Glucose-induced insulin secretion and α₂-adrenergic receptor subtypes

α₂-Adrenoceptor antagonists have been investigated in human in vivo studies as new oral antihyperglycemic agents. α₂-Adrenoceptors are subdivided into α_2A and α_2B subtypes by using receptor-binding methods or cloning methods. This study was designed to determine the α₂-adrenergic receptor subtype(s) involved in glucose-induced insulin and glucagon secretion from the isolated perfused rat pancreas at a glucose concentration of 16.7 mmol/L Both the α_2A-preferentlal agonist oxymetazoline and the non-subtype-selective α₂-agonist p-aminoclonidine, at concentrations above 10^-9 mol/L, significantly inhibited glucose-induced insulin secretion (p < 0.05 and p < 0.01, respectively) and stimulated glucagon secretion from 10^-7 mol/L, as compared with basal levels (p < 0.01, respectively). In contrast, the α₁-selective agonist phenylephrine, at concentrations up to 10^-6 mol/L, affected neither insulin nor glucagon secretion as compared with basal levels. Furthermore, the non-subtype-selective α₂-antagonist rauwolscine, at concentrations above 10^-6 mol/L, and the α_2A-preferential antagonist WB-4101, at 10^-5 mol/L, significantly antagonized the effects of 10^-5 mol/L p-aminoclonidine on both insulin and glucagon secretion (p < 0.01 and p < 0.05, respectively). In contrast, neither the α₁- and α_2B-selective antagonist prazosin nor the α_2B-preferential antagonist chlorpromazine, at concentrations up to 10^-5 mol/L, antagonized the effects of p-aminoclonidine. These results suggest that α_2A rather than α_2B-adrenergic agonism inhibits glucose-induced insulin secretion and stimulates glucagon secretion in the isolated perfused rat pancreas.