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.

References:

- Dorcely B, Katz K, Jagannathan R, et al. Novel biomarkers for prediabetes, diabetes, and associated complications. Diabetes Metab Syndr Obes. 2017;10:345-361.

- Gall WE, Beebe K, Lawton KA, et al. alpha-hydroxybutyrate is an early biomarker of insulin resistance and glucose intolerance in a nondiabetic population. PloS one. 2010;5(5):e10883.

- Paolisso G, Giugliano D, Pizza G, et al. Glutathione infusion potentiates glucose-induced insulin secretion in aged patients with impaired glucose tolerance. Diabetes Care. 1992;15(1):1-7.

- Landaas S, Pettersen JE. Clinical conditions associated with urinary excretion of 2-hydroxybutyric acid. Scand J Clin Lab Invest. 1975;35(3):259-266.