ArticlePLoS genetics2016
Genomic Characterization of Metformin Hepatic Response.
Article in PLoS genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers, 2 of them syntheses that pooled it.
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
33 citing papers in PubMed, 2 syntheses or guidelines pooled it, 48 citations in OpenAlex.
- Genome-Wide Association Study Identifies Pharmacogenomic Variants Associated With Metformin Glycemic Response in African American Patients With Type 2 Diabetes.Diabetes care · 2024Pooled it
- A resource for integrated genomic analysis of the human liver.Scientific reports · 2022Pooled it
- Effect of Metformin Versus Placebo on New Primary Cancers in Canadian Cancer Trials Group MA.32: A Secondary Analysis of a Phase III Randomized Double-Blind Trial in Early Breast Cancer.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2023Trial
- Metformin as an Innate Immune Modulator: Metabolic and Epigenetic Reprogramming of Innate Immune Cells and Therapeutic Implications.Current issues in molecular biology · 2026Review
- DDX10 RNA Helicase: Structure, Function, and Oncogenic Roles Across Solid and Hematologic Tumors.Genes · 2026Review
- Growth differentiation factor 15 (GDF-15) as an emerging biomarker for cardiovascular and kidney diseases, a therapeutic target in cancer and a potential biomarker for preeclampsia.Frontiers in pharmacology · 2026Article
- Harnessing Pharmacomultiomics for Precision Medicine in Diabetes: A Comprehensive Review.Biomedicines · 2025Review
- AMPK, a key molecule regulating aging-related myocardial ischemia-reperfusion injury.Molecular biology reports · 2024Review
- Navigating stem cell culture: insights, techniques, challenges, and prospects.Frontiers in cell and developmental biology · 2024Review
- Activating transcription factor 3, glucolipid metabolism, and metabolic diseases.Journal of molecular cell biology · 2023Article
- Article
- Metformin Treatment Modulates Long Non-Coding RNA Isoforms Expression in Human Cells.Non-coding RNA · 2022Article
- Article
- Metformin in aging and aging-related diseases: clinical applications and relevant mechanisms.Theranostics · 2022Review
- Integrated or Independent Actions of Metformin in Target Tissues Underlying Its Current Use and New Possible Applications in the Endocrine and Metabolic Disorder Area.International journal of molecular sciences · 2021Review
- Metformin Actions on the Liver: Protection Mechanisms Emerging in Hepatocytes and Immune Cells against NASH-Related HCC.International journal of molecular sciences · 2021Review
- Inhibition of mitochondrial function by metformin increases glucose uptake, glycolysis and GDF-15 release from intestinal cells.Scientific reports · 2021Article
- Genomic characterization of the adolescent idiopathic scoliosis-associated transcriptome and regulome.Human molecular genetics · 2021Article
- Restoration of mRNA Expression of Solute Carrier Proteins in Liver of Diet-Induced Obese Mice by Metformin.Frontiers in endocrinology · 2021Article
- Epigenetics of Hepatic Insulin Resistance.Frontiers in endocrinology · 2021Review
Corrections and comments
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Authors and funding
16 authors at 5 institutions in 3 countries.
Funding
Abstract
Metformin is used as a first-line therapy for type 2 diabetes (T2D) and prescribed for numerous other diseases. However, its mechanism of action in the liver has yet to be characterized in a systematic manner. To comprehensively identify genes and regulatory elements associated with metformin treatment, we carried out RNA-seq and ChIP-seq (H3K27ac, H3K27me3) on primary human hepatocytes from the same donor treated with vehicle control, metformin or metformin and compound C, an AMP-activated protein kinase (AMPK) inhibitor (allowing to identify AMPK-independent pathways). We identified thousands of metformin responsive AMPK-dependent and AMPK-independent differentially expressed genes and regulatory elements. We functionally validated several elements for metformin-induced promoter and enhancer activity. These include an enhancer in an ataxia telangiectasia mutated (ATM) intron that has SNPs in linkage disequilibrium with a metformin treatment response GWAS lead SNP (rs11212617) that showed increased enhancer activity for the associated haplotype. Expression quantitative trait locus (eQTL) liver analysis and CRISPR activation suggest that this enhancer could be regulating ATM, which has a known role in AMPK activation, and potentially also EXPH5 and DDX10, its neighboring genes. Using ChIP-seq and siRNA knockdown, we further show that activating transcription factor 3 (ATF3), our top metformin upregulated AMPK-dependent gene, could have an important role in gluconeogenesis repression. Our findings provide a genome-wide representation of metformin hepatic response, highlight important sequences that could be associated with interindividual variability in glycemic response to metformin and identify novel T2D treatment candidates.
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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.