ArticleNature2013
Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP.
Article in Nature, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 430 papers, 3 of them syntheses that pooled it.
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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
430 citing papers in PubMed, 3 syntheses or guidelines pooled it, 825 citations in OpenAlex.
- Pooled it
- Impact of Metformin on Cancer Biomarkers in Non-Diabetic Cancer Patients: A Systematic Review and Meta-Analysis of Clinical Trials.Current oncology (Toronto, Ont.) · 2021Pooled it
- The effect of metformin on biomarkers associated with breast cancer outcomes: a systematic review, meta-analysis, and dose-response of randomized clinical trials.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2020 · on this mapPooled it
- Combined micro-needling with topical metformin versus micro-needling with topical placebo in the treatment of melasma: a concurrent split-face study.Archives of dermatological research · 2024Trial
- Trial
- Effects of mulberry twig alkaloids(Sangzhi alkaloids) and metformin on blood glucose fluctuations in combination with premixed insulin-treated patients with type 2 diabetes.Frontiers in endocrinology · 2023Trial
- Primary results of the randomized trial of metformin administration in polycystic kidney disease (TAME PKD).Kidney international · 2021Trial
- Metformin Lowers Body Weight But Fails to Increase Insulin Sensitivity in Chronic Heart Failure Patients without Diabetes: a Randomized, Double-Blind, Placebo-Controlled Study.Cardiovascular drugs and therapy · 2021Trial
- Effects of Metformin on Left Ventricular Size and Function in Hypertensive Patients with Type 2 Diabetes Mellitus: Results of a Randomized, Controlled, Multicenter, Phase IV Trial.American journal of cardiovascular drugs : drugs, devices, and other interventions · 2020Trial
- Metformin does not compromise energy status in human skeletal muscle at rest or during acute exercise: A randomised, crossover trial.Physiological reports · 2019Trial
- Metformin Attenuates the High-Glucose Effect on MORG1 Expression in HEK293 Cells.Current issues in molecular biology · 2026Article
- Article
- A non-enzymatic function of neuraminidase 1 restrains hepatic glucagon response in mice.Nature communications · 2026Article
- Metformin promotes mitochondrial integrity through AMPK-signaling in Leber's hereditary optic neuropathy.FEBS open bio · 2026Article
- From Metabolism to Longevity: Molecular Mechanisms Underlying Metformin's Anticancer and Anti-Aging Effects.Current issues in molecular biology · 2026Review
- AMPK at the interface of nutrient sensing, metabolic flux and energy homeostasis.Nature metabolism · 2026Review
- Factors potentiating risk of higher lactate level associated with metformin therapy: a cross-sectional study in an ambulatory care setting.Therapeutic advances in endocrinology and metabolism · 2026Article
- The role of combined Metformin and pharmaceutical molecules with anti-androgenic properties in the therapy of PCOS in adult women.Endocrine · 2025Review
- Reframing metformin as a gut-targeted glucose-lowering therapy: Mechanistic insights and translational relevance.Molecular metabolism · 2025Article
- Inhibition of hepatic gluconeogenesis in type 2 diabetes by metformin: complementary role of nitric oxide.Medical gas research · 2025Review
370 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
6 authors at 4 institutions in 2 countries.
Funding
Abstract
Glucose production by the liver is essential for providing a substrate for the brain during fasting. The inability of insulin to suppress hepatic glucose output is a major aetiological factor in the hyperglycaemia of type-2 diabetes mellitus and other diseases of insulin resistance. For fifty years, one of the few classes of therapeutics effective in reducing glucose production has been the biguanides, which include phenformin and metformin, the latter the most frequently prescribed drug for type-2 diabetes. Nonetheless, the mechanism of action of biguanides remains imperfectly understood. The suggestion a decade ago that metformin reduces glucose synthesis through activation of the enzyme AMP-activated protein kinase (AMPK) has recently been challenged by genetic loss-of-function experiments. Here we provide a novel mechanism by which metformin antagonizes the action of glucagon, thus reducing fasting glucose levels. In mouse hepatocytes, metformin leads to the accumulation of AMP and related nucleotides, which inhibit adenylate cyclase, reduce levels of cyclic AMP and protein kinase A (PKA) activity, abrogate phosphorylation of critical protein targets of PKA, and block glucagon-dependent glucose output from hepatocytes. These data support a mechanism of action for metformin involving antagonism of glucagon, and suggest an approach for the development of antidiabetic drugs.
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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.