Cited by 479Metabolism, Diabetes, and CancerDiabetes Treatment and ManagementNatural Antidiabetic Agents Studies

The DOI matches its Crossref record; 99 of the 99 references it cites were found in a registry or an index.

Molecular mechanism of action of metformin: old or new insights?

Open access

Rena, Graham, Pearson, Ewan R., Sakamoto, Kei·2013·Diabetologia

DOI 10.1007/s00125-013-2991-0PMC PMC3737434

Open this paper in CoChat — free account Open PDF

Abstract

Metformin is the first-line drug treatment for type 2 diabetes. Globally, over 100 million patients are prescribed this drug annually. Metformin was discovered before the era of target-based drug discovery and its molecular mechanism of action remains an area of vigorous diabetes research. An improvement in our understanding of metformin's molecular targets is likely to enable target-based identification of second-generation drugs with similar properties, a development that has been impossible up to now. The notion that 5' AMP-activated protein kinase (AMPK) mediates the anti-hyperglycaemic action of metformin has recently been challenged by genetic loss-of-function studies, thrusting the AMPK-independent effects of the drug into the spotlight for the first time in more than a decade. Key AMPK-independent effects of the drug include the mitochondrial actions that have been known for many years and which are still thought to be the primary site of action of metformin. Coupled with recent evidence of AMPK-independent effects on the counter-regulatory hormone glucagon, new paradigms of AMPK-independent drug action are beginning to take shape. In this review we summarise the recent research developments on the molecular action of metformin.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1007/s00125-013-2991-0

Cites

99 of 99 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34)
(1998) · The Lancet · doi:10.1016/s0140-6736(98)07037-8 · Cited by 8,247
Role of AMP-Activated Protein Kinase in Mechanism of Metformin Action
Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci13505 · Cited by 5,652
AMPK: a nutrient and energy sensor that maintains energy homeostasis
Hardie, D. G., Ross, F. A., & Hawley, S. A. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3311 · Cited by 4,602
Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group.
(1998) · PubMed · Cited by 4,290
Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)
Inzucchi, S. E., Bergenstal, R. M., Buse, J. B., Diamant, M., Ferrannini, E., Nauck, M., Peters, A. L., Tsapas, A., Wender, R., & Matthews, D. R. (2012) · Diabetologia · doi:10.1007/s00125-012-2534-0 · Cited by 3,919
Anorexigenic and Orexigenic Hormone Modulation of Mammalian Target of Rapamycin Complex 1 Activity and the Regulation of Hypothalamic Agouti-Related Protein mRNA Expression
Watterson, K. R., Bestow, D., Gallagher, J. R., Hamilton, D. L., Ashford, F. B., Meakin, P. J., & Ashford, M. L. J. (2012) · Neurosignals · doi:10.1159/000334144 · Cited by 3,395
AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism
Kahn, B. B., Alquier, T., Carling, D., & Hardie, D. G. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2004.12.003 · Cited by 2,799
The selectivity of protein kinase inhibitors: a further update
Bain, J., Plater, L., Elliott, M., Shpiro, N., Hastie, C. J., McLauchlan, H., Klevernic, I. V., Arthur, J. S. C., Alessi, D. R., & Cohen, P. (2007) · Biochemical Journal · doi:10.1042/bj20070797 · Cited by 2,522
Metformin and reduced risk of cancer in diabetic patients
Evans, J. M. M., Donnelly, L. A., Emslie-Smith, A. M., Alessi, D. R., & Morris, A. D. (2005) · BMJ · doi:10.1136/bmj.38415.708634.f7 · Cited by 2,388
Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain
OWEN, M. R., DORAN, E., & HALESTRAP, A. P. (2000) · Biochemical Journal · doi:10.1042/bj3480607 · Cited by 2,157

Flagged first, then by citations

Show all 98 references

Research works printed but not linked: 2

Ray RK, Kauffman GB (1999) Metal and non-metal biguanide complexes. New Age International Publishers, New Delhi
Kazda CM, Garhyan P, Kelly RP et al (2012) 12-week treatment with glucagon receptor antagonist LY2409021 significantly lowers HbA1c and is well tolerated in patients with type 2 diabetes mellitus. Diabetologia 55(Suppl 1):S51, Abstr. 112

Sorted by citations

Items 101–200 of 479

Combatting type 2 diabetes by turning up the heat
Schrauwen, P., & Lichtenbelt, W. D. V. M. (2016) · Diabetologia · doi:10.1007/s00125-016-4068-3 · Cited by 63
Pharmacokinetics of metformin in patients with gastrointestinal intolerance
MCCREIGHT, L. J., Stage, T. B., Connelly, P. J., Lonergan, M. E., Nielsen, F., Prehn, C. P., Adamski, J., Brøsen, K., & Pearson, E. R. (2018) · Diabetes Obesity and Metabolism · doi:10.1111/dom.13264 · Cited by 59
Self-citation
A Systematic Review on Synthetic Drugs and Phytopharmaceuticals Used to Manage Diabetes
Banerjee, M., Khursheed, R., Yadav, A., Singh, S. K., Gulati, M., Pandey, D. K., Prabhakar, P. K., Kumar, R., Porwal, O., Awasthi, A., et al. (2019) · Current Diabetes Reviews · doi:10.2174/1573399815666190822165141 · Cited by 57
A-769662 potentiates the effect of other AMP-activated protein kinase activators on cardiac glucose uptake
Timmermans, A. D., Balteau, M., Gélinas, R., Renguet, E., Ginion, A., de Meester, C., Sakamoto, K., Balligand, J., Bontemps, F., Vanoverschelde, J., et al. (2014) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00965.2013 · Cited by 57
Self-citation
Increased Methylglyoxal Formation with Upregulation of Renin Angiotensin System in Fructose Fed Sprague Dawley Rats
Dhar, I., Dhar, A., Wu, L., & Desai, K. M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0074212 · Cited by 56
Metformin: Past, Present, and Future
Chaudhary, S., & Kulkarni, A. (2024) · Current Diabetes Reports · doi:10.1007/s11892-024-01539-1 · Cited by 64
Diabetes and Osteoarthritis: Exploring the Interactions and Therapeutic Implications of Insulin, Metformin, and GLP-1-Based Interventions
Halabitska, I., Бабинец, Л. С., Oksenych, V., & Kamyshnyi, O. (2024) · Biomedicines · doi:10.3390/biomedicines12081630 · Cited by 57
Effect comparison of metformin with insulin treatment for gestational diabetes: a meta-analysis based on RCTs
Li, G., Zhao, S., Cui, S., Li, L., Xu, Y., & Li, Y. (2015) · Archives of Gynecology and Obstetrics · doi:10.1007/s00404-014-3566-0 · Cited by 54
Effect of a long-term treatment with metformin in dystrophic mdx mice: A reconsideration of its potential clinical interest in Duchenne muscular dystrophy
Mantuano, P., Sanarica, F., Conte, E., Morgese, M. G., Capogrosso, R. F., Cozzoli, A., Fonzino, A., Quaranta, A., Rolland, J., Bellis, M. D., et al. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.04.022 · Cited by 55
Repurposing Drugs to Target the Diabetes Epidemic
Turner, N. A., Zeng, X., Osborne, B., Rogers, S., & Ye, J.-M. (2016) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2016.01.007 · Cited by 59
Metformin ameliorates activation of hepatic stellate cells and hepatic fibrosis by succinate and GPR91 inhibition
Nguyen, G., Park, S. Y., Le, C. T., Park, W. S., Choi, D. H., & Cho, E.-H. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.12.143 · Cited by 54
AMPK Alpha-1 Intrinsically Regulates the Function and Differentiation of Tumor Myeloid-Derived Suppressor Cells
Trillo-Tinoco, J., Sierra, R. A., Mohamed, E. T., Cao, Y. W., Pulido, Á. D. M., Gilvary, D. L., Anadon, C. M., Costich, T. L., Wei, S., Flores, E. R., et al. (2019) · Cancer Research · doi:10.1158/0008-5472.can-19-0880 · Cited by 53
Effect of metformin on the fertilizing ability of mouse spermatozoa
Bertoldo, M. J., Guibert, E., Tartarin, P., Guillory, V., & Froment, P. (2014) · Cryobiology · doi:10.1016/j.cryobiol.2014.02.006 · Cited by 56
Biomolecular Mode of Action of Metformin in Relation to Its Copper Binding Properties
Repiščák, P., Erhardt, S., Rena, G., & Paterson, M. J. (2014) · Biochemistry · doi:10.1021/bi401444n · Cited by 55
Self-citation
Prevention by metformin of alterations induced by chronic exposure to high glucose in human islet beta cells is associated with preserved ATP/ADP ratio
Masini, M., Anello, M., Bugliani, M., Marselli, L., Filipponi, F., Boggi, U., Purrello, F., Occhipinti, M., Martino, L., Marchetti, P., et al. (2014) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2013.12.031 · Cited by 56
Metformin Use in Children and Adolescents with Prediabetes
Khokhar, A., Umpaichitra, V., Chin, V. L., & Perez-Colon, S. (2017) · Pediatric Clinics of North America · doi:10.1016/j.pcl.2017.08.010 · Cited by 54
Biguanides drugs: Past success stories and promising future for drug discovery
Grytsai, O., Myrgorodska, I., Rocchi, S., Ronco, C., & Benhida, R. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113726 · Cited by 51
Metformin use and its effect on survival in diabetic patients with advanced non-small cell lung cancer
Arrieta, O. G., Varela‐Santoyo, E., Soto‐Pérez‐de‐Celis, E., Sánchez-Reyes, R., la Torre-Vallejo, M. D., Muñiz‐Hernández, S., & Cardona, A. F. (2016) · BMC Cancer · doi:10.1186/s12885-016-2658-6 · Cited by 51
Metformin mitigates carbon tetrachloride-induced TGF-β1/Smad3 signaling and liver fibrosis in mice
Fan, K., Wu, K., Lin, L., Ge, P., Dai, J., He, X., Hu, K., & Zhang, L. (2017) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2017.03.079 · Cited by 50
Metformin Use Is Associated With a Lower Risk of Hospitalization for Heart Failure in Patients With Type 2 Diabetes Mellitus: a Retrospective Cohort Analysis
Tseng, C. (2019) · Journal of the American Heart Association · doi:10.1161/jaha.118.011640 · Cited by 51
Biological Properties of Transition Metal Complexes with Metformin and Its Analogues
Rusanov, D. A., Zou, J., & Babak, M. V. (2022) · Pharmaceuticals · doi:10.3390/ph15040453 · Cited by 50
Metformin prevents DMH ‐induced colorectal cancer in diabetic rats by reversing the warburg effect
Jia, Y., Ma, Z., Liu, X., Zhou, W., He, S., Xu, X., Ren, G., Xu, G., & Tian, K. (2015) · Cancer Medicine · doi:10.1002/cam4.521 · Cited by 50
Functional interplay between liver X receptor and AMP‐activated protein kinase α inhibits atherosclerosis in apolipoprotein E‐deficient mice − a new anti‐atherogenic strategy
Ma, C., Zhang, W., Yang, X., Liu, Y., Liu, L., Feng, K., Zhang, X., Yang, S., Sun, L., Yu, M., et al. (2018) · British Journal of Pharmacology · doi:10.1111/bph.14156 · Cited by 49
Stability-indicating capillary electrophoresis method for the simultaneous determination of metformin hydrochloride, saxagliptin hydrochloride, and dapagliflozin in pharmaceutical tablets
Maher, H. M., Abdelrahman, A. E., Alzoman, N. Z., & Aljohar, H. I. (2019) · Journal of Liquid Chromatography & Related Technologies · doi:10.1080/10826076.2019.1590208 · Cited by 47
Metformin inhibits β-catenin phosphorylation on Ser-552 through an AMPK/PI3K/Akt pathway in colorectal cancer cells
Amable, G., Martínez-León, E., Picco, M. E., Siervi, N. D., Davio, C. A., Rozengurt, E., & Rey, O. (2019) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2019.05.004 · Cited by 47
Overview of Metformin and Neurodegeneration: A Comprehensive Review
Kruczkowska, W., Gałęziewska, J., Buczek, P., Płuciennik, E., Kciuk, M., & Śliwińska, A. (2025) · Pharmaceuticals · doi:10.3390/ph18040486 · Cited by 52
Repurposing of Drugs Targeting YAP-TEAD Functions
Elisi, G. M., Santucci, M., D’Arca, D., Lauriola, A., Marverti, G., Losi, L., Scalvini, L., Bolognesi, M. L., Mor, M., & Costi, M. P. (2018) · Cancers · doi:10.3390/cancers10090329 · Cited by 47
A Review of the Impact of Pharmacogenetics and Metabolomics on the Efficacy of Metformin in Type 2 Diabetes
Damanhouri, Z. A., Alkreathy, H. M., Alharbi, F. A., Abualhamail, H., & Ahmad, M. S. (2023) · International Journal of Medical Sciences · doi:10.7150/ijms.77206 · Cited by 49
Nutrients in Energy and One-Carbon Metabolism: Learning from Metformin Users
Luciano‐Mateo, F., Hernández‐Aguilera, A., Cabré, N., Camps, J., Fernández‐Arroyo, S., López‐Miranda, J., Menéndez, J. A., & Joven, J. (2017) · Nutrients · doi:10.3390/nu9020121 · Cited by 44
Metabolic benefits of annatto-extracted tocotrienol on glucose homeostasis, inflammation, and gut microbiome
Chung, E., Elmassry, M. M., Kottapalli, P., Kottapalli, K. R., Kaur, G., Dufour, J. M., Wright, K., Ramalingam, L., Moustaïd‐Moussa, N., Wang, R., et al. (2020) · Nutrition Research · doi:10.1016/j.nutres.2020.04.001 · Cited by 44
Therapeutic efficacy of liraglutide versus metformin in modulating the gut microbiota for treating type 2 diabetes mellitus complicated with nonalcoholic fatty liver disease
Ying, X., Rongjiong, Z., Kahaer, M., Chunhui, J., & Wulasihan, M. (2023) · Frontiers in Microbiology · doi:10.3389/fmicb.2023.1088187 · Cited by 47
Combined Treatment with Exendin-4 and Metformin Attenuates Prostate Cancer Growth
Tsutsumi, Y., Nomiyama, T., Kawanami, T., Hamaguchi, Y., Terawaki, Y., Tanaka, T., Murase, K., Motonaga, R., Tanabe, M., & Yanase, T. (2015) · PLoS ONE · doi:10.1371/journal.pone.0139709 · Cited by 47
Metformin Use and Lung Cancer Risk in Patients with Diabetes
Sakoda, L. C., Ferrara, A. M., Achacoso, N. S., Peng, T., Ehrlich, S. F., Quesenberry, C. P., & Habel, L. A. (2015) · Cancer Prevention Research · doi:10.1158/1940-6207.capr-14-0291 · Cited by 44
Immunity and Inflammation: From Jekyll to Hyde
Xu, W., & Larbi, A. (2017) · Experimental Gerontology · doi:10.1016/j.exger.2017.11.018 · Cited by 48
Baicalin regulates SirT1/STAT3 pathway and restrains excessive hepatic glucose production
Xu, J., Li, Y., Lou, M., Xia, W., Liu, Q., Xie, G., Liu, L., Liu, B., Yang, J., & Qin, M. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.08.018 · Cited by 45
Recent Progress in Metabolic Signaling Pathways Regulating Aging and Life Span
Newgard, C. B., & Pessin, J. E. (2014) · The Journals of Gerontology Series A · doi:10.1093/gerona/glu058 · Cited by 44
To Use or Not to Use Metformin in Cerebral Ischemia: A Review of the Application of Metformin in Stroke Rodents
Arbeláez-Quintero, I., & Palacios, M. (2017) · Stroke Research and Treatment · doi:10.1155/2017/9756429 · Cited by 44
Negative Effects of Chronic Rapamycin Treatment on Behavior in a Mouse Model of Fragile X Syndrome
Saré, R. M., Song, A., Loutaev, I., Cook, A. K., Maita, I., Lemons, A. H. S., Sheeler, C. A., & Smith, C. B. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00452 · Cited by 45
Concise Review: Macrophages: Versatile Gatekeepers During Pancreatic β-Cell Development, Injury, and Regeneration
Gassen, N. V., Staels, W., Overmeire, E. V., Groef, S. D., Sojoodi, M., Heremans, Y., Leuckx, G., de Casteele, M. V., Ginderachter, J. A. V., Heimberg, H., et al. (2015) · Stem Cells Translational Medicine · doi:10.5966/sctm.2014-0272 · Cited by 43
The Role of Glucagon in the Pathophysiology and Management of Diabetes
Kulina, G., & Rayfield, E. J. (2016) · Endocrine Practice · doi:10.4158/ep15984.ra · Cited by 45
Reduced mitochondrial activity in colonocytes facilitates AMPKα2‐dependent inflammation
Heller, S., Penrose, H. M., Cable, C., Biswas, D., Nakhoul, H. N., Baddoo, M., Flemington, E. F., Crawford, S. E., & Savkovic, S. D. (2017) · The FASEB Journal · doi:10.1096/fj.201600976r · Cited by 43
Metformin causes a futile intestinal–hepatic cycle which increases energy expenditure and slows down development of a type 2 diabetes-like state
Schommers, P., Thurau, A., Bultmann-Mellin, I., Guschlbauer, M., Klatt, A. R., Rozman, J., Klingenspor, M., de Angelis, M. H., Alber, J., Gründemann, D., et al. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.05.002 · Cited by 42
Novel therapeutic targets of metformin: metabolic syndrome and cardiovascular disease
Ladeiras‐Lopes, R., Fontes‐Carvalho, R., Bettencourt, N., Sampaio, F., Gama, V., & Leite-Moreira, A. F. (2015) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2015.1025051 · Cited by 44
Metformin: an old drug with new potential
Hajjar, J., Habra, M. A., & Naing, A. (2013) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2013.833604 · Cited by 42
The Gut Microbiota-Related Antihyperglycemic Effect of Metformin
Szymczak-Pajor, I., Drzewoski, J., Kozłowska, M., Krekora, J., & Śliwińska, A. (2025) · Pharmaceuticals · doi:10.3390/ph18010055 · Cited by 43
The emerging role of metformin in gestational diabetes mellitus
Gray, S. G., McGuire, T. M., Cohen, N., & Little, P. J. (2017) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12893 · Cited by 40
AMP‐activated protein kinase (AMPK) regulates autophagy, inflammation and immunity and contributes to osteoclast differentiation and functionabs
Tong, X., Ganta, R. R., & Liu, Z. (2020) · Biology of the Cell · doi:10.1111/boc.202000008 · Cited by 42
A landscape analysis of the potential role of polyphenols for the treatment of Polycystic Ovarian Syndrome (PCOS)
Rani, R., Hajam, Y. A., Kumar, R., Bhat, R. A., Rai, S., & Rather, M. A. (2021) · Phytomedicine Plus · doi:10.1016/j.phyplu.2021.100161 · Cited by 45
Endogenous glucose production increases in response to metformin treatment in the glycogen-depleted state in humans: a randomised trial
Christensen, M. M. H., Højlund, K., Nielsen, O. H., Stage, T. B., Damkier, P., Beck‐Nielsen, H., & Brøsen, K. (2015) · Diabetologia · doi:10.1007/s00125-015-3733-2 · Cited by 39
Antidiabetic effects of the Cimicifuga racemosa extract Ze 450 in vitro and in vivo in ob/ob mice
Moser, C. D., Vickers, S. P., Brammer, R. J., Cheetham, S. C., & Drewe, J. (2014) · Phytomedicine · doi:10.1016/j.phymed.2014.06.002 · Cited by 39
Metformin: An Inhibitor of mTORC1 Signaling
Melnik, B. C., & Schmitz, G. (2014) · Cited by 39
MiRNA-27b Regulates Angiogenesis by Targeting AMPK in Mouse Ischemic Stroke Model
Yuan, Y., Zhang, Z., Wang, Z., & Liu, J. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2018.11.041 · Cited by 37
Interferon-inducer antivirals: Potential candidates to combat COVID-19
Bagheri, A., Moezzi, S. M. I., Mosaddeghi, P., Parashkouhi, S. N., Hoseini, S. M. F., Badakhshan, F., & Negahdaripour, M. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.107245 · Cited by 39
Physiologically‐Based Pharmacokinetic Modeling Analysis for Quantitative Prediction of Renal Transporter–Mediated Interactions Between Metformin and Cimetidine
Nishiyama, K., Toshimoto, K., Lee, W., Ishiguro, N., Bister, B., & Sugiyama, Y. (2019) · CPT Pharmacometrics & Systems Pharmacology · doi:10.1002/psp4.12398 · Cited by 40
Metformin prevents cerebellar granule neurons against glutamate-induced neurotoxicity
Zhou, C., Sun, R., Zhuang, S., Sun, C., Jiang, Y., Cui, Y., Li, S., Xiao, Y., Du, Y., Gu, H., et al. (2016) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2016.02.009 · Cited by 38
AMPK inhibits liver gluconeogenesis: fact or fiction?
Johanns, M., Hue, L., & Rider, M. H. (2023) · Biochemical Journal · doi:10.1042/bcj20220582 · Cited by 46
Metformin attenuated endotoxin-induced acute myocarditis via activating AMPK
Liu, G., Wu, K., Zhang, L., Dai, J., Huang, W., Lin, L., Ge, P., Luo, F., & Lei, H. (2017) · International Immunopharmacology · doi:10.1016/j.intimp.2017.04.002 · Cited by 37
Recent Advances in Anti-Aging Medicine
Son, D., Park, W.-J., & Lee, Y. (2019) · Korean Journal of Family Medicine · doi:10.4082/kjfm.19.0087 · Cited by 38
Anti-metastatic effect of metformin via repression of interleukin 6-induced epithelial–mesenchymal transition in human colon cancer cells
Kang, S., Kim, B. R., Kang, M. H., Kim, D. Y., Lee, D.-H., Oh, S. C., Min, B. W., & Um, J. W. (2018) · PLoS ONE · doi:10.1371/journal.pone.0205449 · Cited by 36
Photobiomodulation reduces hepatic lipogenesis and enhances insulin sensitivity through activation of CaMKKβ/AMPK signaling pathway
Guo, S., Gong, L., Shen, Q., & Xing, D. (2020) · Journal of Photochemistry and Photobiology B Biology · doi:10.1016/j.jphotobiol.2020.112075 · Cited by 37
Sequential cleavage of insulin receptor by calpain 2 and γ-secretase impairs insulin signalling
Yuasa, T., Amo-Shiinoki, K., Ishikura, S., Takahara, M., Matsuoka, T., Kaneto, H., Kuroda, A., Matsuhisa, M., & Hashida, S. (2016) · Diabetologia · doi:10.1007/s00125-016-4102-5 · Cited by 36
Metformin and its gastrointestinal problems: A review
Fatima, M., Sadeeqa, S., & Nazir, S. U. R. (2018) · Biomedical Research - India · doi:10.4066/biomedicalresearch.40-18-526 · Cited by 37
Metabolic and Mitochondrial Dysregulations in Diabetic Cardiac Complications
Tashkandi, A. J. A., Gorman, A., Mathers, E. M., Carney, G., Yacoub, A., Setyaningsih, W. A. W., Kuburas, R., & Margariti, A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26073016 · Cited by 35
Re-sensitization of radiation resistant colorectal cancer cells to radiation through inhibition of AMPK pathway
Jin, H., Gao, S., Guo, H., REN, S., Ji, F., LIU, Z., & Chen, X. (2016) · Oncology Letters · doi:10.3892/ol.2016.4339 · Cited by 34
Interventions to slow cardiovascular aging: Dietary restriction, drugs and novel molecules
Heiß, C., Spyridopoulos, I., & Haendeler, J. (2017) · Experimental Gerontology · doi:10.1016/j.exger.2017.06.015 · Cited by 36
Development, Maintenance, and Reversal of Multiple Drug Resistance: At the Crossroads of TFPI1, ABC Transporters, and HIF1
Arnason, T., & Harkness, T. A. A. (2015) · Cancers · doi:10.3390/cancers7040877 · Cited by 33
Predicting Clostridium difficile infection in diabetic patients and the effect of metformin therapy: a retrospective, case–control study
Eliakim‐Raz, N., Fishman, G., Yahav, D., Goldberg, E., Stein, G. Y., Zvi, H. B., Barsheshet, A., & Bishara, J. (2015) · European Journal of Clinical Microbiology & Infectious Diseases · doi:10.1007/s10096-015-2348-3 · Cited by 35
Metformin use improves the survival of diabetic combined small-cell lung cancer patients
Kong, F., Gao, F., Liu, H., Chen, L., Zheng, R., Yu, J., Li, X., Liu, G., & Jia, Y. (2015) · Tumor Biology · doi:10.1007/s13277-015-3549-1 · Cited by 33
HS218 as an FXR antagonist suppresses gluconeogenesis by inhibiting FXR binding to PGC-1α promoter
Xu, X., Shi, X., Chen, Y., Zhou, T., Wang, J., Xu, X. Y., Chen, L., Hu, L., & Shen, X. (2018) · Metabolism · doi:10.1016/j.metabol.2018.03.016 · Cited by 34
Is metformin a possible treatment for diabetic neuropathy?
Wei, J., Wei, Y., Huang, M., Wang, P., & Jia, S. (2022) · Journal of Diabetes · doi:10.1111/1753-0407.13310 · Cited by 32
Big data and machine learning to tackle diabetes management
Pina, A. F., Meneses, M. J., Sousa‐Lima, I., Henriques, R., Raposo, J. F., & Macedo, M. P. (2022) · European Journal of Clinical Investigation · doi:10.1111/eci.13890 · Cited by 32
The insulin sensitiser metformin regulates chicken Sertoli and germ cell populations
Faure, M., Guibert, E., Alves, S., Pain, B., Ramé, C., Dupont, J., Brillard, J. P., & Froment, P. (2016) · Reproduction · doi:10.1530/rep-15-0565 · Cited by 36
Shared signaling pathways in Alzheimer’s and metabolic disease may point to new treatment approaches
Suresh, J., Khor, I. W., Kaur, P., Heng, H. L., Torta, F. T., Dawe, G. S., Tai, E. S., & Tolwinski, N. S. (2020) · FEBS Journal · doi:10.1111/febs.15540 · Cited by 34
An update on mode of action of metformin in modulation of meta-inflammation and inflammaging
Khodadadi, M., Jafari-Gharabaghlou, D., & Zarghami, N. (2022) · Pharmacological Reports · doi:10.1007/s43440-021-00334-z · Cited by 34
Impact of Metformin on Male Reproduction
Ferreira, C., Sousa, M., Rabaça, A., Oliveira, P. F., Alves, M. G., & Sá, R. (2015) · Current Pharmaceutical Design · doi:10.2174/1381612821666150710150041 · Cited by 33
T Cell Metabolism in Cancer Immunotherapy
Aksoylar, H., Tijaro-Ovalle, N. M., Boussiotis, V. A., & Patsoukis, N. (2020) · Immunometabolism · doi:10.20900/immunometab20200020 · Cited by 31
The Potential Therapeutic Role of Metformin in Diabetic and Non-Diabetic Bone Impairment
Mu, W., Liang, G., Feng, Y., Jiang, Y., & Qu, F. (2022) · Pharmaceuticals · doi:10.3390/ph15101274 · Cited by 30
Recessive mutations in the cancer gene Ataxia Telangiectasia Mutated ( ATM ), at a locus previously associated with metformin response, cause dysglycaemia and insulin resistance
Connelly, P. J., Smith, N. F., Chadwick, R., Exley, A., Shneerson, J. M., & Pearson, E. R. (2015) · Diabetic Medicine · doi:10.1111/dme.13037 · Cited by 30
Self-citation
Metformin activates KDM2A to reduce rRNA transcription and cell proliferation by dual regulation of AMPK activity and intracellular succinate level
Tanaka, Y., Konishi, A., Obinata, H., & Tsuneoka, M. (2019) · Scientific Reports · doi:10.1038/s41598-019-55075-0 · Cited by 31
Compound- and fiber type-selective requirement of AMPKγ3 for insulin-independent glucose uptake in skeletal muscle
Rhein, P., Desjardins, E. M., Rong, P., Ahwazi, D., Bonhoure, N., Stolte, J., Santos, M. D., Ovens, A. J., Ehrlich, A. M., Garcia, J. L. S., et al. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101228 · Cited by 28
Self-citation
Progression of established non-diabetic chronic kidney disease is halted by metformin treatment in rats
Corremans, R., Neven, E., Maudsley, S. R., Leysen, H., Broe, M. E. D., D’Haese, P. C., Vervaet, B. A., & Verhulst, A. (2022) · Kidney International · doi:10.1016/j.kint.2022.01.037 · Cited by 30
Prognosis of small cell lung cancer patients with diabetes treated with metformin
Xu, T., Liang, G., Yang, L., & Zhang, F. (2015) · Clinical & Translational Oncology · doi:10.1007/s12094-015-1311-1 · Cited by 30
Hibiscus sabdariffa (roselle) polyphenol-rich extract averts cardiac functional and structural abnormalities in type 1 diabetic rats
Yusof, N. L. M., Zainalabidin, S., Fauzi, N. M., & Budin, S. B. (2018) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/apnm-2018-0084 · Cited by 32
Of mice and men: Is there a future for metformin in the treatment of hepatic steatosis?
Green, C., Marjot, T., Tomlinson, J., & Hodson, L. (2018) · Diabetes Obesity and Metabolism · doi:10.1111/dom.13592 · Cited by 29
A Common Variant at the 14q32 Endometrial Cancer Risk Locus Activates AKT1 through YY1 Binding
Painter, J. N., Kaufmann, S., O’Mara, T. A., Hillman, K. M., Sivakumaran, H., Darabi, H., Cheng, T. H. T., Pearson, J. V., Kazakoff, S. H., Waddell, N., et al. (2016) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2016.04.012 · Cited by 28
Effect of antidiabetic drugs on the risk of atrial fibrillation: mechanistic insights from clinical evidence and translational studies
Lee, T.-W., Lee, T.-I., Lin, Y.-K., Chen, Y.-C., Kao, Y.-H., & Chen, Y.-J. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03648-y · Cited by 27
Rotenone, a mitochondrial respiratory complex I inhibitor, ameliorates lipopolysaccharide/D-galactosamine-induced fulminant hepatitis in mice
Ai, Q., Jing, Y., Jiang, R., Lin, L., Dai, J., Che, Q., Zhou, D., Jia, M., Wan, J., & Zhang, L. (2014) · International Immunopharmacology · doi:10.1016/j.intimp.2014.04.028 · Cited by 27
Effect of diacerein as an add-on to metformin in patients with type 2 diabetes mellitus and inadequate glycemic control
Villar, M. M.-D., Martínez‐Abundis, E., Preciado-Márquez, R. O., & González-Ortíz, M. (2017) · Archives of Endocrinology and Metabolism · doi:10.1590/2359-3997000000242 · Cited by 27
Glycemic control and neonatal outcomes in women with gestational diabetes mellitus treated using glyburide, metformin, or insulin: a pairwise and network meta-analysis
Yu, D., Xu, G., Teng, X., Xu, J., Tang, L., Feng, C., Rao, J., Jin, M., & Wang, L. (2021) · BMC Endocrine Disorders · doi:10.1186/s12902-021-00865-9 · Cited by 50
A Co-Doped Carbon Dot/Silver Nanoparticle Nanocomposite-Based Fluorescence Sensor for Metformin Hydrochloride Detection
Le, T. H., Kim, J.-H., & Park, S. (2022) · Nanomaterials · doi:10.3390/nano12081297 · Cited by 27
Miocardiopatía diabética
Lorenzo-Almorós, A., Cepeda-Rodrigo, J. M., & Lorenzo, Ó. (2020) · Revista Clínica Española · doi:10.1016/j.rce.2019.10.013 · Cited by 31
Antidiabetic Plants for the Treatment of Type 2 Diabetes Mellitus and Associated Bacterial Infections
Tienda-Vázquez, M. A., Melchor-Martínez, E. M., Elizondo‐Luévano, J. H., Parra‐Saldívar, R., Lara-Ortiz, J. S., Luna-Sosa, B., & Scheckhuber, C. Q. (2023) · Processes · doi:10.3390/pr11051299 · Cited by 28
Metformin attenuates palmitic acid-induced insulin resistance in L6 cells through the AMP-activated protein kinase/sterol regulatory element-binding protein-1c pathway
Wu, W., Tang, S., JUNFENG, S., WENWEN, Y., SHU, C., Bu, R., DALONG, Z., & Bi, Y. (2015) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2015.2187 · Cited by 27
Metformin one in a Million Efficient Medicines for Rheumatoid Arthritis Complications: Inflammation, Osteoblastogenesis, Cardiovascular Disease, Malignancies
Rajaei, E., Haybar, H., Mowla, K., & Zayeri, Z. D. (2018) · Current Rheumatology Reviews · doi:10.2174/1573397114666180717145745 · Cited by 27
Revisiting "Vegetables" to combat modern epidemic of imbalanced glucose homeostasis
Tiwari, A. K. (2014) · Pharmacognosy Magazine · doi:10.4103/0973-1296.133211 · Cited by 27
Bilayer tablets with sustained-release metformin and immediate-release sitagliptin: preparation and in vitro/in vivo evaluation
Nguyen, N. N. T., Phạm, D. T., Nguyen, D. T., & Trinh, T. T. L. (2021) · Journal of Pharmaceutical Investigation · doi:10.1007/s40005-021-00533-z · Cited by 26
AMPK activation alleviated dextran sulfate sodium ‐induced colitis by inhibiting ferroptosis
Sun, S., Lü, B., Li, H., Weng, C., Chen, J. J., Lou, Y. J., Lyu, D., & Lü, B. (2023) · Journal of Digestive Diseases · doi:10.1111/1751-2980.13176 · Cited by 26
Activation of the metabolic sensor AMP-activated protein kinase inhibits aquaporin-2 function in kidney principal cells
Al‐bataineh, M. M., Li, H., Ohmi, K., Gong, F., Marciszyn, A. L., Naveed, S., Zhu, X., Neumann, D., Wu, Q., Cheng, L., et al. (2016) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00308.2016 · Cited by 25
Metformin and risk of chronic obstructive pulmonary disease in diabetes patients
Tseng, C. (2018) · Diabetes & Metabolism · doi:10.1016/j.diabet.2018.05.001 · Cited by 26
NHX-5, an endosomal Na+/H+ exchanger, is associated with metformin action
Kim, J., Lee, H.-Y., Ahn, J., Hyun, M., Lee, I., Min, K.-J., & You, Y.-J. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.c116.744037 · Cited by 25

Authors: Rena, G., Pearson, E. R., & Sakamoto, K.
Affiliations: University of Dundee (GB)
École Polytechnique Fédérale de Lausanne (CH)
Corresponding author: Rena, Graham
Sakamoto, Kei
ORCID: Rena, Graham
Pearson, Ewan R.
Sakamoto, Kei
Venue: Diabetologia
Publisher: Springer Science and Business Media LLC
Published: 2013-07-09
Volume: 56
Issue: 9
Pages: 1898-1906
ISSN: 0012-186X (ISSN-L)
1432-0428
DOI: 10.1007/s00125-013-2991-0
PMC: PMC3737434
OpenAlex: W2025130292
Cited by: 479
References: 98
Citations by year: 2026: 9 · 2025: 22 · 2024: 20 · 2023: 33 · 2022: 22 · 2021: 52 · 2020: 33 · 2019: 38 · 2018: 58 · 2017: 51 · 2016: 37 · 2015: 52 · 2014: 43 · 2013: 8
FWCI: 4.39
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc
creativecommons.org/licenses/by-nc/2.0 (unspecified)
Locations: Diabetologia (publishedVersion, cc-by-nc)
Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
PubMed Central (publishedVersion, cc-by-nc)
PubMed (publishedVersion)
reroDoc Digital Library (submittedVersion)
Discovery Research Portal (University of Dundee) (submittedVersion)
Funders: Medical Research Council (MR/K012924/1)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
Keywords: metformin, molecular mechanisms of action, type 2 diabetes, AMPK, glucagon, therapeutic target
MeSH terms: Diabetes Mellitus, Type 2, Energy Metabolism, Gluconeogenesis, Humans, Metformin, Models, Biological, AMP-Activated Protein Kinases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Molecular mechanism of action of metformin: old or new insights?

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks