Adrenergic Modification of Glucose‐Induced Biphasic Insulin Release from Perifused Rat Pancreas

Abstract

Immediate and deferred effects of agents stimulating or inhibiting α or β adrenergic receptors have been studied in a perifusion preparation of rat pancreas in which glucose induces a biphasio pattern of IRI release. Epinephrine directly inhibited both the primary and the secondary phases of IRI release during the period of glucose stimulation. Propranolol inhibited only the secondary response. Low concentrations of isoproterenol stimulated, yet high concentrations inhibited both primary and secondary glucose‐induced IRI responses. Prestimulation with either epinephrine or nor‐epinephrine, followed by replacement of the adrenergic agent with stimulating concentrations of glucose, produced a marked enhancement of the glucose‐induced primary response. This deferred enhancement was abolished by the further addition of either α or β receptor blocking agents during prestimulation. — These results suggests that adrenergic stimulation may both enhance and depress glucose‐stimulated IRI release and that the suppressive α‐type effect is exerted at a point distal to the enhancing β‐type effect in the chain of events leading to IRI release; that α and β types of effects are not mutualy exclusive; that adrenergic suppression of IRI release may act to ‘prime’ the B‐cell such that subsequent immediate responses become more marked. Since adrenergic ‘priming’ of B‐cells selectively affects the primary phase of glucose‐stimulated IRI release, the possibility that inadequate function of this priming mechanism may contribute to the delayed response in diabetes must be considered.

Cholinergic Modification of Glucose-Induced Biphasic Insulin Release in Vitro

“…These observations, about acute responsiveness of the bursa-derived cell to AcCh and the apparent presence of reflex pathways, have potential significance in that there appears to be a "delay" in insulin release in diabetics (38)(39)(40). These results may also be considered in light of previous data suggesting that while both phases of glucose induced insulin release may be influenced by similar agents, there are differences, at least in emphasis, in the major mechanisms through which these phases are generated (12,19,29,41,42). Thus, it is observed that while muscarinic agents can stimulate biphasic insulin release in the presence of glucose, it is evident that the dose-response relationships are different for the two phases.…”

“…This method provides an accurate assessment of the total amount of insulin released in the second phase, as confirmed in this and in previous studies, by measuring the insulin content of all the perifusate collected over the appropriate period (12,19). For those studies that exhibited flat responses, phases were arbitrarily defined by reference to appropriate matching experiments (12,19). Statistics used either the Wilcoxon rank test and/or the Student t test.…”

“…This study utilized a modification of the perifusion system previously described (12,19,28,29). In the present system pancreatic islets were used in lieu of pancreatic pieces: although this is more complicated, some advantages have accrued.…”

“…insulin release in vitro (11,12) and in vivo (13,14), an effect ascribed to a-adrenergic receptor activation (12,15,16), possibly mediated through modification in calcium flux (15). In contrast to the a-adrenergic effect, a stimulatory effect of 13-adrenergic agents on insulin release has been demonstrated (12,17,18).…”

“…In contrast to the a-adrenergic effect, a stimulatory effect of 13-adrenergic agents on insulin release has been demonstrated (12,17,18). Further, prior exposure of pancreatic pieces to the adrenergic agents epinephrine, norepinephrine (12), and diazoxide (19) has resulted in enhancement of the insulin response to subsequent glucose challenge, an effect apparently dependent on the integrity of both a-and 3-adrenergic receptors. Data have also accumulated to support a role for the parasympathetic autonomic nervous system in modifying insulin release.…”