Methylsuccinic acid

Optimal Result: 0.13 - 2.14 mmol/mol.

Methylsuccinic acid is a normal metabolite found in human fluids and is an intermediate metabolite in the breakdown of fatty acids. Increased urinary levels of methylsuccinic acid (together with ethylmalonic acid) are the main biochemical measurable features in ethylmalonic encephalopathy.


Urpi-Sarda M, Almanza-Aguilera E, Llorach R, Vázquez-Fresno R, Estruch R, Corella D, Sorli JV, Carmona F, Sanchez-Pla A, Salas-Salvadó J, Andres-Lacueva C. Non-targeted metabolomic biomarkers and metabotypes of type 2 diabetes: A cross-sectional study of PREDIMED trial participants. Diabetes Metab. 2019 Apr;45(2):167-174. doi: 10.1016/j.diabet.2018.02.006. Epub 2018 Feb 20. PMID: 29555466.

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What does it mean if your Methylsuccinic acid result is too low?

Low levels of methylsuccinate can occur if there are low levels of precursors (ethylmalonate), if there are nutritional enzyme inhibitions, or if a low-activity enzyme variant is inherited.

Methylsuccinate is taken up by pancreatic beta-cells to stimulate the release of insulin. Methylsuccinate uptake by the pancreas and other cells may protect against mitochondrial damage from biguanide medications (metformin, etc.) often given to diabetic patients.

Methylsuccinate, like ethylmalonate, is primarily derived from branch-chain fatty acids. Low levels of branch-chain fatty acids (dairy, beef) may result in lower methylsuccinate levels.

→ Consider supporting methylsuccinate synthesis with adenosyl-cobalamin (B12), biotin, magnesium, and L-carnitine. Increasing healthy fats or proteins in the diet may also increase methylmalonate levels. If B-12 is deficient, methylmalonate and ethylmalonate may be high.

→ Methylmalonate is derived primarily from the amino acid valine. If alpha- ketoisovalerate is high, there may be a downstream block that prevents the formation of methylmalonate, and levels may be lower than expected even if there is a vitamin B-12 deficiency present.

→ Succinate cannot be methylated if there are enzyme inhibitions that prevent the synthesis of methyl groups. Problems on the methylation pathway may increase levels of ethylmalonate, methylmalonate, 5-hydroxyindoleacetate and decrease levels of homovanillate and vanilmandelate.

What does it mean if your Methylsuccinic acid result is too high?

Increased levels of methylsuccinate may occur when there are nutritional enzyme inhibitions of the breakdown pathways, inherited low-activity enzymes are present, or if there are high levels of precursors (ethylmalonate).

Methylsuccinate is normally taken up by pancreatic beta-cells where it stimulates insulin release; high levels may indicate a problem with the pancreas or with cellular uptake mechanisms.

Obesity may increase methylsuccinate levels. If liver beta-oxidation of fatty acids is impaired methylsuccinate can increase. Mobilization of stored body fat during fasting or calorie restriction may also increase ethylmalonate and methylsuccinate levels. High- fat or -protein diets, or the use of branch-chain amino acid supplements, may also increase methylmalonate levels.

→ Consider supporting liver beta-oxidation with vitamins B2, B3, iron (if deficient), L-carnitine, sulforaphane and resveratrol. Low activity enzyme variants may benefit from a lower protein or lower fat diet. If using a high-protein diet or branch-chain amino acids consider vitamins B1, B2, B3, B6, and lipoic acid to support their breakdown.

→ Type II diabetes or metabolic syndrome can increase suberate, adipate, alpha-hydroxybutyrate, lactate, and pyruvate.

→ Phthalate exposures can inhibit liver beta-oxidation and increase levels of adipate, suberate, ethylmalonate, and methylsuccinate. 

Increased urinary levels of methylsuccinic acid (together with ethylmalonic acid) are the main biochemical measurable features in ethylmalonic encephalopathy, a rare metabolic disorder with an autosomal recessive mode of inheritance that is clinically characterized by neuromotor delay, hyperlactic acidemia, recurrent petechiae, orthostatic acrocyanosis, and chronic diarrhea. The underlying biochemical defect involves isoleucine catabolism. 

Other inborn errors:

Moreover, methylsuccinic acid is found to be associated with isovaleric acidemia, and medium-chain acyl-CoA dehydrogenase deficiency, which are also inborn errors of metabolism.

High Methylsuccinic levels may also be due to:

- carnitine deficiency, 
- fasting, 
- increased intake of the medium-chain triglycerides found in coconut oil, MCT oil, and some infant formulas. 

Regardless of cause, supplementation with L-carnitine or acetyl-L-carnitine (500-1000 mg per day) may be beneficial.

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