The development and benefits of metformin in various diseases

doi:10.1007/s11684-023-0998-6

Front. Med.

2023, Vol. 17

Issue (3) : 388-431 https://doi.org/10.1007/s11684-023-0998-6

REVIEW

The development and benefits of metformin in various diseases

Ying Dong¹, Yingbei Qi^1,⁵, Haowen Jiang¹, Tian Mi¹, Yunkai Zhang^1,², Chang Peng^1,², Wanchen Li^1,², Yongmei Zhang^1,⁵, Yubo Zhou^1,⁷(

), Yi Zang^1,^3,⁵(

), Jia Li^1,^2,^4,^5,⁶(

)

¹. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
². University of Chinese Academy of Sciences, Beijing 100049, China
³. Lingang Laboratory, Shanghai 201203, China
⁴. Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266237, China
⁵. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
⁶. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China
⁷. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China

Download: PDF(2917 KB) HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks

Abstract

Metformin has been used for the treatment of type II diabetes mellitus for decades due to its safety, low cost, and outstanding hypoglycemic effect clinically. The mechanisms underlying these benefits are complex and still not fully understood. Inhibition of mitochondrial respiratory-chain complex I is the most described downstream mechanism of metformin, leading to reduced ATP production and activation of AMP-activated protein kinase (AMPK). Meanwhile, many novel targets of metformin have been gradually discovered. In recent years, multiple pre-clinical and clinical studies are committed to extend the indications of metformin in addition to diabetes. Herein, we summarized the benefits of metformin in four types of diseases, including metabolic associated diseases, cancer, aging and age-related diseases, neurological disorders. We comprehensively discussed the pharmacokinetic properties and the mechanisms of action, treatment strategies, the clinical application, the potential risk of metformin in various diseases. This review provides a brief summary of the benefits and concerns of metformin, aiming to interest scientists to consider and explore the common and specific mechanisms and guiding for the further research. Although there have been countless studies of metformin, longitudinal research in each field is still much warranted.

Keywords metformin metabolism cancer aging neurological disorder

Corresponding Author(s): Yubo Zhou,Yi Zang,Jia Li

Just Accepted Date: 06 May 2023 Online First Date: 30 June 2023 Issue Date: 28 July 2023

Cite this article:

Ying Dong,Yingbei Qi,Haowen Jiang, et al. The development and benefits of metformin in various diseases[J]. Front. Med., 2023, 17(3): 388-431.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-023-0998-6
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I3/388

Tab.1 The history of metformin

Fig.1 The effects of metformin on metabolic regulation. Metformin exerts various regulatory effects in systemic metabolism beyond the hypoglycemic effect. Metformin improves the metabolism in the key metabolic organs including the liver, muscle, and adipose tissue. In the pancreas, metformin reduces adverse factors such as oxidative and endoplasmic stress, inflammation, and β cell apoptosis to increase the release of insulin to lower blood glucose. Moreover, even not the direct metabolic organ, the anorexia effect of brain and the changed constitution of the microbe, and the number of beneficial metabolites in the intestine also coordinate body metabolism.

Fig.2 Potential molecular mechanisms of metformin in cancer. The anti-tumor effect of metformin is probably a combination of indirect and direct effects. In indirect action, metformin lowers systemic glucose and insulin levels, and may reduce cancer risk through anti-inflammatory effects and promoting immune response to tumor cells. In the other direct context, AMPK-dependent and AMPK-independent mechanisms have been described, which are likely to coexist and interact together to suppress tumor development.

Title (NCT No.)	Phases	Tumor type	Drug	Status
The Effect of Metformin on Breast Cancer Patients (NCT04559308)	Phase 2	Breast cancer	Metformin, doxorubicin, cyclophosphamide, paclitaxel	Unknown
Evaluation of the Effect of Metformin on Metastatic Breast Cancer as Adjuvant Treatment (NCT04143282)	Phase 2	Breast cancer	Metformin, chemotherapy	Completed
Advanced Lung Cancer Treatment With Metformin and Chemo-Radiotherapy (NCT02115464)	Phase 2	Lung cancer	Metformin, cisplatin	Terminated
Role of Adding Metformin to Neoadjuvant Chemotherapy in Patients With Breast Cancer (NCT04170465)	Phase 2	Breast cancer	Metformin, doxorubicin, cyclophosphamide, paclitaxel	Unknown
Metformin-Docetaxel Association in Metastatic Hormone-refractory Prostate Cancer (NCT01796028)	Phase 2	Prostate cancer	Metformin, docetaxel	Completed
Study of Metformin With Carboplatin/Paclitaxel Chemotherapy in Patients With Advanced Ovarian Cancer (NCT02312661)	Phase 1	Epithelial ovarian cancer	Metformin, carboplatin, paclitaxel	Completed
Metformin Combined With Chemotherapy for Pancreatic Cancer (NCT01210911)	Phase 2	Pancreatic cancer	Metformin, gemcitabine, erlotinib	Completed
Safety and Efficacy of Metronomic Cyclophosphamide, Metformin and Olaparib in Endometrial Cancer Patients (NCT02755844)	Phases 1 and 2	Endometrial cancer	Metformin, olaparib, cyclophosphamide	Completed
Combination Chemotherapy With or Without Metformin Hydrochloride in Treating Patients With Metastatic Pancreatic Cancer (NCT01167738)	Phase 2	Pancreatic cancer	Metformin, capecitabine, csplatin, epirubicin, gemcitabine	Terminated
Neoadjuvant FDC With Melatonin or Metformin for Locally Advanced Breast Cancer (NCT02506777)	Phase 2	Breast cancer	Metformin, fluoruracil, doxorubicin, cyclophosphamide, melatonin	Unknown
Metformin Plus Irinotecan for Refractory Colorectal Cancer (NCT01930864)	Phase 2	Colorectal cancer	Metformin, irinotecan	Unknown
Metformin in Children With Relapsed or Refractory Solid Tumors (NCT01528046)	Phase 1	Solid tumors	Metformin, vincristine, irinotecan, temozolomide	Active, not recruiting
Metformin Plus Paclitaxel for Metastatic or Recurrent Head and Neck Cancer (NCT01333852)	Phase 2	Head and neck neoplasms	Metformin, paclitaxel	Terminated
Metformin Plus Modified FOLFOX 6 in Metastatic Pancreatic Cancer (NCT01666730)	Phase 2	Metastatic pancreatic cancer	Metformin, oxaliplatin, leucovorin, fuorouracil	Completed
Metformin Combined With Gemcitabine as Adjuvant Therapy for Pancreatic Cancer After Curative Resection (NCT02005419)	Phase 2	Pancreatic cancer	Metformin, gemcitabine	Completed
Paclitaxel and Carboplatin With or Without Metformin Hydrochloride in Treating Patients With Stage III, IV, or Recurrent Endometrial Cancer (NCT02065687)	Phases 2 and 3	Endometrial cancer	Metformin, carboplatin, paclitaxel	Active, not recruiting
Myocet + Cyclophosphamide + Metformin Vs Myocet + Cyclophosphamide in 1st Line Treatment of HER2 Neg. Metastatic Breast Cancer Patients (NCT01885013)	Phase 2	Breast cancer	Metformin, myocet, cyclophosphamide	Completed
Dose-finding Study of Metformin With Chemoradiation in Locally Advanced Head and Neck Squamous Cell Carcinoma (NCT02325401)	Phase 1	Head and neck squamous cell carcinoma	Metformin, cisplatin	Completed
NeoMET Study in Neoadjuvant Treatment of Breast Cancer (NCT01929811)	Phase 2	Breast cancer	Metformin, docetaxel, epirubicin, cyclophosphomide	Terminated
Chemotherapy and Radiation Therapy With or Without Metformin Hydrochloride in Treating Patients With Stage III Non-small Cell Lung Cancer (NCT02186847)	Phase 2	Non small cell lung cancer	Metformin, carboplatin, paclitaxel	Active, not recruiting
Treatment of Patients With Advanced Pancreatic Cancer After Gemcitabine Failure (NCT01971034)	Phase 2	Pancreatic cancer	Metformin, paclitaxel	Completed
Study of Paclitaxel, Carboplatin and Oral Metformin in the Treatment of Advanced Stage Ovarian Carcinoma (NCT02437812)	Phase 2	Ovarian carcinoma	Metformin, paclitaxel, carboplatin	Unknown
Oxidative Phosphorylation Targeting In Malignant Glioma Using Metformin Plus Radiotherapy Temozolomide (NCT04945148)	Phase 2	Glioblastoma	Metformin, temozolomide	Not yet recruiting
Metformin in Combined With Cisplatin Plus Paclitaxel With Advanced Esophageal Squamous Cell Carcinoma (NCT03833466)	Phase 2	Esophageal squamous cell carcinoma	Metformin, paclitaxel, cisplatin	Unknown
Study on Low Dose Temozolomide Plus Metformin or Placebo in Patient With Recurrent or Refractory Glioblastoma (NCT03243851)	Phase 2	Glioblastoma	Metformin, temozolomide	Completed
Comparison of Melatonin or Metformin and Dacarbazine Combination Versus Dacarbazine Alone in Disseminated Melanoma (NCT02190838)	Phase 2	Melanoma	Metformin, dacarbazine, melatonin	Terminated
Vincristine, Dexamethasone, Doxorubicin, and PEG-asparaginase (VPLD) and Metformin for Relapsed Childhood Acute Lymphoblastic Leukemia (ALL) (NCT01324180)	Phase 1	Acute lymphoblastic leukemia	Metformin, Vincristine, dexamethasone, asparaginase, doxorubicin	Completed
Temozolomide, Memantine Hydrochloride, Mefloquine, and Metformin Hydrochloride in Treating Patients With Glioblastoma Multiforme After Radiation Therapy (NCT01430351)	Phase 1	Glioblastoma	Metformin, temozolomide	Active, not recruiting
Metformin + Cytarabine for the Treatment of Relapsed/Refractory AML (NCT01849276)	Phase 1	Acute myeloid leukemia	Metformin, cytarabine	Terminated

Tab.2 Clinical trials on metformin in combination with chemotherapeutic agents in cancer (data from ClinicalTrails.gov)

Title (NCT No.)	Phases	Tumor type	Drug	Status
Study of Erlotinib and Metformin in Triple Negative Breast Cancer (NCT01650506)	Phase 1	Breast cancer	Metformin, erlotinib	Completed
Randomized Trial of Neo-adjuvant Chemotherapy With or Without Metformin for HER2 Positive Operable Breast Cancer (NCT03238495)	Phase 2	Breast cancer	Metformin, taxotere, carboplatin, herceptin, pertuzumab	Recruiting
Temsirolimus in Combination With Metformin in Patients With Advanced Cancers (NCT01529593)	Phase 1	Advanced cancers	Metformin, temsirolimus	Active, not recruiting
Study of Safety and Efficacy of Dapagliflozin + Metformin XR Versus Metformin XR in Participants With HR + , HER2-, Advanced Breast Cancer While on Treatment With Alpelisib and Fulvestrant (NCT04899349)	Phase 2	Breast cancer	Metformin, alpelisib, fulvestrant	Recruiting
A Study of Liposomal Doxorubicin + Docetaxel + Trastuzumab + Metformin in Operable and Locally Advanced HER2 Positive Breast Cancer (NCT02488564)	Phase 2	Breast cancer	Metformin, doxorubicin, docetaxel, trastuzumab	Completed
Modulation of Response to Hormonal Therapy With Lapatinib and/or Metformin in Patients With Metastatic Breast Cancer (NCT01477060)	Phase 2	Breast cancer	Metformin, lapatinib	Terminated
Lapatinib With Sirolimus or Metformin (NCT01087983)	Phase 1	Advanced cancers	Metformin, lapatinib	Completed
Study to Evaluate the Effect of Metformin in the Prevention of HG in HR[+]/HER2[–] PIK3CA-mut Advanced BC Patients (NCT04300790)	Phase 2	Breast cancer	Metformin, alpelisib, fulvestrant, letrozole, exemestane	Active, not recruiting
A Pharmacokinetic Interaction Study Between Apatinib and Rosuvastatin or Metformin in Solid Tumor Subjects (NCT04428086)	Phase 1	Solid tumor	Metformin, apatinib	Completed
An Efficacy and Safety Study of Erdafitinib (JNJ-42756493) in Participants With Urothelial Cancer (NCT02365597)	Phase 2	Urothelial cancer	Metformin, erdafitinib	Recruiting
Combination of Metformin With Gefitinib to Treat NSCLC (NCT01864681)	Phase 2	Non small cell lung cancer	Metformin, gefitinib	Completed
Metformin And Chloroquine in IDH1/2-mutated Solid Tumors (NCT02496741)	Phases 1 and 2	IDH1/2-mutated solid tumor	Metformin, chloroquine	Completed
Metformin, Nelfinavir, and Bortezomib in Treating Patients With Relapsed and/or Refractory Multiple Myeloma (NCT03829020)	Phase 1	Multiple myeloma	Metformin, bortezomib, nelfinavir	Recruiting
A Phase I/II Trial of Vemurafenib and Metforminto Melanoma Patients (NCT01638676)	Phases 1 and 2	Melanoma	Metformin, vemurafenib	Recruiting
Study of Dabrafenib, Trametinib and Metformin for Melanoma Patients (NCT02143050)	Phases 1 and 2	Melanoma	Metformin, dabrafenib, trametinib	Recruiting
Study of Metformin Plus Paclitaxel/Carboplatin/Bevacizumab in Patients With Adenocarcinoma (NCT01578551)	Phase 2	Lung adenocarcinoma	Metformin, paclitaxel, carboplatin, bevacizumab	Terminated
Paxalisib With a High Fat, Low Carb Diet and Metformin for Glioblastoma (NCT05183204)	Phase 2	Glioblastoma	Metformin, paxalisib	Not yet recruiting
Metformin in Combination With Standard Induction Therapy for Large B cell Lymphoma (NCT02531308)	Phase 2	Diffuse large B cell lymphoma	Metformin, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone, pegfilgrastim	Terminated

Tab.3 Clinical trials on metformin in combination with molecular target drugs in cancer (data from ClinicalTrails.gov)

Tab.4 Clinical trials on metformin in combination with immunotherapy in cancer (data from ClinicalTrails.gov)

Fig.3 Modulation of TIME by metformin. Metformin treatment directly augments CD8⁺ T cell and NK cell antitumor function in the tumor microenvironment and indirectly restores cytotoxic effector cells function by modulating suppressive immune cells, ultimately sensitizing cancer immunotherapy.

Tab.5 Clinical trials studying effects of metformin on human aging (Data from ClinicalTrails.gov)

Fig.4 Primary molecular mechanisms of metformin in aging. The anti-aging effect of metformin is probably a combination of multiple mechanisms, including the improvement of the deregulated nutrient-sensing and genomic instability, the suppression of cell senescence and pro-inflammation responses and enhancing autophagy.

Fig.5 Overview of metformin’s effect on neurological disorders. (A) Metformin’s effect in neurons through activating AMPK and its pathways that lead to neuronal protection. (B) Metformin’s effect on neurological disorders; the arrows represent increase or (activated) and decrease or (inhibited), while the “–” sign represents uncertainty or contradictory research. Red is negative effect, green is positive effect, and blue is contradictory results.

1	B Viollet, B Guigas, N Sanz Garcia, J Leclerc, M Foretz, F Andreelli. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) 2012; 122(6): 253–270 https://doi.org/10.1042/CS20110386 pmid: 22117616
2	SR Salpeter, NS Buckley, JA Kahn, EE Salpeter. Meta-analysis: metformin treatment in persons at risk for diabetes mellitus. Am J Med 2008; 121(2): 149–157.e2 https://doi.org/10.1016/j.amjmed.2007.09.016 pmid: 18261504
3	M Foretz, B Guigas, L Bertrand, M Pollak, B Viollet. Metformin: from mechanisms of action to therapies. Cell Metab 2014; 20(6): 953–966 https://doi.org/10.1016/j.cmet.2014.09.018 pmid: 25456737
4	D Carling. AMPK signalling in health and disease. Curr Opin Cell Biol 2017; 45: 31–37 https://doi.org/10.1016/j.ceb.2017.01.005 pmid: 28232179
5	CJ Bailey. Metformin: historical overview. Diabetologia 2017; 60(9): 1566–1576 https://doi.org/10.1007/s00125-017-4318-z pmid: 28776081
6	CJ Bailey, C Day. Metformin: its botanical background. Pract Diabetes Int 2004; 21(3): 115–117 https://doi.org/10.1002/pdi.606
7	J Hill. The Vegetable System, or, The Internal Structure and The Life of Plants. London: the author, 1761–1775
8	CK Watanabe. Studies in the metabolic changes induced by administration of guanidine bases. J Biol Chem 1918; 34(1): 51–63 https://doi.org/10.1016/S0021-9258(18)86531-0
9	JL Ríos, F Francini, GR Schinella. Natural products for the treatment of type 2 diabetes mellitus. Planta Med 2015; 81(12–13): 975–994 https://doi.org/10.1055/s-0035-1546131 pmid: 26132858
10	CT Pineda, S Ramanathan, K Fon Tacer, JL Weon, MB Potts, YH Ou, MA White, PR Potts. Degradation of AMPK by a cancer-specific ubiquitin ligase. Cell 2015; 160(4): 715–728 https://doi.org/10.1016/j.cell.2015.01.034 pmid: 25679763
11	GS Wang, C Hoyte. Review of biguanide (metformin) toxicity. J Intensive Care Med 2019; 34(11–12): 863–876 https://doi.org/10.1177/0885066618793385 pmid: 30126348
12	IM Rabinowitch. Observations on the use of synthalin in the treatment of diabetes mellitus. Can Med Assoc J 1927; 17(8): 901–904 pmid: 20316450
13	KH Slotta. Tschesche RJEJoIC. Über Biguanide, II: Die blutzucker-senkende Wirkung der Biguanide. 1929; 62: 1398–1405
14	E Hesse. Taubmann GJN-SAfePuP. Die Wirkung des Biguanids und seiner Derivate auf den Zuckerstoffwechsel. 1929; 142: 290–308
15	CJ Bailey, RC Turner. Metformin. N Engl J Med 1996; 334(9): 574–579 https://doi.org/10.1056/NEJM199602293340906 pmid: 8569826
16	EA Werner, J Bell. CCXIV—The preparation of methylguanidine, and of ββ-dimethylguanidine by the interaction of dicyanodiamide, and methylammonium and dimethylammonium chlorides respectively. J Chem Soc Trans 1922; 121(0): 1790–1794 https://doi.org/10.1039/CT9222101790
17	L Sylow, M Kleinert, EA Richter, TE Jensen. Exercise-stimulated glucose uptake—regulation and implications for glycaemic control. Nat Rev Endocrinol 2017; 13(3): 133–148 https://doi.org/10.1038/nrendo.2016.162 pmid: 27739515
18	SL SamsonAJ Garber. Metformin and other biguanides: pharmacology and therapeutic usage. International Textbook of Diabetes Mellitus. 2015. 641–656
19	CL Meinert. Clinical Trials: Design, Conduct and Analysis. Oxford University Press, 1986
20	G Schäfer. Biguanides. A review of history, pharmacodynamics and therapy. Diabete Metab 1983; 9(2): 148–163 pmid: 6352352
21	TE LaMoia, GI Shulman. Cellular and molecular mechanisms of metformin action. Endocr Rev 2021; 42(1): 77–96 https://doi.org/10.1210/endrev/bnaa023 pmid: 32897388
22	EY GARCIA. Flumamine, a new synthetic analgesic and anti-flu drug. J Philipp Med Assoc 1950; 26(7): 287–293 pmid: 14779282
23	FHS Curd, DG Davey, FL Rose. Studies on synthetic antimalarial drugs; some biguanide derivatives as new types of antimalarial substances with both therapeutic and causal prophylactic activity. Ann Trop Med Parasitol 1945; 39(3–4): 208–216 https://doi.org/10.1080/00034983.1945.11685237 pmid: 21013252
24	JJMM Sterne. Du nouveau dans les antidiabetiques. La NN dimethylamine guanyl guanide (NNDG). 1957; 36: 1295–1296
25	J Sterne. Blood sugar-lowering effect of 1,1-dimethylbiguanide. Therapie 1958; 13(4): 650–659 (in French) pmid: 13603402
26	A Beringer. Treatment of diabetes mellitus with biguanides. Wien Med Wochenschr 1958; 108(43): 880–882 pmid: 13604270
27	A Woods, D Vertommen, D Neumann, R Turk, J Bayliss, U Schlattner, T Wallimann, D Carling, MH Rider. Identification of phosphorylation sites in AMP-activated protein kinase (AMPK) for upstream AMPK kinases and study of their roles by site-directed mutagenesis. J Biol Chem 2003; 278(31): 28434–28442 https://doi.org/10.1074/jbc.M303946200 pmid: 12764152
28	KENDRY JB Mc, K Kuwayti, PP Rado. Clinical experience with DBI (phenformin) in the management of diabetes. Can Med Assoc J 1959; 80(10): 773–778 pmid: 13652024
29	G Ungar, L Freedman, SL Shapiro. Pharmacological studies of a new oral hypoglycemic drug. Proc Soc Exp Biol Med 1957; 95(1): 190–192 https://doi.org/10.3181/00379727-95-23163 pmid: 13432032
30	P King, I Peacock, R Donnelly. The UK prospective diabetes study (UKPDS): clinical and therapeutic implications for type 2 diabetes. Br J Clin Pharmacol 1999; 48(5): 643–648 https://doi.org/10.1046/j.1365-2125.1999.00092.x pmid: 10594464
31	RC Turner. The U. K. prospective diabetes study. A review. Diabetes Care 1998; 21(Suppl 3): C35–C38 https://doi.org/10.2337/diacare.21.3.C35 pmid: 9850487
32	RR Holman, SK Paul, MA Bethel, DR Matthews, HA Neil. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359(15): 1577–1589 https://doi.org/10.1056/NEJMoa0806470 pmid: 18784090
33	SS Lund, P Rossing, AA Vaag. Follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2009; 360(4): 416–418 https://doi.org/10.1056/NEJMc082275 pmid: 19164195
34	P Kumar, K Khan. Effects of metformin use in pregnant patients with polycystic ovary syndrome. J Hum Reprod Sci 2012; 5(2): 166–169 https://doi.org/10.4103/0974-1208.101012 pmid: 23162354
35	GS Ghazeeri, AH Nassar, Z Younes, JT Awwad. Pregnancy outcomes and the effect of metformin treatment in women with polycystic ovary syndrome: an overview. Acta Obstet Gynecol Scand 2012; 91(6): 658–678 https://doi.org/10.1111/j.1600-0412.2012.01385.x pmid: 22375613
36	W Nicholson, S Bolen, CT Witkop, D Neale, L Wilson, E Bass. Benefits and risks of oral diabetes agents compared with insulin in women with gestational diabetes: a systematic review. Obstet Gynecol 2009; 113(1): 193–205 https://doi.org/10.1097/AOG.0b013e318190a459 pmid: 19104375
37	YJ Choi. Efficacy of adjunctive treatments added to olanzapine or clozapine for weight control in patients with schizophrenia: a systematic review and meta-analysis. ScientificWorldJournal 2015; 2015: 970730 https://doi.org/10.1155/2015/970730 pmid: 25664341
38	JM Campbell, MD Stephenson, B de Courten, I Chapman, SM Bellman, E Aromataris. Metformin use associated with reduced risk of dementia in patients with diabetes: a systematic review and meta-analysis. J Alzheimers Dis 2018; 65(4): 1225–1236 https://doi.org/10.3233/JAD-180263 pmid: 30149446
39	Y Yang. Metformin for cancer prevention. Front Med 2011; 5(2): 115–117 https://doi.org/10.1007/s11684-011-0112-3 pmid: 21695613
40	CJ Bailey, C Day. Traditional plant medicines as treatments for diabetes. Diabetes Care 1989; 12(8): 553–564 https://doi.org/10.2337/diacare.12.8.553 pmid: 2673695
41	T Kato, T Kondo, K Mizuno. Occurrence of guanidino compounds in several plants. Soil Sci Plant Nutr 1986; 32(3): 487–491 https://doi.org/10.1080/00380768.1986.10557530
42	B Rathke. Ueber biguanid. Ber Dtsch Chem Ges 1879; 12(1): 776–784 https://doi.org/10.1002/cber.187901201219
43	Metformin (Glucophage(R)). Mother To Baby \| Fact Sheets. Brentwood: Organization of Teratology Information Specialists (OTIS). Copyright by OTIS. January 2022
44	RA DeFronzo, AM Goodman. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med 1995; 333(9): 541–549 https://doi.org/10.1056/NEJM199508313330902 pmid: 7623902
45	WC Knowler, E Barrett-Connor, SE Fowler, RF Hamman, JM Lachin, EA Walker, DM; Diabetes Prevention Program Research Group Nathan. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346(6): 393–403 https://doi.org/10.1056/NEJMoa012512 pmid: 11832527
46	The Selection and Use of Essential Medicines. World Health Organ Tech Rep Ser 2015; vii-xv: 1–546
47	GG Graham, J Punt, M Arora, RO Day, MP Doogue, JK Duong, TJ Furlong, JR Greenfield, LC Greenup, CM Kirkpatrick, JE Ray, P Timmins, KM Williams. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 2011; 50(2): 81–98 https://doi.org/10.2165/11534750-000000000-00000 pmid: 21241070
48	PJ Pentikäinen, PJ Neuvonen, A Penttilä. Pharmacokinetics of metformin after intravenous and oral administration to man. Eur J Clin Pharmacol 1979; 16(3): 195–202 https://doi.org/10.1007/BF00562061 pmid: 499320
49	N Idkaidek, T Arafat. Metformin IR versus XR pharmacokinetics in humans. J Bioequiv Availab 2011; 3: 233–235 https://doi.org/10.4172/jbb.1000092
50	Y Harahap, S Purnasari, H Hayun, K Dianpratami, M Wulandari. Bioequivalence Study of Metformin HCl XR Caplet Formulations in Healthy Indonesian Volunteers. J Bioequiv Availab 2011; 3: 16–19
51	MG Oefelein, W Tong, S Kerr, K Bhasi, RK Patel, D Yu. Effect of concomitant administration of trospium chloride extended release on the steady-state pharmacokinetics of metformin in healthy adults. Clin Drug Investig 2013; 33(2): 123–131 https://doi.org/10.1007/s40261-012-0049-6 pmid: 23325481
52	P Timmins, S Donahue, J Meeker, P Marathe. Steady-state pharmacokinetics of a novel extended-release metformin formulation. Clin Pharmacokinet 2005; 44(7): 721–729 https://doi.org/10.2165/00003088-200544070-00004 pmid: 15966755
53	SJ Rhee, S Lee, SH Yoon, JY Cho, IJ Jang, KS Yu. Pharmacokinetics of the evogliptin/metformin extended-release (5/1,000 mg) fixed-dose combination formulation compared to the corresponding loose combination, and food effect in healthy subjects. Drug Des Devel Ther 2016; 10: 1411–1418 pmid: 27110098
54	M Zhou, L Xia, J Wang. Metformin transport by a newly cloned proton-stimulated organic cation transporter (plasma membrane monoamine transporter) expressed in human intestine. Drug Metab Dispos 2007; 35(10): 1956–1962 https://doi.org/10.1124/dmd.107.015495 pmid: 17600084
55	F Kawoosa, ZA Shah, SR Masoodi, A Amin, R Rasool, KM Fazili, AH Dar, A Lone, S Ul Bashir. Role of human organic cation transporter-1 (OCT-1/SLC22A1) in modulating the response to metformin in patients with type 2 diabetes. BMC Endocr Disord 2022; 22(1): 140 https://doi.org/10.1186/s12902-022-01033-3 pmid: 35619086
56	Y Shu, SA Sheardown, C Brown, RP Owen, S Zhang, RA Castro, AG Ianculescu, L Yue, JC Lo, EG Burchard, CM Brett, KM Giacomini. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest 2007; 117(5): 1422–1431 https://doi.org/10.1172/JCI30558 pmid: 17476361
57	MMH Christensen, K Højlund, O Hother-Nielsen, TB Stage, P Damkier, H Beck-Nielsen, K Brøsen. Steady-state pharmacokinetics of metformin is independent of the OCT1 genotype in healthy volunteers. Eur J Clin Pharmacol 2015; 71(6): 691–697 https://doi.org/10.1007/s00228-015-1853-8 pmid: 25939711
58	EC Chen, X Liang, SW Yee, EG Geier, SL Stocker, L Chen, KM Giacomini. Targeted disruption of organic cation transporter 3 attenuates the pharmacologic response to metformin. Mol Pharmacol 2015; 88(1): 75–83 https://doi.org/10.1124/mol.114.096776 pmid: 25920679
59	N Lee, MF Hebert, DJ Wagner, TR Easterling, CJ Liang, K Rice, J Wang. Organic cation transporter 3 facilitates fetal exposure to metformin during pregnancy. Mol Pharmacol 2018; 94(4): 1125–1131 https://doi.org/10.1124/mol.118.112482 pmid: 30012584
60	L Chen, Y Shu, X Liang, EC Chen, SW Yee, AA Zur, S Li, L Xu, KR Keshari, MJ Lin, HC Chien, Y Zhang, KM Morrissey, J Liu, J Ostrem, NS Younger, J Kurhanewicz, KM Shokat, K Ashrafi, KM Giacomini. OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. Proc Natl Acad Sci USA 2014; 111(27): 9983–9988 https://doi.org/10.1073/pnas.1314939111 pmid: 24961373
61	J Müller, KS Lips, L Metzner, RH Neubert, H Koepsell, M Brandsch. Drug specificity and intestinal membrane localization of human organic cation transporters (OCT). Biochem Pharmacol 2005; 70(12): 1851–1860 https://doi.org/10.1016/j.bcp.2005.09.011 pmid: 16263091
62	N Nakamichi, H Shima, S Asano, T Ishimoto, T Sugiura, K Matsubara, H Kusuhara, Y Sugiyama, Y Sai, K Miyamoto, A Tsuji, Y Kato. Involvement of carnitine/organic cation transporter OCTN1/SLC22A4 in gastrointestinal absorption of metformin. J Pharm Sci 2013; 102(9): 3407–3417 https://doi.org/10.1002/jps.23595 pmid: 23666872
63	H Takane, E Shikata, K Otsubo, S Higuchi, I Ieiri. Polymorphism in human organic cation transporters and metformin action. Pharmacogenomics 2008; 9(4): 415–422 https://doi.org/10.2217/14622416.9.4.415 pmid: 18384255
64	H Yoon, HY Cho, HD Yoo, SM Kim, YB Lee. Influences of organic cation transporter polymorphisms on the population pharmacokinetics of metformin in healthy subjects. AAPS J 2013; 15(2): 571–580 https://doi.org/10.1208/s12248-013-9460-z pmid: 23417334
65	X Liang, HC Chien, SW Yee, MM Giacomini, EC Chen, M Piao, J Hao, J Twelves, EI Lepist, AS Ray, KM Giacomini. Metformin is a substrate and inhibitor of the human thiamine transporter, THTR-2 (SLC19A3). Mol Pharm 2015; 12(12): 4301–4310 https://doi.org/10.1021/acs.molpharmaceut.5b00501 pmid: 26528626
66	TK Han, WR Proctor, CL Costales, H Cai, RS Everett, DR Thakker. Four cation-selective transporters contribute to apical uptake and accumulation of metformin in Caco-2 cell monolayers. J Pharmacol Exp Ther 2015; 352(3): 519–528 https://doi.org/10.1124/jpet.114.220350 pmid: 25563903
67	J Kurlovics, DM Zake, L Zaharenko, K Berzins, J Klovins, E Stalidzans. Metformin transport rates between plasma and red blood cells in humans. Clin Pharmacokinet 2022; 61(1): 133–142 https://doi.org/10.1007/s40262-021-01058-2 pmid: 34309806
68	M Markowicz-Piasecka, KM Huttunen, L Mateusiak, E Mikiciuk-Olasik, J Sikora. Is metformin a perfect drug? Updates in pharmacokinetics and pharmacodynamics. Curr Pharm Des 2017; 23(17): 2532–2550 pmid: 27908266
69	AJ Scheen. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 1996; 30(5): 359–371 https://doi.org/10.2165/00003088-199630050-00003 pmid: 8743335
70	R Song. Mechanism of metformin: a tale of two sites. Diabetes Care 2016; 39(2): 187–189 https://doi.org/10.2337/dci15-0013 pmid: 26798149
71	N Lee, H Duan, MF Hebert, CJ Liang, KM Rice, J Wang. Taste of a pill: organic cation transporter-3 (OCT3) mediates metformin accumulation and secretion in salivary glands. J Biol Chem 2014; 289(39): 27055–27064 https://doi.org/10.1074/jbc.M114.570564 pmid: 25107910
72	JE Hibma, AA Zur, RA Castro, MB Wittwer, RJ Keizer, SW Yee, S Goswami, SL Stocker, X Zhang, Y Huang, CM Brett, RM Savic, KM Giacomini. The effect of famotidine, a MATE1-selective inhibitor, on the pharmacokinetics and pharmacodynamics of metformin. Clin Pharmacokinet 2016; 55(6): 711–721 https://doi.org/10.1007/s40262-015-0346-3 pmid: 26597253
73	RA Posma, LH Venema, TM Huijink, AC Westerkamp, AMA Wessels, NJ De Vries, F Doesburg, J Roggeveld, PJ Ottens, DJ Touw, MW Nijsten, HGD Leuvenink. Increasing metformin concentrations and its excretion in both rat and porcine ex vivo normothermic kidney perfusion model. BMJ Open Diabetes Res Care 2020; 8: e000816 https://doi.org/10.1136/bmjdrc-2019-000816 pmid: 32816871
74	Ma YR, Zhou Y, Huang J, Qin HY, Wang P, Wu XA. The urinary excretion of metformin, ceftizoxime and ofloxacin in high serum creatinine rats: can creatinine predict renal tubular elimination? Life Sci 2018; 196: 110–117 doi:10.1016/j.lfs.2018.01.017 pmid: 29355545
75	L Gong, S Goswami, KM Giacomini, RB Altman, TE Klein. Metformin pathways: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics 2012; 22(11): 820–827 https://doi.org/10.1097/FPC.0b013e3283559b22 pmid: 22722338
76	LJ McCreight, CJ Bailey, ER Pearson. Metformin and the gastrointestinal tract. Diabetologia 2016; 59(3): 426–435 https://doi.org/10.1007/s00125-015-3844-9 pmid: 26780750
77	CR Sirtori, G Franceschini, M Galli-Kienle, G Cighetti, G Galli, A Bondioli, F Conti. Disposition of metformin (N,N-dimethylbiguanide) in man. Clin Pharmacol Ther 1978; 24(6): 683–693 https://doi.org/10.1002/cpt1978246683 pmid: 710026
78	GT Tucker, C Casey, PJ Phillips, H Connor, JD Ward, HF Woods. Metformin kinetics in healthy subjects and in patients with diabetes mellitus. Br J Clin Pharmacol 1981; 12(2): 235–246 https://doi.org/10.1111/j.1365-2125.1981.tb01206.x pmid: 7306436
79	I Szymczak-Pajor, S Wenclewska, A Śliwińska. Metabolic action of metformin. Pharmaceuticals (Basel) 2022; 15(7): 810 https://doi.org/10.3390/ph15070810 pmid: 35890109
80	L He, FE Wondisford. Metformin action: concentrations matter. Cell Metab 2015; 21(2): 159–162 https://doi.org/10.1016/j.cmet.2015.01.003 pmid: 25651170
81	T Ma, X Tian, B Zhang, M Li, Y Wang, C Yang, J Wu, X Wei, Q Qu, Y Yu, S Long, JW Feng, C Li, C Zhang, C Xie, Y Wu, Z Xu, J Chen, Y Yu, X Huang, Y He, L Yao, L Zhang, M Zhu, W Wang, ZC Wang, M Zhang, Y Bao, W Jia, SY Lin, Z Ye, HL Piao, X Deng, CS Zhang, SC Lin. Low-dose metformin targets the lysosomal AMPK pathway through PEN2. Nature 2022; 603(7899): 159–165 https://doi.org/10.1038/s41586-022-04431-8 pmid: 35197629
82	G Rena, DG Hardie, ER Pearson. The mechanisms of action of metformin. Diabetologia 2017; 60(9): 1577–1585 https://doi.org/10.1007/s00125-017-4342-z pmid: 28776086
83	CH Saely, K Geiger, H Drexel. Brown versus white adipose tissue: a mini-review. Gerontology 2012; 58(1): 15–23 https://doi.org/10.1159/000321319 pmid: 21135534
84	A Abdullahi, MG Jeschke. Taming the flames: targeting white adipose tissue browning in hypermetabolic conditions. Endocr Rev 2017; 38(6): 538–549 https://doi.org/10.1210/er.2017-00163 pmid: 28938469
85	P Breining, JB Jensen, EI Sundelin, LC Gormsen, S Jakobsen, M Busk, L Rolighed, P Bross, P Fernandez-Guerra, LK Markussen, NE Rasmussen, JB Hansen, SB Pedersen, B Richelsen, N Jessen. Metformin targets brown adipose tissue in vivo and reduces oxygen consumption in vitro. Diabetes Obes Metab 2018; 20(9): 2264–2273 https://doi.org/10.1111/dom.13362 pmid: 29752759
86	KA Virtanen, K Hällsten, R Parkkola, T Janatuinen, F Lönnqvist, T Viljanen, T Rönnemaa, J Knuuti, R Huupponen, P Lönnroth, P Nuutila. Differential effects of rosiglitazone and metformin on adipose tissue distribution and glucose uptake in type 2 diabetic subjects. Diabetes 2003; 52(2): 283–290 https://doi.org/10.2337/diabetes.52.2.283 pmid: 12540598
87	I Karise, TC Bargut, M Del Sol, MB Aguila, CA Mandarim-de-Lacerda. Metformin enhances mitochondrial biogenesis and thermogenesis in brown adipocytes of mice. Biomed Pharmacother 2019; 111: 1156–1165 https://doi.org/10.1016/j.biopha.2019.01.021 pmid: 30841429
88	I Çakır, CK Hadley, PL Pan, RA Bagchi, M Ghamari-Langroudi, DT Porter, Q Wang, MJ Litt, S Jana, S Hagen, P Lee, A White, JD Lin, TA McKinsey, RD Cone. Histone deacetylase 6 inhibition restores leptin sensitivity and reduces obesity. Nat Metab 2022; 4(1): 44–59 https://doi.org/10.1038/s42255-021-00515-3 pmid: 35039672
89	I Tokubuchi, Y Tajiri, S Iwata, K Hara, N Wada, T Hashinaga, H Nakayama, H Mifune, K Yamada. Beneficial effects of metformin on energy metabolism and visceral fat volume through a possible mechanism of fatty acid oxidation in human subjects and rats. PLoS One 2017; 12(2): e0171293 https://doi.org/10.1371/journal.pone.0171293 pmid: 28158227
90	Y Hu, AJ Young, EA Ehli, D Nowotny, PS Davies, EA Droke, TJ Soundy, GE Davies. Metformin and berberine prevent olanzapine-induced weight gain in rats. PLoS One 2014; 9(3): e93310 https://doi.org/10.1371/journal.pone.0093310 pmid: 24667776
91	T Qi, Y Chen, H Li, Y Pei, SL Woo, X Guo, J Zhao, X Qian, J Awika, Y Huo, C Wu. A role for PFKFB3/iPFK2 in metformin suppression of adipocyte inflammatory responses. J Mol Endocrinol 2017; 59(1): 49–59 https://doi.org/10.1530/JME-17-0066 pmid: 28559290
92	Y Jing, F Wu, D Li, L Yang, Q Li, R Li. Metformin improves obesity-associated inflammation by altering macrophages polarization. Mol Cell Endocrinol 2018; 461: 256–264 https://doi.org/10.1016/j.mce.2017.09.025 pmid: 28935544
93	G Marcelin, EL Gautier, K Clément. Adipose tissue fibrosis in obesity: etiology and challenges. Annu Rev Physiol 2022; 84(1): 135–155 https://doi.org/10.1146/annurev-physiol-060721-092930 pmid: 34752708
94	T Luo, A Nocon, J Fry, A Sherban, X Rui, B Jiang, XJ Xu, J Han, Y Yan, Q Yang, Q Li, M Zang. AMPK activation by metformin suppresses abnormal extracellular matrix remodeling in adipose tissue and ameliorates insulin resistance in obesity. Diabetes 2016; 65(8): 2295–2310 https://doi.org/10.2337/db15-1122 pmid: 27207538
95	H Waki, P Tontonoz. Endocrine functions of adipose tissue. Annu Rev Pathol 2007; 2(1): 31–56 https://doi.org/10.1146/annurev.pathol.2.010506.091859 pmid: 18039092
96	Y Naghiaee, R Didehdar, F Pourrajab, M Rahmanian, N Heiranizadeh, A Mohiti, J Mohiti-Ardakani. Metformin downregulates miR223 expression in insulin-resistant 3T3L1 cells and human diabetic adipose tissue. Endocrine 2020; 70(3): 498–508 https://doi.org/10.1007/s12020-020-02459-2 pmid: 32970287
97	S Cruciani, G Garroni, F Balzano, R Pala, E Bellu, ML Cossu, GC Ginesu, C Ventura, M Maioli. Tuning adipogenic differentiation in ADSCs by metformin and vitamin D: involvement of miRNAs. Int J Mol Sci 2020; 21(17): 6181 https://doi.org/10.3390/ijms21176181 pmid: 32867201
98	G Zhou, R Myers, Y Li, Y Chen, X Shen, J Fenyk-Melody, M Wu, J Ventre, T Doebber, N Fujii, N Musi, MF Hirshman, LJ Goodyear, DE Moller. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001; 108(8): 1167–1174 https://doi.org/10.1172/JCI13505 pmid: 11602624
99	RJ Shaw, KA Lamia, D Vasquez, SH Koo, N Bardeesy, RA Depinho, M Montminy, LC Cantley. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 2005; 310(5754): 1642–1646 https://doi.org/10.1126/science.1120781 pmid: 16308421
100	MD Fullerton, S Galic, K Marcinko, S Sikkema, T Pulinilkunnil, ZP Chen, HM O’Neill, RJ Ford, R Palanivel, M O’Brien, DG Hardie, SL Macaulay, JD Schertzer, JR Dyck, Denderen BJ van, BE Kemp, GR Steinberg. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat Med 2013; 19(12): 1649–1654 https://doi.org/10.1038/nm.3372 pmid: 24185692
101	E Bonora, M Cigolini, O Bosello, C Zancanaro, L Capretti, I Zavaroni, C Coscelli, U Butturini. Lack of effect of intravenous metformin on plasma concentrations of glucose, insulin, C-peptide, glucagon and growth hormone in non-diabetic subjects. Curr Med Res Opin 1984; 9(1): 47–51 https://doi.org/10.1185/03007998409109558 pmid: 6373159
102	JB Buse, RA DeFronzo, J Rosenstock, T Kim, C Burns, S Skare, A Baron, M Fineman. The primary glucose-lowering effect of metformin resides in the gut, not the circulation: results from short-term pharmacokinetic and 12-week dose-ranging studies. Diabetes Care 2016; 39(2): 198–205 https://doi.org/10.2337/dc15-0488 pmid: 26285584
103	H Lee, G Ko. Effect of metformin on metabolic improvement and gut microbiota. Appl Environ Microbiol 2014; 80(19): 5935–5943 https://doi.org/10.1128/AEM.01357-14 pmid: 25038099
104	NR Shin, JC Lee, HY Lee, MS Kim, TW Whon, MS Lee, JW Bae. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 2014; 63(5): 727–735 https://doi.org/10.1136/gutjnl-2012-303839 pmid: 23804561
105	X Fu, X Wang, Z Duan, C Zhang, X Fu, J Yang, X Liu, J He. Histone H3k9 and H3k27 acetylation regulates IL-4/STAT6-mediated Igε transcription in B lymphocytes. Anat Rec (Hoboken) 2015; 298(8): 1431–1439 https://doi.org/10.1002/ar.23172 pmid: 25952120
106	FH Karlsson, V Tremaroli, I Nookaew, G Bergström, CJ Behre, B Fagerberg, J Nielsen, F Bäckhed. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 2013; 498(7452): 99–103 https://doi.org/10.1038/nature12198 pmid: 23719380
107	K Forslund, F Hildebrand, T Nielsen, G Falony, Chatelier E Le, S Sunagawa, E Prifti, S Vieira-Silva, V Gudmundsdottir, HK Pedersen, M Arumugam, K Kristiansen, AY Voigt, H Vestergaard, R Hercog, PI Costea, JR Kultima, J Li, T Jørgensen, F Levenez, J; MetaHIT consortium; Nielsen HB Dore, S Brunak, J Raes, T Hansen, J Wang, SD Ehrlich, P Bork, O Pedersen. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 2015; 528(7581): 262–266 https://doi.org/10.1038/nature15766 pmid: 26633628
108	NT Mueller, MK Differding, M Zhang, NM Maruthur, SP Juraschek, ER 3rd Miller, LJ Appel, HC Yeh. Metformin affects gut microbiome composition and function and circulating short-chain fatty acids: a randomized trial. Diabetes Care 2021; 44(7): 1462–1471 https://doi.org/10.2337/dc20-2257 pmid: 34006565
109	F Cabreiro, C Au, KY Leung, N Vergara-Irigaray, HM Cochemé, T Noori, D Weinkove, E Schuster, ND Greene, D Gems. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell 2013; 153(1): 228–239 https://doi.org/10.1016/j.cell.2013.02.035 pmid: 23540700
110	PV Bauer, FA Duca, TMZ Waise, BA Rasmussen, MA Abraham, HJ Dranse, A Puri, CA O’Brien, TKT Lam. Metformin alters upper small intestinal microbiota that impact a glucose-SGLT1-sensing glucoregulatory pathway. Cell Metab 2018; 27(1): 101–117.e5 https://doi.org/10.1016/j.cmet.2017.09.019 pmid: 29056513
111	R Pryor, P Norvaisas, G Marinos, L Best, LB Thingholm, LM Quintaneiro, Haes W De, D Esser, S Waschina, C Lujan, RL Smith, TA Scott, D Martinez-Martinez, O Woodward, K Bryson, M Laudes, W Lieb, RH Houtkooper, A Franke, L Temmerman, I Bjedov, HM Cochemé, C Kaleta, F Cabreiro. Host-microbe-drug-nutrient screen identifies bacterial effectors of metformin therapy. Cell 2019; 178(6): 1299–1312.e29 https://doi.org/10.1016/j.cell.2019.08.003 pmid: 31474368
112	AE Kitabchi, M Temprosa, WC Knowler, SE Kahn, SE Fowler, SM Haffner, R Andres, C Saudek, SL Edelstein, R Arakaki, MB Murphy, H; Diabetes Prevention Program Research Group Shamoon. Role of insulin secretion and sensitivity in the evolution of type 2 diabetes in the diabetes prevention program: effects of lifestyle intervention and metformin. Diabetes 2005; 54(8): 2404–2414 https://doi.org/10.2337/diabetes.54.8.2404 pmid: 16046308
113	M Hashemitabar, S Bahramzadeh, S Saremy, F Nejaddehbashi. Glucose plus metformin compared with glucose alone on β-cell function in mouse pancreatic islets. Biomed Rep 2015; 3(5): 721–725 https://doi.org/10.3892/br.2015.476 pmid: 26405552
114	R Lupi, S Del Guerra, C Tellini, R Giannarelli, A Coppelli, M Lorenzetti, M Carmellini, F Mosca, R Navalesi, P Marchetti. The biguanide compound metformin prevents desensitization of human pancreatic islets induced by high glucose. Eur J Pharmacol 1999; 364(2–3): 205–209 https://doi.org/10.1016/S0014-2999(98)00807-3 pmid: 9932725
115	G Patanè, S Piro, AM Rabuazzo, M Anello, R Vigneri, F Purrello. Metformin restores insulin secretion altered by chronic exposure to free fatty acids or high glucose: a direct metformin effect on pancreatic beta-cells. Diabetes 2000; 49(5): 735–740 https://doi.org/10.2337/diabetes.49.5.735 pmid: 10905481
116	J Cen, E Sargsyan, A Forslund, P Bergsten. Mechanisms of beneficial effects of metformin on fatty acid-treated human islets. J Mol Endocrinol 2018; 61(3): 91–99 https://doi.org/10.1530/JME-17-0304 pmid: 30307162
117	JS Moon, U Karunakaran, S Elumalai, IK Lee, HW Lee, YW Kim, KC Won. Metformin prevents glucotoxicity by alleviating oxidative and ER stress-induced CD36 expression in pancreatic beta cells. J Diabetes Complications 2017; 31(1): 21–30 https://doi.org/10.1016/j.jdiacomp.2016.09.001 pmid: 27662780
118	SN LiuQ LiuSJ SunSC HouY WangZF Shen. Metformin ameliorates β-cell dysfunction by regulating inflammation production, ion and hormone homeostasis of pancreas in diabetic KKAy mice. Acta Pharmaceutica Sinica (Yao Xue Xue Bao) 2014; 49(11): 1554–1562 (in Chinese) pmid: 25757281
119	Y Jiang, W Huang, J Wang, Z Xu, J He, X Lin, Z Zhou, J Zhang. Metformin plays a dual role in MIN6 pancreatic β cell function through AMPK-dependent autophagy. Int J Biol Sci 2014; 10(3): 268–277 https://doi.org/10.7150/ijbs.7929 pmid: 24644425
120	S Lablanche, C Cottet-Rousselle, F Lamarche, PY Benhamou, S Halimi, X Leverve, E Fontaine. Protection of pancreatic INS-1 β-cells from glucose- and fructose-induced cell death by inhibiting mitochondrial permeability transition with cyclosporin A or metformin. Cell Death Dis 2011; 2(3): e134 https://doi.org/10.1038/cddis.2011.15 pmid: 21430707
121	TW Jung, MW Lee, YJ Lee, SM Kim. Metformin prevents endoplasmic reticulum stress-induced apoptosis through AMPK-PI3K-c-Jun NH2 pathway. Biochem Biophys Res Commun 2012; 417(1): 147–152 https://doi.org/10.1016/j.bbrc.2011.11.073 pmid: 22138650
122	A Lee, JE Morley. Metformin decreases food consumption and induces weight loss in subjects with obesity with type II non-insulin-dependent diabetes. Obes Res 1998; 6(1): 47–53 https://doi.org/10.1002/j.1550-8528.1998.tb00314.x pmid: 9526970
123	G Paolisso, L Amato, R Eccellente, A Gambardella, MR Tagliamonte, G Varricchio, C Carella, D Giugliano, F D’Onofrio. Effect of metformin on food intake in obese subjects. Eur J Clin Invest 1998; 28(6): 441–446 https://doi.org/10.1046/j.1365-2362.1998.00304.x pmid: 9693934
124	CJ Glueck, RN Fontaine, P Wang, MT Subbiah, K Weber, E Illig, P Streicher, L Sieve-Smith, TM Tracy, JE Lang, P McCullough. Metformin reduces weight, centripetal obesity, insulin, leptin, and low-density lipoprotein cholesterol in nondiabetic, morbidly obese subjects with body mass index greater than 30. Metabolism 2001; 50(7): 856–861 https://doi.org/10.1053/meta.2001.24192 pmid: 11436194
125	C Chau-Van, M Gamba, R Salvi, RC Gaillard, FP Pralong. Metformin inhibits adenosine 5′-monophosphate-activated kinase activation and prevents increases in neuropeptide Y expression in cultured hypothalamic neurons. Endocrinology 2007; 148(2): 507–511 https://doi.org/10.1210/en.2006-1237 pmid: 17095593
126	D Stevanovic, K Janjetovic, M Misirkic, L Vucicevic, M Sumarac-Dumanovic, D Micic, V Starcevic, V Trajkovic. Intracerebroventricular administration of metformin inhibits ghrelin-induced hypothalamic AMP-kinase signalling and food intake. Neuroendocrinology 2012; 96(1): 24–31 https://doi.org/10.1159/000333963 pmid: 22343549
127	YW Kim, JY Kim, YH Park, SY Park, KC Won, KH Choi, JY Huh, KH Moon. Metformin restores leptin sensitivity in high-fat-fed obese rats with leptin resistance. Diabetes 2006; 55(3): 716–724 https://doi.org/10.2337/diabetes.55.03.06.db05-0917 pmid: 16505235
128	G Aubert, V Mansuy, MJ Voirol, L Pellerin, FP Pralong. The anorexigenic effects of metformin involve increases in hypothalamic leptin receptor expression. Metabolism 2011; 60(3): 327–334 https://doi.org/10.1016/j.metabol.2010.02.007 pmid: 20303124
129	SE Mullican, X Lin-Schmidt, CN Chin, JA Chavez, JL Furman, AA Armstrong, SC Beck, VJ South, TQ Dinh, TD Cash-Mason, CR Cavanaugh, S Nelson, C Huang, MJ Hunter, SM Rangwala. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat Med 2017; 23(10): 1150–1157 https://doi.org/10.1038/nm.4392 pmid: 28846097
130	PJ Emmerson, F Wang, Y Du, Q Liu, RT Pickard, MD Gonciarz, T Coskun, MJ Hamang, DK Sindelar, KK Ballman, LA Foltz, A Muppidi, J Alsina-Fernandez, GC Barnard, JX Tang, X Liu, X Mao, R Siegel, JH Sloan, PJ Mitchell, BB Zhang, RE Gimeno, B Shan, X Wu. The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL. Nat Med 2017; 23(10): 1215–1219 https://doi.org/10.1038/nm.4393 pmid: 28846098
131	T Borner, ED Shaulson, MY Ghidewon, AB Barnett, CC Horn, RP Doyle, HJ Grill, MR Hayes, BC De Jonghe. GDF15 induces anorexia through nausea and emesis. Cell Metab 2020; 31(2): 351–362.e5 https://doi.org/10.1016/j.cmet.2019.12.004 pmid: 31928886
132	AP Coll, M Chen, P Taskar, D Rimmington, S Patel, JA Tadross, I Cimino, M Yang, P Welsh, S Virtue, DA Goldspink, EL Miedzybrodzka, AR Konopka, RR Esponda, JT Huang, YCL Tung, S Rodriguez-Cuenca, RA Tomaz, HP Harding, A Melvin, GSH Yeo, D Preiss, A Vidal-Puig, L Vallier, KS Nair, NJ Wareham, D Ron, FM Gribble, F Reimann, N Sattar, DB Savage, BB Allan, S O’Rahilly. GDF15 mediates the effects of metformin on body weight and energy balance. Nature 2020; 578(7795): 444–448 https://doi.org/10.1038/s41586-019-1911-y pmid: 31875646
133	AB Klein, TS Nicolaisen, K Johann, AM Fritzen, CV Mathiesen, C Gil, NS Pilmark, K Karstoft, MB Blond, JS Quist, RJ Seeley, K Færch, J Lund, M Kleinert, C Clemmensen. The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance. Cell Rep 2022; 40(8): 111258 https://doi.org/10.1016/j.celrep.2022.111258 pmid: 36001956
134	EA Day, RJ Ford, BK Smith, P Mohammadi-Shemirani, MR Morrow, RM Gutgesell, R Lu, AR Raphenya, M Kabiri, AG McArthur, N McInnes, S Hess, G Paré, HC Gerstein, GR Steinberg. Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss. Nat Metab 2019; 1(12): 1202–1208 https://doi.org/10.1038/s42255-019-0146-4 pmid: 32694673
135	Diabetes Association Professional Practice Committee American. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2022. Diabetes Care 2022; 45(Suppl 1): S125–S143 https://doi.org/10.2337/dc22-S009 pmid: 34964831
136	M Stumvoll, HU Häring, S Matthaei. Metformin. Endocr Res 2007; 32(1–2): 39–57 https://doi.org/10.1080/07435800701743828 pmid: 18271504
137	C Wang, F Liu, Y Yuan, J Wu, H Wang, L Zhang, P Hu, Z Li, Q Li, J Ye. Metformin suppresses lipid accumulation in skeletal muscle by promoting fatty acid oxidation. Clin Lab 2014; 60(6): 887–896 https://doi.org/10.7754/Clin.Lab.2013.130531 pmid: 25016691
138	P Zabielski, M Chacinska, K Charkiewicz, M Baranowski, J Gorski, AU Blachnio-Zabielska. Effect of metformin on bioactive lipid metabolism in insulin-resistant muscle. J Endocrinol 2017; 233(3): 329–340 https://doi.org/10.1530/JOE-16-0381 pmid: 28522731
139	K Pavlovic, N Krako Jakovljevic, AM Isakovic, T Ivanovic, I Markovic, NM Lalic. Therapeutic vs. suprapharmacological metformin concentrations: different effects on energy metabolism and mitochondrial function in skeletal muscle cells in vitro. Front Pharmacol 2022; 13: 930308 https://doi.org/10.3389/fphar.2022.930308 pmid: 35873556
140	SK Malin, NR Stewart. Metformin may contribute to inter-individual variability for glycemic responses to exercise. Front Endocrinol (Lausanne) 2020; 11: 519 https://doi.org/10.3389/fendo.2020.00519 pmid: 32849302
141	A Natali, E Ferrannini. Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review. Diabetologia 2006; 49(3): 434–441 https://doi.org/10.1007/s00125-006-0141-7 pmid: 16477438
142	Z Zhou, Y Tang, X Jin, C Chen, Y Lu, L Liu, C Shen. Metformin inhibits advanced glycation end products-induced inflammatory response in murine macrophages partly through AMPK activation and RAGE/NFκB pathway suppression. J Diabetes Res 2016; 2016: 4847812 https://doi.org/10.1155/2016/4847812 pmid: 27761470
143	L He, A Sabet, S Djedjos, R Miller, X Sun, MA Hussain, S Radovick, FE Wondisford. Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell 2009; 137(4): 635–646 https://doi.org/10.1016/j.cell.2009.03.016 pmid: 19450513
144	JM Lee, WY Seo, KH Song, D Chanda, YD Kim, DK Kim, MW Lee, D Ryu, YH Kim, JR Noh, CH Lee, JY Chiang, SH Koo, HS Choi. AMPK-dependent repression of hepatic gluconeogenesis via disruption of CREB. CRTC2 complex by orphan nuclear receptor small heterodimer partner. J Biol Chem 2010; 285(42): 32182–32191 https://doi.org/10.1074/jbc.M110.134890 pmid: 20688914
145	PW Caton, NK Nayuni, J Kieswich, NQ Khan, MM Yaqoob, R Corder. Metformin suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5. J Endocrinol 2010; 205(1): 97–106 https://doi.org/10.1677/JOE-09-0345 pmid: 20093281
146	AK Madiraju, DM Erion, Y Rahimi, XM Zhang, DT Braddock, RA Albright, BJ Prigaro, JL Wood, S Bhanot, MJ MacDonald, MJ Jurczak, JP Camporez, HY Lee, GW Cline, VT Samuel, RG Kibbey, GI Shulman. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 2014; 510(7506): 542–546 https://doi.org/10.1038/nature13270 pmid: 24847880
147	HZ Lin, SQ Yang, C Chuckaree, F Kuhajda, G Ronnet, AM Diehl. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med 2000; 6(9): 998–1003 https://doi.org/10.1038/79697 pmid: 10973319
148	SL Woo, H Xu, H Li, Y Zhao, X Hu, J Zhao, X Guo, T Guo, R Botchlett, T Qi, Y Pei, J Zheng, Y Xu, X An, L Chen, L Chen, Q Li, X Xiao, Y Huo, C Wu. Metformin ameliorates hepatic steatosis and inflammation without altering adipose phenotype in diet-induced obesity. PLoS One 2014; 9(3): e91111 https://doi.org/10.1371/journal.pone.0091111 pmid: 24638078
149	MY El-Mir, V Nogueira, E Fontaine, N Avéret, M Rigoulet, X Leverve. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 2000; 275(1): 223–228 https://doi.org/10.1074/jbc.275.1.223 pmid: 10617608
150	MR Owen, E Doran, AP Halestrap. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 2000; 348(3): 607–614 https://doi.org/10.1042/bj3480607 pmid: 10839993
151	X Stephenne, M Foretz, N Taleux, GC van der Zon, E Sokal, L Hue, B Viollet, B Guigas. Metformin activates AMP-activated protein kinase in primary human hepatocytes by decreasing cellular energy status. Diabetologia 2011; 54(12): 3101–3110 https://doi.org/10.1007/s00125-011-2311-5 pmid: 21947382
152	C Batandier, B Guigas, D Detaille, MY El-Mir, E Fontaine, M Rigoulet, XM Leverve. The ROS production induced by a reverse-electron flux at respiratory-chain complex 1 is hampered by metformin. J Bioenerg Biomembr 2006; 38(1): 33–42 https://doi.org/10.1007/s10863-006-9003-8 pmid: 16732470
153	E Fontaine. Metformin-induced mitochondrial complex I inhibition: facts, uncertainties, and consequences. Front Endocrinol (Lausanne) 2018; 9: 753 https://doi.org/10.3389/fendo.2018.00753 pmid: 30619086
154	I Pernicova, M Korbonits. Metformin—mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol 2014; 10(3): 143–156 https://doi.org/10.1038/nrendo.2013.256 pmid: 24393785
155	A Vancura, P Bu, M Bhagwat, J Zeng, I Vancurova. Metformin as an anticancer agent. Trends Pharmacol Sci 2018; 39(10): 867–878 https://doi.org/10.1016/j.tips.2018.07.006 pmid: 30150001
156	JM Evans, LA Donnelly, AM Emslie-Smith, DR Alessi, AD Morris. Metformin and reduced risk of cancer in diabetic patients. BMJ 2005; 330(7503): 1304–1305 https://doi.org/10.1136/bmj.38415.708634.F7 pmid: 15849206
157	M Monami, C Colombi, D Balzi, I Dicembrini, S Giannini, C Melani, V Vitale, D Romano, A Barchielli, N Marchionni, CM Rotella, E Mannucci. Metformin and cancer occurrence in insulin-treated type 2 diabetic patients. Diabetes Care 2011; 34(1): 129–131 https://doi.org/10.2337/dc10-1287 pmid: 20980415
158	J Kasznicki, A Sliwinska, J Drzewoski. Metformin in cancer prevention and therapy. Ann Transl Med 2014; 2(6): 57 pmid: 25333032
159	M Peng, KO Darko, T Tao, Y Huang, Q Su, C He, T Yin, Z Liu, X Yang. Combination of metformin with chemotherapeutic drugs via different molecular mechanisms. Cancer Treat Rev 2017; 54: 24–33 https://doi.org/10.1016/j.ctrv.2017.01.005 pmid: 28161619
160	KC Wen, PL Sung, ATH Wu, PC Chou, JH Lin, CF Huang, SJ Yeung, MH Lee. Neoadjuvant metformin added to conventional chemotherapy synergizes anti-proliferative effects in ovarian cancer. J Ovarian Res 2020; 13(1): 95 https://doi.org/10.1186/s13048-020-00703-x pmid: 32825834
161	HH Zhang, XL Guo. Combinational strategies of metformin and chemotherapy in cancers. Cancer Chemother Pharmacol 2016; 78(1): 13–26 https://doi.org/10.1007/s00280-016-3037-3 pmid: 27118574
162	R Mallik, TA Chowdhury. Metformin in cancer. Diabetes Res Clin Pract 2018; 143: 409–419 https://doi.org/10.1016/j.diabres.2018.05.023 pmid: 29807101
163	SJ Skuli, S Alomari, H Gaitsch, A Bakayoko, N Skuli, BM Tyler. Metformin and cancer, an ambiguanidous relationship. Pharmaceuticals (Basel) 2022; 15(5): 626 https://doi.org/10.3390/ph15050626 pmid: 35631452
164	BM Heckman-Stoddard, A DeCensi, VV Sahasrabuddhe, LG Ford. Repurposing metformin for the prevention of cancer and cancer recurrence. Diabetologia 2017; 60(9): 1639–1647 https://doi.org/10.1007/s00125-017-4372-6 pmid: 28776080
165	YC Long, JR Zierath. AMP-activated protein kinase signaling in metabolic regulation. J Clin Invest 2006; 116(7): 1776–1783 https://doi.org/10.1172/JCI29044 pmid: 16823475
166	X Huang, S Wullschleger, N Shpiro, VA McGuire, K Sakamoto, YL Woods, W McBurnie, S Fleming, DR Alessi. Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem J 2008; 412(2): 211–221 https://doi.org/10.1042/BJ20080557 pmid: 18387000
167	M Zakikhani, R Dowling, IG Fantus, N Sonenberg, M Pollak. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res 2006; 66(21): 10269–10273 https://doi.org/10.1158/0008-5472.CAN-06-1500 pmid: 17062558
168	C Gao, L Fang, H Zhang, WS Zhang, XO Li, SY Du. Metformin induces autophagy via the AMPK-mTOR signaling pathway in human hepatocellular carcinoma cells. Cancer Manag Res 2020; 12: 5803–5811 https://doi.org/10.2147/CMAR.S257966 pmid: 32765083
169	RJ Dowling, M Zakikhani, IG Fantus, M Pollak, N Sonenberg. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res 2007; 67(22): 10804–10812 https://doi.org/10.1158/0008-5472.CAN-07-2310 pmid: 18006825
170	P Shen, LC Reineke, E Knutsen, M Chen, M Pichler, H Ling, GA Calin. Metformin blocks MYC protein synthesis in colorectal cancer via mTOR-4EBP-eIF4E and MNK1-eIF4G-eIF4E signaling. Mol Oncol 2018; 12(11): 1856–1870 https://doi.org/10.1002/1878-0261.12384 pmid: 30221473
171	Y Wang, W Xu, Z Yan, W Zhao, J Mi, J Li, H Yan. Metformin induces autophagy and G0/G1 phase cell cycle arrest in myeloma by targeting the AMPK/mTORC1 and mTORC2 pathways. J Exp Clin Cancer Res 2018; 37(1): 63 https://doi.org/10.1186/s13046-018-0731-5 pmid: 29554968
172	CC Lu, JH Chiang, FJ Tsai, YM Hsu, YN Juan, JS Yang, HY Chiu. Metformin triggers the intrinsic apoptotic response in human AGS gastric adenocarcinoma cells by activating AMPK and suppressing mTOR/AKT signaling. Int J Oncol 2019; 54(4): 1271–1281 https://doi.org/10.3892/ijo.2019.4704 pmid: 30720062
173	YH Chen, SF Yang, CK Yang, HD Tsai, TH Chen, MC Chou, YH Hsiao. Metformin induces apoptosis and inhibits migration by activating the AMPK/p53 axis and suppressing PI3K/AKT signaling in human cervical cancer cells. Mol Med Rep 2021; 23(1): 88 pmid: 33236135
174	Y Sun, C Tao, X Huang, H He, H Shi, Q Zhang, H Wu. Metformin induces apoptosis of human hepatocellular carcinoma HepG2 cells by activating an AMPK/p53/miR-23a/FOXA1 pathway. Onco Targets Ther 2016; 9: 2845–2853 pmid: 27274280
175	HG Kim, TT Hien, EH Han, YP Hwang, JH Choi, KW Kang, KI Kwon, BH Kim, SK Kim, GY Song, TC Jeong, HG Jeong. Metformin inhibits P-glycoprotein expression via the NF-κB pathway and CRE transcriptional activity through AMPK activation. Br J Pharmacol 2011; 162(5): 1096–1108 https://doi.org/10.1111/j.1476-5381.2010.01101.x pmid: 21054339
176	L Zheng, W Yang, F Wu, C Wang, L Yu, L Tang, B Qiu, Y Li, L Guo, M Wu, G Feng, D Zou, H Wang. Prognostic significance of AMPK activation and therapeutic effects of metformin in hepatocellular carcinoma. Clin Cancer Res 2013; 19(19): 5372–5380 https://doi.org/10.1158/1078-0432.CCR-13-0203 pmid: 23942093
177	Z Zheng, Y Bian, Y Zhang, G Ren, G Li. Metformin activates AMPK/SIRT1/NF-κB pathway and induces mitochondrial dysfunction to drive caspase3/GSDME-mediated cancer cell pyroptosis. Cell Cycle 2020; 19(10): 1089–1104 https://doi.org/10.1080/15384101.2020.1743911 pmid: 32286137
178	Y Dong, H Hu, X Zhang, Y Zhang, X Sun, H Wang, W Kan, MJ Tan, H Shi, Y Zang, J Li. Phosphorylation of PHF2 by AMPK releases the repressive H3K9me2 and inhibits cancer metastasis. Signal Transduct Target Ther 2023; 8(1): 95 https://doi.org/10.1038/s41392-022-01302-6 pmid: 36872368
179	TJ Lynch, DW Bell, R Sordella, S Gurubhagavatula, RA Okimoto, BW Brannigan, PL Harris, SM Haserlat, JG Supko, FG Haluska, DN Louis, DC Christiani, J Settleman, DA Haber. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350(21): 2129–2139 https://doi.org/10.1056/NEJMoa040938 pmid: 15118073
180	K Isoda, JL Young, A Zirlik, LA MacFarlane, N Tsuboi, N Gerdes, U Schönbeck, P Libby. Metformin inhibits proinflammatory responses and nuclear factor-kappaB in human vascular wall cells. Arterioscler Thromb Vasc Biol 2006; 26(3): 611–617 https://doi.org/10.1161/01.ATV.0000201938.78044.75 pmid: 16385087
181	Y Hattori, K Suzuki, S Hattori, K Kasai. Metformin inhibits cytokine-induced nuclear factor kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells. Hypertension 2006; 47(6): 1183–1188 https://doi.org/10.1161/01.HYP.0000221429.94591.72 pmid: 16636195
182	Q Guo, Z Liu, L Jiang, M Liu, J Ma, C Yang, L Han, K Nan, X Liang. Metformin inhibits growth of human non-small cell lung cancer cells via liver kinase B-1-independent activation of adenosine monophosphate-activated protein kinase. Mol Med Rep 2016; 13(3): 2590–2596 https://doi.org/10.3892/mmr.2016.4830 pmid: 26847819
183	B Faubert, G Boily, S Izreig, T Griss, B Samborska, Z Dong, F Dupuy, C Chambers, BJ Fuerth, B Viollet, OA Mamer, D Avizonis, RJ DeBerardinis, PM Siegel, RG Jones. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab 2013; 17(1): 113–124 https://doi.org/10.1016/j.cmet.2012.12.001 pmid: 23274086
184	C Algire, L Amrein, M Zakikhani, L Panasci, M Pollak. Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. Endocr Relat Cancer 2010; 17(2): 351–360 https://doi.org/10.1677/ERC-09-0252 pmid: 20228137
185	M Buzzai, RG Jones, RK Amaravadi, JJ Lum, RJ DeBerardinis, F Zhao, B Viollet, CB Thompson. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res 2007; 67(14): 6745–6752 https://doi.org/10.1158/0008-5472.CAN-06-4447 pmid: 17638885
186	Y Xie, JL Wang, M Ji, ZF Yuan, Z Peng, Y Zhang, JG Wen, HR Shi. Regulation of insulin-like growth factor signaling by metformin in endometrial cancer cells. Oncol Lett 2014; 8(5): 1993–1999 https://doi.org/10.3892/ol.2014.2466 pmid: 25289085
187	J Lee, EM Hong, JH Kim, JH Jung, SW Park, DH Koh, MH Choi, HJ Jang, SH Kae. Metformin induces apoptosis and inhibits proliferation through the AMP-activated protein kinase and insulin-like growth factor 1 receptor pathways in the bile duct cancer cells. J Cancer 2019; 10(7): 1734–1744 https://doi.org/10.7150/jca.26380 pmid: 31205529
188	E Karnevi, K Said, R Andersson, AH Rosendahl. Metformin-mediated growth inhibition involves suppression of the IGF-I receptor signalling pathway in human pancreatic cancer cells. BMC Cancer 2013; 13(1): 235 https://doi.org/10.1186/1471-2407-13-235 pmid: 23663483
189	V Birzniece, T Lam, M McLean, N Reddy, H Shahidipour, A Hayden, H Gurney, G Stone, R Hjortebjerg, J Frystyk. Insulin-like growth factor role in determining the anti-cancer effect of metformin: RCT in prostate cancer patients. Endocr Connect 2022; 11(4): e210375 https://doi.org/10.1530/EC-21-0375 pmid: 35324467
190	M Zakikhani, MJ Blouin, E Piura, MN Pollak. Metformin and rapamycin have distinct effects on the AKT pathway and proliferation in breast cancer cells. Breast Cancer Res Treat 2010; 123(1): 271–279 https://doi.org/10.1007/s10549-010-0763-9 pmid: 20135346
191	SC Chaudhary, D Kurundkar, CA Elmets, L Kopelovich, M Athar. Metformin, an antidiabetic agent reduces growth of cutaneous squamous cell carcinoma by targeting mTOR signaling pathway. Photochem Photobiol 2012; 88(5): 1149–1156 https://doi.org/10.1111/j.1751-1097.2012.01165.x pmid: 22540890
192	R Würth, A Pattarozzi, M Gatti, A Bajetto, A Corsaro, A Parodi, R Sirito, M Massollo, C Marini, G Zona, D Fenoglio, G Sambuceti, G Filaci, A Daga, F Barbieri, T Florio. Metformin selectively affects human glioblastoma tumor-initiating cell viability: a role for metformin-induced inhibition of Akt. Cell Cycle 2013; 12(1): 145–156 https://doi.org/10.4161/cc.23050 pmid: 23255107
193	I Ben Sahra, C Regazzetti, G Robert, K Laurent, Y Le Marchand-Brustel, P Auberger, JF Tanti, S Giorgetti-Peraldi, F Bost. Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res 2011; 71(13): 4366–4372 https://doi.org/10.1158/0008-5472.CAN-10-1769 pmid: 21540236
194	SK Jang, SE Hong, DH Lee, JY Kim, JY Kim, SK Ye, J Hong, IC Park, HO Jin. Inhibition of mTORC1 through ATF4-induced REDD1 and Sestrin2 expression by metformin. BMC Cancer 2021; 21(1): 803 https://doi.org/10.1186/s12885-021-08346-x pmid: 34253170
195	MA Pierotti, F Berrino, M Gariboldi, C Melani, A Mogavero, T Negri, P Pasanisi, S Pilotti. Targeting metabolism for cancer treatment and prevention: metformin, an old drug with multi-faceted effects. Oncogene 2013; 32(12): 1475–1487 https://doi.org/10.1038/onc.2012.181 pmid: 22665053
196	G Yenmis, E Yaprak Sarac, N Besli, T Soydas, C Tastan, D Dilek Kancagi, M Yilanci, K Senol, OO Karagulle, CG Ekmekci, E Ovali, M Tuncdemir, T Ulutin, G Kanigur Sultuybek. Anti-cancer effect of metformin on the metastasis and invasion of primary breast cancer cells through mediating NF-kB activity. Acta Histochem 2021; 123(4): 151709 https://doi.org/10.1016/j.acthis.2021.151709 pmid: 33711726
197	WW Wheaton, SE Weinberg, RB Hamanaka, S Soberanes, LB Sullivan, E Anso, A Glasauer, E Dufour, GM Mutlu, GS Budigner, NS Chandel. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. eLife 2014; 3: e02242 https://doi.org/10.7554/eLife.02242 pmid: 24843020
198	D Soranna, L Scotti, A Zambon, C Bosetti, G Grassi, A Catapano, C La Vecchia, G Mancia, G Corrao. Cancer risk associated with use of metformin and sulfonylurea in type 2 diabetes: a meta-analysis. Oncologist 2012; 17(6): 813–822 https://doi.org/10.1634/theoncologist.2011-0462 pmid: 22643536
199	X Sui, Y Xu, J Yang, Y Fang, H Lou, W Han, M Zhang, W Chen, K Wang, D Li, W Jin, F Lou, Y Zheng, H Hu, L Gong, X Zhou, Q Pan, H Pan, X Wang, C He. Use of metformin alone is not associated with survival outcomes of colorectal cancer cell but AMPK activator AICAR sensitizes anticancer effect of 5-fluorouracil through AMPK activation. PLoS One 2014; 9(5): e97781 https://doi.org/10.1371/journal.pone.0097781 pmid: 24849329
200	L Guo, J Cui, H Wang, R Medina, S Zhang, X Zhang, Z Zhuang, Y Lin. Metformin enhances anti-cancer effects of cisplatin in meningioma through AMPK-mTOR signaling pathways. Mol Ther Oncolytics 2021; 20: 119–131 https://doi.org/10.1016/j.omto.2020.11.004 pmid: 33575476
201	J Deng, M Peng, Z Wang, S Zhou, D Xiao, J Deng, X Yang, J Peng, X Yang. Novel application of metformin combined with targeted drugs on anticancer treatment. Cancer Sci 2019; 110(1): 23–30 https://doi.org/10.1111/cas.13849 pmid: 30358009
202	C Saengboonmee, T Sanlung, S Wongkham. Repurposing metformin for cancer treatment: a great challenge of a promising drug. Anticancer Res 2021; 41(12): 5913–5918 https://doi.org/10.21873/anticanres.15410 pmid: 34848445
203	MG Morale, RE Tamura, IGS Rubio. Metformin and cancer hallmarks: molecular mechanisms in thyroid, prostate and head and neck cancer models. Biomolecules 2022; 12(3): 357 https://doi.org/10.3390/biom12030357 pmid: 35327549
204	D Hanahan, RA Weinberg. Hallmarks of cancer: the next generation. Cell 2011; 144(5): 646–674 https://doi.org/10.1016/j.cell.2011.02.013 pmid: 21376230
205	A Luengo, DY Gui, MG Vander Heiden. Targeting metabolism for cancer therapy. Cell Chem Biol 2017; 24(9): 1161–1180 https://doi.org/10.1016/j.chembiol.2017.08.028 pmid: 28938091
206	P Ranganathan, HL McLeod. Methotrexate pharmacogenetics: the first step toward individualized therapy in rheumatoid arthritis. Arthritis Rheum 2006; 54(5): 1366–1377 https://doi.org/10.1002/art.21762 pmid: 16645965
207	EM Pålsson-McDermott, LAJ O’Neill. Targeting immunometabolism as an anti-inflammatory strategy. Cell Res 2020; 30(4): 300–314 https://doi.org/10.1038/s41422-020-0291-z pmid: 32132672
208	L Di Martino, V Tosello, E Peroni, E Piovan. Insights on metabolic reprogramming and its therapeutic potential in acute leukemia. Int J Mol Sci 2021; 22(16): 8738 https://doi.org/10.3390/ijms22168738 pmid: 34445444
209	M Ogawa, T Matsuda, A Ogata, T Hamasaki, A Kumanogoh, T Toyofuku, T Tanaka. DNA damage in rheumatoid arthritis: an age-dependent increase in the lipid peroxidation-derived DNA adduct, heptanone-etheno-2′-deoxycytidine. Autoimmune Dis 2013; 2013: 183487 https://doi.org/10.1155/2013/183487 pmid: 24222845
210	AA El-Sheikh, MA Morsy, AM Abdalla, AH Hamouda, IA Alhaider. Mechanisms of thymoquinone hepatorenal protection in methotrexate-induced toxicity in rats. Mediators Inflamm 2015; 2015: 859383 https://doi.org/10.1155/2015/859383 pmid: 26089605
211	FH Rizk, AAE Saadany, L Dawood, HH Elkaliny, NI Sarhan, R Badawi, S Abd-Elsalam. Metformin ameliorated methotrexate-induced hepatorenal toxicity in rats in addition to its antitumor activity: two birds with one stone. J Inflamm Res 2018; 11: 421–429 https://doi.org/10.2147/JIR.S178767 pmid: 30519070
212	SE Owumi, IJ Ajijola, OM Agbeti. Hepatorenal protective effects of protocatechuic acid in rats administered with anticancer drug methotrexate. Hum Exp Toxicol 2019; 38(11): 1254–1265 https://doi.org/10.1177/0960327119871095 pmid: 31431087
213	Y Wang, H Lu, L Sun, X Chen, H Wei, C Suo, J Feng, M Yuan, S Shen, W Jia, Y Wang, H Zhang, Z Li, X Zhong, P Gao. Metformin sensitises hepatocarcinoma cells to methotrexate by targeting dihydrofolate reductase. Cell Death Dis 2021; 12(10): 902 https://doi.org/10.1038/s41419-021-04199-1 pmid: 34601503
214	KL Poulsen, J Olivero-Verbel, KM Beggs, PE Ganey, RA Roth. Trovafloxacin enhances lipopolysaccharide-stimulated production of tumor necrosis factor-α by macrophages: role of the DNA damage response. J Pharmacol Exp Ther 2014; 350(1): 164–170 https://doi.org/10.1124/jpet.114.214189 pmid: 24817034
215	K Harada, T Ferdous, T Harada, Y Ueyama. Metformin in combination with 5-fluorouracil suppresses tumor growth by inhibiting the Warburg effect in human oral squamous cell carcinoma. Int J Oncol 2016; 49(1): 276–284 https://doi.org/10.3892/ijo.2016.3523 pmid: 27210058
216	S Honjo, JA Ajani, AW Scott, Q Chen, HD Skinner, J Stroehlein, RL Johnson, S Song. Metformin sensitizes chemotherapy by targeting cancer stem cells and the mTOR pathway in esophageal cancer. Int J Oncol 2014; 45(2): 567–574 https://doi.org/10.3892/ijo.2014.2450 pmid: 24859412
217	Y Tian, B Tang, C Wang, D Sun, R Zhang, N Luo, Z Han, R Liang, Z Gao, L Wang. Metformin mediates resensitivity to 5-fluorouracil in hepatocellular carcinoma via the suppression of YAP. Oncotarget 2016; 7(29): 46230–46241 https://doi.org/10.18632/oncotarget.10079 pmid: 27323827
218	VC Miranda, MI Braghiroli, LD Faria, G Bariani, A Alex, JE Bezerra Neto, FC Capareli, J Sabbaga, JF Lobo Dos Santos, PM Hoff, RP Riechelmann. Phase 2 trial of metformin combined with 5-fluorouracil in patients with refractory metastatic colorectal cancer. Clin Colorectal Cancer 2016; 15(4): 321–328.e1 https://doi.org/10.1016/j.clcc.2016.04.011 pmid: 27262895
219	R You, B Wang, P Chen, X Zheng, D Hou, X Wang, B Zhang, L Chen, D Li, X Lin, H Huang. Metformin sensitizes AML cells to chemotherapy through blocking mitochondrial transfer from stromal cells to AML cells. Cancer Lett 2022; 532: 215582 https://doi.org/10.1016/j.canlet.2022.215582 pmid: 35122876
220	Y Zhang, A Paikari, P Sumazin, CC Ginter Summarell, JR Crosby, E Boerwinkle, MJ Weiss, VA Sheehan. Metformin induces FOXO3-dependent fetal hemoglobin production in human primary erythroid cells. Blood 2018; 132(3): 321–333 https://doi.org/10.1182/blood-2017-11-814335 pmid: 29884740
221	K Taba, Y Kuramitsu, S Ryozawa, K Yoshida, T Tanaka, S Maehara, Y Maehara, I Sakaida, K Nakamura. Heat-shock protein 27 is phosphorylated in gemcitabine-resistant pancreatic cancer cells. Anticancer Res 2010; 30(7): 2539–2543 pmid: 20682980
222	B Baron, Y Wang, S Maehara, Y Maehara, Y Kuramitsu, K Nakamura. Resistance to gemcitabine in the pancreatic cancer cell line KLM1-R reversed by metformin action. Anticancer Res 2015; 35(4): 1941–1949 pmid: 25862846
223	X Chai, H Chu, X Yang, Y Meng, P Shi, S Gou. Metformin increases sensitivity of pancreatic cancer cells to gemcitabine by reducing CD133+ cell populations and suppressing ERK/P70S6K signaling. Sci Rep 2015; 5(1): 14404 https://doi.org/10.1038/srep14404 pmid: 26391180
224	Y Yi, L Gao, M Wu, J Ao, C Zhang, X Wang, M Lin, J Bergholz, Y Zhang, ZJ Xiao. Metformin sensitizes leukemia cells to vincristine via activation of AMP-activated protein kinase. J Cancer 2017; 8(13): 2636–2642 https://doi.org/10.7150/jca.19873 pmid: 28900501
225	M Trucco, JC Barredo, J Goldberg, GM Leclerc, GA Hale, J Gill, B Setty, T Smith, R Lush, JK Lee, DR Reed. A phase I window, dose escalating and safety trial of metformin in combination with induction chemotherapy in relapsed refractory acute lymphoblastic leukemia: Metformin with induction chemotherapy of vincristine, dexamethasone, PEG-asparaginase, and doxorubicin. Pediatr Blood Cancer 2018; 65(9): e27224 https://doi.org/10.1002/pbc.27224 pmid: 29856514
226	X Fan, HJ Zhong, BB Zhao, BS Ou Yang, Y Zhao, J Ye, YM Lu, CF Wang, H Xiong, SJ Chen, A Janin, L Wang, WL Zhao. Metformin prolonged the survival of diffuse large B-cell lymphoma and grade 3b follicular lymphoma patients responding to first-line treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone: a prospective phase II clinical trial. Transl Cancer Res 2018; 7(4): 1044–1053 https://doi.org/10.21037/tcr.2018.07.20
227	RK Hanna, C Zhou, KM Malloy, L Sun, Y Zhong, PA Gehrig, VL Bae-Jump. Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway. Gynecol Oncol 2012; 125(2): 458–469 https://doi.org/10.1016/j.ygyno.2012.01.009 pmid: 22252099
228	GZ Rocha, MM Dias, ER Ropelle, F Osório-Costa, FA Rossato, AE Vercesi, MJ Saad, JB Carvalheira. Metformin amplifies chemotherapy-induced AMPK activation and antitumoral growth. Clin Cancer Res 2011; 17(12): 3993–4005 https://doi.org/10.1158/1078-0432.CCR-10-2243 pmid: 21543517
229	Y Zhao, X Zeng, H Tang, D Ye, J Liu. Combination of metformin and paclitaxel suppresses proliferation and induces apoptosis of human prostate cancer cells via oxidative stress and targeting the mitochondria-dependent pathway. Oncol Lett 2019; 17(5): 4277–4284 https://doi.org/10.3892/ol.2019.10119 pmid: 30944622
230	SC Tseng, YC Huang, HJ Chen, HC Chiu, YJ Huang, TY Wo, SH Weng, YW Lin. Metformin-mediated downregulation of p38 mitogen-activated protein kinase-dependent excision repair cross-complementing 1 decreases DNA repair capacity and sensitizes human lung cancer cells to paclitaxel. Biochem Pharmacol 2013; 85(4): 583–594 https://doi.org/10.1016/j.bcp.2012.12.001 pmid: 23228696
231	E Lengyel, LM Litchfield, AK Mitra, KM Nieman, A Mukherjee, Y Zhang, A Johnson, M Bradaric, W Lee, IL Romero. Metformin inhibits ovarian cancer growth and increases sensitivity to paclitaxel in mouse models. Am J Obstet Gynecol. 2015; 212(4): 479.e1–479.e10 https://doi.org/10.1016/j.ajog.2014.10.026 pmid: 25446664
232	MJ Mayer, LH Klotz, V Venkateswaran. The effect of metformin use during docetaxel chemotherapy on prostate cancer specific and overall survival of diabetic patients with castration resistant prostate cancer. J Urol 2017; 197(4): 1068–1075 https://doi.org/10.1016/j.juro.2016.10.069 pmid: 27984108
233	MJ Mayer, LH Klotz, V Venkateswaran. Evaluating metformin as a potential chemosensitizing agent when combined with docetaxel chemotherapy in castration-resistant prostate cancer cells. Anticancer Res 2017; 37(12): 6601–6607 pmid: 29187435
234	MA Babcook, S Shukla, P Fu, EJ Vazquez, MA Puchowicz, JP Molter, CZ Oak, GT MacLennan, CA Flask, DJ Lindner, Y Parker, F Daneshgari, S Gupta. Synergistic simvastatin and metformin combination chemotherapy for osseous metastatic castration-resistant prostate cancer. Mol Cancer Ther 2014; 13(10): 2288–2302 https://doi.org/10.1158/1535-7163.MCT-14-0451 pmid: 25122066
235	AM Fontebasso, J Schwartzentruber, DA Khuong-Quang, XY Liu, D Sturm, A Korshunov, DT Jones, H Witt, M Kool, S Albrecht, A Fleming, D Hadjadj, S Busche, P Lepage, A Montpetit, A Staffa, N Gerges, M Zakrzewska, K Zakrzewski, PP Liberski, P Hauser, M Garami, A Klekner, L Bognar, G Zadeh, D Faury, SM Pfister, N Jabado, J Majewski. Mutations in SETD2 and genes affecting histone H3K36 methylation target hemispheric high-grade gliomas. Acta Neuropathol 2013; 125(5): 659–669 https://doi.org/10.1007/s00401-013-1095-8 pmid: 23417712
236	Y Li, J Luo, MT Lin, P Zhi, WW Guo, M Han, J You, JQ Gao. Co-delivery of metformin enhances the antimultidrug resistant tumor effect of doxorubicin by improving hypoxic tumor microenvironment. Mol Pharm 2019; 16(7): 2966–2979 https://doi.org/10.1021/acs.molpharmaceut.9b00199 pmid: 31095914
237	AE Ashour, MM Sayed-Ahmed, AR Abd-Allah, HM Korashy, ZH Maayah, H Alkhalidi, M Mubarak, A Alhaider. Metformin rescues the myocardium from doxorubicin-induced energy starvation and mitochondrial damage in rats. Oxid Med Cell Longev 2012; 2012: 434195 https://doi.org/10.1155/2012/434195 pmid: 22666520
238	AH Ajzashokouhi, HB Bostan, V Jomezadeh, AW Hayes, G Karimi. A review on the cardioprotective mechanisms of metformin against doxorubicin. Hum Exp Toxicol 2020; 39(3): 237–248 https://doi.org/10.1177/0960327119888277 pmid: 31735071
239	LC Kobashigawa, YC Xu, JF Padbury, YT Tseng, N Yano. Metformin protects cardiomyocyte from doxorubicin induced cytotoxicity through an AMP-activated protein kinase dependent signaling pathway: an in vitro study. PLoS One 2014; 9(8): e104888 https://doi.org/10.1371/journal.pone.0104888 pmid: 25127116
240	V Shafiei-Irannejad, N Samadi, B Yousefi, R Salehi, K Velaei, N Zarghami. Metformin enhances doxorubicin sensitivity via inhibition of doxorubicin efflux in P-gp-overexpressing MCF-7 cells. Chem Biol Drug Des 2018; 91(1): 269–276 https://doi.org/10.1111/cbdd.13078 pmid: 28782285
241	G Chen, S Xu, K Renko, M Derwahl. Metformin inhibits growth of thyroid carcinoma cells, suppresses self-renewal of derived cancer stem cells, and potentiates the effect of chemotherapeutic agents. J Clin Endocrinol Metab 2012; 97(4): E510–E520 https://doi.org/10.1210/jc.2011-1754 pmid: 22278418
242	HA Hirsch, D Iliopoulos, K Struhl. Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc Natl Acad Sci USA 2013; 110(3): 972–977 https://doi.org/10.1073/pnas.1221055110 pmid: 23277563
243	D Iliopoulos, HA Hirsch, K Struhl. Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res 2011; 71(9): 3196–3201 https://doi.org/10.1158/0008-5472.CAN-10-3471 pmid: 21415163
244	JO Lee, MJ Kang, WS Byun, SA Kim, IH Seo, JA Han, JW Moon, JH Kim, SJ Kim, EJ Lee, S In Park, SH Park, HS Kim. Metformin overcomes resistance to cisplatin in triple-negative breast cancer (TNBC) cells by targeting RAD51. Breast Cancer Res 2019; 21(1): 115 https://doi.org/10.1186/s13058-019-1204-2 pmid: 31640742
245	CC Lin, HH Yeh, WL Huang, JJ Yan, WW Lai, WP Su, HH Chen, WC Su. Metformin enhances cisplatin cytotoxicity by suppressing signal transducer and activator of transcription-3 activity independently of the liver kinase B1-AMP-activated protein kinase pathway. Am J Respir Cell Mol Biol 2013; 49(2): 241–250 https://doi.org/10.1165/rcmb.2012-0244OC pmid: 23526220
246	TC Jr Tortelli, RE Tamura, Souza Junqueira M de, Silva Mororó J da, SO Bustos, RJM Natalino, S Russell, L Désaubry, BE Strauss, R Chammas. Metformin-induced chemosensitization to cisplatin depends on P53 status and is inhibited by Jarid1b overexpression in non-small cell lung cancer cells. Aging (Albany NY) 2021; 13(18): 21914–21940 https://doi.org/10.18632/aging.203528 pmid: 34528900
247	L Shi, Y Mei, X Duan, B Wang. Effects of cisplatin combined with metformin on proliferation and apoptosis of nasopharyngeal carcinoma cells. Comput Math Methods Med 2022; 2022: 2056247 https://doi.org/10.1155/2022/2056247 pmid: 35422875
248	A Yasmeen, MC Beauchamp, E Piura, E Segal, M Pollak, WH Gotlieb. Induction of apoptosis by metformin in epithelial ovarian cancer: involvement of the Bcl-2 family proteins. Gynecol Oncol 2011; 121(3): 492–498 https://doi.org/10.1016/j.ygyno.2011.02.021 pmid: 21388661
249	K He, Z Li, K Ye, Y Zhou, M Yan, H Qi, H Hu, Y Dai, Y Tang. Novel sequential therapy with metformin enhances the effects of cisplatin in testicular germ cell tumours via YAP1 signalling. Cancer Cell Int 2022; 22(1): 113 https://doi.org/10.1186/s12935-022-02534-w pmid: 35264157
250	Z Liang, T Zhang, T Zhan, G Cheng, W Zhang, H Jia, H Yang. Metformin alleviates cisplatin-induced ototoxicity by autophagy induction possibly via the AMPK/FOXO3a pathway. J Neurophysiol 2021; 125(4): 1202–1212 https://doi.org/10.1152/jn.00417.2020 pmid: 33625942
251	W Zhou, A Kavelaars, CJ Heijnen. Metformin prevents cisplatin-induced cognitive impairment and brain damage in mice. PLoS One 2016; 11(3): e0151890 https://doi.org/10.1371/journal.pone.0151890 pmid: 27018597
252	CS Haas, CJ Creighton, X Pi, I Maine, AE Koch, GK Haines, S Ling, AM Chinnaiyan, J Holoshitz. Identification of genes modulated in rheumatoid arthritis using complementary DNA microarray analysis of lymphoblastoid B cell lines from disease-discordant monozygotic twins. Arthritis Rheum 2006; 54(7): 2047–2060 https://doi.org/10.1002/art.21953 pmid: 16804865
253	AF Tohamy, S Hussein, IM Moussa, H Rizk, S Daghash, RA Alsubki, AS Mubarak, HO Alshammari, KS Al-Maary, HA Hemeg. Lucrative antioxidant effect of metformin against cyclophosphamide induced nephrotoxicity. Saudi J Biol Sci 2021; 28(5): 2755–2761 https://doi.org/10.1016/j.sjbs.2021.03.039 pmid: 34025161
254	S Ling, Q Shan, P Liu, T Feng, X Zhang, P Xiang, K Chen, H Xie, P Song, L Zhou, J Liu, S Zheng, X Xu. Metformin ameliorates arsenic trioxide hepatotoxicity via inhibiting mitochondrial complex I. Cell Death Dis 2017; 8(11): e3159 https://doi.org/10.1038/cddis.2017.482 pmid: 29095437
255	X Yang, D Sun, Y Tian, S Ling, L Wang. Metformin sensitizes hepatocellular carcinoma to arsenic trioxide-induced apoptosis by downregulating Bcl2 expression. Tumour Biol 2015; 36(4): 2957–2964 https://doi.org/10.1007/s13277-014-2926-5 pmid: 25492486
256	S Ling, H Xie, F Yang, Q Shan, H Dai, J Zhuo, X Wei, P Song, L Zhou, X Xu, S Zheng. Metformin potentiates the effect of arsenic trioxide suppressing intrahepatic cholangiocarcinoma: roles of p38 MAPK, ERK3, and mTORC1. J Hematol Oncol 2017; 10(1): 59 https://doi.org/10.1186/s13045-017-0424-0 pmid: 28241849
257	DL Wheeler, EF Dunn, PM Harari. Understanding resistance to EGFR inhibitors-impact on future treatment strategies. Nat Rev Clin Oncol 2010; 7(9): 493–507 https://doi.org/10.1038/nrclinonc.2010.97 pmid: 20551942
258	H Chen, Y Wang, C Lin, C Lu, R Han, L Jiao, L Li, Y He. Vorinostat and metformin sensitize EGFR-TKI resistant NSCLC cells via BIM-dependent apoptosis induction. Oncotarget 2017; 8(55): 93825–93838 https://doi.org/10.18632/oncotarget.21225 pmid: 29212192
259	L Li, R Han, H Xiao, C Lin, Y Wang, H Liu, K Li, H Chen, F Sun, Z Yang, J Jiang, Y He. Metformin sensitizes EGFR-TKI-resistant human lung cancer cells in vitro and in vivo through inhibition of IL-6 signaling and EMT reversal. Clin Cancer Res 2014; 20(10): 2714–2726 https://doi.org/10.1158/1078-0432.CCR-13-2613 pmid: 24644001
260	YH Pan, L Jiao, CY Lin, CH Lu, L Li, HY Chen, YB Wang, Y He. Combined treatment with metformin and gefitinib overcomes primary resistance to EGFR-TKIs with EGFR mutation via targeting IGF-1R signaling pathway. Biologics 2018; 12: 75–86 pmid: 30154647
261	MW Saif. Pancreatic neoplasm in 2011: an update. JOP 2011; 12(4): 316–321 pmid: 21737886
262	G Ariaans, M Jalving, EG Vries, S Jong. Anti-tumor effects of everolimus and metformin are complementary and glucose-dependent in breast cancer cells. BMC Cancer 2017; 17(1): 232 https://doi.org/10.1186/s12885-017-3230-8 pmid: 28356082
263	E Fuentes-Mattei, G Velazquez-Torres, L Phan, F Zhang, PC Chou, JH Shin, HH Choi, JS Chen, R Zhao, J Chen, C Gully, C Carlock, Y Qi, Y Zhang, Y Wu, FJ Esteva, Y Luo, WL McKeehan, J Ensor, GN Hortobagyi, L Pusztai, W Fraser Symmans, MH Lee, SC Yeung. Effects of obesity on transcriptomic changes and cancer hallmarks in estrogen receptor-positive breast cancer. J Natl Cancer Inst 2014; 106(7): dju158 https://doi.org/10.1093/jnci/dju158 pmid: 24957076
264	S Pusceddu, C Vernieri, Maio M Di, R Marconcini, F Spada, S Massironi, T Ibrahim, MP Brizzi, D Campana, A Faggiano, D Giuffrida, M Rinzivillo, S Cingarlini, F Aroldi, L Antonuzzo, R Berardi, L Catena, Divitiis C De, P Ermacora, V Perfetti, A Fontana, P Razzore, C Carnaghi, MV Davì, C Cauchi, M Duro, S Ricci, N Fazio, F Cavalcoli, A Bongiovanni, Salvia A La, N Brighi, A Colao, I Puliafito, F Panzuto, S Ortolani, A Zaniboni, Costanzo F Di, M Torniai, E Bajetta, S Tafuto, SK Garattini, D Femia, N Prinzi, L Concas, Russo G Lo, M Milione, L Giacomelli, R Buzzoni, Fave G Delle, V Mazzaferro, Braud F de. Metformin use is associated with longer progression-free survival of patients with diabetes and pancreatic neuroendocrine tumors receiving everolimus and/or somatostatin analogues. Gastroenterology 2018; 155(2): 479–489.e7 https://doi.org/10.1053/j.gastro.2018.04.010 pmid: 29655834
265	HP Gerber, N Ferrara. Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res 2005; 65(3): 671–680 https://doi.org/10.1158/0008-5472.671.65.3 pmid: 15705858
266	N Ferrara, KJ Hillan, HP Gerber, W Novotny. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004; 3(5): 391–400 https://doi.org/10.1038/nrd1381 pmid: 15136787
267	S Indraccolo, G Randon, E Zulato, M Nardin, C Aliberti, F Pomerri, A Casarin, MO Nicoletto. Metformin: a modulator of bevacizumab activity in cancer? A case report. Cancer Biol Ther 2015; 16(2): 210–214 https://doi.org/10.1080/15384047.2014.1002366 pmid: 25607951
268	A Markowska, S Sajdak, J Markowska, A Huczyński. Angiogenesis and cancer stem cells: new perspectives on therapy of ovarian cancer. Eur J Med Chem 2017; 142: 87–94 https://doi.org/10.1016/j.ejmech.2017.06.030 pmid: 28651817
269	LN Klapper, H Waterman, M Sela, Y Yarden. Tumor-inhibitory antibodies to HER-2/ErbB-2 may act by recruiting c-Cbl and enhancing ubiquitination of HER-2. Cancer Res 2000; 60(13): 3384–3388 pmid: 10910043
270	M Zeglinski, A Ludke, DS Jassal, PK Singal. Trastuzumab-induced cardiac dysfunction: a ‘dual-hit’. Exp Clin Cardiol 2011; 16(3): 70–74 pmid: 22065936
271	HA Hirsch, D Iliopoulos, PN Tsichlis, K Struhl. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res 2009; 69(19): 7507–7511 https://doi.org/10.1158/0008-5472.CAN-09-2994 pmid: 19752085
272	B Liu, Z Fan, SM Edgerton, X Yang, SE Lind, AD Thor. Potent anti-proliferative effects of metformin on trastuzumab-resistant breast cancer cells via inhibition of erbB2/IGF-1 receptor interactions. Cell Cycle 2011; 10(17): 2959–2966 https://doi.org/10.4161/cc.10.17.16359 pmid: 21862872
273	FH Groenendijk, WW Mellema, E van der Burg, E Schut, M Hauptmann, HM Horlings, SM Willems, MM van den Heuvel, J Jonkers, EF Smit, R Bernards. Sorafenib synergizes with metformin in NSCLC through AMPK pathway activation. Int J Cancer 2015; 136(6): 1434–1444 https://doi.org/10.1002/ijc.29113 pmid: 25080865
274	G Chen, D Nicula, K Renko, M Derwahl. Synergistic anti-proliferative effect of metformin and sorafenib on growth of anaplastic thyroid cancer cells and their stem cells. Oncol Rep 2015; 33(4): 1994–2000 https://doi.org/10.3892/or.2015.3805 pmid: 25683253
275	SC Hsieh, JP Tsai, SF Yang, MJ Tang, YH Hsieh. Metformin inhibits the invasion of human hepatocellular carcinoma cells and enhances the chemosensitivity to sorafenib through a downregulation of the ERK/JNK-mediated NF-κB-dependent pathway that reduces uPA and MMP-9 expression. Amino Acids 2014; 46(12): 2809–2822 https://doi.org/10.1007/s00726-014-1838-4 pmid: 25245054
276	HY Lai, HH Tsai, CJ Yen, LY Hung, CC Yang, CH Ho, HY Liang, FW Chen, CF Li, JM Wang. Metformin resensitizes sorafenib-resistant HCC cells through AMPK-dependent autophagy activation. Front Cell Dev Biol 2021; 8: 596655 https://doi.org/10.3389/fcell.2020.596655 pmid: 33681180
277	R Mitchell, LEM Hopcroft, P Baquero, EK Allan, K Hewit, D James, G Hamilton, A Mukhopadhyay, J O’Prey, A Hair, JV Melo, E Chan, KM Ryan, V Maguer-Satta, BJ Druker, RE Clark, S Mitra, P Herzyk, FE Nicolini, P Salomoni, E Shanks, B Calabretta, TL Holyoake, GV Helgason. Targeting BCR-ABL-independent TKI resistance in chronic myeloid leukemia by mTOR and autophagy inhibition. J Natl Cancer Inst 2018; 110(5): 467–478 https://doi.org/10.1093/jnci/djx236 pmid: 29165716
278	E Vakana, JK Altman, H Glaser, NJ Donato, LC Platanias. Antileukemic effects of AMPK activators on BCR-ABL-expressing cells. Blood 2011; 118(24): 6399–6402 https://doi.org/10.1182/blood-2011-01-332783 pmid: 22021366
279	S Bagchi, R Yuan, EG Engleman. Immune checkpoint inhibitors for the treatment of cancer: clinical impact and mechanisms of response and resistance. Annu Rev Pathol 2021; 16(1): 223–249 https://doi.org/10.1146/annurev-pathol-042020-042741 pmid: 33197221
280	JH Cha, WH Yang, W Xia, Y Wei, LC Chan, SO Lim, CW Li, T Kim, SS Chang, HH Lee, JL Hsu, HL Wang, CW Kuo, WC Chang, S Hadad, CA Purdie, AM McCoy, S Cai, Y Tu, JK Litton, EA Mittendorf, SL Moulder, WF Symmans, AM Thompson, H Piwnica-Worms, CH Chen, KH Khoo, MC Hung. Metformin promotes antitumor immunity via endoplasmic-reticulum-associated degradation of PD-L1. Mol Cell 2018; 71(4): 606–620.e7 https://doi.org/10.1016/j.molcel.2018.07.030 pmid: 30118680
281	P Darvin, SM Toor, V Sasidharan Nair, E Elkord. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med 2018; 50(12): 1–11 https://doi.org/10.1038/s12276-018-0191-1 pmid: 30546008
282	M Philip, A Schietinger. CD8+ T cell differentiation and dysfunction in cancer. Nat Rev Immunol 2022; 22(4): 209–223 https://doi.org/10.1038/s41577-021-00574-3 pmid: 34253904
283	JS Yi, MA Cox, AJ Zajac. T-cell exhaustion: characteristics, causes and conversion. Immunology 2010; 129(4): 474–481 https://doi.org/10.1111/j.1365-2567.2010.03255.x pmid: 20201977
284	S Eikawa, M Nishida, S Mizukami, C Yamazaki, E Nakayama, H Udono. Immune-mediated antitumor effect by type 2 diabetes drug, metformin. Proc Natl Acad Sci USA 2015; 112(6): 1809–1814 https://doi.org/10.1073/pnas.1417636112 pmid: 25624476
285	Z Zhang, F Li, Y Tian, L Cao, Q Gao, C Zhang, K Zhang, C Shen, Y Ping, NR Maimela, L Wang, B Zhang, Y Zhang. Metformin enhances the antitumor activity of CD8+ T lymphocytes via the AMPK-miR-107-Eomes-PD-1 Pathway. J Immunol 2020; 204(9): 2575–2588 https://doi.org/10.4049/jimmunol.1901213 pmid: 32221038
286	MZ Afzal, RR Mercado, K Shirai. Efficacy of metformin in combination with immune checkpoint inhibitors (anti-PD-1/anti-CTLA-4) in metastatic malignant melanoma. J Immunother Cancer 2018; 6(1): 64 https://doi.org/10.1186/s40425-018-0375-1 pmid: 29966520
287	YM Chung, PP Khan, H Wang, WB Tsai, Y Qiao, B Yu, JW Larrick, MC Hu. Sensitizing tumors to anti-PD-1 therapy by promoting NK and CD8+ T cells via pharmacological activation of FOXO3. J Immunother Cancer 2021; 9(12): e002772 https://doi.org/10.1136/jitc-2021-002772 pmid: 34887262
288	LE Munoz, L Huang, R Bommireddy, R Sharma, L Monterroza, RN Guin, SG Samaranayake, CD Pack, S Ramachandiran, SJC Reddy, M Shanmugam, P Selvaraj. Metformin reduces PD-L1 on tumor cells and enhances the anti-tumor immune response generated by vaccine immunotherapy. J Immunother Cancer 2021; 9(11): e002614 https://doi.org/10.1136/jitc-2021-002614 pmid: 34815353
289	NE Scharping, AV Menk, RD Whetstone, X Zeng, GM Delgoffe. Efficacy of PD-1 blockade is potentiated by metformin-induced reduction of tumor hypoxia. Cancer Immunol Res 2017; 5(1): 9–16 https://doi.org/10.1158/2326-6066.CIR-16-0103 pmid: 27941003
290	SY Wu, T Fu, YZ Jiang, ZM Shao. Natural killer cells in cancer biology and therapy. Mol Cancer 2020; 19(1): 120 https://doi.org/10.1186/s12943-020-01238-x pmid: 32762681
291	C Xia, C Liu, Z He, Y Cai, J Chen. Metformin inhibits cervical cancer cell proliferation by modulating PI3K/Akt-induced major histocompatibility complex class I-related chain A gene expression. J Exp Clin Cancer Res 2020; 39(1): 127 https://doi.org/10.1186/s13046-020-01627-6 pmid: 32631421
292	W Xia, X Qi, M Li, Y Wu, L Sun, X Fan, Y Yuan, J Li. Metformin promotes anticancer activity of NK cells in a p38 MAPK dependent manner. OncoImmunology 2021; 10(1): 1995999 https://doi.org/10.1080/2162402X.2021.1995999 pmid: 34745769
293	RJ Tesi. MDSC; the most important cell you have never heard of. Trends Pharmacol Sci 2019; 40(1): 4–7 https://doi.org/10.1016/j.tips.2018.10.008 pmid: 30527590
294	P Xu, K Yin, X Tang, J Tian, Y Zhang, J Ma, H Xu, Q Xu, S Wang. Metformin inhibits the function of granulocytic myeloid-derived suppressor cells in tumor-bearing mice. Biomed Pharmacother 2019; 120: 109458 https://doi.org/10.1016/j.biopha.2019.109458 pmid: 31550676
295	G Qin, J Lian, L Huang, Q Zhao, S Liu, Z Zhang, X Chen, D Yue, L Li, F Li, L Wang, V Umansky, B Zhang, S Yang, Y Zhang. Metformin blocks myeloid-derived suppressor cell accumulation through AMPK-DACH1-CXCL1 axis. OncoImmunology 2018; 7(7): e1442167 https://doi.org/10.1080/2162402X.2018.1442167 pmid: 29900050
296	L Li, L Wang, J Li, Z Fan, L Yang, Z Zhang, C Zhang, D Yue, G Qin, T Zhang, F Li, X Chen, Y Ping, D Wang, Q Gao, Q He, L Huang, H Li, J Huang, X Zhao, W Xue, Z Sun, J Lu, JJ Yu, J Zhao, B Zhang, Y Zhang. Metformin-induced reduction of CD39 and CD73 blocks myeloid-derived suppressor cell activity in patients with ovarian cancer. Cancer Res 2018; 78(7): 1779–1791 https://doi.org/10.1158/0008-5472.CAN-17-2460 pmid: 29374065
297	L Ding, G Liang, Z Yao, J Zhang, R Liu, H Chen, Y Zhou, H Wu, B Yang, Q He. Metformin prevents cancer metastasis by inhibiting M2-like polarization of tumor associated macrophages. Oncotarget 2015; 6(34): 36441–36455 https://doi.org/10.18632/oncotarget.5541 pmid: 26497364
298	CF Chiang, TT Chao, YF Su, CC Hsu, CY Chien, KC Chiu, SG Shiah, CH Lee, SY Liu, YS Shieh. Metformin-treated cancer cells modulate macrophage polarization through AMPK-NF-κB signaling. Oncotarget 2017; 8(13): 20706–20718 https://doi.org/10.18632/oncotarget.14982 pmid: 28157701
299	JC Wang, X Sun, Q Ma, GF Fu, LL Cong, H Zhang, DF Fan, J Feng, SY Lu, JL Liu, GY Li, PJ Liu. Metformin’s antitumour and anti-angiogenic activities are mediated by skewing macrophage polarization. J Cell Mol Med 2018; 22(8): 3825–3836 https://doi.org/10.1111/jcmm.13655 pmid: 29726618
300	S Wang, Y Lin, X Xiong, L Wang, Y Guo, Y Chen, S Chen, G Wang, P Lin, H Chen, SJ Yeung, E Bremer, H Zhang. Low-dose metformin reprograms the tumor immune microenvironment in human esophageal cancer: results of a phase II clinical trial. Clin Cancer Res 2020; 26(18): 4921–4932 https://doi.org/10.1158/1078-0432.CCR-20-0113 pmid: 32646922
301	A Saito, J Kitayama, H Horie, K Koinuma, H Ohzawa, H Yamaguchi, H Kawahira, T Mimura, AK Lefor, N Sata. Metformin changes the immune microenvironment of colorectal cancer in patients with type 2 diabetes mellitus. Cancer Sci 2020; 111(11): 4012–4020 https://doi.org/10.1111/cas.14615 pmid: 32794612
302	Y Kunisada, S Eikawa, N Tomonobu, S Domae, T Uehara, S Hori, Y Furusawa, K Hase, A Sasaki, H Udono. Attenuation of CD4+CD25+ regulatory T cells in the tumor microenvironment by metformin, a type 2 diabetes drug. EBioMedicine 2017; 25: 154–164 https://doi.org/10.1016/j.ebiom.2017.10.009 pmid: 29066174
303	R Veeramachaneni, W Yu, JM Newton, JO Kemnade, HD Skinner, AG Sikora, VC Sandulache. Metformin generates profound alterations in systemic and tumor immunity with associated antitumor effects. J Immunother Cancer 2021; 9(7): e002773 https://doi.org/10.1136/jitc-2021-002773 pmid: 34230113
304	JP da Costa, R Vitorino, GM Silva, C Vogel, AC Duarte, T Rocha-Santos. A synopsis on aging—theories, mechanisms and future prospects. Ageing Res Rev 2016; 29: 90–112 https://doi.org/10.1016/j.arr.2016.06.005 pmid: 27353257
305	BG Childs, M Durik, DJ Baker, JM van Deursen. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med 2015; 21(12): 1424–1435 https://doi.org/10.1038/nm.4000 pmid: 26646499
306	E Rudnicka, P Napierała, A Podfigurna, B Męczekalski, R Smolarczyk, M Grymowicz. The World Health Organization (WHO) approach to healthy ageing. Maturitas 2020; 139: 6–11 https://doi.org/10.1016/j.maturitas.2020.05.018 pmid: 32747042
307	CA Bannister, SE Holden, S Jenkins-Jones, CL Morgan, JP Halcox, G Schernthaner, J Mukherjee, CJ Currie. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes Obes Metab 2014; 16(11): 1165–1173 https://doi.org/10.1111/dom.12354 pmid: 25041462
308	J Chen, Y Ou, Y Li, S Hu, LW Shao, Y Liu. Metformin extends C. elegans lifespan through lysosomal pathway. eLife 2017; 6: e31268 https://doi.org/10.7554/eLife.31268 pmid: 29027899
309	A Martin-Montalvo, EM Mercken, SJ Mitchell, HH Palacios, PL Mote, M Scheibye-Knudsen, AP Gomes, TM Ward, RK Minor, MJ Blouin, M Schwab, M Pollak, Y Zhang, Y Yu, KG Becker, VA Bohr, DK Ingram, DA Sinclair, NS Wolf, SR Spindler, M Bernier, R de Cabo. Metformin improves healthspan and lifespan in mice. Nat Commun 2013; 4(1): 2192 https://doi.org/10.1038/ncomms3192 pmid: 23900241
310	AS Kulkarni, EF Brutsaert, V Anghel, K Zhang, N Bloomgarden, M Pollak, JC Mar, M Hawkins, JP Crandall, N Barzilai. Metformin regulates metabolic and nonmetabolic pathways in skeletal muscle and subcutaneous adipose tissues of older adults. Aging Cell 2018; 17(2): e12723 https://doi.org/10.1111/acel.12723 pmid: 29383869
311	JN Justice, L Niedernhofer, PD Robbins, VR Aroda, MA Espeland, SB Kritchevsky, GA Kuchel, N Barzilai. Development of clinical trials to extend healthy lifespan. Cardiovasc Endocrinol Metab 2018; 7(4): 80–83 https://doi.org/10.1097/XCE.0000000000000159 pmid: 30906924
312	N Barzilai, JP Crandall, SB Kritchevsky, MA Espeland. Metformin as a tool to target aging. Cell Metab 2016; 23(6): 1060–1065 https://doi.org/10.1016/j.cmet.2016.05.011 pmid: 27304507
313	AL Blitzer, SA Ham, KA Colby, D Skondra. Association of metformin use with age-related macular degeneration: a case-control study. JAMA Ophthalmol 2021; 139(3): 302–309 https://doi.org/10.1001/jamaophthalmol.2020.6331 pmid: 33475696
314	RB Goldberg, VR Aroda, DA Bluemke, E Barrett-Connor, M Budoff, JP Crandall, D Dabelea, ES Horton, KJ Mather, TJ Orchard, D Schade, K Watson, M; Diabetes Prevention Program Research Group Temprosa. Effect of long-term metformin and lifestyle in the diabetes prevention program and its outcome study on coronary artery calcium. Circulation 2017; 136(1): 52–64 https://doi.org/10.1161/CIRCULATIONAHA.116.025483 pmid: 28476766
315	AV Zilov, SI Abdelaziz, A AlShammary, A Al Zahrani, A Amir, SH Assaad Khalil, K Brand, N Elkafrawy, AAK Hassoun, A Jahed, N Jarrah, S Mrabeti, I Paruk. Mechanisms of action of metformin with special reference to cardiovascular protection. Diabetes Metab Res Rev 2019; 35(7): e3173 https://doi.org/10.1002/dmrr.3173 pmid: 31021474
316	Y Han, H Xie, Y Liu, P Gao, X Yang, Z Shen. Effect of metformin on all-cause and cardiovascular mortality in patients with coronary artery diseases: a systematic review and an updated meta-analysis. Cardiovasc Diabetol 2019; 18(1): 96 https://doi.org/10.1186/s12933-019-0900-7 pmid: 31362743
317	A Havas, S Yin, PD Adams. The role of aging in cancer. Mol Oncol 2022; 16(18): 3213–3219 https://doi.org/10.1002/1878-0261.13302 pmid: 36128609
318	DR Morales, AD Morris. Metformin in cancer treatment and prevention. Annu Rev Med 2015; 66(1): 17–29 https://doi.org/10.1146/annurev-med-062613-093128 pmid: 25386929
319	C Coyle, FH Cafferty, C Vale, RE Langley. Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis. Ann Oncol 2016; 27(12): 2184–2195 https://doi.org/10.1093/annonc/mdw410 pmid: 27681864
320	SA Farr, E Roesler, ML Niehoff, DA Roby, A McKee, JE Morley. Metformin improves learning and memory in the SAMP8 mouse model of Alzheimer’s disease. J Alzheimers Dis 2019; 68(4): 1699–1710 https://doi.org/10.3233/JAD-181240 pmid: 30958364
321	K Samaras, S Makkar, JD Crawford, NA Kochan, W Wen, B Draper, JN Trollor, H Brodaty, PS Sachdev. Metformin use is associated with slowed cognitive decline and reduced incident dementia in older adults with type 2 diabetes: the Sydney Memory and Ageing Study. Diabetes Care 2020; 43(11): 2691–2701 https://doi.org/10.2337/dc20-0892 pmid: 32967921
322	JB Zhou, X Tang, M Han, J Yang, R Simó. Impact of antidiabetic agents on dementia risk: a Bayesian network meta-analysis. Metabolism 2020; 109: 154265 https://doi.org/10.1016/j.metabol.2020.154265 pmid: 32446679
323	L Bettedi, LC Foukas. Growth factor, energy and nutrient sensing signalling pathways in metabolic ageing. Biogerontology 2017; 18(6): 913–929 https://doi.org/10.1007/s10522-017-9724-6 pmid: 28795262
324	TD Admasu, K Chaithanya Batchu, D Barardo, LF Ng, VYM Lam, L Xiao, A Cazenave-Gassiot, MR Wenk, NS Tolwinski, J Gruber. Drug synergy slows aging and improves healthspan through IGF and SREBP lipid signaling. Dev Cell 2018; 47(1): 67–79.e5 https://doi.org/10.1016/j.devcel.2018.09.001 pmid: 30269951
325	VN Anisimov, LM Berstein, PA Egormin, TS Piskunova, IG Popovich, MA Zabezhinski, ML Tyndyk, MV Yurova, IG Kovalenko, TE Poroshina, AV Semenchenko. Metformin slows down aging and extends life span of female SHR mice. Cell Cycle 2008; 7(17): 2769–2773 https://doi.org/10.4161/cc.7.17.6625 pmid: 18728386
326	AP Sunjaya, AF Sunjaya. Targeting ageing and preventing organ degeneration with metformin. Diabetes Metab 2021; 47(1): 101203 https://doi.org/10.1016/j.diabet.2020.09.009 pmid: 33148437
327	N Kubben, T Misteli. Shared molecular and cellular mechanisms of premature ageing and ageing-associated diseases. Nat Rev Mol Cell Biol 2017; 18(10): 595–609 https://doi.org/10.1038/nrm.2017.68 pmid: 28792007
328	MXR Foo, PF Ong, O Dreesen. Premature aging syndromes: from patients to mechanism. J Dermatol Sci 2019; 96(2): 58–65 https://doi.org/10.1016/j.jdermsci.2019.10.003 pmid: 31727429
329	TES Kauppila, A Bratic, MB Jensen, F Baggio, L Partridge, H Jasper, S Grönke, NG Larsson. Mutations of mitochondrial DNA are not major contributors to aging of fruit flies. Proc Natl Acad Sci USA 2018; 115(41): E9620–E9629 https://doi.org/10.1073/pnas.1721683115 pmid: 30249665
330	AS Kulkarni, S Gubbi, N Barzilai. Benefits of metformin in attenuating the hallmarks of aging. Cell Metab 2020; 32(1): 15–30 https://doi.org/10.1016/j.cmet.2020.04.001 pmid: 32333835
331	Y Jiang, Y Dong, Y Luo, S Jiang, FL Meng, M Tan, J Li, Y Zang. AMPK-mediated phosphorylation on 53BP1 promotes c-NHEJ. Cell Rep 2021; 34(7): 108713 https://doi.org/10.1016/j.celrep.2021.108713 pmid: 33596428
332	K Kudabayeva, R Kosmuratova, Y Bazargaliyev, A Sartayeva, N Kereyeva. Effects of metformin on lymphocyte DNA damage in obese individuals among Kazakh population. Diabetes Metab Syndr 2022; 16(8): 102569 https://doi.org/10.1016/j.dsx.2022.102569 pmid: 35853300
333	B Chukwunonso Obi, T Chinwuba Okoye, VE Okpashi, C Nonye Igwe, E Olisah Alumanah. Comparative study of the antioxidant effects of metformin, glibenclamide, and repaglinide in alloxan-induced diabetic rats. J Diabetes Res 2016; 2016: 1635361 https://doi.org/10.1155/2016/1635361 pmid: 26824037
334	JS Allard, EJ Perez, K Fukui, P Carpenter, DK Ingram, R de Cabo. Prolonged metformin treatment leads to reduced transcription of Nrf2 and neurotrophic factors without cognitive impairment in older C57BL/6J mice. Behav Brain Res 2016; 301: 1–9 https://doi.org/10.1016/j.bbr.2015.12.012 pmid: 26698400
335	VN Anisimov, LM Berstein, IG Popovich, MA Zabezhinski, PA Egormin, TS Piskunova, AV Semenchenko, ML Tyndyk, MN Yurova, IG Kovalenko, TE Poroshina. If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice. Aging (Albany NY) 2011; 3(2): 148–157 https://doi.org/10.18632/aging.100273 pmid: 21386129
336	J Fang, J Yang, X Wu, G Zhang, T Li, X Wang, H Zhang, CC Wang, GH Liu, L Wang. Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7. Aging Cell 2018; 17(4): e12765 https://doi.org/10.1111/acel.12765 pmid: 29659168
337	O Moiseeva, X Deschênes-Simard, E St-Germain, S Igelmann, G Huot, AE Cadar, V Bourdeau, MN Pollak, G Ferbeyre. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κB activation. Aging Cell 2013; 12(3): 489–498 https://doi.org/10.1111/acel.12075 pmid: 23521863
338	N Noren Hooten, A Martin-Montalvo, DF Dluzen, Y Zhang, M Bernier, AB Zonderman, KG Becker, M Gorospe, R de Cabo, MK Evans. Metformin-mediated increase in DICER1 regulates microRNA expression and cellular senescence. Aging Cell 2016; 15(3): 572–581 https://doi.org/10.1111/acel.12469 pmid: 26990999
339	A Bektas, SH Schurman, R Sen, L Ferrucci. Aging, inflammation and the environment. Exp Gerontol 2018; 105: 10–18 https://doi.org/10.1016/j.exger.2017.12.015 pmid: 29275161
340	D Piber, R Olmstead, JH Cho, T Witarama, C Perez, N Dietz, TE Seeman, EC Breen, SW Cole, MR Irwin. Inflammaging: age and systemic, cellular, and nuclear inflammatory biology in older adults. J Gerontol A Biol Sci Med Sci 2019; 74(11): 1716–1724 https://doi.org/10.1093/gerona/glz130 pmid: 31107949
341	IM Rea, DS Gibson, V McGilligan, SE McNerlan, HD Alexander, OA Ross. Age and age-related diseases: role of inflammation triggers and cytokines. Front Immunol 2018; 9: 586 https://doi.org/10.3389/fimmu.2018.00586 pmid: 29686666
342	C Franceschi, J Campisi. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci 2014; 69(Suppl 1): S4–S9 https://doi.org/10.1093/gerona/glu057 pmid: 24833586
343	AM Tizazu, MSZ Nyunt, O Cexus, K Suku, E Mok, CH Xian, J Chong, C Tan, W How, S Hubert, E Combet, T Fulop, TP Ng, A Larbi. Metformin monotherapy downregulates diabetes-associated inflammatory status and impacts on mortality. Front Physiol 2019; 10: 572 https://doi.org/10.3389/fphys.2019.00572 pmid: 31178745
344	W Chen, X Liu, S Ye. Effects of metformin on blood and urine pro-inflammatory mediators in patients with type 2 diabetes. J Inflamm (Lond) 2016; 13(1): 34 https://doi.org/10.1186/s12950-016-0142-3 pmid: 27904436
345	X Xu, S Lin, Y Chen, X Li, S Ma, Y Fu, C Wei, C Wang, W Xu. The effect of metformin on the expression of GPR109A, NF-κB and IL-1β in peripheral blood leukocytes from patients with type 2 diabetes mellitus. Ann Clin Lab Sci 2017; 47(5): 556–562 pmid: 29066482
346	W Xu, YY Deng, L Yang, S Zhao, J Liu, Z Zhao, L Wang, P Maharjan, S Gao, Y Tian, X Zhuo, Y Zhao, J Zhou, Z Yuan, Y Wu. Metformin ameliorates the proinflammatory state in patients with carotid artery atherosclerosis through sirtuin 1 induction. Transl Res 2015; 166(5): 451–458 https://doi.org/10.1016/j.trsl.2015.06.002 pmid: 26141671
347	Y Saisho. Metformin and inflammation: its potential beyond glucose-lowering effect. Endocr Metab Immune Disord Drug Targets 2015; 15(3): 196–205 https://doi.org/10.2174/1871530315666150316124019 pmid: 25772174
348	R Kristófi, JW Eriksson. Metformin as an anti-inflammatory agent: a short review. J Endocrinol 2021; 251(2): R11–R22 https://doi.org/10.1530/JOE-21-0194 pmid: 34463292
349	L Gou, G Liu, R Ma, A Regmi, T Zeng, J Zheng, X Zhong, L Chen. High fat-induced inflammation in vascular endothelium can be improved by Abelmoschus esculentus and metformin via increasing the expressions of miR-146a and miR-155. Nutr Metab (Lond) 2020; 17(1): 35 https://doi.org/10.1186/s12986-020-00459-7 pmid: 32467714
350	X Luo, R Hu, Y Zheng, S Liu, Z Zhou. Metformin shows anti-inflammatory effects in murine macrophages through Dicer/microribonucleic acid-34a-5p and microribonucleic acid-125b-5p. J Diabetes Investig 2020; 11(1): 101–109 https://doi.org/10.1111/jdi.13074 pmid: 31102492
351	MS Hipp, P Kasturi, FU Hartl. The proteostasis network and its decline in ageing. Nat Rev Mol Cell Biol 2019; 20(7): 421–435 https://doi.org/10.1038/s41580-019-0101-y pmid: 30733602
352	M Kitada, D Koya. Autophagy in metabolic disease and ageing. Nat Rev Endocrinol 2021; 17(11): 647–661 https://doi.org/10.1038/s41574-021-00551-9 pmid: 34508250
353	AM Leidal, B Levine, J Debnath. Autophagy and the cell biology of age-related disease. Nat Cell Biol 2018; 20(12): 1338–1348 https://doi.org/10.1038/s41556-018-0235-8 pmid: 30482941
354	A Meléndez, Z Tallóczy, M Seaman, EL Eskelinen, DH Hall, B Levine. Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 2003; 301(5638): 1387–1391 https://doi.org/10.1126/science.1087782 pmid: 12958363
355	ÁF Fernández, S Sebti, Y Wei, Z Zou, M Shi, KL McMillan, C He, T Ting, Y Liu, WC Chiang, DK Marciano, GG Schiattarella, G Bhagat, OW Moe, MC Hu, B Levine. Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice. Nature 2018; 558(7708): 136–140 https://doi.org/10.1038/s41586-018-0162-7 pmid: 29849149
356	S Bhansali, A Bhansali, P Dutta, R Walia, V Dhawan. Metformin upregulates mitophagy in patients with T2DM: a randomized placebo-controlled study. J Cell Mol Med 2020; 24(5): 2832–2846 https://doi.org/10.1111/jcmm.14834 pmid: 31975558
357	LP Bharath, M Agrawal, G McCambridge, DA Nicholas, H Hasturk, J Liu, K Jiang, R Liu, Z Guo, J Deeney, CM Apovian, J Snyder-Cappione, GS Hawk, RM Fleeman, RMF Pihl, K Thompson, AC Belkina, L Cui, EA Proctor, PA Kern, BS Nikolajczyk. Metformin enhances autophagy and normalizes mitochondrial function to alleviate aging-associated inflammation. Cell Metab 2020; 32(1): 44–55.e6 https://doi.org/10.1016/j.cmet.2020.04.015 pmid: 32402267
358	B Xu, W Dai, L Liu, H Han, J Zhang, X Du, X Pei, X Fu. Metformin ameliorates polycystic ovary syndrome in a rat model by decreasing excessive autophagy in ovarian granulosa cells via the PI3K/AKT/mTOR pathway. Endocr J 2022; 69(7): 863–875 https://doi.org/10.1507/endocrj.EJ21-0480 pmid: 35228471
359	M Li, A Sharma, C Yin, X Tan, Y Xiao. Metformin ameliorates hepatic steatosis and improves the induction of autophagy in HFD-induced obese mice. Mol Med Rep 2017; 16(1): 680–686 https://doi.org/10.3892/mmr.2017.6637 pmid: 28560428
360	G You, X Long, F Song, J Huang, M Tian, Y Xiao, S Deng, Q Wu. Metformin activates the AMPK-mTOR pathway by modulating lncRNA TUG1 to induce autophagy and inhibit atherosclerosis. Drug Des Devel Ther 2020; 14: 457–468 https://doi.org/10.2147/DDDT.S233932 pmid: 32099330
361	M Kodali, S Attaluri, LN Madhu, B Shuai, R Upadhya, JJ Gonzalez, X Rao, AK Shetty. Metformin treatment in late middle age improves cognitive function with alleviation of microglial activation and enhancement of autophagy in the hippocampus. Aging Cell 2021; 20(2): e13277 https://doi.org/10.1111/acel.13277 pmid: 33443781
362	K Whittemore, E Vera, E Martínez-Nevado, C Sanpera, MA Blasco. Telomere shortening rate predicts species life span. Proc Natl Acad Sci USA 2019; 116(30): 15122–15127 https://doi.org/10.1073/pnas.1902452116 pmid: 31285335
363	J Huang, X Peng, K Dong, J Tao, Y Yang. The association between antidiabetic agents and leukocyte telomere length in the novel classification of type 2 diabetes mellitus. Gerontology 2021; 67(1): 60–68 https://doi.org/10.1159/000511362 pmid: 33321495
364	J Liu, Y Ge, S Wu, D Ma, W Xu, Y Zhang, Y Yang. Association between antidiabetic agents use and leukocyte telomere shortening rates in patients with type 2 diabetes. Aging (Albany NY) 2019; 11(2): 741–755 https://doi.org/10.18632/aging.101781 pmid: 30694216
365	ECCC Rosa, RRC Dos Santos, LFA Fernandes, FAR Neves, MS Coelho, AA Amato. Leukocyte telomere length correlates with glucose control in adults with recently diagnosed type 2 diabetes. Diabetes Res Clin Pract 2018; 135: 30–36 https://doi.org/10.1016/j.diabres.2017.10.020 pmid: 29107760
366	N Sun, RJ Youle, T Finkel. The mitochondrial basis of aging. Mol Cell 2016; 61(5): 654–666 https://doi.org/10.1016/j.molcel.2016.01.028 pmid: 26942670
367	AR Konopka, JL Laurin, HM Schoenberg, JJ Reid, WM Castor, CA Wolff, RV Musci, OD Safairad, MA Linden, LM Biela, SM Bailey, KL Hamilton, BF Miller. Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Aging Cell 2019; 18(1): e12880 https://doi.org/10.1111/acel.12880 pmid: 30548390
368	JY Jang, A Blum, J Liu, T Finkel. The role of mitochondria in aging. J Clin Invest 2018; 128(9): 3662–3670 https://doi.org/10.1172/JCI120842 pmid: 30059016
369	S Starling. Metformin reduces ageing adipose senescence. Nat Rev Endocrinol 2021; 17(12): 708 pmid: 34663933
370	S Karnewar, PK Neeli, D Panuganti, S Kotagiri, S Mallappa, N Jain, MK Jerald, S Kotamraju. Metformin regulates mitochondrial biogenesis and senescence through AMPK mediated H3K79 methylation: relevance in age-associated vascular dysfunction. Biochim Biophys Acta Mol Basis Dis 2018; 186(4 Pt A): 1115–1128 https://doi.org/10.1016/j.bbadis.2018.01.018 pmid: 29366775
371	G Vial, D Detaille, B Guigas. Role of mitochondria in the mechanism(s) of action of metformin. Front Endocrinol (Lausanne) 2019; 10: 294 https://doi.org/10.3389/fendo.2019.00294 pmid: 31133988
372	C López-Otín, MA Blasco, L Partridge, M Serrano, G Kroemer. The hallmarks of aging. Cell 2013; 153(6): 1194–1217 https://doi.org/10.1016/j.cell.2013.05.039 pmid: 23746838
373	B Neumann, R Baror, C Zhao, M Segel, S Dietmann, KS Rawji, S Foerster, CR McClain, K Chalut, P van Wijngaarden, RJM Franklin. Metformin restores CNS remyelination capacity by rejuvenating aged stem cells. Cell Stem Cell 2019; 25(4): 473–485.e8 https://doi.org/10.1016/j.stem.2019.08.015 pmid: 31585093
374	HJ Na, JS Park, JH Pyo, HJ Jeon, YS Kim, R Arking, MA Yoo. Metformin inhibits age-related centrosome amplification in Drosophila midgut stem cells through AKT/TOR pathway. Mech Ageing Dev 2015; 149: 8–18 https://doi.org/10.1016/j.mad.2015.05.004 pmid: 25988874
375	EJ Calabrese, E Agathokleous, R Kapoor, G Dhawan, WJ Kozumbo, V Calabrese. Metformin-enhances resilience via hormesis. Ageing Res Rev 2021; 71: 101418 https://doi.org/10.1016/j.arr.2021.101418 pmid: 34365027
376	TSB Schmidt, J Raes, P Bork. The human gut microbiome: from association to modulation. Cell 2018; 172(6): 1198–1215 https://doi.org/10.1016/j.cell.2018.02.044 pmid: 29522742
377	B Antal, LP McMahon, SF Sultan, A Lithen, DJ Wexler, B Dickerson, EM Ratai, LR Mujica-Parodi. Type 2 diabetes mellitus accelerates brain aging and cognitive decline: complementary findings from UK Biobank and meta-analyses. eLife 2022; 11: e73138 https://doi.org/10.7554/eLife.73138 pmid: 35608247
378	DL Jr Smith, CF Jr Elam, JA Mattison, MA Lane, GS Roth, DK Ingram, DB Allison. Metformin supplementation and life span in Fischer-344 rats. J Gerontol A Biol Sci Med Sci 2010; 65(5): 468–474 https://doi.org/10.1093/gerona/glq033 pmid: 20304770
379	L Espada, A Dakhovnik, P Chaudhari, A Martirosyan, L Miek, T Poliezhaieva, Y Schaub, A Nair, N Döring, N Rahnis, O Werz, A Koeberle, J Kirkpatrick, A Ori, MA Ermolaeva. Loss of metabolic plasticity underlies metformin toxicity in aged Caenorhabditis elegans. Nat Metab 2020; 2(11): 1316–1331 https://doi.org/10.1038/s42255-020-00307-1 pmid: 33139960
380	RG Walton, CM Dungan, DE Long, SC Tuggle, K Kosmac, BD Peck, HM Bush, AG Villasante Tezanos, G McGwin, ST Windham, F Ovalle, MM Bamman, PA Kern, CA Peterson. 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. Aging Cell 2019; 18(6): e13039 https://doi.org/10.1111/acel.13039 pmid: 31557380
381	D Xenos, P Mecocci, V Boccardi. A blast from the past: to tame time with metformin. Mech Ageing Dev 2022; 208: 111743 https://doi.org/10.1016/j.mad.2022.111743 pmid: 36279989
382	DG Hardie, FA Ross, SA Hawley. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 2012; 13(4): 251–262 https://doi.org/10.1038/nrm3311 pmid: 22436748
383	C Cantó, J Auwerx. AMP-activated protein kinase and its downstream transcriptional pathways. Cell Mol Life Sci 2010; 67(20): 3407–3423 https://doi.org/10.1007/s00018-010-0454-z pmid: 20640476
384	JN Feige, J Auwerx. Transcriptional coregulators in the control of energy homeostasis. Trends Cell Biol 2007; 17(6): 292–301 https://doi.org/10.1016/j.tcb.2007.04.001 pmid: 17475497
385	D Garcia, RJ Shaw. AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol Cell 2017; 66(6): 789–800 https://doi.org/10.1016/j.molcel.2017.05.032 pmid: 28622524
386	MM Chung, CJ Nicol, YC Cheng, KH Lin, YL Chen, D Pei, CH Lin, YN Shih, CH Yen, SJ Chen, RN Huang, MC Chiang. Metformin activation of AMPK suppresses AGE-induced inflammatory response in hNSCs. Exp Cell Res 2017; 352(1): 75–83 https://doi.org/10.1016/j.yexcr.2017.01.017 pmid: 28159472
387	S Wang, K Kobayashi, Y Kogure, H Yamanaka, S Yamamoto, H Yagi, K Noguchi, Y Dai. Negative regulation of TRPA1 by AMPK in primary sensory neurons as a potential mechanism of painful diabetic neuropathy. Diabetes 2018; 67(1): 98–109 https://doi.org/10.2337/db17-0503 pmid: 29025860
388	R Yuan, Y Wang, Q Li, F Zhen, X Li, Q Lai, P Hu, X Wang, Y Zhu, H Fan, R Yao. Metformin reduces neuronal damage and promotes neuroblast proliferation and differentiation in a cerebral ischemia/reperfusion rat model. Neuroreport 2019; 30(3): 232–240 https://doi.org/10.1097/WNR.0000000000001190 pmid: 30614910
389	J Mertens, ACM Paquola, M Ku, E Hatch, L Böhnke, S Ladjevardi, S McGrath, B Campbell, H Lee, JR Herdy, JT Gonçalves, T Toda, Y Kim, J Winkler, J Yao, MW Hetzer, FH Gage. Directly reprogrammed human neurons retain aging-associated transcriptomic signatures and reveal age-related nucleocytoplasmic defects. Cell Stem Cell 2015; 17(6): 705–718 https://doi.org/10.1016/j.stem.2015.09.001 pmid: 26456686
390	Y Kim, X Zheng, Z Ansari, MC Bunnell, JR Herdy, L Traxler, H Lee, ACM Paquola, C Blithikioti, M Ku, JCM Schlachetzki, J Winkler, F Edenhofer, CK Glass, AA Paucar, BN Jaeger, S Pham, L Boyer, BC Campbell, T Hunter, J Mertens, FH Gage. Mitochondrial aging defects emerge in directly reprogrammed human neurons due to their metabolic profile. Cell Rep 2018; 23(9): 2550–2558 https://doi.org/10.1016/j.celrep.2018.04.105 pmid: 29847787
391	C Rotermund, G Machetanz, JC Fitzgerald. The therapeutic potential of metformin in neurodegenerative diseases. Front Endocrinol (Lausanne) 2018; 9: 400 https://doi.org/10.3389/fendo.2018.00400 pmid: 30072954
392	S Craft, GS Watson. Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol 2004; 3(3): 169–178 https://doi.org/10.1016/S1474-4422(04)00681-7 pmid: 14980532
393	T Ninomiya. Diabetes mellitus and dementia. Curr Diab Rep 2014; 14(5): 487 https://doi.org/10.1007/s11892-014-0487-z pmid: 24623199
394	KF Neumann, L Rojo, LP Navarrete, G Farías, P Reyes, RB Maccioni. Insulin resistance and Alzheimer’s disease: molecular links & clinical implications. Curr Alzheimer Res 2008; 5(5): 438–447 https://doi.org/10.2174/156720508785908919 pmid: 18855585
395	G Verdile, SJ Fuller, RN Martins. The role of type 2 diabetes in neurodegeneration. Neurobiol Dis 2015; 84: 22–38 https://doi.org/10.1016/j.nbd.2015.04.008 pmid: 25926349
396	Z Arvanitakis, RC Shah, DA Bennett. Diagnosis and management of dementia: review. JAMA 2019; 322(16): 1589–1599 https://doi.org/10.1001/jama.2019.4782 pmid: 31638686
397	PV Arriagada, JH Growdon, ET Hedley-Whyte, BT Hyman. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology 1992; 42(3): 631–639 https://doi.org/10.1212/WNL.42.3.631 pmid: 1549228
398	GV Johnson, WH Stoothoff. Tau phosphorylation in neuronal cell function and dysfunction. J Cell Sci 2004; 117(24): 5721–5729 https://doi.org/10.1242/jcs.01558 pmid: 15537830
399	JL Gu, F Liu. Tau in Alzheimer’s disease: pathological alterations and an attractive therapeutic target. Curr Med Sci 2020; 40(6): 1009–1021 https://doi.org/10.1007/s11596-020-2282-1 pmid: 33428128
400	X Sun, K Bromley-Brits, W Song. Regulation of β-site APP-cleaving enzyme 1 gene expression and its role in Alzheimer’s disease. J Neurochem 2012; 120(Suppl 1): 62–70 https://doi.org/10.1111/j.1471-4159.2011.07515.x pmid: 22122349
401	WH Oliveira, CF Braga, DB Lós, SMR Araújo, MR França, E Duarte-Silva, GB Rodrigues, SWS Rocha, CA Peixoto. Metformin prevents p-tau and amyloid plaque deposition and memory impairment in diabetic mice. Exp Brain Res 2021; 239(9): 2821–2839 https://doi.org/10.1007/s00221-021-06176-8 pmid: 34283253
402	Y Chen, K Zhou, R Wang, Y Liu, YD Kwak, T Ma, RC Thompson, Y Zhao, L Smith, L Gasparini, Z Luo, H Xu, FF Liao. Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer’s amyloid peptides via up-regulating BACE1 transcription. Proc Natl Acad Sci USA 2009; 106(10): 3907–3912 https://doi.org/10.1073/pnas.0807991106 pmid: 19237574
403	JS Won, YB Im, J Kim, AK Singh, I Singh. Involvement of AMP-activated-protein-kinase (AMPK) in neuronal amyloidogenesis. Biochem Biophys Res Commun 2010; 399(4): 487–491 https://doi.org/10.1016/j.bbrc.2010.07.081 pmid: 20659426
404	TP Ng, L Feng, KB Yap, TS Lee, CH Tan, B Winblad. Long-term metformin usage and cognitive function among older adults with diabetes. J Alzheimers Dis 2014; 41(1): 61–68 https://doi.org/10.3233/JAD-131901 pmid: 24577463
405	H Yokoyama, M Ogawa, J Honjo, S Okizaki, D Yamada, R Shudo, H Shimizu, H Sone, M Haneda. Risk factors associated with abnormal cognition in Japanese outpatients with diabetes, hypertension or dyslipidemia. Diabetol Int 2015; 6(4): 268–274 https://doi.org/10.1007/s13340-014-0194-7
406	CC Hsu, ML Wahlqvist, MS Lee, HN Tsai. Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin. J Alzheimers Dis 2011; 24(3): 485–493 https://doi.org/10.3233/JAD-2011-101524 pmid: 21297276
407	C Cheng, CH Lin, YW Tsai, CJ Tsai, PH Chou, TH Lan. Type 2 diabetes and antidiabetic medications in relation to dementia diagnosis. J Gerontol A Biol Sci Med Sci 2014; 69(10): 1299–1305 https://doi.org/10.1093/gerona/glu073 pmid: 24899525
408	AR Orkaby, K Cho, J Cormack, DR Gagnon, JA Driver. Metformin vs sulfonylurea use and risk of dementia in US veterans aged ≥65 years with diabetes. Neurology 2017; 89(18): 1877–1885 https://doi.org/10.1212/WNL.0000000000004586 pmid: 28954880
409	P Imfeld, M Bodmer, SS Jick, CR Meier. Metformin, other antidiabetic drugs, and risk of Alzheimer’s disease: a population-based case-control study. J Am Geriatr Soc 2012; 60(5): 916–921 https://doi.org/10.1111/j.1532-5415.2012.03916.x pmid: 22458300
410	CP Wang, C Lorenzo, SL Habib, B Jo, SE Espinoza. Differential effects of metformin on age related comorbidities in older men with type 2 diabetes. J Diabetes Complications 2017; 31(4): 679–686 https://doi.org/10.1016/j.jdiacomp.2017.01.013 pmid: 28190681
411	Z Arvanitakis, M Tatavarthy, DA Bennett. The relation of diabetes to memory function. Curr Neurol Neurosci Rep 2020; 20(12): 64 https://doi.org/10.1007/s11910-020-01085-9 pmid: 33150490
412	FN Emamzadeh, A Surguchov. Parkinson’s disease: biomarkers, treatment, and risk factors. Front Neurosci 2018; 12: 612 https://doi.org/10.3389/fnins.2018.00612 pmid: 30214392
413	BLB Marino, LR de Souza, KPA Sousa, JV Ferreira, EC Padilha, CHTP da Silva, CA Taft, LIS Hage-Melim. Parkinson’s disease: a review from pathophysiology to treatment. Mini Rev Med Chem 2020; 20(9): 754–767 https://doi.org/10.2174/1389557519666191104110908 pmid: 31686637
414	P Damier, EC Hirsch, Y Agid, AM Graybiel. The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson’s disease. Brain 1999; 122(8): 1437–1448 https://doi.org/10.1093/brain/122.8.1437 pmid: 10430830
415	X Zhao, H He, X Xiong, Q Ye, F Feng, S Zhou, W Chen, K Xia, S Qian, Y Yang, C Xie. Lewy body-associated proteins A-synuclein (a-syn) as a plasma-based biomarker for Parkinson’s disease. Front Aging Neurosci 2022; 14: 869797 https://doi.org/10.3389/fnagi.2022.869797 pmid: 35645787
416	JM Tan, ES Wong, KL Lim. Protein misfolding and aggregation in Parkinson’s disease. Antioxid Redox Signal 2009; 11(9): 2119–2134 https://doi.org/10.1089/ars.2009.2490 pmid: 19243238
417	H BraakTredici K DelH BratzkeJ Hamm-ClementD Sandmann-KeilU Rüb. Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson’s disease (preclinical and clinical stages). J Neurol 2002; 249 Suppl 3: III/1–5 doi: 10.1007/s00415-002-1301-4 pmid: 12528692
418	TG Beach, CH Adler, L Lue, LI Sue, J Bachalakuri, J Henry-Watson, J Sasse, S Boyer, S Shirohi, R Brooks, J Eschbacher, CL 3rd White, H Akiyama, J Caviness, HA Shill, DJ Connor, MN Sabbagh, DG; Arizona Parkinson’s Disease Consortium Walker. Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol 2009; 117(6): 613–634 https://doi.org/10.1007/s00401-009-0538-8 pmid: 19399512
419	I Dolasık, SY Sener, K Celebı, ZM Aydın, U Korkmaz, Z Canturk. The effect of metformin on mean platelet volume in dıabetıc patients. Platelets 2013; 24(2): 118–121 https://doi.org/10.3109/09537104.2012.674165 pmid: 22494325
420	A Koçer, A Yaman, E Niftaliyev, H Dürüyen, M Eryılmaz, E Koçer. Assessment of platelet indices in patients with neurodegenerative diseases: mean platelet volume was increased in patients with Parkinson’s disease. Curr Gerontol Geriatr Res 2013; 2013: 986254 https://doi.org/10.1155/2013/986254 pmid: 24382959
421	M Lu, C Su, C Qiao, Y Bian, J Ding, G Hu. Metformin prevents dopaminergic neuron death in MPTP/P-induced mouse model of Parkinson’s disease via autophagy and mitochondrial ROS clearance. Int J Neuropsychopharmacol 2016; 19(9): pyw047 https://doi.org/10.1093/ijnp/pyw047 pmid: 27207919
422	SP Patil, PD Jain, PJ Ghumatkar, R Tambe, S Sathaye. Neuroprotective effect of metformin in MPTP-induced Parkinson’s disease in mice. Neuroscience 2014; 277: 747–754 https://doi.org/10.1016/j.neuroscience.2014.07.046 pmid: 25108167
423	JA Bayliss, MB Lemus, VV Santos, M Deo, JS Davies, BE Kemp, JD Elsworth, ZB Andrews. Metformin prevents nigrostriatal dopamine degeneration independent of AMPK activation in dopamine neurons. PLoS One 2016; 11(7): e0159381 https://doi.org/10.1371/journal.pone.0159381 pmid: 27467571
424	N Katila, S Bhurtel, S Shadfar, S Srivastav, S Neupane, U Ojha, GS Jeong, DY Choi. Metformin lowers α-synuclein phosphorylation and upregulates neurotrophic factor in the MPTP mouse model of Parkinson’s disease. Neuropharmacology 2017; 125: 396–407 https://doi.org/10.1016/j.neuropharm.2017.08.015 pmid: 28807678
425	AA Ismaiel, AM Espinosa-Oliva, M Santiago, A García-Quintanilla, MJ Oliva-Martín, AJ Herrera, JL Venero, Pablos RM de. Metformin, besides exhibiting strong in vivo anti-inflammatory properties, increases mptp-induced damage to the nigrostriatal dopaminergic system. Toxicol Appl Pharmacol 2016; 298: 19–30 https://doi.org/10.1016/j.taap.2016.03.004 pmid: 26971375
426	ML Wahlqvist, MS Lee, CC Hsu, SY Chuang, JT Lee, HN Tsai. Metformin-inclusive sulfonylurea therapy reduces the risk of Parkinson’s disease occurring with type 2 diabetes in a Taiwanese population cohort. Parkinsonism Relat Disord 2012; 18(6): 753–758 https://doi.org/10.1016/j.parkreldis.2012.03.010 pmid: 22498320
427	P McColgan, SJ Tabrizi. Huntington’s disease: a clinical review. Eur J Neurol 2018; 25(1): 24–34 https://doi.org/10.1111/ene.13413 pmid: 28817209
428	MT Montojo, M Aganzo, N González. Huntington’s disease and diabetes: chronological sequence of its association. J Huntingtons Dis 2017; 6(3): 179–188 https://doi.org/10.3233/JHD-170253 pmid: 28968242
429	NM Lalić, J Marić, M Svetel, A Jotić, E Stefanova, K Lalić, N Dragasević, T Milicić, L Lukić, VS Kostić. Glucose homeostasis in Huntington disease: abnormalities in insulin sensitivity and early-phase insulin secretion. Arch Neurol 2008; 65(4): 476–480 https://doi.org/10.1001/archneur.65.4.476 pmid: 18413469
430	TW Boesgaard, TT Nielsen, K Josefsen, T Hansen, T Jørgensen, O Pedersen, A Nørremølle, JE Nielsen, L Hasholt. Huntington’s disease does not appear to increase the risk of diabetes mellitus. J Neuroendocrinol 2009; 21(9): 770–776 https://doi.org/10.1111/j.1365-2826.2009.01898.x pmid: 19602103
431	CV Russo, E Salvatore, F Saccà, T Tucci, C Rinaldi, P Sorrentino, M Massarelli, F Rossi, S Savastano, Maio L Di, A Filla, A Colao, Michele G De. Insulin sensitivity and early-phase insulin secretion in normoglycemic Huntington’s disease patients. J Huntingtons Dis 2013; 2(4): 501–507 https://doi.org/10.3233/JHD-130078 pmid: 25062734
432	D Hervás, V Fornés-Ferrer, AP Gómez-Escribano, MD Sequedo, C Peiró, JM Millán, RP Vázquez-Manrique. Metformin intake associates with better cognitive function in patients with Huntington’s disease. PLoS One 2017; 12(6): e0179283 https://doi.org/10.1371/journal.pone.0179283 pmid: 28632780
433	TC Ju, HM Chen, YC Chen, CP Chang, C Chang, Y Chern. AMPK-α1 functions downstream of oxidative stress to mediate neuronal atrophy in Huntington’s disease. Biochim Biophys Acta 2014; 1842(9): 1668–1680 https://doi.org/10.1016/j.bbadis.2014.06.012 pmid: 24946181
434	A Dziedzic, J Saluk-Bijak, E Miller, M Bijak. Metformin as a potential agent in the treatment of multiple sclerosis. Int J Mol Sci 2020; 21(17): 5957 https://doi.org/10.3390/ijms21175957 pmid: 32825027
435	GR Dos Passos, DK Sato, J Becker, K Fujihara. Th17 cells pathways in multiple sclerosis and neuromyelitis optica spectrum disorders: pathophysiological and therapeutic implications. Mediators Inflamm 2016; 2016: 5314541 https://doi.org/10.1155/2016/5314541 pmid: 26941483
436	S Kalra, C Lowndes, L Durant, RC Strange, A Al-Araji, CP Hawkins, SJ Curnow. Th17 cells increase in RRMS as well as in SPMS, whereas various other phenotypes of Th17 increase in RRMS only. Mult Scler J Exp Transl Clin 2020; 6(1): 2055217319899695 https://doi.org/10.1177/2055217319899695 pmid: 32064115
437	N Álvarez-Sánchez, I Cruz-Chamorro, M Díaz-Sánchez, PJ Lardone, JM Guerrero, A Carrillo-Vico. Peripheral CD39-expressing T regulatory cells are increased and associated with relapsing-remitting multiple sclerosis in relapsing patients. Sci Rep 2019; 9(1): 2302 https://doi.org/10.1038/s41598-019-38897-w pmid: 30783191
438	YF Li, SX Zhang, XW Ma, YL Xue, C Gao, XY Li, AD Xu. The proportion of peripheral regulatory T cells in patients with multiple sclerosis: a meta-analysis. Mult Scler Relat Disord 2019; 28: 75–80 https://doi.org/10.1016/j.msard.2018.12.019 pmid: 30572285
439	H Hofstetter, R Gold, HP Hartung. Th17 cells in MS and experimental autoimmune encephalomyelitis. Int MS J 2009; 16(1): 12–18 pmid: 19413921
440	L Wei, A Laurence, KM Elias, JJ O’Shea. IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner. J Biol Chem 2007; 282(48): 34605–34610 https://doi.org/10.1074/jbc.M705100200 pmid: 17884812
441	H Kebir, K Kreymborg, I Ifergan, A Dodelet-Devillers, R Cayrol, M Bernard, F Giuliani, N Arbour, B Becher, A Prat. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med 2007; 13(10): 1173–1175 https://doi.org/10.1038/nm1651 pmid: 17828272
442	MM Mehta, NS Chandel. Targeting metabolism for lupus therapy. Sci Transl Med 2015; 7(274): 274fs5 https://doi.org/10.1126/scitranslmed.aaa6731 pmid: 25673759
443	R Krysiak, B Okopien. Haemostatic effects of metformin in simvastatin-treated volunteers with impaired fasting glucose. Basic Clin Pharmacol Toxicol 2012; 111(6): 380–384 https://doi.org/10.1111/j.1742-7843.2012.00913.x pmid: 22716204
444	R Krysiak, A Gdula-Dymek, B Okopień. Effect of metformin on selected parameters of hemostasis in fenofibrate-treated patients with impaired glucose tolerance. Pharmacol Rep 2013; 65(1): 208–213 https://doi.org/10.1016/S1734-1140(13)70980-0
445	M Serdyńska-Szuster, B Banaszewska, R Spaczyński, L Pawelczyk. Effects of metformin therapy on markers of coagulation disorders in hyperinsulinemic women with polycystic ovary syndrome. Ginekol Pol 2011; 82(4): 259–264 pmid: 21735693
446	M Markowicz-Piasecka, KM Huttunen, A Sadkowska, J Sikora. Pleiotropic activity of metformin and its sulfonamide derivatives on vascular and platelet haemostasis. Molecules 2019; 25(1): 125 https://doi.org/10.3390/molecules25010125 pmid: 31905674
447	L Negrotto, MF Farez, J Correale. Immunologic effects of metformin and pioglitazone treatment on metabolic syndrome and multiple sclerosis. JAMA Neurol 2016; 73(5): 520–528 https://doi.org/10.1001/jamaneurol.2015.4807 pmid: 26953870
448	S Jang, H Kim, J Jeong, SK Lee, EW Kim, M Park, CH Kim, JE Lee, K Namkoong, E Kim. Blunted response of hippocampal AMPK associated with reduced neurogenesis in older versus younger mice. Prog Neuropsychopharmacol Biol Psychiatry 2016; 71: 57–65 https://doi.org/10.1016/j.pnpbp.2016.06.011 pmid: 27343360
449	AO Dulamea. The contribution of oligodendrocytes and oligodendrocyte progenitor cells to central nervous system repair in multiple sclerosis: perspectives for remyelination therapeutic strategies. Neural Regen Res 2017; 12(12): 1939–1944 https://doi.org/10.4103/1673-5374.221146 pmid: 29323026
450	Y Qi, H Cheng, Q Lou, X Wang, N Lai, C Gao, S Wu, C Xu, Y Ruan, Z Chen, Y Wang. Paradoxical effects of posterior intralaminar thalamic calretinin neurons on hippocampal seizure via distinct downstream circuits. iScience 2022; 25(5): 104218 https://doi.org/10.1016/j.isci.2022.104218 pmid: 35494226
451	K Tóth, L Eross, J Vajda, P Halász, TF Freund, Z Maglóczky. Loss and reorganization of calretinin-containing interneurons in the epileptic human hippocampus. Brain 2010; 133(9): 2763–2777 https://doi.org/10.1093/brain/awq149 pmid: 20576695
452	BS Meldrum. Excitotoxicity and selective neuronal loss in epilepsy. Brain Pathol 1993; 3(4): 405–412 https://doi.org/10.1111/j.1750-3639.1993.tb00768.x pmid: 8293196
453	Y Qi, H Cheng, Y Wang, Z Chen. Revealing the precise role of calretinin neurons in epilepsy: we are on the way. Neurosci Bull 2022; 38(2): 209–222 https://doi.org/10.1007/s12264-021-00753-1 pmid: 34324145
454	AM Hussein, M Eldosoky, M El-Shafey, M El-Mesery, AN Ali, KM Abbas, OA Abulseoud. Effects of metformin on apoptosis and α-synuclein in a rat model of pentylenetetrazole-induced epilepsy. Can J Physiol Pharmacol 2019; 97(1): 37–46 https://doi.org/10.1139/cjpp-2018-0266 pmid: 30308130
455	RR Zhao, XC Xu, F Xu, WL Zhang, WL Zhang, LM Liu, WP Wang. Metformin protects against seizures, learning and memory impairments and oxidative damage induced by pentylenetetrazole-induced kindling in mice. Biochem Biophys Res Commun 2014; 448(4): 414–417 https://doi.org/10.1016/j.bbrc.2014.04.130 pmid: 24802403
456	Y Yang, B Zhu, F Zheng, Y Li, Y Zhang, Y Hu, X Wang. Chronic metformin treatment facilitates seizure termination. Biochem Biophys Res Commun 2017; 484(2): 450–455 https://doi.org/10.1016/j.bbrc.2017.01.157 pmid: 28137587
457	C Moran, A Sanz-Rodriguez, A Jimenez-Pacheco, J Martinez-Villareal, RC McKiernan, EM Jimenez-Mateos, C Mooney, I Woods, JH Prehn, DC Henshall, T Engel. Bmf upregulation through the AMP-activated protein kinase pathway may protect the brain from seizure-induced cell death. Cell Death Dis 2013; 4(4): e606 https://doi.org/10.1038/cddis.2013.136 pmid: 23618904
458	S Mehrabi, N Sanadgol, M Barati, A Shahbazi, G Vahabzadeh, M Barzroudi, M Seifi, M Gholipourmalekabadi, F Golab. Evaluation of metformin effects in the chronic phase of spontaneous seizures in pilocarpine model of temporal lobe epilepsy. Metab Brain Dis 2018; 33(1): 107–114 https://doi.org/10.1007/s11011-017-0132-z pmid: 29080083
459	C Heinrich, S Lähteinen, F Suzuki, L Anne-Marie, S Huber, U Häussler, C Haas, Y Larmet, E Castren, A Depaulis. Increase in BDNF-mediated TrkB signaling promotes epileptogenesis in a mouse model of mesial temporal lobe epilepsy. Neurobiol Dis 2011; 42(1): 35–47 https://doi.org/10.1016/j.nbd.2011.01.001 pmid: 21220014
460	S Amin, AA Mallick, H Edwards, M Cortina-Borja, M Laugharne, M Likeman, FJK O’Callaghan. The metformin in tuberous sclerosis (MiTS) study: a randomised double-blind placebo-controlled trial. EClinicalMedicine 2021; 32: 100715 https://doi.org/10.1016/j.eclinm.2020.100715 pmid: 33681737
461	F Bisulli, L Muccioli, G d’Orsi, L Canafoglia, E Freri, L Licchetta, B Mostacci, P Riguzzi, F Pondrelli, C Avolio, T Martino, R Michelucci, P Tinuper. Treatment with metformin in twelve patients with Lafora disease. Orphanet J Rare Dis 2019; 14(1): 149 https://doi.org/10.1186/s13023-019-1132-3 pmid: 31227012
462	YM Zhang, LY Ye, TY Li, F Guo, F Guo, Y Li, YF Li. New monoamine antidepressant, hypidone hydrochloride (YL-0919), enhances the excitability of medial prefrontal cortex in mice via a neural disinhibition mechanism. Acta Pharmacol Sin 2022; 43(7): 1699–1709 https://doi.org/10.1038/s41401-021-00807-0 pmid: 34811511
463	C Otte, SM Gold, BW Penninx, CM Pariante, A Etkin, M Fava, DC Mohr, AF Schatzberg. Major depressive disorder. Nat Rev Dis Primers 2016; 2(1): 16065 https://doi.org/10.1038/nrdp.2016.65 pmid: 27629598
464	MV Fogaça, RS Duman. Cortical GABAergic dysfunction in stress and depression: new insights for therapeutic interventions. Front Cell Neurosci 2019; 13: 87 https://doi.org/10.3389/fncel.2019.00087 pmid: 30914923
465	RS Duman, G Sanacora, JH Krystal. Altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments. Neuron 2019; 102(1): 75–90 https://doi.org/10.1016/j.neuron.2019.03.013 pmid: 30946828
466	C Fee, M Banasr, E Sibille. Somatostatin-positive gamma-aminobutyric acid interneuron deficits in depression: cortical microcircuit and therapeutic perspectives. Biol Psychiatry 2017; 82(8): 549–559 https://doi.org/10.1016/j.biopsych.2017.05.024 pmid: 28697889
467	S Ghosal, B Hare, RS Duman. Prefrontal cortex GABAergic deficits and circuit dysfunction in the pathophysiology and treatment of chronic stress and depression. Curr Opin Behav Sci 2017; 14: 1–8 https://doi.org/10.1016/j.cobeha.2016.09.012 pmid: 27812532
468	JH Krystal, G Sanacora, H Blumberg, A Anand, DS Charney, G Marek, CN Epperson, A Goddard, GF Mason. Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments. Mol Psychiatry 2002; 7(S1 Suppl 1): S71–S80 https://doi.org/10.1038/sj.mp.4001021 pmid: 11986998
469	B Luscher, Q Shen, N Sahir. The GABAergic deficit hypothesis of major depressive disorder. Mol Psychiatry 2011; 16(4): 383–406 https://doi.org/10.1038/mp.2010.120 pmid: 21079608
470	F Vahid-Ansari, PR Albert. Rewiring of the serotonin system in major depression. Front Psychiatry 2021; 12: 802581 https://doi.org/10.3389/fpsyt.2021.802581 pmid: 34975594
471	WB Chen, J Chen, ZY Liu, B Luo, T Zhou, EK Fei. Metformin enhances excitatory synaptic transmission onto hippocampal CA1 pyramidal neurons. Brain Sci 2020; 10(10): 706 https://doi.org/10.3390/brainsci10100706 pmid: 33020379
472	J Zemdegs, H Martin, H Pintana, S Bullich, S Manta, MA Marqués, C Moro, S Layé, F Ducrocq, N Chattipakorn, SC Chattipakorn, C Rampon, L Pénicaud, X Fioramonti, BP Guiard. Metformin promotes anxiolytic and antidepressant-like responses in insulin-resistant mice by decreasing circulating branched-chain amino acids. J Neurosci 2019; 39(30): 5935–5948 https://doi.org/10.1523/JNEUROSCI.2904-18.2019 pmid: 31160539
473	F Duval, MC Mokrani, P Bailey, H Corrêa, MA Crocq, Diep T Son, JP Macher. Serotonergic and noradrenergic function in depression: clinical correlates. Dialogues Clin Neurosci 2000; 2(3): 299–308 https://doi.org/10.31887/DCNS.2000.2.3/fduval pmid: 22033550
474	N Shivavedi, M Kumar, GNVC Tej, PK Nayak. Metformin and ascorbic acid combination therapy ameliorates type 2 diabetes mellitus and comorbid depression in rats. Brain Res 2017; 1674: 1–9 https://doi.org/10.1016/j.brainres.2017.08.019 pmid: 28827076
475	J Wang, D Gallagher, LM DeVito, GI Cancino, D Tsui, L He, GM Keller, PW Frankland, DR Kaplan, FD Miller. Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation. Cell Stem Cell 2012; 11(1): 23–35 https://doi.org/10.1016/j.stem.2012.03.016 pmid: 22770240
476	M Guo, J Mi, QM Jiang, JM Xu, YY Tang, G Tian, B Wang. Metformin may produce antidepressant effects through improvement of cognitive function among depressed patients with diabetes mellitus. Clin Exp Pharmacol Physiol 2014; 41(9): 650–656 https://doi.org/10.1111/1440-1681.12265 pmid: 24862430
477	T Odaira, O Nakagawasai, K Takahashi, W Nemoto, W Sakuma, JR Lin, K Tan-No. Mechanisms underpinning AMP-activated protein kinase-related effects on behavior and hippocampal neurogenesis in an animal model of depression. Neuropharmacology 2019; 150: 121–133 https://doi.org/10.1016/j.neuropharm.2019.03.026 pmid: 30914305
478	IK Wium-Andersen, M Osler, MB Jørgensen, J Rungby, MK Wium-Andersen. Diabetes, antidiabetic medications and risk of depression — a population-based cohort and nested case-control study. Psychoneuroendocrinology 2022; 140: 105715 https://doi.org/10.1016/j.psyneuen.2022.105715 pmid: 35338947
479	T Leech, N Chattipakorn, SC Chattipakorn. The beneficial roles of metformin on the brain with cerebral ischaemia/reperfusion injury. Pharmacol Res 2019; 146: 104261 https://doi.org/10.1016/j.phrs.2019.104261 pmid: 31170502
480	AS Paintlia, MK Paintlia, S Mohan, AK Singh, I Singh. AMP-activated protein kinase signaling protects oligodendrocytes that restore central nervous system functions in an experimental autoimmune encephalomyelitis model. Am J Pathol 2013; 183(2): 526–541 https://doi.org/10.1016/j.ajpath.2013.04.030 pmid: 23759513
481	CY Xia, S Zhang, Y Gao, ZZ Wang, NH Chen. Selective modulation of microglia polarization to M2 phenotype for stroke treatment. Int Immunopharmacol 2015; 25(2): 377–382 https://doi.org/10.1016/j.intimp.2015.02.019 pmid: 25704852
482	Q Jin, J Cheng, Y Liu, J Wu, X Wang, S Wei, X Zhou, Z Qin, J Jia, X Zhen. Improvement of functional recovery by chronic metformin treatment is associated with enhanced alternative activation of microglia/macrophages and increased angiogenesis and neurogenesis following experimental stroke. Brain Behav Immun 2014; 40: 131–142 https://doi.org/10.1016/j.bbi.2014.03.003 pmid: 24632338
483	J Zhu, K Liu, K Huang, Y Gu, Y Hu, S Pan, Z Ji. Metformin improves neurologic outcome via AMP-activated protein kinase-mediated autophagy activation in a rat model of cardiac arrest and resuscitation. J Am Heart Assoc 2018; 7(12): e008389 https://doi.org/10.1161/JAHA.117.008389 pmid: 29895585
484	S Demaré, A Kothari, NA Calcutt, P Fernyhough. Metformin as a potential therapeutic for neurological disease: mobilizing AMPK to repair the nervous system. Expert Rev Neurother 2021; 21(1): 45–63 https://doi.org/10.1080/14737175.2021.1847645 pmid: 33161784
485	YY Cheng, HB Leu, TJ Chen, CL Chen, CH Kuo, SD Lee, CL Kao. Metformin-inclusive therapy reduces the risk of stroke in patients with diabetes: a 4-year follow-up study. J Stroke Cerebrovasc Dis 2014; 23(2): e99–e105 https://doi.org/10.1016/j.jstrokecerebrovasdis.2013.09.001 pmid: 24119365
486	D Kirpichnikov, SI McFarlane, JR Sowers. Metformin: an update. Ann Intern Med 2002; 137(1): 25–33 https://doi.org/10.7326/0003-4819-137-1-200207020-00009 pmid: 12093242
487	E Badrick, AG Renehan. Diabetes and cancer: 5 years into the recent controversy. Eur J Cancer 2014; 50(12): 2119–2125 https://doi.org/10.1016/j.ejca.2014.04.032 pmid: 24930060

[1]	Yifan Chang, Xianzhi Zhao, Yutian Xiao, Shi Yan, Weidong Xu, Ye Wang, Huojun Zhang, Shancheng Ren. Neoadjuvant radiohormonal therapy for oligo-metastatic prostate cancer: safety and efficacy outcomes from an open-label, dose-escalation, single-center, phase I/II clinical trial[J]. Front. Med., 2023, 17(2): 231-239.
[2]	Xueqing Hu, Ujjwol Khatri, Tao Shen, Jie Wu. Progress and challenges in RET-targeted cancer therapy[J]. Front. Med., 2023, 17(2): 207-219.
[3]	Xue Wang, Ye Zhou, Junxia Min, Fudi Wang. Zooming in and out of ferroptosis in human disease[J]. Front. Med., 2023, 17(2): 173-206.
[4]	Yingxi Du, Yarui Ma, Qing Zhu, Yong Fu, Yutong Li, Ying Zhang, Mo Li, Feiyue Feng, Peng Yuan, Xiaobing Wang. GDF15 negatively regulates chemosensitivity via TGFBR2-AKT pathway-dependent metabolism in esophageal squamous cell carcinoma[J]. Front. Med., 2023, 17(1): 119-131.
[5]	Danhui Weng, Huihua Xiong, Changkun Zhu, Xiaoyun Wan, Yaxia Chen, Xinyu Wang, Youzhong Zhang, Jie Jiang, Xi Zhang, Qinglei Gao, Gang Chen, Hui Xing, Changyu Wang, Kezhen Li, Yaheng Chen, Yuyan Mao, Dongxiao Hu, Zimin Pan, Qingqin Chen, Baoxia Cui, Kun Song, Cunjian Yi, Guangcai Peng, Xiaobing Han, Ruifang An, Liangsheng Fan, Wei Wang, Tingchuan Xiong, Yile Chen, Zhenzi Tang, Lin Li, Xingsheng Yang, Xiaodong Cheng, Weiguo Lu, Hui Wang, Beihua Kong, Xing Xie, Ding Ma. Adjuvant chemotherapy versus adjuvant concurrent chemoradiotherapy after radical surgery for early-stage cervical cancer: a randomized, non-inferiority, multicenter trial[J]. Front. Med., 2023, 17(1): 93-104.
[6]	Jia Zhong, Hua Bai, Zhijie Wang, Jianchun Duan, Wei Zhuang, Di Wang, Rui Wan, Jiachen Xu, Kailun Fei, Zixiao Ma, Xue Zhang, Jie Wang. Treatment of advanced non-small cell lung cancer with driver mutations: current applications and future directions[J]. Front. Med., 2023, 17(1): 18-42.
[7]	Jianhua Shi, Ying Cheng, Qiming Wang, Kai Li, Lin Wu, Baohui Han, Gongyan Chen, Jianxing He, Jie Wang, Haifeng Qin, Xiaoling Li. Anlotinib as third- or further-line therapy for short-term relapsed small-cell lung cancer: subgroup analysis of a randomized phase 2 study (ALTER1202)[J]. Front. Med., 2022, 16(5): 766-772.
[8]	Shi-Yong Sun. Targeting apoptosis to manage acquired resistance to third generation EGFR inhibitors[J]. Front. Med., 2022, 16(5): 701-713.
[9]	Xiang Wang, Minghui Wang, Lin Feng, Jie Song, Xin Dong, Ting Xiao, Shujun Cheng. Four-protein model for predicting prognostic risk of lung cancer[J]. Front. Med., 2022, 16(4): 618-626.
[10]	Yaru Tian, Hairong Tian, Xiaoyang Zhai, Hui Zhu, Jinming Yu. Bevacizumab in combination with pemetrexed and platinum for elderly patients with advanced non-squamous non-small-cell lung cancer: a retrospective analysis[J]. Front. Med., 2022, 16(4): 610-617.
[11]	Pooria Safarzadeh Kozani, Pouya Safarzadeh Kozani, Fatemeh Rahbarizadeh. CAR T cells redirected against tumor-specific antigen glycoforms: can low-sugar antigens guarantee a sweet success?[J]. Front. Med., 2022, 16(3): 322-338.
[12]	Ying Deng, Zhaowei Sun, Lei Wang, Minghui Wang, Jie Yang, Genxi Li. Biosensor-based assay of exosome biomarker for early diagnosis of cancer[J]. Front. Med., 2022, 16(2): 157-175.
[13]	Qiaoli Shi, Fei Xia, Qixin Wang, Fulong Liao, Qiuyan Guo, Chengchao Xu, Jigang Wang. Discovery and repurposing of artemisinin[J]. Front. Med., 2022, 16(1): 1-9.
[14]	Wenjing Zhou, Jing Zhang, Mingkun Yan, Jin Wu, Shuo Lian, Kang Sun, Baiqing Li, Jia Ma, Jun Xia, Chaoqun Lian. Orlistat induces ferroptosis-like cell death of lung cancer cells[J]. Front. Med., 2021, 15(6): 922-932.
[15]	Hongyun Zhao, Fan Luo, Jinhui Xue, Su Li, Rui-Hua Xu. Emerging immunological strategies: recent advances and future directions[J]. Front. Med., 2021, 15(6): 805-828.

Viewed

Full text

Abstract

Cited

Shared

Discussed