ArticleThe Journal of biological chemistry2016
Pyruvate Dehydrogenase Kinase-mediated Glycolytic Metabolic Shift in the Dorsal Root Ganglion Drives Painful Diabetic Neuropathy.
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 53 papers.
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53 citing papers in PubMed, 76 citations in OpenAlex.
- Ligilactobacillus salivarius 8-2 attenuates intestinal mucosal injury in chicks via the mitochondrial fision-glycometabolism reprogramming axis.Poultry science · 2026Article
- Bioenergetic failure in diabetic peripheral neuropathy: from glucotoxicity to multidimensional metabolic imbalance.Journal of neurology · 2026Review
- A Comparative Evaluation of the Therapeutic Effects of Adenosine Triphosphate, Coenzyme Q10, Pyridoxine, and Thiamine Pyrophosphate in a Linezolid-Induced Peripheral Neuropathic Pain Model in Rats.Pharmaceuticals (Basel, Switzerland) · 2026Article
- BRG1 orchestrates diabetic corneal neuropathy via PI3K/AKT-mediated glycolytic reprogramming.Eye and vision (London, England) · 2026Article
- Structural and Functional Impact of Spinal Cord Stimulation in Diabetic Peripheral Neuropathy.Cureus · 2026Review
- Histone Lactylation Contributes to Neuropathic Pain by Facilitating mThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- Metabolic reprogramming in diabetic complications: mechanisms, pathologies, and molecular evidence from multi-organ studies.Frontiers in immunology · 2026Review
- Pain mechanisms in osteoarthritis: recent discoveries and opportunities ahead.Connective tissue research · 2025Review
- Pyruvate Administration Restores Impaired Nociception by Enhancing Neurite Outgrowth in Streptozotocin-Induced Diabetic Mice.International journal of molecular sciences · 2025Article
- Type 3 diabetes and metabolic reprogramming of brain neurons: causes and therapeutic strategies.Molecular medicine (Cambridge, Mass.) · 2025Review
- Gut microbiota and its metabolites promote painful diabetic peripheral neuropathy complicated with cognitive dysfunction in mice.Frontiers in cellular and infection microbiology · 2025Article
- Discovery of Glucose Metabolism-Associated Genes in Neuropathic Pain: Insights from Bioinformatics.International journal of molecular sciences · 2024Article
- Gene expression in the dorsal root ganglion and the cerebrospinal fluid metabolome in polyneuropathy and opioid tolerance in rats.IBRO neuroscience reports · 2024Article
- Role of Exogenous Pyruvate in Maintaining Adenosine Triphosphate Production under High-Glucose Conditions through PARP-Dependent Glycolysis and PARP-Independent Tricarboxylic Acid Cycle.International journal of molecular sciences · 2024Article
- PDK4-mediated metabolic reprogramming is a potential therapeutic target for neovascular age-related macular degeneration.Cell death & disease · 2024Article
- The Role of PKM2 in Multiple Signaling Pathways Related to Neurological Diseases.Molecular neurobiology · 2024Review
- Astrocytic pyruvate dehydrogenase kinase-lactic acid axis involvement in glia-neuron crosstalk contributes to morphine-induced hyperalgesia in mice.Fundamental research · 2024Article
- Recent Advances in Biomolecular Patho-Mechanistic Pathways behind the Development and Progression of Diabetic Neuropathy.Biomedicines · 2024Review
- Genetic exploration of roles of acid-sensing ion channel subtypes in neurosensory mechanotransduction including proprioception.Experimental physiology · 2024Review
- Novel drugs affecting diabetic peripheral neuropathy.Iranian journal of basic medical sciences · 2024Review
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The dorsal root ganglion (DRG) is a highly vulnerable site in diabetic neuropathy. Under diabetic conditions, the DRG is subjected to tissue ischemia or lower ambient oxygen tension that leads to aberrant metabolic functions. Metabolic dysfunctions have been documented to play a crucial role in the pathogenesis of diverse pain hypersensitivities. However, the contribution of diabetes-induced metabolic dysfunctions in the DRG to the pathogenesis of painful diabetic neuropathy remains ill-explored. In this study, we report that pyruvate dehydrogenase kinases (PDK2 and PDK4), key regulatory enzymes in glucose metabolism, mediate glycolytic metabolic shift in the DRG leading to painful diabetic neuropathy. Streptozotocin-induced diabetes substantially enhanced the expression and activity of the PDKs in the DRG, and the genetic ablation of Pdk2 and Pdk4 attenuated the hyperglycemia-induced pain hypersensitivity. Mechanistically, Pdk2/4 deficiency inhibited the diabetes-induced lactate surge, expression of pain-related ion channels, activation of satellite glial cells, and infiltration of macrophages in the DRG, in addition to reducing central sensitization and neuroinflammation hallmarks in the spinal cord, which probably accounts for the attenuated pain hypersensitivity. Pdk2/4-deficient mice were partly resistant to the diabetes-induced loss of peripheral nerve structure and function. Furthermore, in the experiments using DRG neuron cultures, lactic acid treatment enhanced the expression of the ion channels and compromised cell viability. Finally, the pharmacological inhibition of DRG PDKs or lactic acid production substantially attenuated diabetes-induced pain hypersensitivity. Taken together, PDK2/4 induction and the subsequent lactate surge induce the metabolic shift in the diabetic DRG, thereby contributing to the pathogenesis of painful diabetic neuropathy.
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