THE EFFECT OF TYPE 2 DIABETES AND AGING ON GLUTATHIONE SYNTHESIS AND OXODATIV

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Type 2 Diabetes Melitus (T2DM) and the aging process are associated with increased oxidative stress. Both these populations have lower concentrations of glutathione (GSH), a major component of antioxidant defenses, but the mechanisms responsible remain unknown. Glutathione depletion in these groups could result from increased consumption, or diminished synthesis secondary to a shortage of glycine and cysteine (precursor amino acids). On the basis of preliminary data evaluating antioxidant GSH defenses, we hypothesize that (1) Diabetics and the elderly have lower GSH concentrations than younger healthy controls due to decreased synthesis; (2) The lower synthetic rate is due to decreased precursor availability of cysteine and glycine; (3) Dietary Cysteine and glycine supplementation will replenish the GSH pool by increased synthesis, thereby decreasing oxidative stress in the young healthy; young with T2DM; elderly healthy; and elderly with T2DM. We propose a randomized trial with the following aims: (1) Measure cyteine, glycine and leucine kineticws, glutathione synthetic rate in erythrocytes and leukocytes, and plasma markers of oxidant damage and antioxidant capacity, in four groups of 10 subjects each; and (2) Determine the effect of dietary cysteine, glycine, and cysteine plus glycine supplementation on GSH synthesis and concentration, and markers of oxidant damage and antioxidant capacity, in the same four groups. The proposed studies will investigate, for the first time, the mechanism responsible for GSH depletion and its relationship to the metabolism of cyteine and glycine, and thus dtermine mechanisms associated with antioxidant consequences of GSH depletion common to both diabetes and aging, such as cataracts, retinopathy, nephropathy, peripheral vascular disease and coronary artery disease. Additionally, the dietary inteventions may contribute new approaches to the management of diabetic patients and the elderly in a way that will restore GSH homeostasis, theeby preventing complications associated with an impaired antioxidant status.