Two Generations of Insulinotropic Imidazoline Compounds

Abstract

The imidazoline RX871024 increased basal-and glucosestimulated insulin release in vitro and in vivo. The compound inhibited activity of ATP-sensitive K ؉ channels as well as voltage-gated K ؉ channels, which led to membrane depolarization, an increase in the cytosolic Ca 2؉ concentration ([Ca 2؉ ] i ), and insulin release. Importantly, RX871024 also enhanced the insulinotropic effect of glucose in cells with clamped [Ca 2؉ ] i but in the presence of high ATP and Ca 2؉ concentration inside the cell. We believe that the latter effect on insulin exocytosis was at least in part mediated by a rise in diacylglycerol, which then activated protein kinase C (PKC) and increased the generation of arachidonic acid (AA) metabolites. Activation of both the PKC and AA pathways resulted in potentiation of glucose effects on insulin secretion. Unlike RX871024, the novel imidazoline BL11282 did not block ATP-dependent K ؉ channels, but similarly to RX871024, it stimulated insulin secretion in depolarized or permeabilized islets. Accordingly, BL11282 did not influence glucose and insulin levels under basal conditions either in vitro or in vivo, but it markedly enhanced the insulinotropic effects of glucose. BL11282 restored the impaired insulin response to glucose in islets from spontaneously diabetic GK rats. We conclude that BL11282 belongs to a new class of insulinotropic compounds that demonstrate a strong glucose-dependent effect on insulin exocytosis. Diabetes 51 (Suppl. 3):S448 -S454, 2002 G lucose stimulates insulin secretion mainly by activation of two mechanisms: increasing the cytosolic Ca 2ϩ concentration ([Ca 2ϩ ] i ) (1) and directly promoting insulin exocytosis (2). It has been demonstrated that sulfonylureas increase insulin secretion by simulating the effect of glucose on [Ca 2ϩ ] i (3). However, recent data suggest that sulfonylureas also moderately enhance the direct effect of glucose on exocytosis (4,5). The direct insulinotropic effect of sulfonylureas, observed already at normal or moderately increased blood glucose concentrations, may provoke pronounced and prolonged hypoglycemia in patients treated with these drugs (6). Therefore, drugs that solely enhance the exocytotic component of the insulinotropic effect of glucose by influencing transport and fusion of insulin granules could provide a better alternative to sulfonylureas in treatment of type 2 diabetes. It has been shown that glucagon like peptide-1 (GLP-1), a peptide from the gut, shows a glucose-dependent insulinotropic effect and exerts a strong antidiabetic effect (7). However, the necessity of injecting this peptide during the treatment led to the idea to search for small organic compounds possessing glucose-dependent insulinotropic activity similar to GLP-1. Among those compounds, of special interest are novel imidazoline compounds (8,9).Phentolamine, an ␣-adrenergic blocking agent with an imidazoline ring, stimulated basal and glucose-induced insulin release in humans and animals (10 -12). These data were initially interpreted as an indicati...

Essential role of the imidazoline moiety in the insulinotropic effect but not the KATP channel-blocking effect of imidazolines; a comparison of the effects of efaroxan and its imidazole analogue, KU14R

“…On the other hand, several imidazoline compounds have been synthesised recently that do not inhibit K ATP channel activity, but nevertheless stimulate insulin secretion [36,37]. Whether the insulinotropic effect of these second-generation imidazolines [38] is simply due to the K ATP channel-independent mechanism of the conventional imidazolines [17,38] or represents something new is unclear thus far.…”

Pathways in Beta-Cell Stimulus-Secretion Coupling as Targets for Therapeutic Insulin Secretagogues

“…Older members (phentolamine, antazoline) owe their property to blockade of K ATP channels (triggering pathway), whereas newer ones (BL11282) increase the action of Ca 2ϩ on exocytosis (amplifying action). Because these novel compounds do not produce a triggering signal, their effect on insulin secretion is more strongly glucose dependent (97). However, the advantage of this gain in safety could be cancelled by loss of tissue specificity.…”

“…This site is still unidentified and has tentatively been designated "I 3 -imidazoline binding site" (62). A number of experimental arguments suggest that it is involved in the amplification of insulin secretion by PKA and mainly PKC (62,97) and, thus, not in the amplifying pathway of glucose, which is independent of these kinases (4). Although structurally unrelated to imidazolines, ␤-carbolines might be endogenous ligands of the "imidazoline binding sites."…”

“…Compound RX871024 increases insulin release from permeabilized ␤-cells and from islets depolarized with KCl, two preparations in which [Ca 2ϩ ] i is clamped (96). A novel imidazoline (BL11282) has no effects on K ATP channels but increases insulin secretion in vitro (97). Three compounds, RX871024 (98), efaroxan (N.G.…”

Desensitization of Insulin Secretion by Depolarizing Insulin Secretagogues

“…Recently, insulinotropic imidazoline compounds, which do not block K ATP channels, have been described (32). These imidazolines are thought to act solely by mechanisms affecting the transduction of Ca 2ϩ signals into exocytotic events (33). One such mechanism appears to be similar to that of sulfonylureas in that it involves the acidification of secretory granules (34).…”