The possible protective effects in vitro of the hydroxyl radical scavenger dimethyl urea (6 mg/ml) and the poly(ADP-ribose)synthetase inhibitors theophylline (5 mM) and nicotinamide (0.75 mg/ml) against streptozotocin (SZ) induced deterioration of islet metabolism were investigated using isolated mouse pancreatic islets. All these compounds counteracted to different extents the deleterious effects of SZ (4.4 mM) on glucose-stimulated (pro)insulin biosynthesis, dimethyl urea protecting least. No protective effects against SZ were obtained by adding 16.7 mM glucose or 5 mM dibuturyl cAMP. The islet NADH + NAD content decreased drastically when exposed to SZ. Again, nicotinamide and theophylline protected better against the SZ-effects on pyridine nucleotides than dimethyl urea. Furthermore, the maintenance of a linear rate of oxygen uptake was lost after SZ-exposure of the islets, and there was no increase of the respiratory rate when these islets were challenged with high glucose. Also in these islet respiratory studies a partial or total protection by dimethyl urea, theophylline and nicotinamide against SZ was observed. In perifusion experiments SZ rapidly decreased insulin release together with a slightly delayed increased radioactive nucleotide efflux. Later (about 20 min.) a massive leakage of both radioactive nucleotides and insulin occurred in most of the experiments. It is concluded that all the observed impairments of islet metabolism after SZ-exposure can be related to islet NAD depletion, which may depend on poly(ADP-ribose)synthetase activation due to DNA damage. The SZ-induced DNA injury may be mediated by free radicals as suggested by the protective effects of dimethyl urea.