BETA(3)-ADRENERGIC RECEPTORS ARE RESPONSIBLE FOR THE ADRENERGIC INHIBITION OF INSULIN-STIMULATED GLUCOSE-TRANSPORT IN RAT ADIPOCYTES

The inhibition of insulin-stimulated glucose transport by isoprenaline , a mixed 6-adrenergic-receptor (AR) agonist, is well documented in ra t adipocytes. Since it has been described that rat adipocytes possess not only beta1- and beta2- but also beta3-ARs, the influence of variou s subtype-selective beta-AR agonists and antagonists on 2-deoxyglucose (2-DG) transport was assessed in order to characterize the beta-AR su btype involved in the adrenergic counter-regulation of the insulin eff ect. The stimulation of 2-DG transport by insulin was counteracted, in a dose-dependent manner, by all the beta-AR agonists tested, and the magnitude of the inhibition followed the rank order: BRL 37344 > isopr enaline = noradrenaline much greater than dobutamine = procaterol. The same rank order of potency was obtained for lipolysis activation. Thi s is not in accordance with the pharmacological definition of a beta1- or a beta2-adrenergic effect, but agrees with the pharmacological pat tern of a beta3-adrenergic effect. The inhibitory effect of the beta3- agonist BRL 37344 on insulin-stimulated 2-DG transport was not reverse d by either the selective beta1-antagonist ICI 89406 or the beta2-anta gonist ICI 118551. In addition, neither of these beta-antagonists was able to block the isoprenaline and noradrenaline effects, supporting m ajor beta3-adrenoceptor-subtype involvement in the adrenergic inhibiti on of insulin-stimulated 2-DG transport. Like isoprenaline, BRL 37344 inhibited (60 % inhibition) insulin-stimulated glucose transport only when adenosine deaminase was present in the assay. Furthermore, the ma ximal inhibitory effects of isoprenaline and BRL 37344 were not additi ve, and were both dependent on albumin concentration in the incubation medium: they increased when the albumin concentration decreased in th e medium from 3.5 to 1%. To conclude, the similarities between isopren aline and BRL 37344 action on insulin-stimulated 2-DG transport, the p oor efficacy of the beta1-/beta2-agonists and the lack of effect of se lective beta1- and beta2-antagonists are compelling arguments to suppo rt the important role of beta3-adrenoceptors in the adrenergic inhibit ion of glucose transport in rat adipocytes.