ArticleProceedings of the National Academy of Sciences of the United States of America2022
Let-7 underlies metformin-induced inhibition of hepatic glucose production.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis 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.
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Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it, 20 citations in OpenAlex.
- Do We Have Enough Evidence That Metformin Is Superior to Other Antidiabetic Drugs in Pancreatic Cancer Risk Reduction?International journal of molecular sciences · 2026Pooled it
- Reductive death is averted by a conserved de novo lipogenic switch.Molecular cell · 2026Article
- Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycaemic control.Nature metabolism · 2026Article
- The eternal struggle between titans: Fecal microbiota transplant (FMT) versus metformin in type 2 diabetes (T2D) gut dysmotility.Journal of advanced research · 2026Review
- From Metabolism to Longevity: Molecular Mechanisms Underlying Metformin's Anticancer and Anti-Aging Effects.Current issues in molecular biology · 2026Review
- Inhibition of hepatic gluconeogenesis in type 2 diabetes by metformin: complementary role of nitric oxide.Medical gas research · 2025Review
- Unravelling the association between metformin and pan-cancers: Mendelian randomization combined with NHANES database analysis.Discover oncology · 2025Article
- Camel milk exosomes regulate glucose metabolism by inhibiting mitochondrial complex I in hepatocytes.BMC veterinary research · 2025Article
- Advances in Expression Regulation, Molecular Targeting Mechanisms, and Therapeutic Applications of the Let-7 MicroRNA Family in Gastric Cancer.Oncology research · 2025Review
- TET3-overexpressing macrophages promote endometriosis.The Journal of clinical investigation · 2024Article
- Article
- Metformin: From Diabetes to Cancer-Unveiling Molecular Mechanisms and Therapeutic Strategies.Biology · 2024Review
- Skeletal muscle TET3 promotes insulin resistance through destabilisation of PGC-1α.Diabetologia · 2024Article
- Molecular mechanisms of action of metformin: latest advances and therapeutic implications.Clinical and experimental medicine · 2023Review
- Metformin: update on mechanisms of action and repurposing potential.Nature reviews. Endocrinology · 2023Review
- MicroRNA Let-7 Induces M2 Macrophage Polarization in COPD Emphysema Through the IL-6/STAT3 Pathway.International journal of chronic obstructive pulmonary disease · 2023Article
- Prenatal transcript levels and metabolomics analyses reveal metabolic changes associated with intrauterine growth restriction and sex.Open biology · 2022Article
- Review
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
SignificanceA clear mechanistic understanding of metformin's antidiabetic effects is lacking. This is because suprapharmacological concentrations of metformin have been used in most studies. Using mouse models and human primary hepatocytes, we show that metformin, at clinically relevant doses, suppresses hepatic glucose production by activating a conserved regulatory pathway encompassing let-7, TET3, and a fetal isoform of hepatocyte nuclear factor 4 alpha (HNF4α). We demonstrate that metformin no longer has potent antidiabetic actions in a liver-specific let-7 loss-of-function mouse model and that hepatic delivery of let-7 ameliorates hyperglycemia and improves glucose homeostasis. Our results thus reveal an important role of the hepatic let-7/TET3/HNF4α axis in mediating the therapeutic effects of metformin and suggest that targeting this axis may be a potential therapeutic for diabetes.
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What Socratic 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 Socratic graph.