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: 8362227
• 负责人: PETER A LAY
• 金额: $ 0.19万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8362227
• 关键词: Antidiabetic Drugs; Biochemical Pathway; Biodistribution; Biological; Blood Glucose; Cells; Chromium; Clinical Trials; Developed Countries; Diabetes Mellitus; Exhibits; Funding; Generations; Grant; Incidence; Link; Metabolic Diseases; Metals; Muscle; National Center for Research Resources; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Principal Investigator; Process; Property; Radiation; Relative Risks; Research; Research Infrastructure; Resources; Role; Source; Techniques; Testing; United States National Institutes of Health; base; beamline; chromium hexavalent ion; cost; design; diabetic; dietary supplements; oligomycin sensitivity-conferring protein; oxidation; structural biology; uptake

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 2 型糖尿病是一种代谢性疾病，其特征是无法控制血糖浓度。它与肥胖密切相关，在大多数发达国家，糖尿病的发病率最高。虽然磷酸酶抑制是解释 V 复合物抗糖尿病作用的普遍接受的机制，但与 Cr 补充剂的作用相关的争议更多，并且围绕其确切的作用方式、生物分布及其功效相关的功能仍然存在相当大的争议。铬膳食补充剂是继钙补充剂之后第二受欢迎的金属补充剂，据称具有抗糖尿病、减肥和增强肌肉的作用。然而，只有在相对较高浓度的补充剂中才能观察到抗糖尿病作用的功效，我们已经证明，这些补充剂会在细胞内和细胞外产生大量的致癌 Cr(VI)，其产生方式似乎取决于补充剂的性质。为了使用 XANES 研究散装电池中的 Cr 形态，需要使用第三代光束线，因为一些常见补充剂的吸收率较低。使用此类技术将使我们能够确定迄今为止观察到的生物氧化是否对所有 Cr 补充剂或仅某些类型是常见的。这对于评估其相对风险可能很重要。我们还将研究正在进行临床试验或有希望进行试验的 V 复合物的抗糖尿病特性。特别是，我们将测试我们的假设，即 V 通过 V(V) 氧化态或细胞内过程产生的过氧物种（通过与我们在 Cr 中研究的相似的生化途径）表现出这些特性。通过这样做，我们预计我们将能够设计出更安全、更有效的金属抗糖尿病药物。