Glutathione Metabolism in Adolescents With Type 1 Diabetes - Study A

Glutathione is normally present at high (millimolar) levels in blood and plays an important role in the body's defense against oxidative stress, that is, against the damage caused to the body by reactive oxygen species produced by the metabolism of most nutrients, including glucose. Glutathione is a small peptide made from 3 amino acids, glutamate, cysteine, and glycine. This study is looking at how blood sugar levels may affect the way glutathione is made and used by the body. Since glutathione is continuously synthesized and broken down, the amount of glutathione present in blood depends on the balance between its rate of synthesis and its rate of use. In earlier studies, the investigators found that in poorly controlled diabetic teenagers, glutathione was low, not because its production was decreased, but because it was used at an excessive rate. In this study, the investigators want to determine how short-term changes in blood sugar levels affect glutathione levels. This will help improve our understanding of how diabetes affects metabolism.

Adolescents with uncomplicated T1D will receive two, 5-hour infusions of deuterium-labeled cysteine on 2 separate days, a few weeks apart, while blood glucose will be maintained, using intravenous insulin infusion: in the hyper-glycemic range (200-250 mg/dL) on one study day, and near normoglycemia (80-140 mg/dL) on the other study day. The order of the study days will be randomized. We will determine whether the level of blood glucose at the time of study affects blood glutathione concentration, and, if so, whether this is associated with changes in the fractional rate of glutathione synthesis, as determined from the incorporation of labeled cysteine into blood glutathione over the course of the 5-hr infusion of labeled cysteine.

Regular insulin, IV, as needed to maintain blood glucose in near-normoglycemic range (80-140 mg/dL) or hyperglycemic range (200-250 mg/mL) during metabolic studies

Up to 30 minutes post- 5 hour infusion on Day 1 (First Intervention) and up to 30 minutes post- 5 hour infusion on Day 14 (Second Intervention)

Inclusion Criteria: Type 1 diabetes, using usual criteria such as: glycosuria, hyperglycemia prior to treatment BMI <25 kg/m2 Age 14-18 HbA1c>7.5% No evidence of diabetic complications Written informed consent from parents or legal guardian, and assent from patient Exclusion Criteria: Presence of significant anemia (hemoglobin <11g/dL) Presence of intercurrent illness such as infection Presence of chronic disease such as other endocrine deficiency, chronic respiratory or cardiac disease Chronic use of medication other than insulin Use of vitamin or mineral supplements within 2 weeks of study