Glutathione Utilization and Glutathione Depletion in Adolescents With Poorly Controlled Type 1 Diabetes
Dominique Darmaun12, Shiela D. Smith1, Shawn Sweeten1, Brenda K. Sager1, Susan Welch1 and Nelly Mauras1
1Endocrine Research Department, Nemours Children’s Clinic, Jacksonville, Florida
2Human Nutrition Research Center, Institut National de la Santé et de la Recherche Médicale (INSERM) U.539, Nantes, France
Address correspondence and reprint requests to Dominique Darmaun, MD, PhD, Nemours Children’s Clinic, Research Department, 5 North, 807 Children’s Way, Jacksonville, FL 32207. E-mail: email@example.com
Depletion of glutathione, an important antioxidant present in red cells, has been reported in type 1 diabetes, but the mechanism of this depletion has not been fully characterized. Glutathione depletion can occur through decreased synthesis, increased utilization, or a combination of both. To address this issue, 5-h infusions of l-[3,3-2H2]cysteine were performed in 16 diabetic adolescents divided into a well-controlled and a poorly controlled group and in eight healthy nondiabetic teenagers as control subjects (HbA1c 6.3 ± 0.2, 10.5 ± 0.6, and 4.8 ± 0.1%, respectively). Glutathione fractional synthesis rate was determined from 2H2-cysteine incorporation into blood glutathione. We observed that 1) erythrocyte cysteine concentration was 41% lower in poorly controlled patients compared with well-controlled patients (P = 0.009); 2) erythrocyte glutathione concentration was ∼29% and ∼36% lower in well-controlled and poorly controlled patients compared with healthy volunteers; and 3) the fractional synthesis rate of glutathione, although similar in well-controlled and healthy subjects (83 ± 14 vs. 82 ± 11% per day), was substantially higher in the poorly controlled group (141 ± 23% per day, P = 0.038). These findings suggest that in diabetic adolescents, poor control is associated with a significant depletion of blood glutathione and cysteine, due to increased rates of glutathione utilization. This weakened antioxidant defense may play a role in the pathogenesis of diabetes complications.