ArticleAmerican journal of physiology. Cell physiology2016
Ketoisocaproic acid, a metabolite of leucine, suppresses insulin-stimulated glucose transport in skeletal muscle cells in a BCAT2-dependent manner.
Article in American journal of physiology. Cell physiology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 62 citations in OpenAlex.
- Apparent Saturation of Branched-Chain Amino Acid Catabolism After High Dietary Milk Protein Intake in Healthy Adults.The Journal of clinical endocrinology and metabolism · 2025Trial
- Molecular Transducers of Human Skeletal Muscle Remodeling under Different Loading States.Cell reports · 2020Trial
- Branched-chain amino acids in muscle growth: mechanisms, physiological functions, and applications.Journal of animal science and biotechnology · 2025Review
- The Impact of Gut Microbial Metabolomics on Type 2 Diabetes Development in People Living with HIV.Metabolites · 2025Review
- Interventional approaches to combat obesity: Exploring the metabolomic signature of weight loss trials.Metabolism open · 2025Review
- Exogenous Nucleotides Supplementation Attenuates Age-Related Sarcopenia.Journal of cachexia, sarcopenia and muscle · 2025Article
- Alpha-Ketoisocaproate Attenuates Muscle Atrophy in Cancer Cachexia Models.Journal of cachexia, sarcopenia and muscle · 2025Article
- Metabolomics in cardiometabolic diseases: Key biomarkers and therapeutic implications for insulin resistance and diabetes.Journal of internal medicine · 2025Review
- Effects of alpha-ketoisocaproate in oxidative stress-induced C2C12 myotubes via inhibition of p38 MAPK and ERK1/2.Biochemistry and biophysics reports · 2025Article
- 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
- Alpha-ketoglutarate supplementation improves hyperglycemia and attenuates the decrease in GLUT4 and PGC-1α proteins in adipose tissue of streptozotocin-high-fat diet-induced diabetic mice.Journal of nutritional science · 2025Article
- Primary Roles of Branched Chain Amino Acids (BCAAs) and Their Metabolism in Physiology and Metabolic Disorders.Molecules (Basel, Switzerland) · 2024Review
- Sarcopenia: recent advances for detection, progression, and metabolic alterations along with therapeutic targets.Canadian journal of physiology and pharmacology · 2024Review
- Double-Edge Effects of Leucine on Cancer Cells.Biomolecules · 2024Review
- Exploration of Nutraceutical Potentials of Isorhapontigenin, Oxyresveratrol and Pterostilbene: A Metabolomic Approach.International journal of molecular sciences · 2024Article
- BCAAs acutely drive glucose dysregulation and insulin resistance: role of AgRP neurons.Nutrition & diabetes · 2024Article
- Elevated BCAA catabolism reverses the effect of branched-chain ketoacids on glucose transport in mTORC1-dependent manner in L6 myotubes.Journal of nutritional science · 2024Article
- Article
- Depiction of Branched-Chain Amino Acids (BCAAs) in Diabetes with a Focus on Diabetic Microvascular Complications.Journal of clinical medicine · 2023Review
- Effect of Maturity Stage on Cereal and Leguminous Seeds' Metabolome as Analyzed Using Gas Chromatography Mass-Spectrometry (GC-MS) and Chemometric Tools.Metabolites · 2023Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Although leucine has many positive effects on metabolism in multiple tissues, elevated levels of this amino acid and the other branched-chain amino acids (BCAAs) and their metabolites are implicated in obesity and insulin resistance. While some controversies exist about the direct effect of leucine on insulin action in skeletal muscle, little is known about the direct effect of BCAA metabolites. Here, we first showed that the inhibitory effect of leucine on insulin-stimulated glucose transport in L6 myotubes was dampened when other amino acids were present, due in part to a 140% stimulation of basal glucose transport (P < 0.05). Importantly, we also showed that α-ketoisocaproic acid (KIC), an obligatory metabolite of leucine, stimulated mTORC1 signaling but suppressed insulin-stimulated glucose transport (-34%, P < 0.05) in an mTORC1-dependent manner. The effect of KIC on insulin-stimulated glucose transport was abrogated in cells depleted of branched-chain aminotransferase 2 (BCAT2), the enzyme that catalyzes the reversible transamination of KIC to leucine. We conclude that although KIC can modulate muscle glucose metabolism, this effect is likely a result of its transamination back to leucine. Therefore, limiting the availability of leucine, rather than those of its metabolites, to skeletal muscle may be more critical in the management of insulin resistance and its sequelae.
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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.