STIMULATION OF INSULIN-SECRETION AND IMPROVEMENT OF GLUCOSE-TOLERANCEIN RAT AND DOG BY THE P2Y-PURINOCEPTOR AGONIST, ADENOSINE-5'-O-(2-THIODIPHOSPHATE)

1 In vivo effect of a P2y-purinoceptor agonist, adenosine-5'-O-(2-thio diphosphate) (ADPbetaS), on insulin secretion and glycaemia were studi ed both in rats and dogs. 2 In anaesthetized rats, i.v. administered A DPbetaS (0.2 mg kg-1) produced an insulin response dependent on the nu tritional state of the animals, since we observed only a transient inc rease in overnight-fasted rats and a sustained insulin secretion follo wed by a reduction in plasma glucose levels in fed rats. During an i.v . glucose tolerance test, ADPbetaS enhanced insulin release and thus i ncreased the glucose disappearance rate. 3 In anaesthetized fasted dog s, i.v. administered ADPbetaS (0.1 mg kg-1) increased pancreaticoduode nal insulin output and slightly decreased blood glucose levels. 4 In c onscious fasted dogs, orally administered ADPbetaS (0.1 mg kg-1) trans iently increased insulinemia and punctually reduced glycaemia. Further more, during an oral glucose tolerance test, orally administered ADPbe taS at the same dose markedly enhanced insulin secretion and consequen tly reduced the hyperglycaemia. 5 In conclusion, the P2y-agonist, ADPb etaS, is a potent insulin secretagogue in vivo, improves glucose toler ance and is effective after oral administration. Thus, the P2y-purinoc eptors of the beta cell may be a target for new antidiabetic drugs.