ArticleThe Journal of biological chemistry2014
Low concentrations of metformin suppress glucose production in hepatocytes through AMP-activated protein kinase (AMPK).
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 103 papers, 1 of them a synthesis that pooled it.
What it found
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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.
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Who cites it
103 citing papers in PubMed, 1 synthesis or guideline pooled it, 162 citations in OpenAlex.
- Therapeutic Concentrations of Metformin: A Systematic Review.Clinical pharmacokinetics · 2016Pooled it
- Metformin Therapy in Autosomal Dominant Polycystic Kidney Disease: A Feasibility Study.American journal of kidney diseases : the official journal of the National Kidney Foundation · 2022Trial
- Hepatic exposure of metformin in patients with non-alcoholic fatty liver disease.British journal of clinical pharmacology · 2019Trial
- Hyperglucagonemia Mitigates the Effect of Metformin on Glucose Production in Prediabetes.Cell reports · 2016Trial
- Metformin Attenuates the High-Glucose Effect on MORG1 Expression in HEK293 Cells.Current issues in molecular biology · 2026Article
- The coordinated actions of metformin in the intestine and liver improves hyperglycemia.Cell reports · 2026Article
- The Molecular Mechanisms of Metformin's Action on Blood Lipid Profile in Diabetic Patients.International journal of molecular sciences · 2026Review
- PPARβ/δ contributes to the antidiabetic effect and the increase in GDF15 caused by metformin.Acta pharmacologica Sinica · 2026Article
- Metformin treatment impairs the adenine nucleotide translocator activity and energy metabolism in human clear cell renal carcinoma cells.Scientific reports · 2026Article
- Mitochondrial metabolism and signaling direct dendritic cell function in antitumor immunity.Science (New York, N.Y.) · 2026Article
- Targeting negative phosphorylation to activate AMPK.Endocrine connections · 2025Article
- Disease-modifying pharmacological treatments of type 1 diabetes: Molecular mechanisms, target checkpoints, and possible combinatorial treatments.Pharmacological reviews · 2025Review
- Advances in the Use of Metformin for Liver Disease.Current medicinal chemistry · 2025Review
- Mechanism of action and research advancements of Qi-tonifying traditional Chinese medicine in the treatment of type 2 diabetic mellitus.American journal of translational research · 2025Review
- Dual modulation of atherosclerosis by exercise and metformin: convergent pathways, divergent outcomes, and therapeutic potential.Clinical hypertension · 2025Review
- Metabolic Homeostasis of Immune Cells Modulates Cardiovascular Diseases.Research (Washington, D.C.) · 2025Review
- Adipocyte inflammation is the primary driver of hepatic insulin resistance in a human iPSC-based microphysiological system.Nature communications · 2024Article
- Improving Type 2 Diabetes Care with Extended-Release Metformin: Real-Life Insights from a Physician Educational Program.Endocrine, metabolic & immune disorders drug targets · 2024Article
- Pathophysiology of X-Linked Adrenoleukodystrophy: Updates on Molecular Mechanisms.Journal of biotechnology and biomedicine · 2024Article
- Blocking AMPKαS496 phosphorylation improves mitochondrial dynamics and hyperglycemia in aging and obesity.Cell chemical biology · 2023Article
43 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
Metformin is a first-line antidiabetic agent taken by 150 million people across the world every year, yet its mechanism remains only partially understood and controversial. It was proposed that suppression of glucose production in hepatocytes by metformin is AMPK-independent; however, unachievably high concentrations of metformin were employed in these studies. In the current study, we find that metformin, via an AMP-activated protein kinase (AMPK)-dependent mechanism, suppresses glucose production and gluconeogenic gene expression in primary hepatocytes at concentrations found in the portal vein of animals (60-80 μM). Metformin also inhibits gluconeogenic gene expression in the liver of mice administered orally with metformin. Furthermore, the cAMP-PKA pathway negatively regulates AMPK activity through phosphorylation at Ser-485/497 on the α subunit, which in turn reduces net phosphorylation at Thr-172. Because diabetic patients often have hyperglucagonemia, AMPKα phosphorylation at Ser-485/497 is a therapeutic target to improve metformin efficacy.
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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.