ArticleThe Journal of biological chemistry2004
Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo. Role of mitochondrial reactive nitrogen species.
Article in The Journal of biological chemistry, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It has been retracted, and should not be counted. It is linked to trial NCT02633488 (Effect of Metformin on Insulin Sensitivity and Pan-Arterial Vascular Function in Adults With Metabolic Syndrome), which is not on this map. Cited by 178 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Effect of Metformin on Insulin Sensitivity and Pan-Arterial Vascular Function in Adults With Metabolic Syndrome
Who cites it
178 citing papers in PubMed, 479 citations in OpenAlex.
- Trial
- An integrative study identifies KCNC2 as a novel predisposing factor for childhood obesity and the risk of diabetes in the Korean population.Scientific reports · 2016Trial
- Antihyperglycemic mechanism of metformin occurs via the AMPK/LXRα/POMC pathway.Scientific reports · 2015Trial
- High and typical 18F-FDG bowel uptake in patients treated with metformin.European journal of nuclear medicine and molecular imaging · 2008 · on this mapTrial
- Identification of AdipoRon analogues as novel activators of AMPK for the treatment of type 2 diabetes.RSC medicinal chemistry · 2024Article
- Oral delivery of nanomedicine for genetic kidney disease.PNAS nexus · 2024Article
- Effects of Prior Metformin Use on Stroke Outcomes in Diabetes Patients with Acute Ischemic Stroke Receiving Endovascular Treatment.Biomedicines · 2024Article
- Incidence, risk factors, and management of alpelisib-associated hyperglycemia in metastatic breast cancer.Cancer · 2023Article
- Activated AMPK Protects Against Chronic Cerebral Ischemia in Bilateral Carotid Artery Stenosis Mice.Cellular and molecular neurobiology · 2023Article
- Metformin prevents endothelial oxidative stress and microvascular insulin resistance during obesity development in male rats.American journal of physiology. Endocrinology and metabolism · 2022Article
- A human-based multi-gene signature enables quantitative drug repurposing for metabolic disease.eLife · 2022Article
- The Hepatoprotective Effect of Leonurine Hydrochloride Against Alcoholic Liver Disease Based on Transcriptomic and Metabolomic Analysis.Frontiers in nutrition · 2022Article
- Diabetes: Chronic Metformin Treatment and Outcome Following Acute Stroke.Frontiers in neurology · 2022Article
- IL-25 Induced ROS-Mediated M2 Macrophage Polarization via AMPK-Associated Mitophagy.International journal of molecular sciences · 2021Article
- Prevention of Hypertensive Disorders of Pregnancy-Is There a Place for Metformin?Journal of clinical medicine · 2021Review
- Oral delivery of metformin by chitosan nanoparticles for polycystic kidney disease.Journal of controlled release : official journal of the Controlled Release Society · 2021Article
- Novel Experimental Therapies for Treatment of Pulmonary Arterial Hypertension.Journal of experimental pharmacology · 2021Review
- The Comparison of Antioxidant Effect of Aspirin, Metformin, Atorvastatin and Captopril Co-administration in the Heart and Kidney Tissues of Diabetic Rats.Iranian journal of pharmaceutical research : IJPR · 2021Article
- The Modulatory Effect of Metformin on Ethanol-Induced Anxiety, Redox Imbalance, and Extracellular Matrix Levels in the Brains of Wistar Rats.Journal of molecular neuroscience : MN · 2020Article
- Clinical perspectives and concerns of metformin as an anti-aging drug.Aging medicine (Milton (N.S.W)) · 2020Review
118 more citing papers are in PubMed but not listed here.
Corrections and comments
- Retraction · 2019-09-06Duplication of/in Image · Original Data and/or Images not Provided and/or not Available · Upgrade/Update of Prior Notice(s) ·
- Expression of concern · 2019-06-21Concerns/Issues about Data · Concerns/Issues about Results and/or Conclusions · Updated to Retraction ·
- Expression of concern
- Retracted
Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Metformin, one of the most commonly used drugs for the treatment of type II diabetes, was recently found to exert its therapeutic effects, at least in part, by activating the AMP-activated protein kinase (AMPK). However, the site of its action, as well as the mechanism to activate AMPK, remains elusive. Here we report how metformin activates AMPK. In cultured bovine aortic endothelial cells, metformin dose-dependently activated AMPK in parallel with increased detection of reactive nitrogen species (RNS). Further, either depletion of mitochondria or adenoviral overexpression of superoxide dismutases, as well as inhibition of nitric-oxide synthase, abolished the metformin-enhanced phosphorylations and activities of AMPK, implicating that activation of AMPK by metformin might be mediated by the mitochondria-derived RNS. Furthermore, administration of metformin, which increased 3-nitrotyrosine staining in hearts of C57BL6, resulted in parallel activation of AMPK in the aorta and hearts of C57BL6 mice but not in those of endothelial nitric-oxide synthase (eNOS) knockout mice in which metformin had no effect on 3-nitrotyrosine staining. Because the eNOS knockout mice expressed normal levels of AMPK-alpha that was activated by 5-aminoimidazole-4-carboxamide riboside, an AMPK agonist, these data indicate that RNS generated by metformin is required for AMPK activation in vivo. In addition, metformin significantly increased the co-immunoprecipitation of AMPK and its upstream kinase, LKB1, in C57BL6 mice administered to metformin in vivo. Using pharmacological and genetic inhibitors, we found that inhibition of either c-Src or PI3K abolished AMPK that was enhanced by metformin. We conclude that activation of AMPK by metformin might be mediated by mitochondria-derived RNS, and activation of the c-Src/PI3K pathway might generate a metabolite or other molecule inside the cell to promote AMPK activation by the LKB1 complex.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.