The AtlasAmino acidsNonpolar, aliphatic
LeucineLeu · L
The amino acid that is also a message: the one a cell reads to decide whether there is enough to grow.
Molecule · Leu · 9 heavy atoms
Leucine
C6H13NO2131.18 g/mol
The amino acid that is also a message: the one a cell reads to decide whether there is enough to grow.
Built fromthe charted ones open their own entry
- Codes
- Leu · L
- Formula
- C6H13NO2
- Molar mass
- 131.18 g/mol
- Systematic name
- (2S)-2-amino-4-methylpentanoic acid
- Side chain
- Isobutyl: four carbons, branched at the end, entirely nonpolar.
- Class
- Nonpolar, aliphatic
- In the diet
- Essential
- Carbon skeleton
- Ketogenic
- pKa
- α-COOH 2.36 · α-NH3+ 9.60
- Isoelectric point
- pH 5.98
- Hydropathy
- +3.8 (Kyte–Doolittle)
- Codons
UUAUUGCUUCUCCUACUG- Main transporters
- SLC7A5 (LAT1)
pKa and isoelectric point: Nelson and Cox, Lehninger Principles of Biochemistry, table of amino acid properties (free amino acid, 25 °C). Hydropathy: Kyte and Doolittle, J Mol Biol 1982. Essentiality: Reeds, J Nutr 2000. Formula and mass computed from the structure.
In brief
What it is
A branched-chain amino acid: four carbons ending in a fork, wholly water-avoiding, with one stereocentre at the alpha carbon. It has exactly the same atoms as isoleucine, arranged differently, which is why the two weigh the same and a mass spectrometer cannot tell them apart without help 1,2.
Why it matters
Leucine is one of the commonest amino acids in protein, and it is also a signal: a sensor protein called Sestrin2 binds it and releases the brake on mTORC1, the cell’s master switch for growth and protein synthesis 3. It is the reason leucine, rather than protein in general, became the number the supplement industry sells.
Where it runs short
There is no ordinary leucine deficiency; a diet short of protein runs short of everything at once. What runs short is the requirement: measured directly, healthy adults over 60 appear to need about twice the international figure 4,5.
Where it turns
In maple syrup urine disease the enzyme complex that breaks leucine down is missing; leucine climbs to toxic levels and, untreated, injures the brain within days of birth 6,7.
The signal is cheap to send and expensive to break down; the inherited diseases are all on the breakdown side.
The molecule
Leucine’s side chain is an isobutyl group: a short chain that forks into two methyl groups at its end. It contains no oxygen, nitrogen or charge, so it avoids water and, in a folded protein, is usually buried in the core, packed against other oily side chains. The three branched-chain amino acids are the most water-avoiding of the twenty and make up about a fifth to a quarter of most dietary proteins 1.
They are not interchangeable inside a protein. Leucine prefers the alpha helix, the coiled spring that is the commonest shape a protein chain takes, while valine and isoleucine prefer the flat beta sheet 1. That preference is written into one of the most familiar motifs in biology: the leucine zipper, in which a leucine at every seventh position lines one face of a helix, and two such helices interlock like the teeth of a zip to hold a pair of gene-regulating proteins together 8.
Leucine and isoleucine are isomers: the same six carbons, thirteen hydrogens, one nitrogen and two oxygens, arranged differently. They therefore weigh exactly the same, and a mass spectrometer that does not first separate them sees one peak where there are two amino acids, which is a real problem in newborn screening 2.
StereochemistryOne stereocentre, the alpha carbon. Natural leucine is L, which for leucine is S in the Cahn–Ingold–Prelog system. Isoleucine has the same formula and two stereocentres; leucine’s branch sits one carbon further out, so it has only one.
Move across the chart to read the charge at any pH.
Computed from its pKa values (α-carboxyl 2.36, α-amino 9.60) by the Henderson–Hasselbalch equation, for the free amino acid in water at 25 °C. Inside a folded protein the same groups can shift by a unit or more. The faint lines are the other amino acids.
Kyte–Doolittle hydropathy index: positive values avoid water and tend to be buried inside a folded protein, negative values sit on its surface. Each letter is an amino acid; choose one to open it.
| 1st ↓ 2nd → | U | C | A | G | 3rd |
|---|---|---|---|---|---|
| U | UUUPhe | UCUSer | UAUTyr | UGUCys | U |
| UUCPhe | UCCSer | UACTyr | UGCCys | C | |
| UUALeu | UCASer | UAAStop | UGAStop | A | |
| UUGLeu | UCGSer | UAGStop | UGGTrp | G | |
| C | CUULeu | CCUPro | CAUHis | CGUArg | U |
| CUCLeu | CCCPro | CACHis | CGCArg | C | |
| CUALeu | CCAPro | CAAGln | CGAArg | A | |
| CUGLeu | CCGPro | CAGGln | CGGArg | G | |
| A | AUUIle | ACUThr | AAUAsn | AGUSer | U |
| AUCIle | ACCThr | AACAsn | AGCSer | C | |
| AUAIle | ACAThr | AAALys | AGAArg | A | |
| AUGMet | ACGThr | AAGLys | AGGArg | G | |
| G | GUUVal | GCUAla | GAUAsp | GGUGly | U |
| GUCVal | GCCAla | GACAsp | GGCGly | C | |
| GUAVal | GCAAla | GAAGlu | GGAGly | A | |
| GUGVal | GCGAla | GAGGlu | GGGGly | G |
Where it comes from
Humans cannot make leucine. Bacteria and plants build it from pyruvate through a pathway animals do not have, so it has to be eaten, which is what essential means 9. The international adult requirement, set in 2007, is 39 mg per kilogram of body weight per day 4.
That number was extrapolated from young adults, and direct measurement is now pulling it in two directions. Using the indicator amino acid oxidation method, which watches how fast a labelled tracer amino acid is burned as the test amino acid runs short, young men came out at 33.6 mg/kg/day 10, while healthy adults over 60 came out at 78.5 mg/kg/day, roughly double the international figure 5. If the older-adult number holds, current recommendations under-supply exactly the people most at risk of losing muscle.
Leucine is plentiful in ordinary protein. Measured directly, it is 9.0% of milk protein, 7.0% of egg protein and 7.6% of human muscle protein; among plant protein isolates it ranges from 5.1% in hemp to 13.5% in corn 11.
EssentialHumans have no pathway to build it. The international requirement for adults is 39 mg per kilogram per day 4; isotope studies put young men at about 34 and adults over 60 at about 78 5,10.
In the bottle · nature-identicalCommercial L-leucine is made by bacterial fermentation, principally with engineered strains of Corynebacterium glutamicum fed on sugar; the product is the same L isomer the body uses 9.
What the body does with it
Most leucine goes into protein. What makes it unusual is that it is also read as information. The mTORC1 complex, a protein kinase that decides whether a cell has enough raw material to grow, is held off by a protein called Sestrin2. Leucine binds Sestrin2 and releases that brake, with a binding strength of about 20 micromolar, which is the same concentration at which leucine half-activates mTORC1 3. A second leucine sensor, SAR1B, was reported in 2021 and appears to do the same job by a different route 12. Arginine is sensed separately; leucine is the amino acid the growth switch listens to most closely.
That is the mechanism behind the muscle story. In older adults, an essential amino acid drink built like whey protein (26% leucine) failed to raise muscle protein synthesis, while the same drink enriched to 41% leucine did 13. In young men, adding leucine to a small 6.25 g dose of whey made it perform almost like a 25 g dose over the hours after exercise 14. From experiments like these came the leucine trigger idea: that the size of the leucine spike after a meal decides how much muscle is built.
The idea has not held up as neatly as it was sold. A systematic review in 2021 found repeated disconnects between blood leucine curves and the actual rate of muscle protein synthesis, with whole foods and older adults behaving differently from isolated proteins 15. And in a 2023 tracer study, 100 g of protein produced a larger and longer anabolic response than 25 g, with no upper limit in sight, which is hard to square with a fixed leucine threshold that, once crossed, is spent 16.
Leucine and its breakdown products also act on insulin secretion and on metabolism more widely, and these signalling roles are the subject of active research rather than settled physiology 17. One breakdown product, β-hydroxy-β-methylbutyrate, known as HMB, is sold as a supplement in its own right 18.
In three sentences each
A sensor, not a fuel gauge
Sestrin2 holds mTORC1 off until leucine binds it, with a dissociation constant of about 20 micromolar, which is also the concentration at which leucine half-activates the pathway 3. A second sensor, SAR1B, was described in 2021 12.
Past the liver untouched
The liver has little of the enzyme that starts branched-chain breakdown, so most dietary leucine escapes first-pass metabolism and reaches muscle, where breakdown begins 1.
Ketogenic only
Its carbon skeleton ends as acetyl-CoA and acetoacetate, a ketone body, never as glucose. Only leucine and lysine are purely ketogenic 1.
How it is made, moved and broken down
Breakdown starts in muscle rather than in the liver. The first enzyme, branched-chain aminotransferase, moves leucine’s amino group onto another molecule and leaves a keto acid; the liver has little of it, so dietary leucine largely escapes the liver on its first pass and is handled by muscle first 1.
The second step is the one that matters. A large enzyme complex in the mitochondrion, branched-chain α-ketoacid dehydrogenase, irreversibly commits the keto acid to being burned. It is switched off by a kinase, BCKDK, which adds a phosphate to it, and switched back on by a phosphatase, PPM1K, which removes it 19,20. Isotope tracing in mice shows most tissues burn branched-chain amino acids quickly, muscle, brown fat, liver, kidney and heart in the greatest quantities, and the pancreas takes a fifth of the carbon for its central energy cycle from them 20; those are mouse data.
From there leucine’s path is its own. It ends as acetoacetate and acetyl-CoA, which can feed the citric acid cycle or become ketone bodies but cannot be turned back into glucose. That makes leucine, with lysine, one of only two purely ketogenic amino acids 1.
Carbon skeleton · ketogenicBreakdown ends in acetyl-CoA and acetoacetate, so leucine can make ketone bodies but never glucose 1.
- Leucine
- Branched-chain aminotransferaseBCAT2 · vitamin B6 (PLP)
- α-Ketoisocaproate
- BCKDH complexBCKDHA, BCKDHB, DBT · thiamine, lipoate
- Isovaleryl-CoA
- Isovaleryl-CoA dehydrogenaseIVD · FAD
- 3-Methylcrotonyl-CoA
- 3-Methylcrotonyl-CoA carboxylaseMCCC1, MCCC2 · biotin
- 3-Methylglutaconyl-CoA
- Hydratase, then HMG-CoA lyaseAUH, HMGCL
- HMG-CoA → acetoacetate
- BCKDH, active
- BCKDH kinaseBCKDK · ATP
- BCKDH, phosphorylated (off)
- Mitochondrial phosphatasePPM1K
- BCKDH, active
How it crosses membranes
- SLC7A5 · LAT1the blood–brain barrier, placenta and many tumours — the large neutral amino acid carrier, shared with tryptophan and tyrosine, so a large dose of leucine lowers their entry into the brain 21
Where it matters most
- Skeletal muscle
- Where breakdown begins and where most branched-chain amino acid is burned, and the tissue whose protein synthesis leucine most visibly switches on 1,13,20.
- Liver
- Largely bypassed on first pass, because it has little branched-chain aminotransferase; it then completes the oxidation of the keto acids that muscle sends back 1,20.
- Brain
- Leucine competes with tryptophan and tyrosine for the same carrier at the blood–brain barrier, so a large dose lowers serotonin and dopamine synthesis 21.
- Pancreas
- In mice it takes about 20% of the carbon feeding its citric acid cycle from branched-chain amino acids 20.
When it goes wrong
Inherited
Maple syrup urine disease
BCKDHA, BCKDHB, DBT · autosomal recessive
The branched-chain keto acid dehydrogenase complex is missing or weak, so leucine, isoleucine and valine accumulate; classic disease presents in the first days of life with poor feeding, a maple-syrup smell in urine and ear wax, and brain injury if untreated 6. Lifelong diet keeps the numbers acceptable but does not fully prevent cognitive and psychiatric disability, which is why classic disease is still described as morbid and potentially fatal 7. Liver transplantation corrects the levels within hours and raised leucine tolerance more than tenfold in one series; it arrests brain damage but does not reverse it, and the removed liver can be given safely to someone without the disease 22.
How it is foundNewborn screening, then plasma amino acids and alloisoleucine above 5 µmol/L 2,6,23.
Inherited
Isovaleric acidaemia
IVD · autosomal recessive
The third step of leucine breakdown fails and isovaleric acid accumulates. It was the first organic acidaemia recognised in humans and can cause severe crises, yet a common variant found by newborn screening, A282V, usually stays symptom-free 24. Treatment is protein restriction with carnitine and glycine, which carry the acid out 24,25.
How it is foundRaised isovalerylcarnitine (C5) on newborn screening; isovalerylglycine in urine 25.
Inherited
3-Methylcrotonyl-CoA carboxylase deficiency
MCCC1, MCCC2 · autosomal recessive
A biotin-dependent step of leucine breakdown fails. In 88 people, 57% had no symptoms, a number of mothers were found only because their baby screened positive, yet twelve had acute metabolic crises; neither the genes nor the biochemistry predicted who 26.
How it is foundNewborn screening by acylcarnitine profile, then genetic testing 26.
Biomarker
Type 2 diabetes and insulin resistance
PPM1K region
High branched-chain amino acids predict diabetes in people who are not yet diabetic 27, and gene variants that impair their breakdown raise risk, odds ratio 1.85 per standard deviation of leucine 19. Mendelian randomisation also shows insulin resistance raising them 28,29, and a four-week low-branched-chain diet in type 2 diabetes changed insulin secretion after meals without changing insulin sensitivity measured by clamp 30.
How it is foundResearch measure only; no clinical test of branched-chain amino acids for diabetes risk is in routine use.
Drug
Hepatic encephalopathy
Branched-chain amino acid supplements are used in cirrhosis. A Cochrane review of 16 trials found they improved hepatic encephalopathy (risk ratio 0.73) with no effect on mortality, and they increased nausea and vomiting 31.
How it is foundA clinical diagnosis; no amino acid test guides the supplement.
How it is measured
Leucine is almost never measured on its own. It is reported inside a plasma amino acid profile, and the method matters: ion-exchange chromatography with ninhydrin detection is still the commonest reference method, liquid chromatography with mass spectrometry is the newer one, and the flow-injection mass spectrometry used for newborn screening is considered inadequate to diagnose anyone 32.
- Plasma amino acidsThe full profile by ion-exchange chromatography or liquid chromatography with mass spectrometry, ordered to investigate a suspected metabolic disease or monitor one 32.The test a metabolic clinic actually orders, because it separates the isomers that screening cannot 32.The reference method for leucine, isoleucine and valine, which it separates cleanly 32.A non-fasting sample reflects the last meal, and intravenous nutrition raises all three branched-chain amino acids in newborns 2.
- Newborn screening by tandem mass spectrometryA heel-prick blood spot analysed in seconds without separation, which reports leucine, isoleucine, alloisoleucine and hydroxyproline together as one peak 2.Fast and cheap enough to test every baby, which is its purpose; it flags, it does not diagnose 32.It cannot tell the four isomers apart, so a raised peak needs a second-tier test, and a baby on intravenous nutrition can screen falsely positive 2.
- Plasma alloisoleucineA by-product of isoleucine that healthy people barely make. Above 5 µmol/L it is the diagnostic marker of maple syrup urine disease 23.In classic disease it exceeded the cut-off in 2,451 of 2,453 samples; healthy adults run about 1.9 µmol/L 23.Variant, milder forms can sit closer to the line between crises 23.
Food, supplements and the evidence
Establishedreplicated in people, for a named outcome
- In people with cirrhosis, branched-chain amino acid supplements improve the manifestations of hepatic encephalopathy, without reducing deaths 31.
- Acutely, adding leucine to a small dose of protein raises the rate of muscle protein synthesis after exercise 14, and enriching an amino acid drink with leucine restores the response in older adults 13.
Uncertainsmall, short, mixed, surrogate or preclinical
- Whether acute effects become muscle: 7.5 g of leucine a day with meals for three months did not increase muscle mass or strength in healthy older men 33.
- HMB, leucine’s metabolite: an umbrella review found small gains in muscle mass (effect size 0.21) 18, while a 2026 meta-analysis in adults over 50 doing resistance training found no added benefit 34.
- Whether older adults need roughly twice the current leucine recommendation, as one isotope study suggests, awaits replication 5.
- In mice, high branched-chain diets cause overeating and shorter life through amino acid imbalance rather than direct toxicity; this is preclinical 35.
Sold asthe claim on the label, against the evidence
- “BCAAs build muscle on their own.” No human study has measured muscle protein synthesis after oral branched-chain amino acids alone, and in the two intravenous studies they lowered muscle protein turnover, because the other essential amino acids are missing 36.
- “Your body can only use 20 to 30 grams of protein at a time.” 100 g produced a larger and longer anabolic response than 25 g, with no upper limit found 16.
- “BCAA drinks prevent fatigue.” The central fatigue idea, that branched-chain amino acids lower brain serotonin and so delay tiredness, has produced effects that are modest at best 21.
What is strange about it
Pellagra, the skin, gut and brain disease of niacin deficiency, was endemic among people in Hyderabad whose staple grain was sorghum, and by the 1970s the proposed culprit was the grain’s high leucine. In volunteers, extra leucine disturbed the tryptophan-to-niacin pathway in a way vitamin B6 corrected 37. Rats fed extra leucine did not reproduce it 38. As of 2026 the hypothesis has neither been confirmed nor quite gone away.
Raised blood levels of the branched-chain amino acids predict type 2 diabetes years before it arrives, with more than a fivefold risk in the top quarter 27. Whether they help cause it is genuinely disputed. Genetic variants that slow their breakdown raise diabetes risk 19, but genetic variants that raise insulin resistance raise branched-chain amino acid levels, and not the other way round 28,29. The two readings are not mutually exclusive, and the field has not settled which arrow is the thicker one.
Where it connects
In the Atlas
Topics on the map
On the map
A star in The essential amino acids, one of 14. The one amino acid that is also a signal: it activates mTORC1 directly through Sestrin2, which is why it and not protein in general triggers muscle synthesis.
Sources
38 sources, numbered as they are cited. Every one was checked against PubMed or its publisher before it was cited here; the note under each says what it shows and what it does not.
- 1Brosnan JT, Brosnan ME. Branched-chain amino acids: enzyme and substrate regulation.doi:10.1093/jn/136.1.207S · PMID 16365084
Review: BCAAs as structural residues, first-pass escape and the shared first steps of breakdown.
- 2Oglesbee D, Sanders KA, Lacey JM, et al. Second-tier test for quantification of alloisoleucine and branched-chain amino acids in dried blood spots to improve newborn screening for maple syrup urine disease (MSUD).doi:10.1373/clinchem.2007.098434 · PMID 18178665
Screening MS/MS cannot separate the isobars; an LC–MS/MS second tier identified all 16 MSUD patients.
- 3Wolfson RL, Chantranupong L, Saxton RA, et al. Sestrin2 is a leucine sensor for the mTORC1 pathway.doi:10.1126/science.aab2674 · PMID 26449471
Leucine binds Sestrin2 (Kd ~20 µM) and so activates mTORC1; in cultured cells.
- 4Joint WHO/FAO/UNU Expert Consultation. Protein and amino acid requirements in human nutrition.PMID 18330140
The international requirement figures, including 39 mg/kg/day for leucine in adults.
- 5Szwiega S, Pencharz PB, Rafii M, et al. Dietary leucine requirement of older men and women is higher than current recommendations.doi:10.1093/ajcn/nqaa323 · PMID 33330915
Indicator amino acid oxidation in 16 adults over 60: mean requirement 78.5 mg/kg/day. Small study; one method.
- 6Blackburn PR, Gass JM, Vairo FPE, et al. Maple syrup urine disease: mechanisms and management.doi:10.2147/TACG.S125962 · PMID 28919799
Clinical review: presentation, alloisoleucine as the pathognomonic marker, screening and treatment.
- 7Strauss KA, Carson VJ, Soltys K, et al. Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): treatment, biomarkers, and outcomes.doi:10.1016/j.ymgme.2020.01.006 · PMID 31980395
184 patients over three decades: diet does not fully prevent cognitive and psychiatric disability.
- 8Landschulz WH, Johnson PF, McKnight SL. The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins.doi:10.1126/science.3289117 · PMID 3289117
The paper that named the leucine zipper, from a leucine at every seventh position in several transcription factors.
- 9Reifenberg P, Zimmer A. Branched-chain amino acids: physico-chemical properties, industrial synthesis and role in signaling, metabolism and energy production.doi:10.1007/s00726-024-03417-2 · PMID 39198298
Review including industrial production with Corynebacterium glutamicum.
- 10Szwiega S, Pencharz PB, Xu L, et al. Leucine requirement determined in healthy young adult males using the indicator amino acid oxidation method.doi:10.1016/j.ajcnut.2024.08.022 · PMID 39209155
Ten young men: mean requirement 33.6 mg/kg/day (95% CI 26.2–41.0).
- 11Gorissen SHM, Crombag JJR, Senden JMG, et al. Protein content and amino acid composition of commercially available plant-based protein isolates.doi:10.1007/s00726-018-2640-5 · PMID 30167963
Measured leucine content of animal and plant protein sources by UPLC–MS/MS.
- 12Chen J, Ou Y, Luo R, et al. SAR1B senses leucine levels to regulate mTORC1 signalling.doi:10.1038/s41586-021-03768-w · PMID 34290409
A second leucine sensor acting on GATOR2; cells, nematodes and mice.
- 13Katsanos CS, Kobayashi H, Sheffield-Moore M, et al. A high proportion of leucine is required for optimal stimulation of the rate of muscle protein synthesis by essential amino acids in the elderly.doi:10.1152/ajpendo.00488.2005 · PMID 16507602
Acute tracer study: 41% leucine EAA restored muscle protein synthesis in older adults; 26% did not.
- 14Churchward-Venne TA, Breen L, Di Donato DM, et al. Leucine supplementation of a low-protein mixed macronutrient beverage enhances myofibrillar protein synthesis in young men: a double-blind, randomized trial.doi:10.3945/ajcn.113.068775 · PMID 24284442
Forty young men; 6.25 g whey plus leucine approached 25 g whey over 1.5–4.5 h. Acute, not long term.
- 15Zaromskyte G, Prokopidis K, Ioannidis T, et al. Evaluating the leucine trigger hypothesis to explain the post-prandial regulation of muscle protein synthesis in young and older adults: a systematic review.doi:10.3389/fnut.2021.685165 · PMID 34307436
Qualitative systematic review finding disconnects between blood leucine and muscle protein synthesis.
- 16Trommelen J, van Lieshout GAA, Nyakayiru J, et al. The anabolic response to protein ingestion during recovery from exercise has no upper limit in magnitude and duration in vivo in humans.doi:10.1016/j.xcrm.2023.101324 · PMID 38118410
Quadruple-tracer study: 100 g protein gave a larger and longer (>12 h) anabolic response than 25 g.
- 17Neinast M, Murashige D, Arany Z. Branched chain amino acids.doi:10.1146/annurev-physiol-020518-114455 · PMID 30485760
Review of BCAA catabolism and signalling, including insulin secretion.
- 18Bideshki MV, Behzadi M, Jamali M, et al. Ergogenic benefits of β-hydroxy-β-methyl butyrate (HMB) supplementation on body composition and muscle strength: an umbrella review of meta-analyses.doi:10.1002/jcsm.13671 · PMID 39797501
Eleven meta-analyses: small increases in muscle mass (ES 0.21) and strength.
- 19Lotta LA, Scott RA, Sharp SJ, et al. Genetic predisposition to an impaired metabolism of the branched-chain amino acids and risk of type 2 diabetes: a Mendelian randomisation analysis.doi:10.1371/journal.pmed.1002179 · PMID 27898682
Variants near PPM1K that raise BCAAs raise diabetes risk; leucine OR 1.85 per SD.
- 20Neinast MD, Jang C, Hui S, et al. Quantitative analysis of the whole-body metabolic fate of branched-chain amino acids.doi:10.1016/j.cmet.2018.10.013 · PMID 30449684
Isotope tracing in mice: which tissues burn BCAAs, and the effect of BCKDK suppression. Mouse data.
- 21Fernstrom JD. Large neutral amino acids: dietary effects on brain neurochemistry and function.doi:10.1007/s00726-012-1330-y · PMID 22677921
Competition at the blood–brain barrier: BCAAs lower brain tryptophan and tyrosine uptake; performance effects modest at best.
- 22Mazariegos GV, Morton DH, Sindhi R, et al. Liver transplantation for classical maple syrup urine disease: long-term follow-up in 37 patients and comparative United Network for Organ Sharing experience.doi:10.1016/j.jpeds.2011.06.033 · PMID 21839471
Transplant corrected BCAAs within hours; brain damage arrested but not reversed; domino recipients well.
- 23Schadewaldt P, Bodner-Leidecker A, Hammen HW, et al. Significance of L-alloisoleucine in plasma for diagnosis of maple syrup urine disease.PMID 10508118
Reference values and the 5 µmol/L cut-off; above it in 2,451 of 2,453 samples from classic MSUD.
- 24Vockley J, Ensenauer R. Isovaleric acidemia: new aspects of genetic and phenotypic heterogeneity.doi:10.1002/ajmg.c.30089 · PMID 16602101
The first organic acidaemia described; the mild A282V variant found by screening.
- 25Thimm E, Riederer A, Vockley J, et al. Practical considerations for the diagnosis and management of isovaleryl-CoA-dehydrogenase deficiency (isovaleric acidemia): systematic search and review and expert opinions.doi:10.3390/ijns11040092 · PMID 41133704
Current consensus statements on diagnosis and management, including C5-carnitine and isovalerylglycine.
- 26Grünert SC, Stucki M, Morscher RJ, et al. 3-methylcrotonyl-CoA carboxylase deficiency: clinical, biochemical, enzymatic and molecular studies in 88 individuals.doi:10.1186/1750-1172-7-31 · PMID 22642865
Most people found by screening stayed well; a minority had severe crises.
- 27Wang TJ, Larson MG, Vasan RS, et al. Metabolite profiles and the risk of developing diabetes.doi:10.1038/nm.2307 · PMID 21423183
In 2,422 normoglycaemic people followed 12 years, BCAAs and aromatic amino acids predicted diabetes; association, not causation.
- 28Mahendran Y, Jonsson A, Have CT, et al. Genetic evidence of a causal effect of insulin resistance on branched-chain amino acid levels.doi:10.1007/s00125-017-4222-6 · PMID 28184960
Mendelian randomisation: insulin-resistance variants raise BCAAs; BCAA-raising variants did not raise insulin resistance.
- 29Wang Q, Holmes MV, Davey Smith G, et al. Genetic support for a causal role of insulin resistance on circulating branched-chain amino acids and inflammation.doi:10.2337/dc17-1642 · PMID 29046328
Mendelian randomisation in large consortia supporting insulin resistance as a cause of raised BCAAs.
- 30Karusheva Y, Koessler T, Strassburger K, et al. Short-term dietary reduction of branched-chain amino acids reduces meal-induced insulin secretion and modifies microbiome composition in type 2 diabetes: a randomized controlled crossover trial.doi:10.1093/ajcn/nqz191 · PMID 31667519
Four weeks: lower meal-induced insulin secretion; clamp insulin sensitivity unchanged.
- 31Gluud LL, Dam G, Les I, et al. Branched-chain amino acids for people with hepatic encephalopathy.doi:10.1002/14651858.CD001939.pub4 · PMID 28518283
Sixteen trials, 827 people: benefit on encephalopathy (RR 0.73), none on mortality; more nausea and vomiting.
- 32Sharer JD, De Biase I, Matern D, et al. Laboratory analysis of amino acids, 2018 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG).doi:10.1038/s41436-018-0328-6 · PMID 30459394
The laboratory standard: methods, indications, and why flow-injection MS/MS is inadequate for diagnosis.
- 33Verhoeven S, Vanschoonbeek K, Verdijk LB, et al. Long-term leucine supplementation does not increase muscle mass or strength in healthy elderly men.doi:10.3945/ajcn.2008.26668 · PMID 19321567
Thirty men, 7.5 g/day for three months: no change in mass, strength or glycaemic control.
- 34Wang G, Jawed I, Tufail M, et al. Efficacy of HMB supplementation as an adjunct to resistance training in older adults: a comprehensive meta-analysis.doi:10.1093/ageing/afag073 · PMID 41934514
Thirteen trials, 561 participants over 50: no added effect on muscle mass, strength or fat.
- 35Solon-Biet SM, Cogger VC, Pulpitel T, et al. Branched chain amino acids impact health and lifespan indirectly via amino acid balance and appetite control.doi:10.1038/s42255-019-0059-2 · PMID 31656947
Mice: high-BCAA diets caused overeating and shorter lifespan through amino acid imbalance. Preclinical.
- 36Wolfe RR. Branched-chain amino acids and muscle protein synthesis in humans: myth or reality?doi:10.1186/s12970-017-0184-9 · PMID 28852372
Review: no human study of oral BCAAs alone on muscle protein synthesis; infused BCAAs lowered turnover.
- 37Krishnaswamy K, Rao SB, Raghuram TC, et al. Effect of vitamin B6 on leucine-induced changes in human subjects.doi:10.1093/ajcn/29.2.177 · PMID 1251810
Volunteer study behind the leucine–pellagra hypothesis; vitamin B6 corrected the leucine effects.
- 38Cook NE, Carpenter KJ. Leucine excess and niacin status in rats.doi:10.1093/jn/117.3.519 · PMID 2952774
Rats given excess leucine did not support the leucine–pellagra hypothesis.
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