Metal-based anti-diabetic drugs: advances and challenges.

The current status and likely future directions of complexes of V(V/IV), Cr(III), Mo(VI), W(VI), Zn(II), Cu(II), and Mn(III) as potential oral drugs against type 2 diabetes are reviewed. We propose a unified model of extra- and intracellular mechanisms of anti-diabetic efficacies of V(V/IV), Mo(VI), W(VI), and Cr(III), centred on high-oxidation-state oxido/peroxido species that inhibit protein tyrosine phosphatases (PTPs) involved in insulin signalling. The postulated oxidative mechanism of anti-diabetic activity of Cr(III) via carcinogenic Cr(VI/V) (which adds to safety concerns) is consistent with recent clinical trials on Cr(III) picolinate, where activity was apparent only in patients with poorly controlled diabetes (high oxidative stress), and the correlation between the anti-diabetic activities and ease of oxidation of Cr(III) supplements and their metabolites in vivo. Zn(II) and Cu(II) anti-diabetics act via different mechanisms and are unlikely to be used as specific anti-diabetics due to their diverse and unpredictable biological activities. Hence, future research directions are likely to centre on enhancing the bioavailability and selectivity of V(V/IV), Mo(VI), or W(VI) drugs. The strategy of potentiating circulating insulin with metal ions has distinct therapeutic advantages over interventions that stimulate the release of more insulin, or use insulin mimetics, because of many adverse side-effects of increased levels of insulin, including increased risks of cancer and cardiovascular diseases.