ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2014
Uric acid-dependent inhibition of AMP kinase induces hepatic glucose production in diabetes and starvation: evolutionary implications of the uricase loss in hominids.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 91 papers, 1 of them a synthesis that pooled it.
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Who cites it
91 citing papers in PubMed, 1 synthesis or guideline pooled it, 179 citations in OpenAlex.
- Effects of Uric Acid-Lowering Treatment on Glycemia: A Systematic Review and Meta-Analysis.Frontiers in endocrinology · 2020Pooled it
- Uric Acid Extremes and Lipid Dysregulation: Evidence from a Large Population-Based Study.Metabolites · 2026Article
- Deciphering AMP deaminase-2 structure, activators and regulators underpinning cellular function in human fructose and nucleotide metabolism.bioRxiv : the preprint server for biology · 2026Article
- Association of serum biomarkers of dietary purine intake with glycaemic control and risk of preterm birth: two prospective cohort studies among pregnant women.EBioMedicine · 2026Article
- Fructose: metabolic signal and modern hazard.Nature metabolism · 2026Review
- Serum uric acid and its metabolism-a vital factor in the inflammatory transformation of cancer.Journal of advanced research · 2026Review
- New Insight Into Male Infertility: Deviation From Basic Tenets of Life.Oxidative medicine and cellular longevity · 2026Review
- Molecular Impact of Metabolic and Endocrine Disturbance on Endometrial Function in Polycystic Ovary Syndrome.International journal of molecular sciences · 2025Review
- Article
- Genomic insertion of ancestral uricase into human liver cells to determine metabolic consequences of pseudogenization.Scientific reports · 2025Article
- Prediction of insulin resistance using multiple adaptive regression spline in Chinese women.Endocrine journal · 2025Article
- Molecular and Clinical Perspectives on the Regulation of Sleep and Uric Acid Metabolism.Nature and science of sleep · 2025Review
- The interplay between diabetes and atherosclerosis: A review of pathophysiological mechanisms.ARYA atherosclerosis · 2025Review
- Role of AMP deaminase in diabetic cardiomyopathy.Molecular and cellular biochemistry · 2024Review
- The relationship between the systemic immune inflammation index and the nonalcoholic fatty liver disease in American adolescents.BMC gastroenterology · 2024Article
- Xanthine oxidoreductase inhibition ameliorates high glucose-induced glomerular endothelial injury by activating AMPK through the purine salvage pathway.Scientific reports · 2024Article
- Does Serum Uric Acid to Creatinine Ratio Predict Mortality Risk in Patients With Heart Failure?Texas Heart Institute journal · 2024Article
- The Association Between Serum Uric Acid Levels and the Risk of Cognitive Dysfunction in Patients With Atrial Fibrillation.International journal of endocrinology · 2024Article
- The fructose survival hypothesis for obesity.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2023Review
- Insulin Resistance and Hypertension: Mechanisms Involved and Modifying Factors for Effective Glucose Control.Biomedicines · 2023Review
31 more citing papers are in PubMed but not listed here.
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12 authors at 3 institutions in 1 country.
Funding
Abstract
Reduced AMP kinase (AMPK) activity has been shown to play a key deleterious role in increased hepatic gluconeogenesis in diabetes, but the mechanism whereby this occurs remains unclear. In this article, we document that another AMP-dependent enzyme, AMP deaminase (AMPD) is activated in the liver of diabetic mice, which parallels with a significant reduction in AMPK activity and a significant increase in intracellular glucose accumulation in human HepG2 cells. AMPD activation is induced by a reduction in intracellular phosphate levels, which is characteristic of insulin resistance and diabetic states. Increased gluconeogenesis is mediated by reduced TORC2 phosphorylation at Ser171 by AMPK in these cells, as well as by the up-regulation of the rate-limiting enzymes PEPCK and G6Pc. The mechanism whereby AMPD controls AMPK activation depends on the production of a specific AMP downstream metabolite through AMPD, uric acid. In this regard, humans have higher uric acid levels than most mammals due to a mutation in uricase, the enzyme involved in uric acid degradation in most mammals, that developed during a period of famine in Europe 1.5 × 10(7) yr ago. Here, working with resurrected ancestral uricases obtained from early hominids, we show that their expression on HepG2 cells is enough to blunt gluconeogenesis in parallel with an up-regulation of AMPK activity. These studies identify a key role AMPD and uric acid in mediating hepatic gluconeogenesis in the diabetic state, via a mechanism involving AMPK down-regulation and overexpression of PEPCK and G6Pc. The uricase mutation in the Miocene likely provided a survival advantage to help maintain glucose levels under conditions of near starvation, but today likely has a role in the pathogenesis of diabetes.
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