Stimulation of insulin secretion and improvement of glucose tolerance in rat and dog by the P2y-purinoceptor agonist, adenosine-5'-O-(2-thiodiphosphate).

Abstract

1. In vivo effect of a P2y-purinoceptor agonist, adenosine-5'-O-(2-thiodiphosphate) (ADP beta S), on insulin secretion and glycaemia were studied both in rats and dogs. 2. In anaesthetized rats, i.v. administered ADP beta S (0.2 mg kg-1) produced an insulin response dependent on the nutritional state of the animals, since we observed only a transient increase in overnight-fasted rats and a sustained insulin secretion followed by a reduction in plasma glucose levels in fed rats. During an i.v. glucose tolerance test, ADP beta S enhanced insulin release and thus increased the glucose disappearance rate. 3. In anaesthetized fasted dogs, i.v. administered ADP beta S (0.1 mg kg-1) increased pancreaticoduodenal insulin output and slightly decreased blood glucose levels. 4. In conscious fasted dogs, orally administered ADP beta S (0.1 mg kg-1) transiently increased insulinemia and punctually reduced glycaemia. Furthermore, during an oral glucose tolerance test, orally administered ADP beta S at the same dose markedly enhanced insulin secretion and consequently reduced the hyperglycaemia. 5. In conclusion, the P2y-agonist, ADP beta S, is a potent insulin secretagogue in vivo, improves glucose tolerance and is effective after oral administration. Thus, the P2y-purinoceptors of the beta cell may be a target for new antidiabetic drugs.