Generation of nitric oxide from streptozotocin (STZ) in the presence of copper(II) plus ascorbate: implication for the development of STZ-induced diabetes.

Streptozotocin (STZ) is widely used as a strong inducer of insulin-dependent diabetes in experimental animals. Although nitric oxide (NO) generation from STZ has been proposed to be responsible for the toxicity of pancreatic B-cells, the mechanism is yet unknown. We found that STZ generates NO in the presence of Cu(II) plus ascorbate. In addition, nicotinamide, which is an antidiabetic agent against STZ, has been found to inhibit NO generation from STZ during the reaction with Cu(II) plus ascorbate. Since rat pancreatic islets contain both ascorbate and Cu at the concentrations of 3.5 mM and 1. 0 nmol/mg protein, respectively, our present results indicate that (1>) NO generation is responsible for the development of STZ-induced diabetes and (2) mechanism for the protection of diabetes by nicotinamide is due to the inhibition of NO generation from STZ through complex formation between nicotinamide and Cu (I), which is reduced by ascorbate.