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.
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