Diazoxide effects on biphasic insulin release: “adrenergic” suppression and enhancement in the perifused rat pancreas

Abstract

A B S T R A C T An in vitro system for perifusion of rat pancreas has been used to investigate the effects of diazoxide on glucose-induced insulin release. Administration of diazoxide with a stimulating concentration of glucose produced a dose-dependent suppression of insulin release. This effect was partly reversed by phentolamine. In the presence of nonstimulatory-concentrations of glucose, diazoxide plus phentolamine, but neither alone, stimulated a biphasic release of insulin similar to that observed with 1-isopropyl norepinephrine. A prior period of perifusion with a low concentration of diazoxide enhanced the primary component of subsequent glucose-stimulated insulin release, an effect inhibited by addition of either phentolamine or propranolol to the diazoxide during this "prestimulation" period. These effects are similar to those observed with epinephrine. By contrast with epinephrine however, increasing the concentration of diazoxide during the period before glucose stimulation enhanced both the primary and secondary components of subsequent glucoseinduced insulin release. These data suggest that at least some of the direct effects of diazoxide on the pancreas are mediated through a-and P-adrenergic receptor mechanisms.

Interactions of acetylcholine and epinephrine on the dynamics of insulin release in vitro.

“…Pertinent to this report are the observations regarding the effect of adrenergic agents in inhibiting insulin release via a-adrenergic receptors; stimulating release, via P-adrenergic receptors (32), or; "priming" B cells for enhanced responsiveness to subsequent glucose challenge (31,33) and similar data indicating the ability of cholinergic mechanisms to stimulate insulin release (29,(34)(35)(36)(37)(38). Thus, much is known about the independent effects of these autonomic systems on insulin release.…”

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.…”

“…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.…”