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Title: Glutathione synthesis is diminished in patients with uncontrolled diabetes and restored by dietary supplementation with cysteine and glycine

Author
item SEKHAR, RAJAGOPAL - Baylor College Of Medicine
item MCKAY, SIRIPOOM - Baylor College Of Medicine
item PATEL, SANJEET - Baylor College Of Medicine
item GUTHIKONDA, ANURADHA - Baylor College Of Medicine
item REDDY, VASUMATHI - Baylor College Of Medicine
item BALASUBRAMANYAM, ASHOK - Baylor College Of Medicine
item JAHOOR, FAROOK - Children'S Nutrition Research Center (CNRC)

Submitted to: Diabetes Care
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/30/2010
Publication Date: 1/3/2011
Citation: Sekhar, R.V., Mckay, S.V., Patel, S.G., Guthikonda, A.P., Reddy, V.T., Balasubramanyam, A., Jahoor, F. 2011. Glutathione synthesis is diminished in patients with uncontrolled diabetes and restored by dietary supplementation with cysteine and glycine. Diabetes Care. 34(1):162-167.

Interpretive Summary: Patients with diabetes eventually become sicker because of damage to their nerves, eyes and kidneys. Diabetics usually have a high amount of glucose in their blood and this excess glucose is converted into poisonous compounds called oxidants. It is believed that over time oxidants attack the tissues of these organs damaging them. In healthy individuals the amount of oxidants produced is rendered harmless by another compound called glutathione that is made in the cells of the body. In the past we have shown that diabetics do not produce enough glutathione to nullify the amount of oxidants that they were making. We also know that glutathione is made in cells from three other compounds called glutamate, glycine and cysteine. Because we believed that the diabetics were not making enough glutathione because of a shortage of cysteine and glycine, we supplemented their diets with these two compounds for two weeks. After receiving the dietary supplements, the diabetics started making more glutathione and there was far less damage to their tissues.

Technical Abstract: Sustained hyperglycemia is associated with low cellular levels of the antioxidant glutathione (GSH), which leads to tissue damage attributed to oxidative stress. We tested the hypothesis that diminished GSH in adult patients with uncontrolled type 2 diabetes is attributed to decreased synthesis and measured the effect of dietary supplementation with its precursors cysteine and glycine on GSH synthesis rate and oxidative stress. We infused 12 diabetic patients and 12 nondiabetic control subjects with [2H2]-glycine to measure GSH synthesis. We also measured intracellular GSH concentrations, reactive oxygen metabolites, and lipid peroxides. Diabetic patients were restudied after 2 weeks of dietary supplementation with the GSH precursors cysteine and glycine. Compared with control subjects, diabetic subjects had significantly higher fasting glucose (5.0 +/- 0.1 vs. 10.7 +/- 0.5 mmol/l; P < 0.001), lower erythrocyte concentrations of glycine (514.7 +/- 33.1 vs. 403.2 +/- 18.2 umol/l; P < 0.01), and cysteine (25.2 +/- 1.5 vs. 17.8 +/- 1.5 umol/l; P < 0.01); lower concentrations of GSH (6.75 +/- 0.47 vs. 1.65 +/- 0.16 umol/g Hb; P < 0.001); diminished fractional (79.21 +/- 5.75 vs. 44.86 +/- 2.87%/day; P < 0.001), and absolute (5.26 +/- 0.61 vs. 0.74 +/- 0.10 umol/g Hb/day; P < 0.001) GSH synthesis rates; and higher reactive oxygen metabolites (286 +/- 10 vs. 403 +/- 11 Carratelli units [UCarr]; P < 0.001), and lipid peroxides (2.6 +/- 0.4 vs. 10.8 +/- 1.2 pg/ml; P < 0.001). Following dietary supplementation in diabetic subjects, GSH synthesis and concentrations increased significantly and plasma oxidative stress and lipid peroxides decreased significantly. Patients with uncontrolled type 2 diabetes have severely deficient synthesis of glutathione attributed to limited precursor availability. Dietary supplementation with GSH precursor amino acids can restore GSH synthesis and lower oxidative stress and oxidant damage in the face of persistent hyperglycemia.