ArticleThe Journal of biological chemistry2016
Activation of the cAMP-PKA pathway Antagonizes Metformin Suppression of Hepatic Glucose Production.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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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
28 citing papers in PubMed, 39 citations in OpenAlex.
- Genome-wide CRISPR Screening Reveals a PKA-Driven Resistance Mechanism to Metformin for Oral Cancer Prevention That Can Be Exploited by Combination with NSAIDs.Cancer prevention research (Philadelphia, Pa.) · 2026Article
- Targeting negative phosphorylation to activate AMPK.Endocrine connections · 2025Article
- Hepatic PKA Mediates Liver and Pancreatic α-Cell Cross Talk.Diabetes · 2025Article
- Effect of submaximal and maximal training on serum levels of asprosin, metabolic parameters and body composition in overweight and obese women.Journal of diabetes and metabolic disorders · 2025Article
- Semaglutide and High-Intensity Interval Exercise Attenuate Cognitive Impairment in Type 2 Diabetic Mice via BDNF Modulation.Brain sciences · 2025Article
- The AMPK/cAMP Metabolic Signaling Axis as a Possible Therapeutic Target for Diabetes.Current molecular medicine · 2025Review
- TGF-β1 Signaling Impairs Metformin Action on Glycemic Control.International journal of molecular sciences · 2024Article
- Blocking AMPKαS496 phosphorylation improves mitochondrial dynamics and hyperglycemia in aging and obesity.Cell chemical biology · 2023Article
- Prenatal low-dose methylmercury exposure causes premature neuronal differentiation and autism-like behaviors in a rodent model.iScience · 2023Article
- Article
- An update on mode of action of metformin in modulation of meta-inflammation and inflammaging.Pharmacological reports : PR · 2022Review
- Emerging Role of cAMP/AMPK Signaling.Cells · 2022Review
- Metabolic responsiveness to training depends on insulin sensitivity and protein content of exosomes in insulin-resistant males.Science advances · 2021Article
- Metformin prevents p-tau and amyloid plaque deposition and memory impairment in diabetic mice.Experimental brain research · 2021Article
- Metformin Targets Foxo1 to Control Glucose Homeostasis.Biomolecules · 2021Article
- Alterations of Gut Microbiota by Overnutrition Impact Gluconeogenic Gene Expression and Insulin Signaling.International journal of molecular sciences · 2021Review
- PKA functions in metabolism and resistance to obesity: lessons from mouse and human studies.The Journal of endocrinology · 2020Review
- The importance of the AMPK gamma 1 subunit in metformin suppression of liver glucose production.Scientific reports · 2020Article
- Metformin Improves Mitochondrial Respiratory Activity through Activation of AMPK.Cell reports · 2019Article
- Hepatic nitric oxide synthase 1 adaptor protein regulates glucose homeostasis and hepatic insulin sensitivity in obese mice depending on its PDZ binding domain.EBioMedicine · 2019Article
Corrections and comments
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Authors and funding
8 authors at 5 institutions in 1 country.
Funding
Abstract
Metformin is the most commonly prescribed oral anti-diabetic agent worldwide. Surprisingly, about 35% of diabetic patients either lack or have a delayed response to metformin treatment, and many patients become less responsive to metformin over time. It remains unknown how metformin resistance or insensitivity occurs. Recently, we found that therapeutic metformin concentrations suppressed glucose production in primary hepatocytes through AMPK; activation of the cAMP-PKA pathway negatively regulates AMPK activity by phosphorylating AMPKα subunit at Ser-485, which in turn reduces AMPK activity. In this study, we find that metformin failed to suppress glucose production in primary hepatocytes with constitutively activated PKA and did not improve hyperglycemia in mice with hyperglucagonemia. Expression of the AMPKα1(S485A) mutant, which is unable to be phosphorylated by PKA, increased both AMPKα activation and the suppression of glucose production in primary hepatocytes treated with metformin. Intriguingly, salicylate/aspirin prevents the phosphorylation of AMPKα at Ser-485, blocks cAMP-PKA negative regulation of AMPK, and improves metformin resistance. We propose that aspirin/salicylate may augment metformin's hepatic action to suppress glucose production.
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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.