Cited by 5,652Metabolism, Diabetes, and CancerPeroxisome Proliferator-Activated ReceptorsNatural Antidiabetic Agents Studies

The DOI matches its Crossref record; 37 of the 37 references it cites were found in a registry or an index.

Role of AMP-activated protein kinase in mechanism of metformin action

Open access

Zhou, Gaochao, Myers, Robert, Li, Ying, Chen, Yuli, Shen, Xiaolan, Fenyk-Melody, Judy, Wu, Margaret, Ventre, John, Doebber, Thomas, Fujii, Nobuharu, Musi, Nicolas, Hirshman, Michael F., Goodyear, Laurie J., Moller, David E.·2001·Journal of Clinical Investigation

DOI 10.1172/jci13505PMC PMC209533

Open this paper in CoChat — free account Open PDF

Abstract

Metformin is a widely used drug for treatment of type 2 diabetes with no defined cellular mechanism of action. Its glucose-lowering effect results from decreased hepatic glucose production and increased glucose utilization. Metformin's beneficial effects on circulating lipids have been linked to reduced fatty liver. AMP-activated protein kinase (AMPK) is a major cellular regulator of lipid and glucose metabolism. Here we report that metformin activates AMPK in hepatocytes; as a result, acetyl-CoA carboxylase (ACC) activity is reduced, fatty acid oxidation is induced, and expression of lipogenic enzymes is suppressed. Activation of AMPK by metformin or an adenosine analogue suppresses expression of SREBP-1, a key lipogenic transcription factor. In metformin-treated rats, hepatic expression of SREBP-1 (and other lipogenic) mRNAs and protein is reduced; activity of the AMPK target, ACC, is also reduced. Using a novel AMPK inhibitor, we find that AMPK activation is required for metformin's inhibitory effect on glucose production by hepatocytes. In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPK activation. Activation of AMPK provides a unified explanation for the pleiotropic beneficial effects of this drug; these results also suggest that alternative means of modulating AMPK should be useful for the treatment of metabolic disorders.

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 · 10.1172/jci13505

Cites

37 of 37 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.

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
The Mitochondrial Carnitine Palmitoyltransferase System — From Concept to Molecular Analysis
McGarry, J. D., & Brown, N. F. (1997) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1997.00001.x · Cited by 1,616 · cited 1×
“Malonyl-CoA is an initial substrate for de novo fatty acid biosynthesis, and it serves as a potent inhibitor of carnitine palmitoyl transferase I (CPT-I), a rate-limiting step for fatty acid oxidation (34).”
Background
Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I
El-Mir, M.-Y., Nogueira, V., Fontaine, E., Avéret, N., Rigoulet, M., & Leverve, X. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.1.223 · Cited by 1,399
The AMP‐Activated Protein Kinase: Fuel Gauge of the Mammalian Cell?
Hardie, D. G., & Carling, D. (1997) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1997.00259.x · Cited by 1,317
Metabolic effects of metformin in non-insulin-dependent diabetes mellitus
Stumvoll, M., Nurjhan, N., Perriello, G., Dailey, G., & Gerich, J. E. (1995) · New England Journal of Medicine · doi:10.1056/nejm199508313330903 · Cited by 1,148
Mechanism by which metformin reduces glucose production in type 2 diabetes.
Hundal, R. S., Krssak, M., Dufour, S., Laurent, D., Lebon, V, Chandramouli, V, Inzucchi, S. E., Schumann, W. C., Petersen, K. F., Landau, B. R., et al. (2000) · Diabetes · doi:10.2337/diabetes.49.12.2063 · Cited by 1,052 · cited 2×
“It is believed that metformin-mediated inhibition of hepatic glucose production (HGP) plays a major role in its glucose-lowering efficacy (2, 3, 6).”
Background
AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle
Merrill, G. F., Kurth, E. J., Hardie, D. G., & Winder, W. W. (1997) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1997.273.6.e1107 · Cited by 1,048
AMP-activated protein kinase, a metabolic master switch: possible roles in Type 2 diabetes
Winder, W. W., & Hardie, D. G. (1999) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1999.277.1.e1 · Cited by 1,000
Decreased IRS-2 and Increased SREBP-1c Lead to Mixed Insulin Resistance and Sensitivity in Livers of Lipodystrophic and ob/ob Mice
Shimomura, I., Matsuda, M., Hammer, R. E., Bashmakov, Y. K., Brown, M. S., & Goldstein, J. L. (2000) · Molecular Cell · doi:10.1016/s1097-2765(05)00010-9 · Cited by 860
Evidence for 5' AMP-activated protein kinase mediation of the effect of muscle contraction on glucose transport
Hayashi, T., Hirshman, M. F., Kurth, E. J., Winder, W. W., & Goodyear, L. J. (1998) · Diabetes · doi:10.2337/diab.47.8.1369 · Cited by 774
Self-citation

Show all 36 references

Research works printed but not linked: 11

Schafer, 1983, Diabete Metab, 9, 148
10.1210/en.131.3.1165 · DOI
Winder, 1999, Am J Physiol, 277, E1
Merrill, 1997, Am J Physiol, 273, E1107
Goodyear, 2000, Exerc Sport Sci Rev, 28, 113
Cusi, 1998, Diabetes Reviews, 6, 89
Wiernsperger, 1999, Diabetes Metab, 25, 110
Hermann, 1979, Diabete Metab, 5, 233
Sterne, 1979, Research Clinical Forums, 1, 13
10.1042/0264-6021:3480607 · DOI · Paper page
10.1016/S1097-2765(00)00009-5 · DOI

Sorted by citations

Items 801–900 of 1,066

Aβ-induced formation of autophagosomes is mediated by RAGE-CaMKKβ-AMPK signaling
Son, S. M., Jung, E. S., Shin, H. J., Byun, J., & Mook‐Jung, I. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2011.09.039 · Cited by 142
Metformin for aging and cancer prevention
Anisimov, V. N. (2010) · Aging · doi:10.18632/aging.100230 · Cited by 142
Metformin Restores Leptin Sensitivity in High-Fat–Fed Obese Rats With Leptin Resistance
Kim, Y., Kim, J., Park, Y.-H., Park, S., Won, K. C., Choi, K. H., Huh, J.-Y., & Moon, K. (2006) · Diabetes · doi:10.2337/diabetes.55.03.06.db05-0917 · Cited by 145
Anti-diabetic effect of baicalein is associated with the modulation of gut microbiota in streptozotocin and high-fat-diet induced diabetic rats
Zhang, B., Sun, W., Yu, N., Sun, J., Yu, X., Li, X., Xing, Y., Yan, D., Ding, Q., Xiu, Z., et al. (2018) · Journal of Functional Foods · doi:10.1016/j.jff.2018.04.070 · Cited by 139
Energy Depletion Inhibits Phosphatidylinositol 3-Kinase/Akt Signaling and Induces Apoptosis via AMP-activated Protein Kinase-dependent Phosphorylation of IRS-1 at Ser-794
Tzatsos, A., & Tsichlis, P. N. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m610101200 · Cited by 140
Free Fatty Acids and Skeletal Muscle Insulin Resistance
Rachek, L. I. (2014) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-800101-1.00008-9 · Cited by 141
Oligomycin-induced bioenergetic adaptation in cancer cells with heterogeneous bioenergetic organization
Hao, W., Chang, C.-P. B., Tsao, C.-C., & Xu, J. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.084194 · Cited by 138
Metformin: Effects on Micro and Macrovascular Complications in Type 2 Diabetes
Bailey, C. J. (2008) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-008-6092-0 · Cited by 138
Transcriptional regulation of the insulin-responsive glucose transporter GLUT4 gene: from physiology to pathology
Karnieli, E., & Armoni, M. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90306.2008 · Cited by 144
Myc-induced AMPK-phospho p53 pathway activates Bak to sensitize mitochondrial apoptosis
Nieminen, A. I., Eskelinen, V., Haikala, H. M., Tervonen, T. A., Yan, Y., Partanen, J. I., & Klefström, J. T. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1208530110 · Cited by 142
Oxidative stress stimulates skeletal muscle glucose uptake through a phosphatidylinositol 3-kinase-dependent pathway
Higaki, Y., Mikami, T., Fujii, N., Hirshman, M. F., Koyama, K., Seino, T., Tanaka, K., & Goodyear, L. J. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00150.2007 · Cited by 138
Self-citation
Metformin: A review of its therapeutic efficacy and adverse effects
Shurrab, N. T., & Arafa, E. A. (2020) · Obesity Medicine · doi:10.1016/j.obmed.2020.100186 · Cited by 145
Signaling pathways regulating the fate of fibro/adipogenic progenitors (FAPs) in skeletal muscle regeneration and disease
Giuliani, G., Rosina, M., & Reggio, A. (2021) · FEBS Journal · doi:10.1111/febs.16080 · Cited by 144
In Vivo Activation of AMP-Activated Protein Kinase Attenuates Diabetes-Enhanced Degradation of GTP Cyclohydrolase I
Wang, S., Xu, J. C., Song, P., Viollet, B., & Zou, M. (2009) · Diabetes · doi:10.2337/db09-0267 · Cited by 137
Retracted
Metformin as an anti-inflammatory agent: a short review
Kristófi, R., & Eriksson, J. W. (2021) · Journal of Endocrinology · doi:10.1530/joe-21-0194 · Cited by 143
Effects of PGC-1α on TNF-α–Induced MCP-1 and VCAM-1 Expression and NF-κB Activation in Human Aortic Smooth Muscle and Endothelial Cells
Kim, H., Park, K., Yoo, E.-K., Kim, Y.-H., Kim, Y.-N., Kim, H., Kim, H. T., Park, J., Lee, K.-U., Jang, W. G., et al. (2007) · Antioxidants and Redox Signaling · doi:10.1089/ars.2006.1456 · Cited by 137
Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin
Ye, J.-M., Dzamko, N. L., Cleasby, M. E., Hegarty, B. D., Furler, S. M., Cooney, G. J., & Kraegen, E. W. (2004) · Diabetologia · doi:10.1007/s00125-004-1436-1 · Cited by 138
Possible involvement of the α1 isoform of 5′AMP-activated protein kinase in oxidative stress-stimulated glucose transport in skeletal muscle
Toyoda, T., Hayashi, T., Miyamoto, L., Yonemitsu, S., Nakano, M., Tanaka, S., Ebihara, K., Masuzaki, H., Hosoda, K., Inoue, G., et al. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00487.2003 · Cited by 139
AMP-activated protein kinase (AMPK) activating agents cause dephosphorylation of Akt and glycogen synthase kinase-3
King, T. D., Song, L., & Jope, R. S. (2006) · Biochemical Pharmacology · doi:10.1016/j.bcp.2006.03.005 · Cited by 137
Metformin inhibits ovarian cancer growth and increases sensitivity to paclitaxel in mouse models
Lengyel, E. R., Litchfield, L. M., Mitra, A. K., Nieman, K. M., Mukherjee, A., Zhang, Y., Johnson, A., Bradaric, M. J., Lee, W., & Romero, I. L. (2014) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2014.10.026 · Cited by 137
Metabolic requirements for cancer cell proliferation
Keibler, M. A., Wasylenko, T. M., Kelleher, J. K., Iliopoulos, O., Heiden, M. G. V., & Stephanopoulos, G. N. (2016) · Cancer & Metabolism · doi:10.1186/s40170-016-0156-6 · Cited by 141
The strange case of AMPK and cancer: Dr Jekyll or Mr Hyde?
Vara‐Ciruelos, D., Russell, F. M., & Hardie, D. G. (2019) · Open Biology · doi:10.1098/rsob.190099 · Cited by 140
High-fat diet feeding impairs both the expression and activity of AMPKa in rats’ skeletal muscle
Liu, Y., Wan, Q., Guan, Q., Gao, L., & Zhao, J. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.11.068 · Cited by 140
Effects of endurance training on activity and expression of AMP-activated protein kinase isoforms in rat muscles
Durante, P. E., Mustard, K. J., Park, S.-H., Winder, W. W., & Hardie, D. G. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00404.2001 · Cited by 137
Clinical approaches to non-alcoholic fatty liver disease
Schwenger, K. J. P. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i7.1712 · Cited by 139
Adenosine monophosphate–activated protein kinase modulates the activated phenotype of hepatic stellate cells
Caligiuri, A., Bertolani, C., Guerra, C. T., Aleffi, S., Galastri, S., Trappoliere, M., Vizzutti, F., Gelmini, S., Laffi, G., Pinzani, M., et al. (2007) · Hepatology · doi:10.1002/hep.21995 · Cited by 139
Metformin-induced stimulation of AMP-activated protein kinase in β-cells impairs their glucose responsiveness and can lead to apoptosis
Kefas, B. A., Cai, Y., Kerckhofs, K., Ling, Z., Martens, G. A., Heimberg, H., PIPELEERS, D. G., & de Casteele, M. V. (2004) · Biochemical Pharmacology · doi:10.1016/j.bcp.2004.04.003 · Cited by 136
Association of genetic variation in the organic cation transporters OCT1, OCT2 and multidrug and toxin extrusion 1 transporter protein genes with the gastrointestinal side effects and lower BMI in metformin-treated type 2 diabetes patients
Tarāsova, L., Kalniņa, I., Geldnere, K., Bumbure, A., Ritenberga, R., Ņikitina-Zaķe, L., Frīdmanis, D., Vaivade, I., Pīrāgs, V., & Kloviņš, J. (2012) · Pharmacogenetics and Genomics · doi:10.1097/fpc.0b013e3283561666 · Cited by 136
Pharmacophoric Features of Biguanide Derivatives: An Electronic and Structural Analysis
Bharatam, P. V., Patel, D. S., & Iqbal, P. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm050602z · Cited by 134
Chronic metformin treatment improves post‐stroke angiogenesis and recovery after experimental stroke
Venna, V. R., Li, J., Hammond, M. D., Mancini, N. S., & McCullough, L. D. (2014) · European Journal of Neuroscience · doi:10.1111/ejn.12556 · Cited by 140
The consequences of obesity and excess weight gain in pregnancy
Norman, J. E., & Reynolds, R. M. (2011) · Proceedings of The Nutrition Society · doi:10.1017/s0029665111003077 · Cited by 134
Inhibition of mitochondrial complex I improves glucose metabolism independently of AMPK activation
Hou, W., Yin, J., Alimujiang, M., Xue-ying, Y., Ai, L., Bao, Y., Liu, F., & Jia, W. (2017) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.13432 · Cited by 140
Pterostilbene alleviated NAFLD via AMPK/mTOR signaling pathways and autophagy by promoting Nrf2
Shen, B., Wang, Y., Cheng, J., Peng, Y., Zhang, Q., Li, Z., Zhao, L., Deng, X., & Feng, H. (2022) · Phytomedicine · doi:10.1016/j.phymed.2022.154561 · Cited by 134
Metformin – the gold standard in type 2 diabetes: what does the evidence tell us?
Bosi, E. (2009) · Diabetes Obesity and Metabolism · doi:10.1111/j.1463-1326.2008.01031.x · Cited by 135
Adenosine 5′-Monophosphate-Activated Protein Kinase Regulates Progesterone Secretion in Rat Granulosa Cells
Tosca, L., Froment, P., Solnais, P., Ferré, P., Foufelle, F., & Dupont, J. (2005) · Endocrinology · doi:10.1210/en.2005-0301 · Cited by 146
Hepatitis C virus inhibits AKT-tuberous sclerosis complex (TSC), the mechanistic target of rapamycin (MTOR) pathway, through endoplasmic reticulum stress to induce autophagy
Huang, H., Kang, R., Wang, J., Luo, G. G., Yang, W. Z., & Zhao, Z. (2012) · Autophagy · doi:10.4161/auto.22791 · Cited by 133
Is it Time to Test Metformin in Breast Cancer Clinical Trials?
Cazzaniga, M., Bonanni, B., Guerrieri‐Gonzaga, A., & DeCensi, A. (2009) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-08-0871 · Cited by 134
Integrins and Cell Metabolism: An Intimate Relationship Impacting Cancer
Ata, R., & Antonescu, C. N. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18010189 · Cited by 139
Sirt1-Sirt3 axis regulates human blood-brain barrier permeability in response to ischemia
Chen, T., Dai, S., Li, X., Luo, P., Zhu, J., Wang, Y., Fei, Z., & Jiang, X. (2017) · Redox Biology · doi:10.1016/j.redox.2017.09.016 · Cited by 134
Mechanisms of Kaempferol in the treatment of diabetes: A comprehensive and latest review
Yang, Y., Chen, Z., Zhao, X., Xie, H., Du, L., Gao, H. L., & Xie, C. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.990299 · Cited by 140
Direct Activation of Glucose Transport in Primary Human Myotubes After Activation of Peroxisome Proliferator–Activated Receptor δ
Krämer, D. K., Al-Khalili, L., Perrini, S., Skogsberg, J., Wretenberg, P., Kannisto, K., Wallberg-Henriksson, H., Ehrenborg, E., Zierath, J. R., & Krook, A. (2005) · Diabetes · doi:10.2337/diabetes.54.4.1157 · Cited by 132
Glucose metabolism in mammalian cell culture: new insights for tweaking vintage pathways
Mulukutla, B. C., Khan, S., Lange, A., & Hu, W.-S. (2010) · Trends in biotechnology · doi:10.1016/j.tibtech.2010.06.005 · Cited by 132
Induction of apoptosis by metformin in epithelial ovarian cancer: Involvement of the Bcl-2 family proteins
Yasmeen, A., Beauchamp, M.-C., Piura, E., Segal, E., Pollak, M., & Gotlieb, W. H. (2011) · Gynecologic Oncology · doi:10.1016/j.ygyno.2011.02.021 · Cited by 135
Is it still worth pursuing the repurposing of metformin as a cancer therapeutic?
Lord, S., & Harris, A. L. (2023) · British Journal of Cancer · doi:10.1038/s41416-023-02204-2 · Cited by 139
Metformin: Therapeutic profile in the treatment of type 2 diabetes
Bailey, C. J. (2024) · Diabetes Obesity and Metabolism · doi:10.1111/dom.15663 · Cited by 143
Second-hand smoke stimulates lipid accumulation in the liver by modulating AMPK and SREBP-1
Yuan, H., Shyy, J. Y.-J., & Martins‐Green, M. M. (2009) · Journal of Hepatology · doi:10.1016/j.jhep.2009.03.026 · Cited by 133
AMP-activated protein kinase phosphorylates and inactivates liver glycogen synthase
Bultot, L., Guigas, B., Von Wilamowitz-Moellendorff, A., Maisin, L., Vertommen, D., Hussain, N., Beullens, M., Guinovart, J. J., Foretz, M., Viollet, B., et al. (2012) · Biochemical Journal · doi:10.1042/bj20112026 · Cited by 131
Curcumin Attenuates Diet‐Induced Hepatic Steatosis by Activating AMP ‐Activated Protein Kinase
Um, M. Y., Hwang, K. H., Ahn, J., & Ha, T. Y. (2013) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.12076 · Cited by 131
The cardioprotective effects of metformin
Messaoudi, S. E., Rongen, G. A. P. J. M., de Boer, R. A., & Riksen, N. P. (2011) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e32834ae1a7 · Cited by 131
Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials
DeFronzo, R. A., Buse, J. B., Kim, T., Burns, C. M., Skare, S., Baron, A., & Fineman, M. S. (2016) · Diabetologia · doi:10.1007/s00125-016-3992-6 · Cited by 135
AMPK expression and phosphorylation are increased in rodent muscle after chronic leptin treatment
Steinberg, G. R., Rush, J. W. E., & Dyck, D. J. (2003) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00318.2002 · Cited by 132
The serine phosphorylation hypothesis of polycystic ovary syndrome: a unifying mechanism for hyperandrogenemia and insulin resistance
Bremer, A. A., & Miller, W. L. (2008) · Fertility and Sterility · doi:10.1016/j.fertnstert.2008.02.091 · Cited by 135
A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts
van Leeuwen, N., Nijpels, G., Becker, M. L., Deshmukh, H., Zhou, K., Stricker, B. H. C., Uitterlinden, A. G., Albert Hofman, D., Riet, E. V. ‘., Palmer, C. N. A., et al. (2012) · Diabetologia · doi:10.1007/s00125-012-2537-x · Cited by 133
Effect of Metformin vs Placebo on and Metabolic Factors in NCIC CTG MA.32
Goodwin, P. J., Parulekar, W. R., Gelmon, K. A., Shepherd, L. E., Ligibel, J. A., Hershman, D. L., Rastogi, P., Mayer, I. A., Hobday, T. J., Lemieux, J., et al. (2015) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djv006 · Cited by 133
Compound C/Dorsomorphin: Its Use and Misuse as an AMPK Inhibitor
Dasgupta, B., & Seibel, W. L. (2018) · Methods in molecular biology · doi:10.1007/978-1-4939-7598-3_12 · Cited by 133
APPL1 Potentiates Insulin-Mediated Inhibition of Hepatic Glucose Production and Alleviates Diabetes via Akt Activation in Mice
Cheng, K. K. Y., Iglesias, M. A., Lam, K. S. L., Wang, Y., Sweeney, G., Zhu, W., Vanhoutte, P. M., Kraegen, E. W., & Xu, A. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.03.013 · Cited by 133
Metformin Extended Release Treatment of Adolescent Obesity
Glaser Pediatric Research Network Obesity Study Group (2010) · Archives of Pediatrics and Adolescent Medicine · doi:10.1001/archpediatrics.2009.264 · Cited by 130
Dengue Virus Activates the AMP Kinase-mTOR Axis To Stimulate a Proviral Lipophagy
Jordan, T. X., & Randall, G. C. (2017) · Journal of Virology · doi:10.1128/jvi.02020-16 · Cited by 135
Metformin use in pregnancy: promises and uncertainties
Lindsay, R. S., & Loeken, M. R. (2017) · Diabetologia · doi:10.1007/s00125-017-4351-y · Cited by 131
Modulating the Microbiota as a Therapeutic Intervention for Type 2 Diabetes
Huda, M. N., Kim, M., & Bennett, B. J. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.632335 · Cited by 130
Mitochondrial metabolism and type-2 diabetes: a specific target of metformin
Leverve, X. M., Guigas, B., Détaille, D., Batandier, C., Koceir, E.-A., Chauvin, C., Fontaine, E. M., & Wiernsperger, N. F. (2003) · Diabetes & Metabolism · doi:10.1016/s1262-3636(03)72792-x · Cited by 132
Involvement of AMP-activated protein kinase in beneficial effects of betaine on high-sucrose diet-induced hepatic steatosis
Song, Z., Deaciuc, I. V., Zhou, Z., Song, M., Chen, T., Hill, D. B., & McClain, C. J. (2007) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00133.2007 · Cited by 129
AMP-activated protein kinase selectively inhibited by the type II inhibitor SBI-0206965
Dite, T. A., Langendorf, C. G., Hoque, A., Galić, S., Rebello, R. J., Ovens, A. J., Lindqvist, L., Ngoei, K. R. W., Ling, N. X. Y., Furic, L., et al. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.003547 · Cited by 132
Adenosine Monophosphate-Activated Protein Kinase (AMPK) as a New Target for Antidiabetic Drugs: A Review on Metabolic, Pharmacological and Chemical Considerations
Gruzman, A., Babai-Shani, G., & Sasson, S. (2009) · The Review of Diabetic Studies · doi:10.1900/rds.2009.6.13 · Cited by 128
Signalling mechanisms linking hepatic glucose and lipid metabolism
Weickert, M. O., & Pfeiffer, A. F. H. (2006) · Diabetologia · doi:10.1007/s00125-006-0295-3 · Cited by 127
Metformin Beyond Diabetes: Pleiotropic Benefits of Metformin in Attenuation of Atherosclerosis
Forouzandeh, F., Salazar, G., Patrushev, N. A., Xiong, S., Hilenski, L. L., Fei, B., & Alexander, R. W. (2014) · Journal of the American Heart Association · doi:10.1161/jaha.114.001202 · Cited by 129
MDM2-Mediated Ubiquitination of Angiotensin-Converting Enzyme 2 Contributes to the Development of Pulmonary Arterial Hypertension
Shen, H., Zhang, J., Wang, C., Jain, P., Xiong, M., Shi, X., Lei, Y., Chen, S., Yin, Q., Thistlethwaite, P. A., et al. (2020) · Circulation · doi:10.1161/circulationaha.120.048191 · Cited by 130
Metformin ameliorates ionizing irradiation-induced long-term hematopoietic stem cell injury in mice
Xu, G., Wu, H., Zhang, J., Li, D., Wang, Y., Wang, Y., Zhang, H., Lu, L., Li, C., Huang, S. M., et al. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.05.045 · Cited by 132
Activated AMPK inhibits PPAR-α and PPAR-γ transcriptional activity in hepatoma cells
Sozio, M. S., Lu, C., Zeng, Y., Liangpunsakul, S., & Crabb, D. W. (2011) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00432.2010 · Cited by 131
Metformin and exercise reduce muscle FAT/CD36 and lipid accumulation and blunt the progression of high-fat diet-induced hyperglycemia
Smith, A. C., Mullen, K. L., Junkin, K. A., Nickerson, J., Chabowski, A., Bonen, A., & Dyck, D. J. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00677.2006 · Cited by 128
Rutin Inhibits Oleic Acid Induced Lipid Accumulation via Reducing Lipogenesis and Oxidative Stress in Hepatocarcinoma Cells
Wu, C., Lin, M., Wang, H., Yang, M., Jou, M., & Wang, C. (2011) · Journal of Food Science · doi:10.1111/j.1750-3841.2010.02033.x · Cited by 129
Troglitazone but not Metformin Restores Insulin-Stimulated Phosphoinositide 3-Kinase Activity and Increases p110β Protein Levels in Skeletal Muscle of Type 2 Diabetic Subjects
Kim, Y., Ciaraldi, T. P., Kong, A. P. S., Kim, D. S., Chu, N. V., Mohideen, P., Mudaliar, S. R. D., Henry, R. R., & Kahn, B. B. (2002) · Diabetes · doi:10.2337/diabetes.51.2.443 · Cited by 129
Metformin promotes tau aggregation and exacerbates abnormal behavior in a mouse model of tauopathy
Barini, E., Antico, O., Zhao, Y., Asta, F., Tucci, V., Catelani, T., Marotta, R., Xu, H., & Gasparini, L. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0082-7 · Cited by 126
Ginsenoside Rb1 reduces fatty liver by activating AMP-activated protein kinase in obese rats
Shen, L., Xiong, Y., Wang, D. Q. ‐., Howles, P. N., Basford, J. E., Wang, J., Xiong, Y., Hui, D. Y., Woods, S. C., & Liu, M. (2013) · Journal of Lipid Research · doi:10.1194/jlr.m035907 · Cited by 126
CCAAT/Enhancer-binding Protein β Deletion Reduces Adiposity, Hepatic Steatosis, and Diabetes in Lepr Mice
Schroeder‐Gloeckler, J. M., Rahman, S. M., Janssen, R. C., Qiao, L., Shao, J., Roper, M. D., Fischer, S. J., Lowe, E., Orlicky, D. J., McManaman, J. L., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m701329200 · Cited by 126
Structure and function of polarity‐inducing kinase family MARK/Par‐1 within the branch of AMPK/Snf1‐related kinases
Marx, A., Nugoor, C., Panneerselvam, S., & Mandelkow, E. (2010) · The FASEB Journal · doi:10.1096/fj.09-148064 · Cited by 126
Metformin suppresses adipogenesis through both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms
Chen, S. C., Brooks, R. A., Houskeeper, J., Bremner, S., Dunlop, J., Viollet, B., Logan, P. J., Salt, I. P., Ahmed, S. F., & Yarwood, S. J. (2016) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2016.11.011 · Cited by 128
Glucocorticoids Increase Neuropeptide Y and Agouti-Related Peptide Gene Expression via Adenosine Monophosphate-Activated Protein Kinase Signaling in the Arcuate Nucleus of Rats
Shimizu, H., Arima, H., Watanabe, M., Goto, M., Banno, R., Sato, I., Ozaki, N., Nagasaki, H., & Oiso, Y. (2008) · Endocrinology · doi:10.1210/en.2008-0229 · Cited by 128
Protective role of the antidiabetic drug metformin against chronic experimental pulmonary hypertension
Agard, C., Rolli‐Derkinderen, M., de la Roque, E. D., Rio, M., Sagan, C., Savineau, J., Loirand, G., & Pacaud, P. (2009) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2009.00445.x · Cited by 124
Anti-Diabetic Medications and Risk of Pancreatic Cancer in Patients With Diabetes Mellitus: A Systematic Review and Meta-Analysis
Singh, S., Singh, P. P., Singh, A. G., Murad, M. H., McWilliams, R. R., & Chari, S. T. (2013) · The American Journal of Gastroenterology · doi:10.1038/ajg.2013.7 · Cited by 125
Metformin and neoplasia: Implications and indications
Aljada, A., & Mousa, S. A. (2011) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2011.09.004 · Cited by 128
Curcumin decreases renal triglyceride accumulation through AMPK–SREBP signaling pathway in streptozotocin-induced type 1 diabetic rats
Soetikno, V., Sari, F. R., Sukumaran, V., Lakshmanan, A. P., Harima, M., Suzuki, K., Kawachi, H., & Watanabe, K. (2012) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2012.04.013 · Cited by 124
AMPK Activation by Oncogenesis Is Required to Maintain Cancer Cell Proliferation in Astrocytic Tumors
García, M. R., Foretz, M., Viollet, B., Prieto, A., Fraga, M., Costoya, J. A., & Señarís, R. M. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-0861 · Cited by 126
Metformin in breast cancer: preclinical and clinical evidence
De, A., & Kuppusamy, G. (2019) · Current Problems in Cancer · doi:10.1016/j.currproblcancer.2019.06.003 · Cited by 126
Berberine Moderates Glucose and Lipid Metabolism through Multipathway Mechanism
Zhang, Q., Xiao, X., Feng, K., Wang, T., Li, W., Yuan, T., Sun, X., Sun, Q., Xiang, H., & Wang, H. (2010) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2011/924851 · Cited by 124
Role of adenosine monophosphate‐activated protein kinase–p70 ribosomal S6 kinase‐1 pathway in repression of liver X receptor‐alpha–dependent lipogenic gene induction and hepatic steatosis by a novel class of dithiolethiones†
Hwahng, S. H., Ki, S. H., Bae, E. J., Kim, H. E., & Kim, S. G. (2009) · Hepatology · doi:10.1002/hep.22887 · Cited by 129
MicroRNAs in Metabolism and Metabolic DiseasesPreprint
Rottiers, V., Najafi-Shoushtari, S. H., Kristo, F., Gurumurthy, S., Zhong, L., Li, Y., Cohen, D. E., Gerszten, R. E., Bardeesy, N. M., Mostoslavsky, R., et al. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2011.76.011049 · Cited by 126
Self-citation
Metformin Protects Cardiomyocyte from Doxorubicin Induced Cytotoxicity through an AMP-Activated Protein Kinase Dependent Signaling Pathway: An In Vitro Study
Kobashigawa, L. C., Xu, Y. C., Padbury, J. F., Tseng, Y., & Yano, N. (2014) · PLoS ONE · doi:10.1371/journal.pone.0104888 · Cited by 127
FXR Agonists as Therapeutic Agents for Non-alcoholic Fatty Liver Disease
Carr, R. M., & Reid, A. E. (2015) · Current Atherosclerosis Reports · doi:10.1007/s11883-015-0500-2 · Cited by 126
AMP-activated protein kinase agonists increase mRNA content of the muscle-specific ubiquitin ligases MAFbx and MuRF1 in C2C12 cells
Krawiec, B. J., Nystrom, G. J., Frost, R. A., Jefferson, L. S., & Lang, C. H. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00622.2006 · Cited by 125
DNA-PK Promotes the Mitochondrial, Metabolic, and Physical Decline that Occurs During Aging
Park, S. J., Gavrilova, O., Brown, A. L., Soto, J. E., Bremner, S. N., Kim, J., Xu, X., Yang, S., Um, J.-H., Koch, L. G., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.04.008 · Cited by 123
Salidroside inhibits doxorubicin-induced cardiomyopathy by modulating a ferroptosis-dependent pathway
Chen, H., Zhu, J., Le, Y., Pan, J., Liu, Y., Liu, Z., Wang, C., Dou, X., & Lu, D. (2022) · Phytomedicine · doi:10.1016/j.phymed.2022.153964 · Cited by 124
Metformin protects against seizures, learning and memory impairments and oxidative damage induced by pentylenetetrazole-induced kindling in mice
Zhao, R., Xu, X., Xu, F., Zhang, W.-L., Zhang, W.-L., Liu, L.-M., & Wang, W. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.04.130 · Cited by 123
Metformin use in children with nonalcoholic fatty liver disease: An open-label, 24-month, observational pilot study
Nobili, V., Manco, M., Ciampalini, P., Alisi, A., Vito, R. D., Bugianesi, E., MARCELLINI, M., & Marchesini, G. (2008) · Clinical Therapeutics · doi:10.1016/j.clinthera.2008.06.012 · Cited by 125
Prevention and treatment of type 2 diabetes: Current role of lifestyle, natural product, and pharmacological interventions
Hays, N. P., Galassetti, P. R., & Coker, R. H. (2008) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2008.02.003 · Cited by 125
Physical activity as the main therapeutic tool for metabolic syndrome in childhood
Brambilla, P., Pozzobon, G. C., & Pietrobelli, A. (2010) · International Journal of Obesity · doi:10.1038/ijo.2010.255 · Cited by 128
Metformin and berberine, two versatile drugs in treatment of common metabolic diseases
Wang, H., Zhu, C., Ying, Y., Luo, L., Huang, D., & Luo, Z. (2017) · Oncotarget · doi:10.18632/oncotarget.20807 · Cited by 124
Metformin; an old antidiabetic drug with new potentials in bone disorders
Bahrambeigi, S., Yousefi, B., Rahimi, M., & Shafiei‐Irannejad, V. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.11.032 · Cited by 125
Dapagliflozin Alleviates Hepatic Steatosis by Restoring Autophagy via the AMPK-mTOR Pathway
Li, L., Li, Q., Huang, W., Han, Y., Tan, H., An, M., Xiang, Q., Zhou, R., Yang, L., & Cheng, Y. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.589273 · Cited by 125
Drug Insight: insulin-sensitizing drugs in the treatment of polycystic ovary syndrome—a reappraisal
Dunaif, A. E. (2008) · Nature Clinical Practice Endocrinology & Metabolism · doi:10.1038/ncpendmet0787 · Cited by 122

Authors: Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., Musi, N., Hirshman, M. F., Goodyear, L. J., & Moller, D. E.
Affiliations: Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
Corresponding author: Zhou, Gaochao
ORCID: Zhou, Gaochao
Li, Ying
Shen, Xiaolan
Musi, Nicolas
Hirshman, Michael F.
Goodyear, Laurie J.
Moller, David E.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2001-10-15
Volume: 108
Issue: 8
Pages: 1167-1174
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci13505
PMC: PMC209533
OpenAlex: W2138226825
Cited by: 5,652
References: 36
Citations by year: 2026: 149 · 2025: 182 · 2024: 198 · 2023: 234 · 2022: 270 · 2021: 312 · 2020: 272 · 2019: 310 · 2018: 306 · 2017: 304 · 2016: 296 · 2015: 331 · 2014: 307 · 2013: 295 · 2012: 291
FWCI: 26.36
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
Keywords: metformin, AMPK, type 2 diabetes, hepatic glucose production, acetyl-CoA carboxylase, SREBP1, lipogenesis, fatty acid oxidation, glucose uptake, skeletal muscle, hepatic lipid metabolism, AMPK inhibitors
MeSH terms: Aminoimidazole Carboxamide, Animals, Diabetes Mellitus, Type 2, DNA-Binding Proteins, Enzyme Activation, Fatty Acids, Glucose, Humans, Hypoglycemic Agents, Male, Metformin, Multienzyme Complexes, Protein Kinases, Pyrazoles, Pyrimidines, Ribonucleotides, RNA, Messenger, Transcription Factors, Gene Expression, Rats, Sprague-Dawley, Protein Serine-Threonine Kinases, Muscle, Skeletal, CCAAT-Enhancer-Binding Proteins, Hepatocytes, Protein Kinase Inhibitors, Rats, Sterol Regulatory Element Binding Protein 1, AMP-Activated Protein Kinases, In Vitro Techniques

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

Role of AMP-activated protein kinase in mechanism of metformin action

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