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.
There are no known clinical associations with low levels of α-hydroxybutyric acid.
All of the conditions associated with increased 2-Hydroxybutyric acid (aka α-Hydroxybutyrate) excretion may be related to increased rates of hepatic glutathione synthesis from methionine. Elevated 2-Hydroxybutyric acid thus shows increased flow through the hepatic glutathione synthesis pathway as required during times of increased oxidative stress or for detoxification functions.
- Smoking, poor diet, and lack of exercise significantly inhibit the activity of AHBD (=Alpha-Hydroxybutyrate dehydrogenase catalyzes oxidation of AHB to acetate), suggesting that urinary elevation of Alpha-Hydroxybutyrate may be related to these factors via increased glutathione demand.
- High 2-Hydroxybutyric acid is also found during phases of increased lymphocyte destruction in infectious diseases such as measles.
- Elevated 2-Hydroxybutyric acid is found in birth asphyxia and in inherited metabolic diseases such as “cerebral” lactic acidosis, glutaric aciduria type II, dihydrolipoyl dehydrogenase deficiency, and propionic acidemia.
- 2-Hydroxybutyric acid is also an early marker for both insulin resistance and impaired glucose regulation that appears to arise due to increased lipid oxidation and oxidative stress.
- Elevated levels of 2-Hydroxybutyric acid in the plasma is a good marker for early-stage type II diabetes.
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