Insulinotropic effects of hypoglycaemic and hyperglycaemic sulphonamides: The ionophoretic hypothesis

Abstract

Summary.Hypoglycaemic sulphonamides stimulate net uptake of 45Ca+ + and insulin release in isolated pancreatic islets. These effects are antagonized by organic calcium-antagonists (e.g. suloctidil). In an artificial system, hypoglycaemic sulphonamides, such as gliclazide, stimulate the translocation of calcium into or across a hydrophobic immiscible domain, a process enhanced by the antibiotic ionophore A 23187 and antagonized by suloctidil. In this artificial system, the A23187-mediated process of calcium countertransport is stimulated by gliclazide and inhibited by diazoxide. It is postulated that the insulinotropic action of hypoglycaemic and hyperglycaemic sulphonamides is primarily attributable to the ionophoretic action of these drugs.Key words: Hypoglycaemic sulphonylureas, diazoxide, calcium, insulin release, ionophores, organic calcium antagonists.Hypoglycaemic sulphonylureas stimulate insulin release from the pancreatic B-cell. The mechanism of such an insulinotropic effect is poorly understood [1]. Within the framework of current concepts concerning the cytophysiology of insulin release [2], three primary sites of action could be proposed to account for the insulinotropic action of sulphonylureas: a facilitation of nutrient metabolism, an interference with cyclic AMP synthesis or breakdown, or a remodelling of ionic fluxes in the B-cell.Biochemical studies, reviewed elsewhere [1, 3], do not support the first of these 3 hypotheses.Although hypoglycaemic sulphonylureas were occasionally claimed to activate adenylate cyclase [4] and repeatedly found to inhibit phosphodiesterase [5][6][7] in islet homogenates, the relevance of the latter finding may be questioned since sulphonylureas apparently do not penetrate the B-cell beyond the plasma membrane [1]. A drug-induced increase in the cyclic AMP content of intact islets could be secondary to a cytosolic accumulation of Ca 2+ [8].The third hypothesis, namely that of a primary action of hypoglycaemic sulphonylureas upon ionic movements, may involve two distinct mechanisms. First, sulphonylureas may cause a decrease in K § conductance [9,10] leading to subsequent cell depolarization and gating of voltage-dependent Ca 2+ channels; however, under suitable conditions, tolbutamide is able to stimulate Ca 2+ influx and insulin release without decreasing K + conductance [11]. Second, sulphonylureas may directly interfere with an ionophoretic modality of Ca transport across the B-cell plasma membrane [12][13][14][15]. This hypothesis has recently been scrutinized in great detail [16][17][18].The present report documents some selected experimental findings in support of the ionophoretic hypothesis. Methodological ConsiderationsInsulin release was measured in groups of 8 pancreatic islets, removed from fed female albino rats and incubated for 60 min at 37~ in a bicarbonate-buffered solution [19]. The net uptake of 45Ca 2+ by the islets was measured over 90 min incubation, followed by repeated washes of the islets in order to remove extracellular radioactivity [20].Two...

Modalities of Gliclazide-induced Ca2+ Influx into the Pancreatic B-Cell

“…8 As an alternative hypothesis, it has been proposed that sulfonylureas may increase Ca 2+ inflow by acting synergistically with native ionophores possibly responsible for the transport of Ca 2+ and/or .other cations across the B-cell membrane. 9 This view is consistent with the knowledge that sulfonylureas display the ability to translocate cations across hydrophobic domains 10 and both artificial and living membranes. 11 ' 12 In the artificial systems, sulfonylureas act synergistically with either the antibiotic ionophore A23187 or native ionophores extracted from the islets in mediating Ca 2+ transport.…”

Tolbutamide perifusion of rat islets. Sequential changes in calcium, phosphorus, sodium, potassium, and chlorine in single beta cells.

“…As (8). These temporal, phasic relationships underscore the importance of cytosolic elevations of Ca++ as second messengers for the insulin secretory process, and, by direct measurement, support conclusions drawn by others utilizing flux measurements of labeled Ca in whole islets exposed to tolbutamide in vitro (2,3,(5)(6)(7).…”

“…The importance of cytosolic accumulation of Ca++ as an initiator of tolbutamide action has been established by several reports of flux studies of this ion in whole islets (2,3) as well as by other electrophysiologic investigations of the beta cell membrane (4). However, it is not clear how Ca++ movements relate temporally to other important cations, especially K+ (3)(4)(5)(6)(7), in stimulus-secretion coupling.…”

Effect of oral verapamil on glibenclamide stimulated insulin secretion.

“…Hvpoglycaemic sulphonylureas stimulate insulin release from the pancreatic ,B cell probably by causing an intracellular influx of calcium ions (Couturier & Malaisse, 1980). The calcium antagonist, verapamil, has been shown in vitro to inhibit both glucose and sulphonylurea stimulated insulin release (Devis et al, 1975).…”