XAFS STUDIES OF METAL ANTI-DIABETIC SUPPLEMENTS AND DRUGS

金属抗糖尿病补充剂和药物的 XAFS 研究

• 批准号: 7954532
• 负责人: PETER A LAY
• 金额: $ 0.02万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7954532
• 关键词: Antidiabetic Drugs; Biochemical Pathway; Biodistribution; Biological; Blood Glucose; Cells; Chromium; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Developed Countries; Developing Countries; Diabetes Mellitus; Exhibits; Funding; Generations; Grant; Incidence; Institution; Link; Metabolic Diseases; Metals; Muscle; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Process; Property; Relative Risks; Research; Research Personnel; Resources; Role; Source; Techniques; Testing; United States National Institutes of Health; base; beamline; chromium hexavalent ion; design; diabetic; dietary supplements; oligomycin sensitivity-conferring protein; oxidation; structural biology; synchrotron radiation; uptake

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 is a metabolic disorder characterised by an inability to control blood glucose concentrations. It is strongly linked to obesity, with the greatest incidence of diabetes occurring in the most developed countries. While phosphatase inhibition is the generally accepted mechanism to explain the anti-diabetic effects of V complexes there is much more controversy associated with the role of Cr supplements, and considerable debate still surrounds the exact mode of action, biodistribution and the functions associated with their efficacies. Chromium dietary supplements are the second most popular metal supplements after Ca supplements and are taken for their purported activities as anti-diabetic, slimming and muscle-building capacities. However, the efficacy in anti-diabetic effects is only observed at relatively high concentrations of supplements and we have demonstrated that these generate appreciable amounts of carcinogenic Cr(VI) both intra- and extra-cellularly and in a manner that appears to be dependent on the nature of the supplement. To study Cr speciation in bulk cells with XANES, third generation beamlines are required because of the low uptake of some common supplements. The use of such techniques will enable us to in ascertain whether the biological oxidations observed to date are common to all of the Cr supplements or just certain types. This may be important in assessing their relative risks. We will also investigate the anti-diabetic properties of V complexes that are in clinical trials or are promising candidates for trials. In particular, we will test our hypothesis that V exhibits these properties via the V(V) oxidation states or peroxo species generated by intracellular processes via similar biochemical pathways to those we have investigated in Cr. In doing so, we anticipate that we will be able to design safer and more effective metal-based anti-diabetic drugs.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 2型糖尿病是一种代谢紊乱，其特征是无法控制血糖浓度。它与肥胖密切相关，在最发达国家糖尿病发病率最高。虽然磷酸酶抑制是普遍接受的机制来解释V络合物的抗糖尿病作用，但与铬补充剂的作用相关的争议要多得多，并且围绕确切的作用模式、生物分布和与其功效相关的功能仍存在相当大的争议。铬膳食补充剂是仅次于钙补充剂的第二种最受欢迎的金属补充剂，并被用于其所谓的抗糖尿病，减肥和肌肉建设能力的活动。然而，抗糖尿病作用的功效仅在相对高浓度的补充剂下观察到，并且我们已经证明，这些补充剂在细胞内和细胞外以及以似乎依赖于补充剂的性质的方式产生可观量的致癌Cr（VI）。为了研究在散装电池与XANES铬形态，第三代光束线是必需的，因为一些常见的补充剂的低摄取。使用这种技术将使我们能够确定迄今为止观察到的生物氧化是否是所有铬补充剂或仅某些类型所共有的。这在评估其相对风险时可能很重要。我们还将研究V复合物的抗糖尿病特性，这些复合物正在临床试验中或有希望用于试验。特别是，我们将测试我们的假设，V通过V（V）的氧化态或过氧化物种产生的细胞内过程通过类似的生化途径，我们已经调查了铬显示这些属性。在这样做的过程中，我们预计我们将能够设计出更安全，更有效的金属基抗糖尿病药物。