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

Abstract

OBJECTIVESustained 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.RESEARCH DESIGN AND METHODSWe 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.RESULTSCompared 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.CONCLUSIONSPatients 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.

Associations of FPG, A1C and disease duration with protein markers of oxidative damage and antioxidative defense in type 2 diabetes and diabetic retinopathy

“…Our findings are in accordance with previous studies in DM [17][18][19][20][21] and DR patients. 11 However, we could not find reports on both IMA and GSH simultaneously in DM and DR patients.…”

“…12 Moreover, GSH may be utilized as an antioxidant to neutralize excess FR generated in diabetes. Although GSH deficiency has been reported in diabetes, 21 no previous study has reported its relationship to IMA in both DM and DR patients. Could the lower levels of GSH be a result of elevated IMA values, with a greater utilization of GSH as an antioxidant?…”

“…Recent evidence suggests that increasing GSH levels with oral precursor supplementation is a viable antioxidant intervention to target diabetic OS directly and could constitute a novel, safe, and inexpensive form of nutritional treatment. 21 Diabetes remained to be a leading cause of blindness, and OS is an important mechanism whereby diabetes attributes to associated complications like DR. Therefore, in addition to standard glycemic management, IMA and GSH might be considered for evaluation in monitoring OS injury in diabetes and DR.…”

“…Several studies reported a decline in GSH concentrations in diabetes. 20,21 The mechanisms underlying decreased GSH in diabetes are hyperglycemia-associated metabolic disturbances, abnormal protein balance, and inadequate GSH synthesis leading to OS. 7,20 In line with this, we observed a negative association between FPG and GSH, as hyperglycemia could per se influence oxidant-antioxidant homeostasis.…”

“…Although decreased levels of GSH were reported in diabetes, the cause of GSH deficiency is still unclear. 20,21 Moreover, to the best of our knowledge, there are no reports that have evaluated IMA and GSH in relation to hyperglycemia, glycated hemoglobin (A1C), and disease duration in both diabetes and DR (literature was mined by PubMed search using MeSH terms diabetes, diabetic retinopathy, free radicals, reactive oxygen species, oxidative stress, albumin, ischemia modified albumin, and glutathione).…”