α-hydroxybutyric acid (2-hydroxybuturic acid [2-HB]) is a marker that relates to oxidative stress. 2-HB is an organic acid produced from α-ketobutyrate via the enzymes lactate dehydrogenase (LDH) or α-hydroxybutyrate dehydrogenase (HBDH). These enzymes are catalyzed by NADH. Oxidative stress creates an imbalance in NADH/NAD ratios, which leads directly to the production of 2-HB. Being that 2-HB’s precursor α-ketobutyrate is a byproduct in the glutathione (GSH) synthesis pathway, an increased demand for GSH may ultimately result in increased 2-HB. Increased oxidative stress associated with insulin resistance increases the rate of hepatic glutathione synthesis. Plasma 2-HB is highly associated with insulin resistance and may be an effective biomarker for prediabetes.
A study on type 2 diabetics showed that GSH infusion restored the NADH/NAD balance and resulted in improvement of insulin sensitivity and beta cell function.
Decreased urinary alpha-hydroxybutyrate levels if:
→ Protein-calorie malnutrition
→ Phthalate exposure
Low levels of keto-acid alpha-hydroxybutyrate may occur if there are low levels of precursors (amino acids), if there are nutritional enzyme inhibitions, or if a low-activity enzyme variant is inherited. Under normal conditions alpha-hydroxybutyrate levels are inversely associated with insulin sensitivity and impaired glucose regulation. Low levels of precursor may occur if there is a vitamin B6 deficiency or a problem on the pathway that converts cystathionine into cysteine; such patients may also have low glutathione levels. Low levels may also occur if there is an inhibition of the enzyme that interconverts lactate and pyruvate.
→ Consider supporting alpha-hydroxybutyrate and cysteine synthesis with vitamin B6. Poor cysteine synthesis can result in low glutathione levels. Urinary pyroglutamate levels will be elevated if there are problems with glutathione metabolism. Arsenic exposure will inhibit this effect and decrease pyroglutamate levels. Arsenic may also increase pyruvate and alpha-ketoglutarate while it decreases citrate and other Citric Acid Cycle metabolites.
→ Support the interconversion of pyruvate and lactate with vitamin B3.
→ Phthalate exposures can inhibit the enzyme that interconverts pyruvate and lactate.
Increased urinary alpha-hydroxybutyrate levels with:
→ Biotin deficiency
→ Ketosis or lactic acidosis
→ Respiratory chain defects
→ Type II diabetes
→ Increased gut permeability
Elevated levels of alpha-hydroxybutyrate may occur when there are nutritional enzyme inhibitions of the breakdown pathways, inherited low-activity enzymes are present, if there are high levels of precursors (amino acids), or if there are high levels of oxidative stress. Levels of alpha-hydroxybutyrate are associated with insulin sensitivity; higher levels are found in those with metabolic syndrome or type II diabetes when glycemic control is lost. Low biotin levels have been associated with both higher levels of alpha-hydroxybutyrate and insulin dysregulation. Microbial breakdown of the precursor amino acids in the gut may also increase levels. The use of amino acid supplements, methionine supplements, or a high-protein diet may also increase alpha- hydroxybutyrate levels.
→ High levels of methylmalonate, quinolinate and pyroglutamate, with low levels of cis-aconitate and isocitrate may also indicate oxidative stress. Consider antioxidant supports. Antioxidant supports may include resveratrol, CoQ10, alpha-lipoic acid, vitamins C and E, curcumin, etc. Fresh fruits and vegetables are rich in antioxidant compounds.
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