Studies on the mechanism of inhibition of glucose-stimulated insulin secretion by noradrenaline in rat islets of Langerhans

Abstract

Noradrenaline (norepinephrine) was shown to be a potent inhibitor of glucose-induced insulin release from rat pancreatic islets, with half-maximal inhibition of the secretory response to 20 mM-glucose occurring at approx. 0.3 microM, and complete suppression of the response occurring at 4 microM-noradrenaline. Inhibition of insulin secretion by noradrenaline was antagonized by the alpha 2-adrenergic antagonist yohimbine (half maximally effective dose approximately 1 microM), but was largely unaffected by the alpha 1-adrenergic antagonist prazosin at concentrations up to 50 microM, suggesting that the response was mediated by alpha 2-adrenergic receptors. Noradrenaline significantly reduced the extent of 45Ca2+ accumulation in glucose-stimulated islets, although as much as 5 microM-noradrenaline was required for 50% inhibition of this response. The ability of noradrenaline to inhibit islet-cell 45Ca2+ uptake was totally abolished in media containing 1 mM-dibutyryl cyclic AMP, suggesting that the response may have been secondary to lowering of islet cyclic AMP. Under these conditions, however, noradrenaline was still able to inhibit insulin secretion maximally. The data suggest that the site(s) at which noradrenaline acts to mediate inhibition of insulin secretion in rat islets lies distal to both islet-cell cyclic AMP accumulation and Ca2+ uptake.

Catecholamine inhibition of Ca2+‐induced insulin secretion from electrically permeabilised islets of Langerhans

“…However, the effects of o~2-agonists on islet cAMP are variable and do not always parallel the inhibitory effects on insulin secretion [26,27]. Furthermore, there have been several reports that catecholamines inhibit insulin secretion in the presence of membrane-permeable analogues of cAMP [3,15,16], as was confirmed in the present studies using intact islets, suggesting that the inhibition of secretion cannot be solely attributed to a decrease in intracellular cAMP. Note, however, that in our experiments the noradrenaline inhibition of secretion in response to db-cAMP plus glucose was only partial, even at a concentration of noradrenaline well in excess of that required to inhibit totally secretion in response to glucose alone.…”

“…The catecholamine inhibition of secretion is thought to be a direct effect on B-cells [7,14] and to be mediated by cez-adrenoreceptors [15,16], as confirmed in the present studies by the abolition of the inhibitory effects of noradrenaline by the o~2-receptor antagonist, yohimbine. In addition to suppressing glucose-induced insulin secretion from intact islets, noradrenaline also had marked inhibitory effects on Ca2+-induced secretion from electrically permeabilised islets, as has previously been reported in studies using digitonin-treated islets [17].…”

“…A similar conclusion has recently been drawn from less direct studies using intact tissue. Thus, in intact islets, the effects of catecholamines on Ca 2÷ uptake [16] or efflux [18] could be dissociated from the inhibition of insulin secretion, while fluorescence measurements of cytosolic Ca 2÷ in insulin-secreting tumour cells demonstrated that ce2-agonists could inhibit insulin secretion without measurably affecting intracellular concentrations of Ca 2÷ [19].…”

Antagonism of the stimulatory effects of efaroxan and glibenclamide in rat pancreatic islets by the imidazoline, RX801080

“…The method for islet incubation has been described in detail previously (Morgan & Montague, 1985). Briefly, groups of 3 islets were incubated in bicarbonate buffered medium, supplemented with bovine serum albumin (1 mg ml-') and appropriate test reagents.…”

Modulation of the Pancreatic Islet β-Cell-delayed Rectifier Potassium Channel Kv2.1 by the Polyunsaturated Fatty Acid Arachidonate

“…The extent of ␤-cell depolarization and insulin release are regulated in part by the activation of repolarizing ion channels, including the voltage-gated potassium channel, Kv2.1 (2)(3)(4). One mechanism employed by pancreatic ␤-cells to regulate the biophysical activity of the ion channels involved in insulin release involves hydrolysis of membrane phospholipids to yield mediators that include inositol triphosphates and free fatty acids (5)(6)(7)(8).…”