Cytotoxic effects of streptozotocin and N nitrosomethylurea on the pancreatic B cells with special regard to the role of nicotinamide adenine dinucleotide

Abstract

The effects on the pancreatic B cell of streptozotocin and its aglucone derivative N nitroso methyl urea were investigated in obese hyperglycaemic mice and their lean littermates. Both streptozotocin and N nitroso methyl urea were found to be B cytotoxic although N nitroso methyl urea produced less islet damage. Both substances decreased the concentrations of NAD+ in the islet cells to about 10% of the control values within 2 hr after injection. This NAD+ depletion was prevented by injection of nicotinamide 10 min after the administration of streptozotocin or N nitroso methyl urea. In islets taken from animals 10 min after injection of streptozotocin or N nitroso methyl urea there was no stimulatory effect of glucose on the respiration or insulin released and the oxidation of glucose was markedly decreased. Addition of nicotinamide (10 mM) to the incubated islets restored glucose stimulation of both the oxygen consumption and insulin release. It is concluded that islet NAD+ depletion is probably important for the B-cytotoxic action of N nitroso methyl urea and streptozotocin. The glucose residue in the streptozotocin molecule may potentiate the B-cytotoxic action of this drug in mice.