ArticleDiabetes2018
PDK4 Deficiency Suppresses Hepatic Glucagon Signaling by Decreasing cAMP Levels.
Article in Diabetes, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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The trial behind it
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Who cites it
37 citing papers in PubMed, 50 citations in OpenAlex.
- Metabolic Adaptation and Potential Regulatory Mechanisms of Longissimus Dorsi-Derived Skeletal Muscle Satellite Cells from Hu Sheep Under Insulin Induction.Animals : an open access journal from MDPI · 2026Article
- Pharmacological Inhibition of Pyruvate Dehydrogenase Kinase 4 Enhances Insulin Sensitivity in Mouse Models of Diabetes and Obesity.Journal of obesity & metabolic syndrome · 2026Article
- Effects of AMPK/PGC-1α on gluconeogenesis in skeletal muscle of animals under overwintering starvation and its molecular mechanism: review.Animal bioscience · 2026Article
- Hepatic Glucocorticoid Receptor Action and Glucose Homeostasis.Endocrine reviews · 2026Review
- Integrated Transcriptomic and Proteomic Analysis Reveals Differential Gene and Protein Expression and Signaling Pathways During a 20 Km Endurance Exercise and Recovery in Mongolian Horses.Animals : an open access journal from MDPI · 2025Article
- Widespread discordance between mRNA expression, protein abundance andbioRxiv : the preprint server for biology · 2025Article
- Identification and functional analysis of energy metabolism and pyroptosis-related genes in diabetic nephropathy.Heliyon · 2025Article
- Nuclear regulatory disturbances precede and predict the development of Type-2 diabetes in Asian populations.medRxiv : the preprint server for health sciences · 2025Article
- Pyruvate dehydrogenase kinases: key regulators of cellular metabolism and therapeutic targets for metabolic diseases.Journal of physiology and biochemistry · 2025Review
- PDK4-mediated metabolic reprogramming is a potential therapeutic target for neovascular age-related macular degeneration.Cell death & disease · 2024Article
- Reducing Oxidative Stress and Inflammation by Pyruvate Dehydrogenase Kinase 4 Inhibition Is Important in Prevention of Renal Ischemia-Reperfusion Injury in Diabetic Mice.Diabetes & metabolism journal · 2024Article
- Stevioside Ameliorates Palmitic Acid-Induced Abnormal Glucose Uptake via the PDK4/AMPK/TBC1D1 Pathway in C2C12 Myotubes.Endocrinology, diabetes & metabolism · 2024Article
- Exploring Renal Pyruvate Metabolism as a Therapeutic Avenue for Diabetic Kidney Injury.Diabetes & metabolism journal · 2024Article
- Development of novel liver-targeting glucocorticoid prodrugs.Medicine in drug discovery · 2024Article
- Combined transcriptome and metabolome analysis reveals breed-specific regulatory mechanisms in Dorper and Tan sheep.BMC genomics · 2024Article
- Exploring diet-induced promoter hypomethylation and PDK4 overexpression: implications for type 2 diabetes mellitus.Molecular biology reports · 2023Article
- The Role of Pyruvate Metabolism in Mitochondrial Quality Control and Inflammation.Molecules and cells · 2023Review
- CD36 deletion ameliorates diabetic kidney disease by restoring fatty acid oxidation and improving mitochondrial function.Renal failure · 2023Article
- Mitochondrial dysfunctions in T cells: focus on inflammatory bowel disease.Frontiers in immunology · 2023Review
- Narrative Review: Glucocorticoids in Alcoholic Hepatitis-Benefits, Side Effects, and Mechanisms.Journal of xenobiotics · 2022Review
Corrections and comments
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Authors and funding
15 authors at 9 institutions in 2 countries.
Funding
Abstract
In fasting or diabetes, gluconeogenic genes are transcriptionally activated by glucagon stimulation of the cAMP-protein kinase A (PKA)-CREB signaling pathway. Previous work showed pyruvate dehydrogenase kinase (PDK) inhibition in skeletal muscle increases pyruvate oxidation, which limits the availability of gluconeogenic substrates in the liver. However, this study found upregulation of hepatic PDK4 promoted glucagon-mediated expression of gluconeogenic genes, whereas knockdown or inhibition of hepatic PDK4 caused the opposite effect on gluconeogenic gene expression and decreased hepatic glucose production. Mechanistically, PDK4 deficiency decreased ATP levels, thus increasing phosphorylated AMPK (p-AMPK), which increased p-AMPK-sensitive phosphorylation of cyclic nucleotide phosphodiesterase 4B (p-PDE4B). This reduced cAMP levels and consequently p-CREB. Metabolic flux analysis showed that the reduction in ATP was a consequence of a diminished rate of fatty acid oxidation (FAO). However, overexpression of PDK4 increased FAO and increased ATP levels, which decreased p-AMPK and p-PDE4B and allowed greater accumulation of cAMP and p-CREB. The latter were abrogated by the FAO inhibitor etomoxir, suggesting a critical role for PDK4 in FAO stimulation and the regulation of cAMP levels. This finding strengthens the possibility of PDK4 as a target against diabetes.
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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.