Insulin regulatory effects on purine- and pyrimidine metabolism in alloxan diabetic rat liver.

Aim of this study was to elucidate insulin regulatory effects on purine and pyrimidine metabolism. Livers of alloxan diabetic and insulin treated rats were freeze clamped and nucleotide pools measured using HPLC techniques. Activities of key enzymes of de novo and salvage pathways were analyzed with radioassays. In diabetic liver nucleotide triphosphate pools were reduced between 46 and 75% of controls, nucleotide monophosphate concentrations increased. Activities of de novo biosynthetic enzymes amidophosphoribosyltransferase, FGAM synthase, IMP dehydrogenase, GMP synthase, carbamoylphosphate synthase II were curtailed by 16-61%, those of salvage enzymes hypoxanthine-guanine-phosphoribosyltransferase, adenine-phosphoribosyltransferase, thymidine kinase also decreased to 31-58%. Insulin treatment for 2 and 7 days normalized nucleotide pools, activities of key enzymes of de novo and salvage pathways were increased between 2.4 and 4.1 fold compared to diabetic untreated. Activation of nucleic acid metabolism by insulin can be explained by the requirement for high energy phosphates of certain anabolic key enzymes in carbohydrate and lipid metabolism. Impaired synthesis in insulin deficiency of end products of guanylate and pyrimidine pathway required as substrates for a variety of enzymes synthesising membrane structures throw new light on the pathogenesis of some late complications of diabetic disease.