Purinergic receptors on insulin‐secreting cells

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Abstract
Summary—The insulin secreting B cell is fitted with the two types of purinergic receptors: P2(for ATP and/or ADP) and P1(for adenosine). The activation of P2purinoceptors by ATP or ADP evokes a biphasic stimulation of insulin secretion from isolated perfused rat pancreas; this stimulation is dose‐dependent between 10−6and 10−4M. Non hydrolysable structural analogues are also effective, and the relative potency of various agonists (2‐methylthio ATP ≫ ATP = ADP = α, β‐methylene ATP ≫ AMP) gave evidence for a P2ypurinoceptor subtype. Proposed mechanisms include both an increased Ca2+uptake and an increased intracellular Ca2+mobilizationviathe hydrolysis of polyphosphoinositides. ATP (or ADP) potentiates physiological insulin‐secreting agents (glucose and acetylcholine) and P2purinoceptors could play a physiological role in the stimulation of insulin secretion. The activation of P1purinoceptors (adenosine receptors) decreases insulin secretion. Using structural analogues of adenosine, the receptor was characterized as an A1subtype; 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. Recently, a metabolically stable structural analogue of ADP, adenosine‐5′‐0‐(2‐thiodiphosphate) or ADPßS, has been described as a potent secretory agent, effective at nanomolar concentrations on isolated perfused rat pancreas.In vivo, this substance is able to increase insulin secretion and to improve glucose tolerance after IV administration in rats and oral administration in dogs. Furthermore in streptozotocin‐induced diabetes, ADPßS retains its insulin secreting effects. These results suggest that P2ypurinoceptors could be a new target for antidiabetic drugs.