二甲双胍治疗糖尿病肾病的研究进展

doi:10.12114/j.issn.1007-9572.2023.0578

摘要/Abstract

摘要： 糖尿病肾病是糖尿病微血管病变常见的并发症之一，可降低糖尿病患者的生活质量，是造成终末期肾衰竭的主要病因。二甲双胍是治疗糖尿病的主要药物之一，在糖尿病肾病治疗中起至关重要的作用。近年来，研究发现二甲双胍不仅可以通过多种机制降低血糖，还可以阻止糖尿病肾病发展为终末期肾衰竭。多项研究发现二甲双胍对于治疗糖尿病肾病具有临床疗效，应根据肾小球滤过率评估患者药物安全性。本文综述了二甲双胍治疗糖尿病肾病的药理作用和作用机制的研究结果，旨在深入了解二甲双胍对糖尿病肾病的治疗作用，为糖尿病肾病的治疗方案提供参考。

关键词: 糖尿病肾病, 二甲双胍, 药物治疗, 安全性, 作用机制, 综述

Abstract:

Diabetic nephropathy is one of the most common complications of diabetic microangiopathy, which significantly reduces the quality of life of diabetic patients and is the main cause of end-stage renal failure. As one of the main drugs in the treatment of diabetes mellitus, metformin plays a vital role in the treatment of diabetic nephropathy. In recent years, studies have found that metformin can not only lower blood sugar through a variety of mechanisms, but also prevent diabetic kidney disease from developing into end-stage renal failure. Several studies have found that metformin has clinical efficacy in the treatment of diabetic nephropathy, and drug safety in patients should be evaluated by glomerular filtration rate. This review summarizes the results of the clinical effects and mechanism of metformin in the treatment of diabetic nephropathy, aiming to better understand the therapeutic effect of metformin on diabetic nephropathy, and provide reference for the treatment of diabetic nephropathy.

Key words: Diabetic nephropathies, Metformin, Pharmacotherapy, Security, Action mechanism, Review

邓煜璇,黄学君,江妍霞. 二甲双胍治疗糖尿病肾病的研究进展[J]. 中国全科医学, 2024, 27(03): 262-267. DOI: 10.12114/j.issn.1007-9572.2023.0578.
DENG Yuxuan,HUANG Xuejun,JIANG Yanxia. Recent Advances of Metformin in Treatment of Diabetic Nephropathy[J]. Chinese General Practice, 2024, 27(03): 262-267. DOI: 10.12114/j.issn.1007-9572.2023.0578.

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参考文献 56

[1]	WU Y L，DING Y P，TANAKA Y，et al. Risk factors contributing to type 2 diabetes and recent advances in the treatment and prevention[J]. Int J Med Sci，2014，11（11）：1185-1200. DOI：10.7150/ijms.10001.
[2]	TAN S Y，MEI WONG J L，SIM Y J，et al. Type 1 and 2 diabetes mellitus：a review on current treatment approach and gene therapy as potential intervention[J]. Diabetes Metab Syndr，2019，13（1）：364-372. DOI：10.1016/j.dsx.2018.10.008.
[3]	MASSIMINO E，IZZO A，RICCARDI G，et al. The impact of glucose-lowering drugs on sarcopenia in type 2 diabetes：current evidence and underlying mechanisms[J]. Cells，2021，10（8）：1958. DOI：10.3390/cells10081958.
[4]	AFSAR B，ELSURER R. Increased renal resistive index in type 2 diabetes：clinical relevance，mechanisms and future directions[J]. Diabetes Metab Syndr，2017，11（4）：291-296. DOI：10.1016/j.dsx.2016.08.019.
[5]	LV Z Q，GUO Y J. Metformin and its benefits for various diseases[J]. Front Endocrinol，2020，11：191. DOI：10.3389/fendo.2020.00191.
[6]	SONG A N，ZHANG C，MENG X F. Mechanism and application of metformin in kidney diseases：an update[J]. Biomed Pharmacother，2021，138：111454. DOI：10.1016/j.biopha.2021.111454.
[7]	LAMOIA T E，SHULMAN G I. Cellular and molecular mechanisms of metformin action[J]. Endocr Rev，2021，42（1）：77-96. DOI：10.1210/endrev/bnaa023.
[8]	EIBL G，ROZENGURT E. Metformin：review of epidemiology and mechanisms of action in pancreatic cancer[J]. Cancer Metastasis Rev，2021，40（3）：865-878. DOI：10.1007/s10555-021-09977-z.
[9]	HAN Y C，TANG S Q，LIU Y T，et al. AMPK agonist alleviate renal tubulointerstitial fibrosis via activating mitophagy in high fat and streptozotocin induced diabetic mice[J]. Cell Death Dis，2021，12（10）：925. DOI：10.1038/s41419-021-04184-8.
[10]	AGIUS L，FORD B E，CHACHRA S S. The metformin mechanism on gluconeogenesis and AMPK activation：the metabolite perspective[J]. Int J Mol Sci，2020，21（9）：3240. DOI：10.3390/ijms21093240.
[11]	MA T，TIAN X，ZHANG B D，et al. Low-dose metformin targets the lysosomal AMPK pathway through PEN2[J]. Nature，2022，603（7899）：159-165. DOI：10.1038/s41586-022-04431-8.
[12]	FORETZ M，GUIGAS B，VIOLLET B. Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus[J]. Nat Rev Endocrinol，2019，15（10）：569-589. DOI：10.1038/s41574-019-0242-2.
[13]	HUA Y，ZHENG Y，YAO Y R，et al. Metformin and cancer hallmarks：shedding new lights on therapeutic repurposing[J]. J Transl Med，2023，21（1）：403. DOI：10.1186/s12967-023-04263-8.
[14]	XIAO N，WANG J，WANG T，et al. Metformin abrogates pathological TNF-α-producing B cells through mTOR-dependent metabolic reprogramming in polycystic ovary syndrome[J]. Elife，2022，11：e74713. DOI：10.7554/eLife.74713.
[15]	MOHAMMAD H M F，GALAL GOUDA S，ELADL M A，et al. Metformin suppresses LRG1 and TGFβ1/ALK1-induced angiogenesis and protects against ultrastructural changes in rat diabetic nephropathy[J]. Biomed Pharmacother，2023，158：114128. DOI：10.1016/j.biopha.2022.114128.
[16]	PUGLIESE G，PENNO G，NATALI A，et al. Diabetic kidney disease：new clinical and therapeutic issues. Joint position statement of the Italian Diabetes Society and the Italian Society of Nephrology on the natural history of diabetic kidney disease and treatment of hyperglycemia in patients with type 2 diabetes and impaired renal function[J]. J Nephrol，2020，33（1）：9-35. DOI：10.1007/s40620-019-00650-x.
[17]	FADDEN E J，LONGLEY C，MAHAMBREY T. Metformin-associated lactic acidosis[J]. BMJ Case Rep，2021，14（7）：e239154. DOI：10.1136/bcr-2020-239154.
[18]	MARIANO F，BIANCONE L. Metformin，chronic nephropathy and lactic acidosis：a multi-faceted issue for the nephrologist[J]. J Nephrol，2021，34（4）：1127-1135. DOI：10.1007/s40620-020-00941-8.
[19]	MAURO S D，FILIPPELLO A，SCAMPORRINO A，et al. Metformin：when should we fear lactic acidosis?[J]. Int J Mol Sci，2022，23（15）：8320. DOI：10.3390/ijms23158320.
[20]	RAJASURYA V，ANJUM H，SURANI S. Metformin use and metformin-associated lactic acidosis in intensive care unit patients with diabetes[J]. Cureus，2019，11（5）：e4739. DOI：10.7759/cureus.4739.
[21]	THAMMAVARANUCUPT K，PHONYANGNOK B，PARAPIBOON W，et al. Metformin-associated lactic acidosis and factors associated with 30-day mortality[J]. PLoS One，2022，17（8）：e0273678. DOI：10.1371/journal.pone.0273678.
[22]	ALVAREZ C A，HALM E A，PUGH M J V，et al. Lactic acidosis incidence with metformin in patients with type 2 diabetes and chronic kidney disease：a retrospective nested case-control study[J]. Endocrinol Diabetes Metab，2021，4（1）：e00170. DOI：10.1002/edm2.170.
[23]	TRINKLEY K E，ANDERSON H D，NAIR K V，et al. Assessing the incidence of acidosis in patients receiving metformin with and without risk factors for lactic acidosis[J]. Ther Adv Chronic Dis，2018，9（9）：179-190. DOI：10.1177/2040622318779760.
[24]	OSHIMA M，SHIMIZU M，YAMANOUCHI M，et al. Trajectories of kidney function in diabetes：a clinicopathological update[J]. Nat Rev Nephrol，2021，17（11）：740-750. DOI：10.1038/s41581-021-00462-y.
[25]	LIU P，ZHANG Z D，LI Y. Relevance of the pyroptosis-related inflammasome pathway in the pathogenesis of diabetic kidney disease[J]. Front Immunol，2021，12：603416. DOI：10.3389/fimmu.2021.603416.
[26]	SAMSU N. Diabetic nephropathy：challenges in pathogenesis，diagnosis，and treatment[J]. Biomed Res Int，2021，2021：1497449. DOI：10.1155/2021/1497449.
[27]	GUO J，ZHENG H J，ZHANG W T，et al. Accelerated kidney aging in diabetes mellitus[J]. Oxid Med Cell Longev，2020，2020：1-24. DOI：10.1155/2020/1234059.
[28]	PEREIRA P R，CARRAGETA D F，OLIVEIRA P F，et al. Metabolomics as a tool for the early diagnosis and prognosis of diabetic kidney disease[J]. Med Res Rev，2022，42（4）：1518-1544. DOI：10.1002/med.21883.
[29]	JIN J，SHI Y F，GONG J G，et al. Exosome secreted from adipose-derived stem cells attenuates diabetic nephropathy by promoting autophagy flux and inhibiting apoptosis in podocyte[J]. Stem Cell Res Ther，2019，10（1）：95. DOI：10.1186/s13287-019-1177-1.
[30]	SELBY N M，TAAL M W. An updated overview of diabetic nephropathy：diagnosis，prognosis，treatment goals and latest guidelines[J]. Diabetes Obes Metab，2020，22（Suppl 1）：3-15. DOI：10.1111/dom.14007.
[31]	XUE J，WANG L，SUN Z X，et al. Basic research in diabetic nephropathy health care：a study of the renoprotective mechanism of metformin[J]. J Med Syst，2019，43（8）：1-13. DOI：10.1007/s10916-019-1412-4.
[32]	TYPIAK M，KULESZA T，RACHUBIK P，et al. Role of klotho in hyperglycemia：its levels and effects on fibroblast growth factor receptors，glycolysis，and glomerular filtration[J]. Int J Mol Sci，2021，22（15）：7867. DOI：10.3390/ijms22157867.
[33]	CHEN X W，TAN H S，XU J，et al. Klotho-derived peptide 6 ameliorates diabetic kidney disease by targeting Wnt/β-catenin signaling[J]. Kidney Int，2022，102（3）：506-520. DOI：10.1016/j.kint.2022.04.028.
[34]	WANG Q，REN D J，LI Y B，et al. Klotho attenuates diabetic nephropathy in db/db mice and ameliorates high glucose-induced injury of human renal glomerular endothelial cells[J]. Cell Cycle，2019，18（6/7）：696-707. DOI：10.1080/15384101.2019.1580495.
[35]	TYPIAK M，KULESZA T，RACHUBIK P，et al. Role of klotho in hyperglycemia：its levels and effects on fibroblast growth factor receptors，glycolysis，and glomerular filtration[J]. Int J Mol Sci，2021，22（15）：7867. DOI：10.3390/ijms22157867.
[36]	XUE J，WANG L，SUN Z X，et al. Basic research in diabetic nephropathy health care：a study of the renoprotective mechanism of metformin[J]. J Med Syst，2019，43（8）：266. DOI：10.1007/s10916-019-1412-4.
[37]	AL-KURAISHY H M，AL-GAREEB A I，SAAD H M，et al. The potential effect of metformin on fibroblast growth factor 21 in type 2 diabetes mellitus（T2DM）[J]. Inflammopharmacology，2023，31（4）：1751-1760. DOI：10.1007/s10787-023-01255-4.
[38]	GU L Y，TANG H T，XU Z X. Huangkui capsule in combination with metformin ameliorates diabetic nephropathy via the Klotho/TGF-β1/p38MAPK signaling pathway[J]. J Ethnopharmacol，2021，281：113548. DOI：10.1016/j.jep.2020.113548.
[39]	RENA G，HARDIE D G，PEARSON E R. The mechanisms of action of metformin[J]. Diabetologia，2017，60（9）：1577-1585. DOI：10.1007/s00125-017-4342-z.
[40]	REN H W，SHAO Y，WU C，et al. Metformin alleviates oxidative stress and enhances autophagy in diabetic kidney disease via AMPK/SIRT1-FoxO1 pathway[J]. Mol Cell Endocrinol，2020，500：110628. DOI：10.1016/j.mce.2019.110628.
[41]	WANG W N，SUN W X，CHENG Y L，et al. Role of sirtuin-1 in diabetic nephropathy[J]. J Mol Med，2019，97（3）：291-309. DOI：10.1007/s00109-019-01743-7.
[42]	XU J，LIU L Q，XU L L，et al. Metformin alleviates renal injury in diabetic rats by inducing Sirt1/FoxO1 autophagic signal axis[J]. Clin Exp Pharmacol Physiol，2020，47（4）：599-608. DOI：10.1111/1440-1681.13226.
[43]	GAO Y Y，TIAN W，ZHANG H N，et al. Canonical transient receptor potential channels and their modulators：biology，pharmacology and therapeutic potentials[J]. Arch Pharm Res，2021，44（4）：354-377. DOI：10.1007/s12272-021-01319-5.
[44]	SZREJDER M，RACHUBIK P，ROGACKA D，et al. Metformin reduces TRPC6 expression through AMPK activation and modulates cytoskeleton dynamics in podocytes under diabetic conditions[J]. Biochim Biophys Acta Mol Basis Dis，2020，1866（3）：165610. DOI：10.1016/j.bbadis.2019.165610.
[45]	YANG H M，XIE T T，LI D R，et al. Tim-3 aggravates podocyte injury in diabetic nephropathy by promoting macrophage activation via the NF-κB/TNF-α pathway[J]. Mol Metab，2019，23：24-36. DOI：10.1016/j.molmet.2019.02.007.
[46]	OPAZO-RÍOS L，PLAZA A，SÁNCHEZ MATUS Y，et al. Targeting NF-κB by the cell-permeable NEMO-binding domain peptide improves albuminuria and renal lesions in an experimental model of type 2 diabetic nephropathy[J]. Int J Mol Sci，2020，21（12）：4225. DOI：10.3390/ijms21124225.
[47]	ZHANG L，NIU J S，ZHANG X M，et al. Metformin can alleviate the symptom of patient with diabetic nephropathy through reducing the serum level of hcy and IL-33[J]. Open Med，2019，14：625-628. DOI：10.1515/med-2019-0071.
[48]	KANG Z F，ZENG J W，ZHANG T，et al. Hyperglycemia induces NF-κB activation and MCP-1 expression via downregulating GLP-1R expression in rat mesangial cells：inhibition by metformin[J]. Cell Biol Int，2019，43（8）：940-953. DOI：10.1002/cbin.11184.
[49]	PATIAL V，KATOCH S，CHHIMWAL J，et al. Tinospora cordifolia activates PPARγ pathway and mitigates glomerular and tubular cell injury in diabetic kidney disease[J]. Phytomedicine，2021，91：153663. DOI：10.1016/j.phymed.2021.153663.
[50]	ABDELKADER N F，IBRAHIM S M，MOUSTAFA P E，et al. Inosine mitigated diabetic peripheral neuropathy via modulating GLO1/AGEs/RAGE/NF-κB/Nrf2 and TGF-β/PKC/TRPV1 signaling pathways[J]. Biomed Pharmacother，2022，145：112395. DOI：10.1016/j.biopha.2021.112395.
[51]	TANG D，HE W J，ZHANG Z T，et al. Protective effects of Huang-Lian-Jie-Du Decoction on diabetic nephropathy through regulating AGEs/RAGE/Akt/Nrf2 pathway and metabolic profiling in db/db mice[J]. Phytomedicine，2022，95：153777. DOI：10.1016/j.phymed.2021.153777.
[52]	ISHIBASHI Y，MATSUI T，TAKEUCHI M，et al. Beneficial effects of metformin and irbesartan on advanced glycation end products（AGEs）-RAGE-induced proximal tubular cell injury[J]. Pharmacol Res，2012，65（3）：297-302. DOI：10.1016/j.phrs.2011.11.001.
[53]	庞若宇，关美萍，郑宗基，等. 二甲双胍对糖基化终末产物诱导的成纤维细胞凋亡及相关蛋白caspase-3、Bax及Bcl-2表达的影响[J].南方医科大学学报，2015，5（6）：898-902. DOI：10.3969/j.issn.1673-4254.2015.06.024.
[54]	ZHU L L，WANG H Y，TANG T. Effects of miR-195 on diabetic nephropathy rats through targeting TLR4 and blocking NF-κB pathway[J]. Eur Rev Med Pharmacol Sci，2021，25（3）：1522-1529. DOI：10.26355/eurrev_202102_24860.
[55]	XU J，XIANG P，LIU L Q，et al. Metformin inhibits extracellular matrix accumulation，inflammation and proliferation of mesangial cells in diabetic nephropathy by regulating H19/miR-143-3p/TGF-β1 axis[J]. J Pharm Pharmacol，2020，72（8）：1101-1109. DOI：10.1111/jphp.13280.
[56]	LIU S，WU W，LIAO J，et al. MicroRNA-21：a critical pathogenic factor of diabetic nephropathy[J]. Front Endocrinol（Lausanne），2022，13：895010. DOI：10.3389/fendo.2022.895010.