The DOI matches its Crossref record; 36 of the 36 references it cites were found in a registry or an index.
Activation of AMP-Activated Protein Kinase Reduces Hyperglycemia-Induced Mitochondrial Reactive Oxygen Species Production and Promotes Mitochondrial Biogenesis in Human Umbilical Vein Endothelial Cells
Open accessAbstract
We previously proposed that the production of hyperglycemia-induced mitochondrial reactive oxygen species (mtROS) is a key event in the development of diabetes complications. The association between the pathogenesis of diabetes and its complications and mitochondrial biogenesis has been recently reported. Because metformin has been reported to exert a possible additional benefit in preventing diabetes complications, we investigated the effect of metformin and 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) on mtROS production and mitochondrial biogenesis in cultured human umbilical vein endothelial cells. Treatment with metformin and AICAR inhibited hyperglycemia-induced intracellular and mtROS production, stimulated AMP-activated protein kinase (AMPK) activity, and increased the expression of peroxisome proliferator–activated response-γ coactivator-1α (PGC-1α) and manganese superoxide dismutase (MnSOD) mRNAs. The dominant negative form of AMPKα1 diminished the effects of metformin and AICAR on these events, and an overexpression of PGC-1α completely blocked the hyperglycemia-induced mtROS production. In addition, metformin and AICAR increased the mRNA expression of nuclear respiratory factor-1 and mitochondrial DNA transcription factor A (mtTFA) and stimulated the mitochondrial proliferation. Dominant negative–AMPK also reduced the effects of metformin and AICAR on these observations. These results suggest that metformin normalizes hyperglycemia-induced mtROS production by induction of MnSOD and promotion of mitochondrial biogenesis through the activation of AMPK-PGC-1α pathway.
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“Metformin has mitigating effects on ROS production, activates AMPK, and favors mitochondrial proliferation (181, 353).”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [181]
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“AMPK activation has been reported to decrease mitochondrial ROS by upregulating SOD2 in a diabetes animal model [82]”
From Healthy Human Fecal Microbiota Transplantation into Mice Attenuates MPTP-Induced Neurotoxicity via AMPK/SOD2 Pathway (2023) · cites this paper as [82]
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Cites
(1993) · New England Journal of Medicine · doi:10.1056/nejm199309303291401 · Cited by 24,667
Biochemistry and molecular cell biology of diabetic complications
Brownlee, M. (2001) · Nature · doi:10.1038/414813a · Cited by 9,107
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
Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage
Nishikawa, T., Edelstein, D., Du, X. L., Yamagishi, S.-I., Matsumura, T., Kaneda, Y., Yorek, M. A., Beebe, D., Oates, P. J., Hammes, H.-P., et al. (2000) · Nature · doi:10.1038/35008121 · Cited by 4,277
Self-citationWu, Z., Puigserver, P., Andersson, U., Zhang, C., Adelmant, G., Mootha, V., Troy, A., Cinti, S., Lowell, B., Scarpulla, R. C., et al. (1999) · Cell · doi:10.1016/s0092-8674(00)80611-x · Cited by 4,139
Ohkubo, Y., Kishikawa, H., Araki, E., Miyata, T., Isami, S., Motoyoshi, S., Kojima, Y., Furuyoshi, N., & Shichiri, M. (1995) · Diabetes Research and Clinical Practice · doi:10.1016/0168-8227(95)01064-k · Cited by 3,079
Self-citationRole of oxidative stress in diabetic complications: a new perspective on an old paradigm.
Baynes, J. W., & Thorpe, S. R. (1999) · Diabetes · doi:10.2337/diabetes.48.1.1 · Cited by 2,441
Wang, H., & Joseph, J. A. (1999) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(99)00107-0 · Cited by 2,355
Oxidative Stress and Diabetic Vascular Complications
Giugliano, D., Ceriello, A., & Paolisso, G. (1996) · Diabetes Care · doi:10.2337/diacare.19.3.257 · Cited by 1,921
Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress
Kops, G. J. P. L., Dansen, T. B., Polderman, P. E., Saarloos, I., Wirtz, K. W. A., Coffer, P. J., Huang, T.-T., Bos, J. L., Medema, R. H., & Burgering, B. M. T. (2002) · Nature · doi:10.1038/nature01036 · Cited by 1,580
Insulin-regulated hepatic gluconeogenesis through FOXO1–PGC-1α interaction
Puigserver, P., Rhee, J., Donovan, J., Walkey, C. J., Yoon, J. C., Oriente, F., Kitamura, Y., Altomonte, J., Dong, H., Accili, D., et al. (2003) · Nature · doi:10.1038/nature01667 · Cited by 1,487
Peroxisome proliferator–activated receptor γ coactivator-1 promotes cardiac mitochondrial biogenesis
Lehman, J. J., Barger, P. M., Kovacs, A., Saffitz, J. E., Medeiros, D. M., & Kelly, D. P. (2000) · Journal of Clinical Investigation · doi:10.1172/jci10268 · Cited by 1,285
Du, X., Matsumura, T., Edelstein, D., Rossetti, L., Zsengellér, Z. K., Szabó, C., & Brownlee, M. (2003) · Journal of Clinical Investigation · doi:10.1172/jci18127 · Cited by 843
Self-citationLong-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients.
Shichiri, M., Kishikawa, H., Ohkubo, Y., & Wake, N. (2000) · PubMed · Cited by 727
High glucose‐induced oxidative stress and mitochondrial dysfunction in neurons
Russell, J. W., Golovoy, D., Vincent, A. M., Mahendru, P., Olzmann, J. A., Mentzer, A., & Feldman, E. L. (2002) · The FASEB Journal · doi:10.1096/fj.01-1027com · Cited by 520
Sullivan, J. E., Brocklehurst, K. J., Marley, A. E., Carey, F., Carling, D., & Beri, R. K. (1994) · FEBS Letters · doi:10.1016/0014-5793(94)01006-4 · Cited by 488
Vanhorebeek, I., Vos, R. D., Mesotten, D., Wouters, P. J., Wolf‐Peeters, C. D., & den Berghe, G. V. (2005) · The Lancet · doi:10.1016/s0140-6736(04)17665-4 · Cited by 456
Salt, I. P., Celler, J. W., Hawley, S. A., Prescott, A. R., Woods, A., Carling, D., & Hardie, D. G. (1998) · Biochemical Journal · doi:10.1042/bj3340177 · Cited by 437
Neurons Undergo Apoptosis in Animal and Cell Culture Models of Diabetes
Russell, J. W., Sullivan, K. A., Windebank, A. J., Herrmann, D. N., & Feldman, E. L. (1999) · Neurobiology of Disease · doi:10.1006/nbdi.1999.0254 · Cited by 413
Effects of low-intensity prolonged exercise on PGC-1 mRNA expression in rat epitrochlearis muscle
Terada, S., Goto, M., Kato, M., Kawanaka, K., Shimokawa, T., & Tabata, I. (2002) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(02)00881-1 · Cited by 354
Kiritoshi, S., Nishikawa, T., Sonoda, K., Kukidome, D., Senokuchi, T., Matsuo, T., Matsumura, T., Tokunaga, H., Brownlee, M., & Araki, E. (2003) · Diabetes · doi:10.2337/diabetes.52.10.2570 · Cited by 345
Self-citationSatoh, N., Ogawa, Y., Usui, T., Tagami, T., Kono, S., Uesugi, H., Sugiyama, H., Sugawara, A., Yamada, K., Shimatsu, A., et al. (2003) · Diabetes Care · doi:10.2337/diacare.26.9.2493 · Cited by 287
Effect of Troglitazene on Microalbuminuria in Patients With Incipient Diabetic Nephropathy
Imano, E., Kanda, T., Nakatani, Y., Nishida, T., Arai, K., Motomura, M., Kajimoto, Y., Yamasaki, Y., & Hori, M. (1998) · Diabetes Care · doi:10.2337/diacare.21.12.2135 · Cited by 196
Nishikawa, T., Sasahara, T., Kiritoshi, S., Sonoda, K., Senokuchi, T., Matsuo, T., Kukidome, D., Wake, N., Matsumura, T., Miyamura, N., et al. (2003) · Diabetes Care · doi:10.2337/diacare.26.5.1507 · Cited by 190
Self-citationMegamitochondria formation ‐ physiology and pathology
Wakabayashi, T. (2002) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2002.tb00452.x · Cited by 189
Bcl-2 and Mitochondrial Oxygen Radicals
Esposti, M. D., Hatzinisiriou, I., McLennan, H. R., & Ralph, S. J. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.42.29831 · Cited by 179
Uchiba, M., Okajima, K., Oike, Y., Ito, Y., Fukudome, K., Isobe, H., & Suda, T. (2004) · Circulation Research · doi:10.1161/01.res.0000133680.87668.fa · Cited by 162
Wake, N., Hisashige, A., Katayama, T., Kishikawa, H., Ohkubo, Y., Sakai, M., Araki, E., & Shichiri, M. (2000) · Diabetes Research and Clinical Practice · doi:10.1016/s0168-8227(00)00122-4 · Cited by 100
Self-citationSakoda, H., Ogihara, T., Anai, M., Fujishiro, M., Ono, H., Onishi, Y., Katagiri, H., Abe, M., Fukushima, Y., Shojima, N., et al. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00455.2001 · Cited by 95
Regulation of fatty acid oxidation and glucose metabolism in rat soleus muscle: effects of AICAR
Kaushik, V. K., Young, M. E., Dean, D. J., Kurowski, T. G., Saha, A. K., & Ruderman, N. B. (2001) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2001.281.2.e335 · Cited by 81
Mitochondrial Respiratory Impairment in Streptozotocin-Induced Diabetic Rat Heart
Tomita, M., Mukae, S., Geshi, E., Umetsu, K., Nakatani, M., & Katagiri, T. (1996) · Japanese Circulation Journal-english Edition · doi:10.1253/jcj.60.673 · Cited by 65
PGC-1α at the crossroads of type 2 diabetes
Attie, A., & Kendziorski, C. M. (2003) · Nature Genetics · doi:10.1038/ng0703-244 · Cited by 62
Kanazawa, A., Nishio, Y., Kashiwagi, A., Inagaki, H., Kikkawa, R., & Horiike, K. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00255.2001 · Cited by 47
Ultrastructural characteristics of diabetic nephropathy
Nishi, S., Ueno, M., Shimada, H., Iino, N., Iguchi, S., Oyama, Y., Imai, N., Arakawa, M., & Gejyo, F. (2000) · Medical Molecular Morphology · doi:10.1007/s007950070004 · Cited by 44
Cited by
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AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α
Jäger, S., Handschin, C., St.-Pierre, J., & Spiegelman, B. M. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0705070104 · Cited by 2,491
St-Pierre, J., Drori, S., Uldry, M., Silvaggi, J. M., Rhee, J., Jäger, S., Handschin, C., Zheng, K., Lin, J., Yang, W., et al. (2006) · Cell · doi:10.1016/j.cell.2006.09.024 · Cited by 2,233
Cellular and molecular mechanisms of metformin: an overview
Viollet, B., Guigas, B., Garcia, N. S., Leclerc, J., Foretz, M., & Andreelli, F. (2012) · Clinical Science · doi:10.1042/cs20110386 · Cited by 1,720
Metformin: from mechanisms of action to therapies
Foretz, M., Guigas, B., Bertrand, L., Pollak, M., & Viollet, B. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.09.018 · Cited by 1,501
Role of Mitochondrial Dysfunction in Insulin Resistance
Kim, J.-A., Wei, Y., & Sowers, J. R. (2008) · Circulation Research · doi:10.1161/circresaha.107.165472 · Cited by 1,103
Metadata
- Authors
- Kukidome, D., Nishikawa, T., Sonoda, K., Imoto, K., Fujisawa, K., Yano, M., Motoshima, H., Taguchi, T., Matsumura, T., & Araki, E.
- Affiliations
- Kumamoto University (JP)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2006-01-01
- Volume
- 55
- Issue
- 1
- Pages
- 120-127
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2163863334
- Cited by
- 504
- References
- 36
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 18 · 2023: 17 · 2022: 19 · 2021: 23 · 2020: 27 · 2019: 27 · 2018: 20 · 2017: 22 · 2016: 29 · 2015: 39 · 2014: 25 · 2013: 33 · 2012: 27
- FWCI
- 12.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- UCLA - Biblioteca de Ciencias de la Salud (submittedVersion)
- Funders
- American Diabetes Association
- Suzuken Memorial Foundation
- Kato Memorial Bioscience Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Japan Society for the Promotion of Science (16590889)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- AMPK, hyperglycemia, mitochondrial reactive oxygen species, mitochondrial biogenesis, metformin, AICAR, PGC-1α, manganese superoxide dismutase, endothelial cells, diabetes complications, AMPKα1, NRF1, TFAM, oxidative stress
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Aminoimidazole Carboxamide, Cells, Cultured, DNA-Binding Proteins, DNA, Mitochondrial, Enzyme Activation, Heat-Shock Proteins, Humans, Hyperglycemia, Hypoglycemic Agents, Metformin, Mitochondria, Multienzyme Complexes, Ribonucleotides, RNA, Messenger, Superoxide Dismutase, Transcription Factors, Protein Serine-Threonine Kinases, Reactive Oxygen Species, Mitochondrial Proteins, Endothelial Cells, NF-E2-Related Factor 1, AMP-Activated Protein Kinases
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