A new hypothesis for alloxan diabetes.

A new hypothesis ("Pi-pH hypothesis") for alloxan diabetes is presented. It is based upon data from our own studies and from the literature. The following data and interpreatations are assumed to be of special importance for the B-cytotoxicity of alloxan: Inhibition of a mitochondrial sulfhydryl dependent transport system for inorganic phosphate (Pi) leading to increased concentration of Pi and decreased pH in the cytosol, and to inhibition of NAD-dependent oxidations and oxidative phosphorylation; mitochondrial lesion because of altered localization and concentration of Pi; inhibited synthesis and glucose induced release of insulin, at least partly due to a fall in intracellular pH; and finally necrosis because of absent mitochondrial function. An inverse relationship between Pi and pH may exist in the B-cells; alloxan sensitivity being associated with high Pi and low pH. Alloxan antagonism may be due to induction of low Pi and high pH in the cytosol. The selectivity of the B-cell for alloxan is believed to be associated with its free permeability for glucose.