Isoleucine

Isoleucine is an amino acid, one of the building blocks of protein. The WHO (World Health Organization), the US National Academies and EFSA (the EU’s food safety agency) all list it as essential, or indispensable. That means food has to supply it.

It has the same chemical formula as leucine, and that is where its name comes from. The German chemist Felix Ehrlich found it in 1903 in sugar beet molasses, as a second form of leucine. With leucine and valine it makes up the branched-chain amino acids (BCAAs). They are named for the forked shape of their side chains.

Isoleucine is not the starting material for a hormone or a brain signal. Apart from going into protein, what the body makes from it is fuel. Muscle and other tissues break it down in two steps into acetyl-CoA and propionyl-CoA. The National Academies call the BCAAs both ketogenic (they can become ketone bodies) and glucogenic (they can become glucose).

Here is what most readers do not know. Adult hemoglobin, the oxygen carrier in red blood cells, contains no isoleucine at all. It is the only amino acid missing from it. So the malaria parasite, which digests hemoglobin for food, has to take isoleucine from the blood instead.

Also, although isoleucine is essential, nobody has measured the adult need directly. The WHO’s 20 mg per kg a day was calculated from the leucine figure. In practice it hardly matters, because 1 cup of soybeans holds 1.39 g. That is about the WHO figure for a 70 kg adult (our arithmetic).

Health benefits of isoleucine

• ★★Less muscle soreness after hard exerciseIn 18 trials in healthy, active people, BCAA blends eased soreness from 24 to 96 hours after exercise, but not right after. These blends contain leucine, isoleucine and valine, so the result is not for isoleucine alone.
• ★★Possibly less hepatic encephalopathy in cirrhosisIn 934 adults with cirrhosis, fewer on BCAA blends had no improvement in hepatic encephalopathy (liver-related brain problems; 0.79 times the risk). The evidence is low certainty, and deaths did not differ.
• ★★Higher muscle index, but no clear strength gainIn 12 trials of older adults with muscle loss (sarcopenia) who did resistance training, BCAA-rich supplements raised skeletal muscle index. Grip strength, walking speed and lean mass did not change clearly.
• ★Mixed effects on blood sugar after a drinkIsoleucine (10 g placed in the stomach before a sugary drink) lowered peak blood sugar in two small trials of healthy people. It did not in 14 men with type 2 diabetes, nor in 12 adults given 0.3 g per kg of lean body mass.
• ★More muscle protein building after a BCAA drinkIn 10 trained men, a 5.6 g BCAA drink after leg exercise raised muscle protein synthesis by 22% over 4 hours. A 2024 review adds that this is smaller than after a complete protein.

Foods high in isoleucine

Soybeans lead our USDA ranking per serving: 1 cup (172 g) holds 1.39 g. Chicken breast follows with 1.25 g in 4 oz, then a chicken drumstick (1.11 g) and a can of sardines (1.04 g). Per 100 g, hemp seeds (1.29 g) and pumpkin seeds (1.28 g) come first, then sunflower seeds (1.14 g).

Per 100 kcal, cod (1 g), tuna (0.98 g) and chicken breast (0.92 g) lead. Two vegetables also make that list: bok choy (0.65 g) and spinach (0.64 g). The ranking below shows the full lists.

Isoleucine is in every protein, so a diet with enough protein has enough isoleucine. The National Academies list 63 mg per g of protein in eggs, 60 in milk, 42 in navy beans and 40 in whole wheat flour. So plant proteins hold somewhat less than animal ones. All of them sit above the WHO’s adult requirement pattern of 30 mg per g of protein.

PDCAAS is a score of protein quality. In it, the National Academies’ reference level for isoleucine is 25 mg per g of protein. The WHO also compared food proteins with its requirement pattern. The BCAAs as a group scored 115% of the pattern in cassava and 120% or more in every other protein and diet.

The WHO names lysine, not isoleucine, as the amino acid cereals fall short of. By our arithmetic, 1 cup of soybeans (1.39 g) gives 99% of the WHO figure of 1.4 g for a 70 kg adult. Chicken breast gives 89% in 4 oz (1.25 g), and a can of sardines (1.04 g) gives 74%.

How isoleucine works

Most of what follows comes from reviews, biochemistry, lab work with parasites and cells, and animal studies. Human trials of isoleucine on its own are few, and they are on the cards above.

The main ideas: isoleucine is built into protein and burned for fuel, and it shares enzymes and carriers with leucine and valine. It acts on blood sugar differently from leucine, its blood level tracks metabolic health, and one parasite depends on it. Here is each, and then what has been seen in people.

It is built into protein, and some is burned for fuel

Most of the body’s isoleucine sits in protein, at 35 mg per g of whole-body protein in the WHO’s tissue pattern. The part that is broken down follows a route unlike most amino acids. The first enzymes are found mainly outside the liver, with skeletal muscle as the starting site, according to the National Academies and a 2018 review.

First, an enzyme called branched-chain aminotransferase turns isoleucine into its keto acid, α-keto-β-methylvalerate (KMV). This step can run backward. Then the branched-chain keto acid dehydrogenase complex (BCKD), found in the mitochondria, takes it apart for good into acetyl-CoA and propionyl-CoA.

Propionyl-CoA ends up as succinyl-CoA, which can be turned into glucose. Acetyl-CoA can go to ketone bodies. So isoleucine is both glucogenic and ketogenic.

It shares enzymes and carriers with leucine and valine

All three BCAAs go through the same two enzymes, so a lot of one can crowd out the others. They also compete with other large neutral amino acids, especially tryptophan and tyrosine. They compete for the carriers that move amino acids into cells and across the blood-brain barrier. In rats, brain tryptophan falls as the ratio of tryptophan to the other large neutral amino acids, BCAAs included, falls.

Also in rats on low-protein diets, the growth stunting caused by a high-leucine diet could be prevented by giving isoleucine and valine. In older adults, adding 3 g of leucine to 20 g of an essential amino acid mix lowered blood isoleucine by 16%. Its keto acid KMV fell by 22%. Whether any of this matters for people who eat enough protein has not been shown.

It acts on blood sugar differently from leucine

Single doses of free isoleucine changed the blood sugar response in some small trials. Ten grams placed in the stomach lowered the rise in glucose after a mixed drink in healthy volunteers, without raising insulin. Leucine, by contrast, raised insulin. In men with type 2 diabetes, the same dose did nothing.

In another trial isoleucine raised the gut hormone GIP, but GIP did not follow insulin or glucose. Mice show more. A low-isoleucine diet, but not a low-leucine one, raised liver insulin sensitivity, ketone production and energy use, and restored metabolic health in obese animals.

In a randomized trial in people, a moderate protein-restricted diet improved metabolic markers. In mice, a diet low only in BCAAs matched its effect on glucose tolerance and body composition. We found no trial of a low-isoleucine diet in people.

A high blood level is a warning sign, and a cause is not proven

Blood BCAAs are higher in people with type 2 diabetes and obesity. In a study of 2,422 people free of diabetes, blood levels of five amino acids predicted who developed diabetes over the next 12 years. They were isoleucine, leucine, valine, tyrosine and phenylalanine.

Genetic analysis of about 250,000 people suggests that high BCAA levels mostly follow poor metabolic health rather than cause it. It also points to a possible effect on triglycerides and HDL cholesterol. A 2018 review says lower BCKD activity helps explain higher BCAA levels in diabetes and obesity. It adds that it is not known whether the amino acids are only markers.

Diet adds to the puzzle. In three US cohorts, a higher intake of isoleucine went with more type 2 diabetes. In a Spanish cohort, BCAA intake did not.

The malaria parasite needs it from the blood

Isoleucine is the only amino acid missing from adult human hemoglobin. The malaria parasite Plasmodium falciparum lives inside red blood cells and digests hemoglobin for amino acids. So it has to take isoleucine from outside the cell. Infected cells took up isoleucine about 5 times faster than healthy cells, through channels the parasite adds to the cell membrane.

When isoleucine was removed from the culture medium, the parasite slowed its metabolism and stayed viable for 72 hours. It resumed rapid growth when isoleucine came back. This is lab work with cultured parasites, and we found no trial of changing isoleucine intake in people with malaria.

When the breakdown is blocked: maple syrup urine disease

In maple syrup urine disease (MSUD), the BCKD complex is low or missing. The National Academies describe very high blood BCAAs, especially leucine. The disorder can be diagnosed in newborns, is associated with intellectual disability and even early death, and is treated by tight dietary control of BCAAs.

That diet can push isoleucine and valine too low, so doctors also give targeted isoleucine and valine supplements. Low isoleucine can cause a skin rash (see the cards above). The disease is named for the sweet smell of the urine. A 1999 study traced the smell to sotolone, a compound also found in fenugreek, lovage and maple syrup.

What has been seen in people

The firmest human findings are about blends, not isoleucine. Blends led to fewer unimproved cases of hepatic encephalopathy in cirrhosis and to less soreness after hard exercise. They also gave a short-lived rise in muscle protein building, smaller than after a complete protein.

Isoleucine on its own lowered the blood sugar rise in two small trials of healthy people, but not in a third. It did not lower it in type 2 diabetes either. A BCAA blend did not slow ALS, and lung function fell faster.

The link between BCAAs and diabetes is consistent for blood levels and mixed for intake. The diet experiments that excite researchers have so far been done only in mice.

How much isoleucine do you need?

Adults need about 20 mg of isoleucine per kg of body weight a day, according to the WHO, FAO and UN University (2007). That is about 1,400 mg for a 70 kg adult. The US National Academies (2005) set a lower average requirement of 15 mg per kg for adults 19 and older. Their recommended allowance (the amount that covers nearly everyone) is 19 mg per kg, about 1,330 mg for a 70 kg adult.

Neither is a direct measurement. The site has no Daily Value for isoleucine, because neither the FDA nor the EU has set one.

Source	Requirement (mg per kg a day)	For a 70 kg adult	Notes
WHO/FAO/UNU 2007, adults	20	1,400 mg	Average requirement, 30 mg per g of protein. No reliable direct data exist: the report estimated it from the leucine requirement (39 mg per kg). It adds 24% for a safe level, about 25 mg per kg (our arithmetic). The same pattern is used for older adults.
NASEM 2005, adults 19 and older, EAR	15	1,050 mg	No direct measurement in adults. Calculated from the protein requirement and multiplied by 1.55, the average ratio for leucine and valine.
NASEM 2005, adults 19 and older, RDA	19	1,330 mg	EAR plus 24% (1.24 times the EAR, rounded).
NASEM 2005, pregnancy	20 (EAR), 25 (RDA)	1,400 mg (EAR), 1,750 mg (RDA)	Essentially no data. The EAR for nonpregnant women times 1.33.
NASEM 2005, breastfeeding	24 (EAR), 30 (RDA)	1,680 mg (EAR), 2,100 mg (RDA)	Adds the isoleucine secreted in human milk to the adult EAR.

Children need more per kg of body weight because they are growing. The WHO gives 36 mg per kg a day at 6 months, 27 at 1 to 2 years and 23 at 3 to 10 years. It gives 22 at 11 to 14 years and 21 at 15 to 18 years, against 20 for adults.

The National Academies’ recommended allowance is 43 mg per kg at 7 to 12 months and 28 at 1 to 3 years. It is 22 at 4 to 8 years, then 22 for boys and 21 for girls at 9 to 13 years. At 14 to 18 years it is 21 for boys and 19 for girls.

For babies up to 6 months they set an adequate intake of 88 mg per kg a day (529 mg a day). It is based on human milk. An adequate intake is a target used when the data are too thin for an allowance.

Indicator amino acid tracer studies measured all three BCAAs together and gave 110 to 134 mg per kg a day. That is higher than the 85 that the WHO’s separate figures add up to (39 + 20 + 26, our arithmetic). The WHO says more work is needed in this area.

Most people eat well above these figures. In US survey data from 1988 to 1994, the mean intake of isoleucine from food and supplements across all groups was 3.6 g a day. The 99th percentile for men aged 51 to 70 was 8.2 g, according to the National Academies. By our arithmetic, 3.6 g is about 2.6 times the WHO figure for a 70 kg adult.

Isoleucine deficiency: signs and who is at risk

A shortfall from diet alone is not known in people who eat enough protein, and we found no report of one. The National Academies note that healthy full-term infants fed only human milk show no signs of amino acid or protein deficiency. The setting where low isoleucine is documented is maple syrup urine disease.

The strict BCAA-limited diet can push blood isoleucine too low. In a review of 20 reported patients, mostly infants, low isoleucine went with a scaly, eroded rash around the mouth, hands and feet. It improved when isoleucine was given. That is why people with the disease take measured isoleucine and valine supplements.

Blood BCAA levels also change in illness. The National Academies say these imbalances appear to result from the diseases, not cause them. A 2018 review reports low BCAA levels in liver cirrhosis, because muscle uses BCAAs to clear ammonia. It reports high levels in maple syrup urine disease, type 2 diabetes and obesity.

Forms of isoleucine: absorption and effects

Isoleucine is sold as the free amino acid, most often inside BCAA blends and essential amino acid mixes. It is also bound in the protein of food. Isoleucine has four possible stereoisomers, the same atoms arranged differently in space. Only one is the natural form found in proteins, and that is the one sold.

Unlike minerals, there is no list of forms with known absorption rates. We found no human trial that compared free isoleucine with isoleucine from food protein for any health outcome. Nor did we find a trial that compared one form of an isoleucine supplement with another.

The honest bottom line: the trials that gave isoleucine alone used a single dose of the free amino acid. The ones with a health outcome used blends of three, so what the blend does is not what isoleucine does. A blend’s ratio matters too, since extra leucine lowered blood isoleucine in older adults.

The ratio sold most often is 2:1:1, which means 2 parts leucine to 1 each of isoleucine and valine. So isoleucine is a quarter of the blend (our arithmetic). A 2024 review found that BCAAs alone raise the rate of muscle protein building less than a complete protein does.

Form	What it is	What studies show	Source
Free L-isoleucine (powder, capsules, ready-to-use liquid)	The single amino acid, not bound in protein	5 g and 10 g placed in the stomach of 12 healthy volunteers: 10 g lowered the blood sugar rise after a drink, 5 g did not. 10 g did nothing for blood sugar in 14 men with type 2 diabetes. A liquid form was well tolerated in 5 children with maple syrup urine disease and a lower dose was needed. No trial compared it with isoleucine from protein.	2, 3, 4
BCAA blends (leucine, isoleucine, valine; often 2:1:1)	Free amino acids mixed, isoleucine about a quarter in 2:1:1	Most supplement trials. 5.6 g raised muscle protein building 22% in 10 men, 100 mg per kg a day of a 2:1:1 blend helped 20 older adults in a pilot, and a blend with 8 g of isoleucine a day for six months did not help in ALS. The cirrhosis trials in the Cochrane review gave BCAAs by mouth or by vein. None of these results belongs to isoleucine alone.	5, 6, 7, 8
Essential amino acid (EAA) mixes	All nine essential amino acids, free	In 11 older adults, 3 g of leucine added to 20 g of an EAA mix lowered blood isoleucine by 16%. A 2024 review says BCAAs alone raise muscle protein building less than a complete protein.	9, 10
Isoleucine in food protein	Bound in protein, 40 to 63 mg per g in the foods the National Academies list	Food covers the requirement without supplements (see Foods high in isoleucine). We found no human study that compared how fast or how much isoleucine is absorbed from protein and from the free form.	1, 14
Keto acid of isoleucine (KMV) and ketoanalogue mixes	The product of the first breakdown step; sold in mixed keto acid products	The body makes KMV from isoleucine. Mixed keto acid products with a low-protein diet in advanced kidney disease were tested in 16 trials with 1,344 participants and gave a higher filtration rate and lower urea nitrogen and phosphorus. The abstract does not list which keto acids were used, and we found no trial of the isoleucine keto acid alone.	1, 11
4-Hydroxyisoleucine (fenugreek extract)	A related amino acid from fenugreek, not a form of isoleucine	Blood levels peaked within half an hour of a 150 mg dose in 12 healthy volunteers. Effects on blood sugar were simulated, not measured in people.	12

Here are the studies that compare forms or test a related product, strongest evidence first, three in all.

Is isoleucine safe? Supplements, dose and interactions

Isoleucine from food is not a concern. The US National Academies set no tolerable upper intake level (the most you can take each day without likely harm) for isoleucine or for BCAAs. It found no adequate dose-response data from people or animals.

It found no reports of harm from normal diets, nor from healthy people given single infused BCAA doses as high as 9.75 g. But it called those studies highly limited, because most used one dose and none checked function.

We found no EFSA upper level for isoleucine, and EFSA’s 2012 opinion on protein says the data are not sufficient to set one for protein. For scale, the National Academies put mean US isoleucine intake from food and supplements at 3.6 g a day. At the 99th percentile for men aged 51 to 70, it was 8.2 g.

• Doses and side effects. Trials gave 10 g of isoleucine as a single dose. A trial in people with ALS gave 8 g a day inside a BCAA blend for six months. A trial in older adults gave 100 mg per kg a day of a 2:1:1 blend for 8 weeks. The ALS trial called the amino acids well tolerated, but lung function fell faster on the blend. In the Cochrane review of cirrhosis, nausea and diarrhea were reported in 12% on BCAAs against 3% on diets, with very low certainty. These are single studies’ doses, not official limits.
• Animal findings. In a 13-week rat study, 2.5% of the diet (about 1,800 mg per kg a day) caused no change. At 8%, urine volume and kidney weight rose. Isoleucine and leucine promoted bladder tumors in rats first given a cancer-causing chemical, at 2% and 4% of the diet, and neither caused tumors alone. The National Academies judged that such two-stage rat data cannot reliably assess human risk. Pregnant rats on a low-protein diet with 5% isoleucine had lighter fetuses than pair-fed controls. No study has tested oral BCAAs in human pregnancy.
• Brain amino acids and medicines. BCAAs compete with tryptophan and tyrosine for entry into the brain. In rats this lowered the brain’s supply, though the National Academies call its relevance to people uncertain. Dietary protein, through the amino acids it releases, can reduce the absorption of levodopa, a Parkinson’s disease drug. We found no study of isoleucine pills and levodopa.
• Conditions. BCAA supplements are unsuitable in maple syrup urine disease, where BCAA intake must be severely limited. A 2018 review says new strategies are needed to avoid adverse effects of BCAAs on ammonia production in cirrhosis and urea cycle disorders. A BCAA blend did not help in ALS, and higher intake has been linked with diabetes in some cohorts.
• Who should ask a doctor. Anyone who is pregnant or breastfeeding, has diabetes, kidney or liver disease, ALS, Parkinson’s disease, or an inherited metabolic disorder, or takes levodopa.

How to get more isoleucine

• Best food. One cup of soybeans gives 1.39 g, 4 oz of chicken breast 1.25 g and a can of sardines 1.04 g. Per 100 g, hemp seeds lead with 1.29 g.
• Eat enough protein from varied foods. Eggs hold 63 mg of isoleucine per g of protein, milk 60, navy beans 42 and whole wheat flour 40. All are above the WHO pattern of 30, so isoleucine is rarely the amino acid to plan around. The WHO flags lysine in cereals.
• Skip single isoleucine pills. No trial shows a health benefit for healthy people, and the blood sugar results come from one-time doses that did nothing in diabetes. BCAA blends eased soreness in a meta-analysis, but they contain leucine and valine too.

History of isoleucine

Isoleucine was found in 1903 by the German chemist Felix Ehrlich. He was studying the makeup of sugar beet molasses, a by-product of sugar making. His 1908 paper calls it the natural isomer of leucine and notes that four stereoisomers are possible. It says the natural form was first obtained from beet molasses.

In 1907 he showed that it also occurs in proteins, among them fibrin, egg albumin, gluten and beef muscle. The French chemists Bouveault and Locquin reported a synthetic version in 1905.

How much people need was long a guess. The first adult figure from the FAO and WHO, in 1973 and 1985, was 10 mg per kg a day. It was derived from 700 mg a day in a 1957 review of adult amino acid requirements by W. C. Rose.

A recalculation of old nitrogen balance data gave about 18. The WHO’s 2007 report set 20, calculated from leucine because no reliable direct measurement exists.

Maple syrup urine disease took its name from the sweet smell of patients’ body fluids. Only in 1999 did a study identify the compound, sotolone, in the urine of seven patients and not in healthy controls. Sotolone also gives fenugreek its smell. In 2001, doctors reported newborns whose mothers had eaten fenugreek during labor. The babies smelled of maple syrup, which led to a false suspicion of the disease.

Frequently asked questions about isoleucine

Is isoleucine good for you?

Yes, you need it: the body cannot make isoleucine, and the WHO, the US National Academies and EFSA all list it as indispensable. Food covers it easily: mean US intake from food and supplements was 3.6 g a day. By the WHO figure, a 70 kg adult needs about 1.4 g (our arithmetic). Extra isoleucine from pills has not been shown to help healthy people, because the trials are small, single-dose, or tested blends.

What is the difference between isoleucine and leucine?

They have the same chemical formula but a different shape, and the body treats them differently. By the WHO figures, adults need about 20 mg of isoleucine per kg a day against 39 mg of leucine. In 12 healthy volunteers, 10 g of leucine raised insulin, while 10 g of isoleucine lowered the blood sugar rise without raising it. In mice, a low-isoleucine diet improved metabolic health while a low-leucine diet did not.

How many grams of isoleucine is enough in a day?

About 1.4 g for a 70 kg adult by the WHO figure of 20 mg per kg (our arithmetic). The National Academies’ allowance of 19 mg per kg gives 1.33 g (our arithmetic). Needs per kg are higher in children (27 mg at 1 to 2 years by the WHO). The National Academies’ allowance is 25 mg per kg in pregnancy and 30 while breastfeeding. Nobody has measured the adult need directly, since both figures were calculated from leucine. Mean US intake is about 2.6 times the WHO figure (our arithmetic).

Which foods are highest in isoleucine?

Soybeans lead our USDA ranking per serving, with 1.39 g per cup. Chicken breast follows (1.25 g in 4 oz), then a chicken drumstick (1.11 g) and a can of sardines (1.04 g). Per 100 g, hemp seeds lead with 1.29 g, then pumpkin seeds (1.28 g), sunflower seeds (1.14 g) and sardines (1.13 g). Per 100 kcal, cod (1 g), tuna (0.98 g) and chicken breast (0.92 g) come first.

Does isoleucine lower blood sugar?

In healthy people a single large dose did in some small trials, but not in type 2 diabetes. A 10 g dose lowered the rise in blood sugar after a mixed drink in 12 healthy volunteers and in 15 healthy men. Yet in 14 men with type 2 diabetes, peak glucose was 12.0 mmol/L on both isoleucine and control. No long-term trial exists. In three US cohorts a higher isoleucine intake went with more diabetes (1.13 times the risk). A Spanish cohort found no link for BCAAs combined. So it is not a treatment.

Are BCAA supplements worth taking?

For most people who eat enough protein, the evidence for a benefit is thin. A meta-analysis of 18 trials found less soreness after hard exercise. In 12 trials of older adults with sarcopenia, only skeletal muscle index rose. In cirrhosis, BCAAs lowered the risk of unimproved hepatic encephalopathy with low certainty. BCAA blends hold leucine and valine as well, so no result belongs to isoleucine alone.

Do vegans get enough isoleucine?

Probably yes: whole wheat flour and navy beans hold 40 and 42 mg of isoleucine per g of protein. The WHO adult pattern is 30 mg per g, and the WHO names lysine, not isoleucine, as the amino acid cereals lack. One cup of soybeans gives 1.39 g. We found no study that measured isoleucine status in vegans.

Does isoleucine have side effects?

At food amounts none are expected, and the National Academies set no upper limit because the data are not adequate. Trials gave 10 g as a single dose, and 8 g a day inside a BCAA blend for six months. People with ALS tolerated the blend, though their lung function fell faster. In a Cochrane review, nausea and diarrhea were reported in 12% on BCAAs against 3% on diets, with very low certainty. People with maple syrup urine disease must limit BCAAs.