The Novel Imidazoline Compound BL11282 Potentiates Glucose-Induced Insulin Secretion in Pancreatic β-Cells in the Absence of Modulation of KATP Channel Activity

Abstract

The insulinotropic activity of the novel imidazoline compound BL11282 was investigated. Intravenous administration of BL11282 (0.3 mg ⅐ kg -1 ⅐ min -1 ) to anesthetized rats did not change blood glucose and insulin levels under basal conditions, but produced a higher increase in blood insulin levels and a faster glucose removal from the blood after glucose infusion. Similarly, in isolated Wistar rat pancreatic islets, 0.1-100 mol/l BL11282 potently stimulated glucose-induced insulin secretion but did not modulate basal insulin secretion. Unlike previously described imidazolines, BL11282 did not block ATP-dependent K ؉ channels. Furthermore, the compound stimulated insulin secretion in islets depolarized with high concentrations of KCl or permeabilized with electric shock. Insulinotropic activity of BL11282 was dependent on activity of protein kinases A and C. In pancreatic islets from spontaneously diabetic GK rats, the imidazoline compound restored the impaired insulin response to glucose. In conclusion, the imidazoline BL11282 constitutes a new class of insulinotropic compounds that exerts an exclusive glucose-dependent insulinotropic activity in pancreatic islets by stimulating insulin exocytosis. Diabetes 50:797-802, 2001 C ompounds with imidazoline structure are potent stimulators of insulin secretion in pancreatic ␤-cells (1). This effect is thought to be due to the blockade of ATP-dependent K ϩ channel (K ATP ) activity and the increase in cytosolic free Ca 2ϩ concentration ([Ca 2ϩ ] i ) (2). Recently, we have shown that the imidazoline compound RX871024, in addition to blocking K ATP channels and increasing [Ca 2ϩ ] i , exerts its insulinotropic effect by enhancing insulin exocytosis at stages distal to the increase in [Ca 2ϩ ] i (3-5). This direct stimulation of exocytosis was only observed at elevated glucose concentrations and required activation of protein kinases A and C.Sulfonylurea drugs, which are currently used in the treatment of type 2 diabetes, block K ATP channels in ␤-cells and stimulate insulin secretion at both low and high glucose concentrations (6). The strong insulinotropic effect of sulfonylureas observed at low glucose concentrations often provokes pronounced hypoglycemia in patients treated with these drugs (7). Therefore, agents that do not stimulate basal insulin secretion but augment glucoseinduced insulin secretion by modulating Ca 2ϩ -stimulated insulin exocytosis could provide a better therapeutic alternative to sulfonylureas.We now demonstrate that an imidazoline compound, BL11282 (Fig. 1A, insert), represents a new class of insulinotropic compounds that do not stimulate basal insulin secretion and lack the effect on K ATP channel activity, but markedly potentiate glucose-induced insulin secretion. RESEARCH DESIGN AND METHODS BL11282 and LY333531 were obtained from Eli Lilly (Indianapolis, IN).Rp-cAMPS was from Calbiochem (San Diego, CA). All other reagents were from Sigma (St. Louis, MO). Intravenous glucose tolerance test. The intravenous glucose tolerance test ...

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

“…One guanidinium compound with insulinotropic property (BTS 67 582) was explored as an oral antidiabetic agent, assuming that it acts as an imidazoline analogue [20,34,35]. 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.…”

Voltage-dependent K + channels in pancreatic beta cells: Role, regulation and potential as therapeutic targets

“…3) raises the possibility of developing Kv channel based therapeutics. The enormous interest in potential glucosedependent therapeutics is evidenced by current research into glucose-dependent secretagogues such as the incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) and their analogues [68], the imidazoline compounds [69,70], and agonists of the protein kinase A (PKA) signalling pathway [71]. The theory behind the glucose-dependence of Kv channel antagonists is quite simple.…”

Two Generations of Insulinotropic Imidazoline Compounds

“…Similarly, others have shown that imidazoline substances increased insulin release after irreversible blockade or downregulation of ␣ 2 -adrenoceptors, and they proposed that the stimulatory effect of the compounds on insulin release was probably related to their imidazoline moiety (15-17). Importantly, some imidazoline compounds exerted a strong effect on the exocytotic component of the insulinotropic effect of glucose (8,18). Furthermore, several imidazolines have already shown promising antihyperglycemic effects in animal models of diabetes and in human subjects (19 -21).…”

“…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).…”