PURINERGIC RECEPTORS ON INSULIN-SECRETING CELLS

The insulin secreting B cell is fitted with the two types of purinergi c receptors: P2 (for ATP and/or ADP) and P1 (for adenosine). The activ ation of P2 purinoceptors by ATP or ADP evokes a biphasic stimulation of insulin secretion from isolated perfused rat pancreas; this stimula tion is dose-dependent between 10-6 and 10-4 M. Non hydrolysable struc tural analogues are also effective, and the relative potency of variou s agonists (2-methylthio ATP >> ATP = ADP = alpha, beta-methylene ATP >> AMP) gave evidence for a P2y purinoceptor subtype. Proposed mechani sms include both an increased Ca2+ uptake and an increased intracellul ar Ca2+ mobilization via the hydrolysis of polyphosphoinositides. ATP (or ADP) potentiates physiological insulin-secreting agents (glucose a nd acetylcholine) and P2 purinoceptors could play a physiological role in the stimulation of insulin secretion. The activation of P1 purinoc eptors (adenosine receptors) decreases insulin secretion. Using struct ural analogues of adenosine, the receptor was characterized as an A1 s ubtype; it is coupled to a pertussis toxin sensitive G protein and it inhibits adenylate cyclase. It is of physiological relevance that the B cell has the two types of purinoceptors with opposite effects. Recen tly, a metabolically stable structural analogue of ADP, adenosine-5'-O -(2-thiodiphosphate) or ADPbetaS, has been described as a potent secre tory agent, effective at nanomolar concentrations on isolated perfused rat pancreas. In vivo, this substance is able to increase insulin sec retion and to improve glucose tolerance after IV administration in rat s and oral administration in dogs. Furthermore in streptozotocin-induc ed diabetes, ADPbetaS retains its insulin secreting effects. These res ults suggest that P2y purinoceptors could be a new target for antidiab etic drugs.