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.
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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.
- Check your serum homocysteine levels. If elevated disruptions in methylation ability or genetic SNPs in the CBS pathway (when homocysteine is broken down to create cysteine) should be explored. If the homocysteine value is low/normal, there is a need to explore the possibility of toxic exposure since the CBS pathway is upregulated. In cases of elevated 2HB and increased ketones or lactic acid (markers 43/44 and 22 on the OAT), also consider further testing regarding blood sugar regulation. At the very least, with this marker elevated, we know there is oxidative damage. Antioxidant support can be added to mitigate the stress as we explore all the possibilities of why it is elevated.
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