ArticleThe Journal of biological chemistry2020
Branched-chain ketoacid overload inhibits insulin action in the muscle.
Article in The Journal of biological chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers, 1 of them a synthesis that pooled it.
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Who cites it
35 citing papers in PubMed, 1 synthesis or guideline pooled it, 50 citations in OpenAlex.
- Causal role of genetically predicted impairment of branched-chain amino acid catabolism on insulin secretion and insulin resistance in type 2 diabetes.Diabetes, obesity & metabolism · 2026Pooled it
- Association of BCAAs/BCKAs with pancreatic steatosis in patients with type 2 diabetes mellitus: A cross-sectional study.Journal of diabetes investigation · 2026Article
- Plasma metabolites after 10-weeks of glucose vs fructose-sweetened beverages in subjects with overweight/obesity.Journal of the Endocrine Society · 2026Article
- Branched-chain α-keto acids impair glucose-stimulated insulin secretion in pancreatic β-cells under diabetes by reactivating the LDHA-lactate axis.Nature communications · 2026Article
- BCAA Metabolic Dyshomeostasis in Cardiovascular Disease: Pathogenic Mechanisms and Intervention.American journal of cardiovascular drugs : drugs, devices, and other interventions · 2026Review
- Gut microbiota in type 2 diabetes mellitus: mechanistic links between dysbiosis, insulin resistance, and chronic low-grade inflammation.Frontiers in endocrinology · 2026Review
- Association between PMFrontiers in public health · 2026Article
- Branched-chain amino acid metabolism and macrophage polarization: potential regulatory nodes and therapeutic targets in diabetes-associated metabolic inflammation.Frontiers in cellular and infection microbiology · 2026Review
- Impact of keto leucine and isoleucine on CHO cell central carbon metabolism and performance in fed-batch and steady-state perfusion.Frontiers in bioengineering and biotechnology · 2026Article
- Angel or demon? The dual role of branched-chain amino acids in chronic inflammatory and injury-related diseases.Frontiers in immunology · 2026Review
- Multimodal Therapeutic Strategies Targeting BCAA Metabolism in Diabetic Cardiomyopathy: A Path to Cardioprotection.Cardiovascular toxicology · 2025Review
- Branched-Chain α Keto-Acid Dehydrogenase Kinase-Mediated AKT Phosphorylation Promotes RCC Tumorigenesis and Drug Resistance.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- The regulatory role of exercise in heart failure and myocardial energy metabolism: A review.Biomolecules & biomedicine · 2025Review
- Alpha-Ketoisocaproate Attenuates Muscle Atrophy in Cancer Cachexia Models.Journal of cachexia, sarcopenia and muscle · 2025Article
- Circulating BCKAs are closely associated with adipose tissue insulin resistance in type 2 diabetes.Diabetology & metabolic syndrome · 2025Article
- Dysregulated maternal and newborn fatty acid, sugar and amino acid metabolism associated with high birth weight.International journal of obesity (2005) · 2025Article
- Metabolomics in cardiometabolic diseases: Key biomarkers and therapeutic implications for insulin resistance and diabetes.Journal of internal medicine · 2025Review
- Branched-chain amino acid metabolism: Pathophysiological mechanism and therapeutic intervention in metabolic diseases.Obesity reviews : an official journal of the International Association for the Study of Obesity · 2025Review
- Role of gut microbiota and its metabolites in diabetic cardiomyopathy: from pathogenesis to interventions.Frontiers in cardiovascular medicine · 2025Review
- Brown Fat and Metabolic Health: The Diverse Functions of Dietary Components.Endocrinology and metabolism (Seoul, Korea) · 2024Review
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Branched-chain α-keto acids (BCKAs) are catabolites of branched-chain amino acids (BCAAs). Intracellular BCKAs are cleared by branched-chain ketoacid dehydrogenase (BCKDH), which is sensitive to inhibitory phosphorylation by BCKD kinase (BCKDK). Accumulation of BCKAs is an indicator of defective BCAA catabolism and has been correlated with glucose intolerance and cardiac dysfunction. However, it is unclear whether BCKAs directly alter insulin signaling and function in the skeletal and cardiac muscle cell. Furthermore, the role of excess fatty acids (FAs) in perturbing BCAA catabolism and BCKA availability merits investigation. By using immunoblotting and ultra-performance liquid chromatography MS/MS to analyze the hearts of fasted mice, we observed decreased BCAA-catabolizing enzyme expression and increased circulating BCKAs, but not BCAAs. In mice subjected to diet-induced obesity (DIO), we observed similar increases in circulating BCKAs with concomitant changes in BCAA-catabolizing enzyme expression only in the skeletal muscle. Effects of DIO were recapitulated by simulating lipotoxicity in skeletal muscle cells treated with saturated FA, palmitate. Exposure of muscle cells to high concentrations of BCKAs resulted in inhibition of insulin-induced AKT phosphorylation, decreased glucose uptake, and mitochondrial oxygen consumption. Altering intracellular clearance of BCKAs by genetic modulation of BCKDK and BCKDHA expression showed similar effects on AKT phosphorylation. BCKAs increased protein translation and mTORC1 activation. Pretreating cells with mTORC1 inhibitor rapamycin restored BCKA's effect on insulin-induced AKT phosphorylation. This study provides evidence for FA-mediated regulation of BCAA-catabolizing enzymes and BCKA content and highlights the biological role of BCKAs in regulating muscle insulin signaling and function.
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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.