XAFS STUDIES OF METAL ANTI-DIABETIC SUPPLEMENTS AND DRUGS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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，糖尿病发病率最高的国家是最发达的国家。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更多，关于其确切的作用模式、生物分布和与其有效性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，据称其抗糖尿病、减肥和肌肉锻炼能力。然而，只有在相对较高浓度的补充剂下才能观察到抗糖尿病的效果，我们已经证明，这些补充剂在细胞内和细胞外都会产生相当数量的致癌铬(VI)，而且这种方式似乎取决于补充剂的性质。为了用XANES研究块状细胞中的铬形态，需要第三代光束线，因为一些常见的补充剂的摄取率很低。这种技术的使用将使我们能够确定迄今为止观察到的生物氧化是所有铬补充剂共同的，还是只对某些类型的铬补充剂通用。这在评估它们的相对风险时可能很重要。我们还将研究正在进行临床试验或有望进行试验的V络合物的抗糖尿病特性。特别是，我们将检验我们的假设，即V通过细胞内过程产生的V(V)氧化态或过氧物物种显示这些特性，其生物化学途径与我们在铬中所研究的相似。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。

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.