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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。2型糖尿病（T2 DM）和衰老过程与氧化应激增加有关。这两个群体都有较低浓度的谷胱甘肽（GSH），抗氧化防御的主要组成部分，但负责的机制仍然未知。这些组中的谷氨酸耗尽可能是由于消耗增加或继发于甘氨酸和半胱氨酸（前体氨基酸）短缺的合成减少。根据评估抗氧化剂GSH防御的初步数据，我们假设：（1）糖尿病患者和老年人由于合成减少，GSH浓度低于年轻健康对照组;（2）合成速率降低是由于半胱氨酸和甘氨酸前体可用性降低;（3）饮食中补充半胱氨酸和甘氨酸将通过增加合成来补充GSH库，从而降低年轻健康者的氧化应激;年轻T2 DM患者;健康老年人;和老年T2 DM患者。我们提出一项随机试验，目的如下：（1）测定四组受试者（每组10人）的半胱氨酸、甘氨酸和亮氨酸的动力学、红细胞和白细胞谷胱甘肽合成率以及血浆氧化损伤和抗氧化能力的标志物;和（2）测定饮食半胱氨酸、甘氨酸和半胱氨酸加甘氨酸补充对GSH合成和浓度的影响，以及氧化损伤和抗氧化能力的标志物。拟议的研究将首次调查GSH耗竭的机制及其与半胱氨酸和甘氨酸代谢的关系，从而确定与糖尿病和衰老常见的GSH耗竭的抗氧化后果相关的机制，如白内障，视网膜病，肾病，外周血管疾病和冠状动脉疾病。此外，饮食干预可能有助于新的方法来管理糖尿病患者和老年人的方式，将恢复GSH稳态，通过预防与受损的抗氧化状态相关的并发症。

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.