Glutathione Synthesis Is Diminished in Patients With Uncontrolled Diabetes and Restored by Dietary Supplementation With Cysteine and Glycine [2010](IR93)

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Glutathione Synthesis Is Diminished in Patients With Uncontrolled Diabetes and Restored by Dietary Supplementation With Cysteine and Glycine [2010](IR93) - full text

http://care.diabetesjournals.org/content/34/1/162.full
http://www.ncbi.nlm.nih.gov/pubmed/20929994

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Published online before print October 7, 2010, doi: 10.2337/dc10-1006 Diabetes Care January 2011 vol. 34 no. 1 162-167

Glutathione Synthesis Is Diminished in Patients With Uncontrolled Diabetes and Restored by Dietary Supplementation With Cysteine and Glycine

Rajagopal V. Sekhar, MD1,2, Siripoom V. McKay, MD3,4, Sanjeet G. Patel, MD1,2, Anuradha P. Guthikonda, MD1,2, Vasumathi T. Reddy, PHD1,2, Ashok Balasubramanyam, MD1,2 and
Farook Jahoor, PHD3,4

- Author Affiliations

1Translational Metabolism Unit, Baylor College of Medicine, Houston, Texas; 2Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, Texas; 3Department of Pediatrics, Baylor College of Medicine, Houston, Texas; 4Children's Nutrition Research Center, Agriculture Research Service, U.S. Department of Agriculture, Baylor College of Medicine, Houston, Texas. Corresponding author: Rajagopal V. Sekhar, rsekhar@bcm.edu.

Abstract

OBJECTIVE
Sustained hyperglycemia (高血糖血症) 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.

RESEARCH DESIGN AND METHODS
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.

RESULTS
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 μmol/l; P < 0.01), and cysteine (25.2 ± 1.5 vs. 17.8 ± 1.5 μmol/l; P < 0.01); lower concentrations of GSH (6.75 ± 0.47 vs. 1.65 ± 0.16 μmol/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 μmol/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.

CONCLUSIONS
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 (高血糖血症).

Diabetes is the leading worldwide cause of blindness (失明), end-stage renal disease (終末期腎臟疾病), and amputations (截肢). Diabetes also is associated with an elevated risk of macrovascular complications including myocardial ischemia and strokes. Although multiple pathways are involved in mediating tissue damage, including the polyol pathway, advanced glycation end product formation, protein kinase C activation, and the hexosamine pathway, a common feature is increased oxidative stress marked by elevated levels of reactive oxygen species (ROS) (1). The ability of a cell to resist damage caused by oxidative stress is determined by the capacity of an array of antioxidant defense systems, among which reduced glutathione (GSH) is the most ubiquitous and abundantly available within human cells. GSH is a tripeptide synthesized from glutamate, cysteine, and glycine in two steps catalyzed by γ-l-glutamyl-l-cysteine:glycine ligase and glutathione synthetase. Diabetes is associated with decreased cellular glutathione concentrations (2–5), but the cause of GSH deficiency currently is unknown. Oxidative stress and ROS formation are markedly increased by uncontrolled hyperglycemia (高血糖血症) (2,6); conversely, lowering blood glucose concentrations lowers oxidative stress (7,8). Decreased oxidative stress could be an important mechanism whereby glycemic control diminishes the incidence of diabetic microvascular complications (9,10). However, there are practical limitations to blunting oxidative stress through glycemic control alone, despite strenuous attempts to implement evidence-based guidelines, a majority of patients are unable to achieve the glycemic goals (e.g., A1C <7 advocated="" american="" and="" as="" association="" blindness="" by="" cause="" clear="" complications="" consequently="" control="" despite="" diabetes="" excellent="" for="" glycemic="" landmark="" leading="" message="" need="" of="" prospective="" regarding="" remains="" span="" study="" such="" the="" trial="" trials="" uk="">失明), renal failure, and amputations (截肢). There is an urgent need for novel strategies to reduce the rate of diabetes complications in patients unable to achieve stable glycemic control. We therefore investigated whether oxidative stress associated with low levels of GSH could be ameliorated through the alternative strategy of increasing cellular GSH levels in diabetic patients with uncontrolled hyperglycemia (高血糖血症). Because circulating concentrations of a protein depend on the balance between its rates of production and consumption, we hypothesized that GSH deficiency in uncontrolled diabetes occurs because of diminished synthesis. We further hypothesized that short-term dietary supplementation of two key amino acid precursors of GSH, glycine and cysteine, would increase intracellular GSH synthesis and concentrations and thus lower oxidative stress, despite continuing hyperglycemia (高血糖血症). To test these hypotheses, we used stable isotope (同位素) methods to compare GSH synthesis rates and concentrations within erythrocytes, as well as plasma markers of oxidant damage, in adult patients with poorly controlled type 2 diabetes matched to nondiabetic control subjects. The diabetic patients were studied before and after 14 days of dietary supplementation with cysteine and glycine.

RESEARCH DESIGN AND METHODS

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