ArticleProceedings of the National Academy of Sciences of the United States of America2015
L-cysteine reversibly inhibits glucose-induced biphasic insulin secretion and ATP production by inactivating PKM2.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 68 citations in OpenAlex.
- Antioxidant therapy, N-acetyl-L-cysteine, effects on pancreatic β cells: therapeutic promise or potential harm?Endocrinology · 2026Review
- Upregulated PKM2 Protects Dopaminergic Neurons From Oxidative Damage Through Nrf2 Transactivation in an MPTP-Induced Mouse Model of Parkinson's Disease.CNS neuroscience & therapeutics · 2026Article
- Circulating metabolites, genetics and lifestyle factors in relation to future risk of type 2 diabetes.Nature medicine · 2026Article
- The antioxidant, N-acetyl-L-cysteine, affects beta cell oxidative stress, insulin secretion, and intracellular signaling pathways in MIN6 cells.Cell and tissue research · 2025Article
- Beyond Protein Building Blocks: A Review of Biological Roles and Therapeutic Potential of Free Amino Acids.International journal of molecular sciences · 2025Review
- Exploring glycolytic enzymes in disease: potential biomarkers and therapeutic targets in neurodegeneration, cancer and parasitic infections.Open biology · 2025Review
- Hydrogen sulfide coordinates glucose metabolism switch through destabilizing tetrameric pyruvate kinase M2.Nature communications · 2024Article
- Protective Factors and the Pathogenesis of Complications in Diabetes.Endocrine reviews · 2024Review
- Glucose-lowering effects of a synbiotic combination containing Pediococcus acidilactici in C. elegans and mice.Diabetologia · 2023Article
- The Replicative DnaE Polymerase ofLife (Basel, Switzerland) · 2023Article
- Identification of residues involved in allosteric signal transmission from amino acid binding site of pyruvate kinase muscle isoform 2.PloS one · 2023Article
- Metabolic rearrangements and intratumoral heterogeneity for immune response in hepatocellular carcinoma.Frontiers in immunology · 2023Review
- Nicotinamide mononucleotide improves spermatogenic function in streptozotocin-induced diabetic mice via modulating the glycolysis pathway.Acta biochimica et biophysica Sinica · 2022Article
- Cancer-cell-secreted extracellular vesicles suppress insulin secretion through miR-122 to impair systemic glucose homeostasis and contribute to tumour growth.Nature cell biology · 2022Article
- Regeneration of glomerular metabolism and function by podocyte pyruvate kinase M2 in diabetic nephropathy.JCI insight · 2022Article
- The Role of PKM2 in Diabetic Microangiopathy.Diabetes, metabolic syndrome and obesity : targets and therapy · 2022Review
- Article
- The Role of PKM2 in Metabolic Reprogramming: Insights into the Regulatory Roles of Non-Coding RNAs.International journal of molecular sciences · 2021Review
- Molecular Insight Into the Therapeutic Potential of Long Non-coding RNA-Associated Competing Endogenous RNA Axes in Alzheimer's Disease: A Systematic Scoping Review.Frontiers in aging neuroscience · 2021Article
- Role of PKM2-Mediated Immunometabolic Reprogramming on Development of Cytokine Storm.Frontiers in immunology · 2021Review
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Increase in the concentration of plasma L-cysteine is closely associated with defective insulin secretion from pancreatic β-cells, which results in type 2 diabetes (T2D). In this study, we investigated the effects of prolonged L-cysteine treatment on glucose-stimulated insulin secretion (GSIS) from mouse insulinoma 6 (MIN6) cells and from mouse pancreatic islets, and found that the treatment reversibly inhibited glucose-induced ATP production and resulting GSIS without affecting proinsulin and insulin synthesis. Comprehensive metabolic analyses using capillary electrophoresis time-of-flight mass spectrometry showed that prolonged L-cysteine treatment decreased the levels of pyruvate and its downstream metabolites. In addition, methyl pyruvate, a membrane-permeable form of pyruvate, rescued L-cysteine-induced inhibition of GSIS. Based on these results, we found that both in vitro and in MIN6 cells, L-cysteine specifically inhibited the activity of pyruvate kinase muscle isoform 2 (PKM2), an isoform of pyruvate kinases that catalyze the conversion of phosphoenolpyruvate to pyruvate. L-cysteine also induced PKM2 subunit dissociation (tetramers to dimers/monomers) in cells, which resulted in impaired glucose-induced ATP production for GSIS. DASA-10 (NCGC00181061, a substituted N,N'-diarylsulfonamide), a specific activator for PKM2, restored the tetramer formation and the activity of PKM2, glucose-induced ATP production, and biphasic insulin secretion in L-cysteine-treated cells. Collectively, our results demonstrate that impaired insulin secretion due to exposure to L-cysteine resulted from its direct binding and inactivation of PKM2 and suggest that PKM2 is a potential therapeutic target for T2D.
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