 654-667. doi: 10.1038/s41574-020-0386-0
[14] SARAN R, ROBINSON B, ABBOTT K C, et al. US Renal Data System 2019 Annual Data Report: Epidemiology of Kidney Disease in the United States[J]. Am J Kidney Dis, 2020, 75(1 Suppl 1): A6-A7. http://www.cghjournal.org/article/S0272-6386(15)00744-1/pdf
[15] AN S Y, LEE M S, YI S A, et al. Serum fibroblast growth factor 21 was elevated in subjects with type 2 diabetes mellitus and was associated with the presence of carotid artery plaques[J]. Diabetes Research and Clinical Practice, 2012, 96(2): 196-203. doi: 10.1016/j.diabres.2012.01.004
[16] HINDRICKS J, EBERT T, BACHMANN A, et al. Serum levels of fibroblast growth factor-21 are increased in chronic and acute renal dysfunction[J]. Clin Endocrinol: Oxf, 2014, 80(6): 918-924. doi: 10.1111/cen.12380
[17] JIAN W X, PENG W H, JIN J, et al. Association between serum fibroblast growth factor 21 and diabetic nephropathy[J]. Metabolism, 2012, 61(6): 853-859. doi: 10.1016/j.metabol.2011.10.012
[18] LEE C H, HUI E Y, WOO Y C, et al. Circulating fibroblast growth factor 21 levels predict progressive kidney disease in subjects with type 2 diabetes and normoalbuminuria[J]. J Clin Endocrinol Metab, 2015, 100(4): 1368-1375. doi: 10.1210/jc.2014-3465
[19] ZHANG C, SHAO M, YANG H, et al. Attenuation of hyperlipidemia- and diabetes-induced early-stage apoptosis and late-stage renal dysfunction via administration of fibroblast growth factor-21 is associated with suppression of renal inflammation[J]. PLoS One, 2013, 8(12): e82275. doi: 10.1371/journal.pone.0082275
[20] KIM H W, LEE J E, CHA J J, et al. Fibroblast growth factor 21 improves insulin resistance and ameliorates renal injury in db/db mice[J]. Endocrinology, 2013, 154(9): 3366-3376. doi: 10.1210/en.2012-2276
[21] LIN S, YU L, NI Y, et al. Fibroblast Growth Factor 21 Attenuates Diabetes-Induced Renal Fibrosis by Negatively Regulating TGF-β-p53-Smad2/3-Mediated Epithelial-to-Mesenchymal Transition via Activation of AKT[J]. Diabetes Metab J, 2020, 44(1): 158-172. doi: 10.4093/dmj.2018.0235
[22] LIN Y, XIAO Y C, ZHU H, et al. Serum fibroblast growth factor 21 levels are correlated with the severity of diabetic retinopathy[J]. J Diabetes Res, 2014, 2014: 929756. http://www.biomedsearch.com/attachments/00/24/89/56/24895642/JDR2014-929756.pdf
[23] ESTEGHAMATI A, MOMENI A, ABDOLLAHI A, et al. Serum fibroblast growth factor 21 concentrations in type 2 diabetic retinopathy patients[J]. Ann Endocrinol (Paris), 2016, 77(5): 586-592. doi: 10.1016/j.ando.2016.01.005
[24] ONG K L, JANUSZEWSKI A S, O'CONNELL R, et al. Relationship of fibroblast growth factor 21 with baseline and new on-study microvascular disease in the Fenofibrate Intervention and Event Lowering in Diabetes study[J]. Diabetologia, 2015, 58(9): 2035-2044. doi: 10.1007/s00125-015-3652-2
[25] JUNG C H, JUNG S H, KIM B Y, et al. The U-shaped relationship between fibroblast growth factor 21 and microvascular complication in type 2 diabetes mellitus[J]. J Diabetes Complications, 2017, 31(1): 134-140. doi: 10.1016/j.jdiacomp.2016.10.017
[26] STRUIK D, DOMMERHOLT M B, JONKER J W. Fibroblast growth factors in control of lipid metabolism: from biological function to clinical application[J]. Curr Opin Lipidol, 2019, 30(3): 235-243. doi: 10.1097/MOL.0000000000000599
[27] FU Z, LOFQVIST C A, SHAO Z, et al. Dietary ω-3 polyunsaturated fatty acids decrease retinal neovascularization by adipose-endoplasmic reticulum stress reduction to increase adiponectin[J]. Am J Clin Nutr, 2015, 101(4): 879-888. doi: 10.3945/ajcn.114.099291
[28] FU Z, WANG Z, LIU C H, et al. Fibroblast Growth Factor 21 Protects Photoreceptor Function in Type 1 Diabetic Mice[J]. Diabetes, 2018, 67(5): 974-985. doi: 10.2337/db17-0830
[29] CHOW W S, XU A, WOO Y C, et al. Serum fibroblast growth factor-21 levels are associated with carotid atherosclerosis independent of established cardiovascular risk factors[J]. Arterioscler Thromb Vasc Biol, 2013, 33(10): 2454-2459. doi: 10.1161/ATVBAHA.113.301599
[30] YAFEI S, ELSEWY F, YOUSSEF E, et al. Fibroblast growth factor 21 association with subclinical atherosclerosis and arterial stiffness in type 2 diabetes[J]. Diabetes Metab Syndr, 2019, 13(1): 882-888. doi: 10.1016/j.dsx.2018.12.007
[31] XIAO Y, LIU L, XU A, et al. Serum fibroblast growth factor 21 levels are related to subclinical atherosclerosis in patients with type 2 diabetes[J]. Cardiovasc Diabetol, 2015, 14: 72. doi: 10.1186/s12933-015-0229-9
[32] LIN Z, PAN X, WU F, et al. Fibroblast growth factor 21 prevents atherosclerosis by suppression of hepatic sterol regulatory element-binding protein-2 and induction of adiponectin in mice[J]. Circulation, 2015, 131(21): 1861-1871. doi: 10.1161/CIRCULATIONAHA.115.015308
[33] 叶青, 董朝晖. 血清成纤维细胞生长因子-21在2型糖尿病合并冠心病中的作用研究[J]. 全科医学临床与教育, 2012, 10(5): 496-499. doi: 10.3969/j.issn.1672-3686.2012.05.005 [34] 伍熙, 赵东晖, 范谦, 等. 成纤维细胞生长因子21对载脂蛋白E基因敲除小鼠动脉粥样硬化病变中内质网应激诱导的凋亡的影响[J]. 中国动脉硬化杂志, 2014, 22(4): 325-329. https://www.cnki.com.cn/Article/CJFDTOTAL-KDYZ201404001.htm [35] LENART-LIPIÑSKA M, MATYJASZEK-MATUSZEK B, GERNAND W, et al. Serum fibroblast growth factor 21 is predictive of combined cardiovascular morbidity and mortality in patients with type 2 diabetes at a relatively short-term follow-up[J]. Diabetes Res Clin Pract, 2013, 101(2): 194-200. doi: 10.1016/j.diabres.2013.04.010
[36] ONG K L, JANUSZEWSKI A S, O'CONNELL R, et al. The relationship of fibroblast growth factor 21 with cardiovascular outcome events in the Fenofibrate Intervention and Event Lowering in Diabetes study[J]. Diabetologia, 2015, 58(3): 464-473. doi: 10.1007/s00125-014-3458-7
[37] LEE C H, WOO Y C, CHOW W S, et al. Role of Circulating Fibroblast Growth Factor 21 Measurement in Primary Prevention of Coronary Heart Disease Among Chinese Patients With Type 2 Diabetes Mellitus[J]. J Am Heart Assoc, 2017, 6(6): 115-118.
[38] JIN L, LIN Z, XU A. Fibroblast Growth Factor 21 Protects against Atherosclerosis via Fine-Tuning the Multiorgan Crosstalk[J]. Diabetes Metab J, 2016, 40(1): 22-31. doi: 10.4093/dmj.2016.40.1.22
[39] SHI Y, WANG S, PENG H, et al. Fibroblast Growth Factor 21 Attenuates Vascular Calcification by Alleviating Endoplasmic Reticulum Stress Mediated Apoptosis in Rats[J]. Int J Biol Sci, 2019, 15(1): 138-147. doi: 10.7150/ijbs.28873
[40] ZHU W, WANG C, LIU L, et al. Effects of fibroblast growth factor 21 on cell damage in vitro and atherosclerosis in vivo[J]. Can J Physiol Pharmacol, 2014, 92(11): 927-935. doi: 10.1139/cjpp-2014-0227
[41] LIU S Q, ROBERTS D, KHARITONENKOV A, et al. Endocrine protection of ischemic myocardium by FGF21 from the liver and adipose tissue[J]. Scientific reports, 2013, 3: 2767. doi: 10.1038/srep02767
[42] 刘雪莲, 谢丽华, 王丽华. 糖尿病合并下肢大血管病变患者血浆FGF-21、SDF-1、Lp(a)水平变化及其临床意义[J]. 临床医学, 2020, 40(4): 63-65. https://www.cnki.com.cn/Article/CJFDTOTAL-EBED202004027.htm [43] GIMENO R E, MOLLER D E. FGF21-based pharmacotherapy--potential utility for metabolic disorders[J]. Trends Endocrinol Metab, 2014, 25(6): 303-311. doi: 10.1016/j.tem.2014.03.001
[44] GAICH G, CHIEN J Y, FU H, et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes[J]. Cell Metab, 2013, 18(3): 333-340. doi: 10.1016/j.cmet.2013.08.005
[45] BERGLUND E D, LI C Y, BINA H A, et al. Fibroblast growth factor 21 controls glycemia via regulation of hepatic glucose flux and insulin sensitivity[J]. Endocrinology, 2009, 150(9): 4084-4093. doi: 10.1210/en.2009-0221
[46] SHI G J, SHI G R, ZHOU J Y, et al. Involvement of growth factors in diabetes mellitus and its complications: A general review[J]. Biomed Pharmacother, 2018, 101: 510-527. doi: 10.1016/j.biopha.2018.02.105
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1. 黄欣瑶,韩红彦. 成纤维细胞生长因子21在冠心病中的研究进展. 疑难病杂志. 2023(11): 1219-1222+1227 . 百度学术 其他类型引用(1)
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