Diabetogenic action of alloxan-like compounds: cytotoxic effects of 5-hydroxy-pseudouric acid and dehydrouramil hydrate hydrochloride on rat pancreatic β cells

The effects on islet morphology and blood glucose concentration of intravenous administration of alloxan to rats have been compared with those of two new diabetogenic agents, 5-hydroxy-pseudouric acid (5-HPUA) and dehydrouramil hydrate hydrochloride (DHU). Administration of alloxan (0.35 mmol/kg) caused a classical triphasic change in blood glucose characterised by initial hyperglycaemia, subsequent hypoglycaemia and a delayed persistent hyperglycaemia. In contrast, 5-HPUA and DHU elicited persistent hyperglycaemia as early as 30 min after administration. Morphological evidence for degranulation, pyknosis, necrosis and widening of pericapillary spaces was obtained with all three agents. However, both 5-HPUA and DHU elicit considerably more rapid and extensive changes than alloxan, with evidence for extensive pyknosis occurring as early as 15 min after administration of DHU and 5-HPUA compared with 24 h for alloxan. The more marked potency of DHU and 5-HPUA may be at least partially attributable to the greater stability of these agents compared with alloxan, since solutions of DHU or 5-HPUA kept for 15 min prior to administration retained full diabetogenic activity, whereas similar treatment of alloxan solution completely abolished its diabetogenic activity. Since both 5-HPUA and DHU are potential metabolites of uric acid, their marked diabetogenic potency raises the possibility of a role for uric acid metabolites in the pathogenesis of diabetes mellitus.