Imidazoline RX871024 Raises Diacylglycerol Levels in Rat Pancreatic Islets

Efanov, Alexander M.; Зайцев, С. В.; Berggren, Per Olof; Mest, Hans-Juergen; Efendić, Suad

doi:10.1006/bbrc.2001.4483

Cited by 5 publications

(7 citation statements)

References 21 publications

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“…Measurements of DAG levels in rat pancreatic islets demonstrated that 50 mol/l RX871024 induced a twofold increase in DAG concentration ( Fig. 5) (25). The same amplitude of DAG increase was reached with an agonist of muscarinic receptors that activates phospholipase C (PLC), 200 mol/l carbamylcholine (CCh).…”

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confidence: 80%

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Two Generations of Insulinotropic Imidazoline Compounds

et al. 2002

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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...

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“…The effects of RX871024 and CCh on DAG levels were further compared with the effects of these compounds on insulin secretion in rat pancreatic islets (25). At 3.3 mmol/l glucose, 10 -50 mol/l RX871024 induced insulin secretion, with a maximal stimulation of 500%.…”

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Two Generations of Insulinotropic Imidazoline Compounds

et al. 2002

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“…Furthermore, the imidazoline clonidine inhibited insulin release when given alone, as a result of its ␣ 2 AR agonist action, but elicited insulin release through a nonadrenergic mechanism after ␣ 2 AR blockade. More recent studies have identified selective imidazoline agents that stimulate insulin release from the pancreas while lacking adrenergic actions (Efanova et al, 1998;Efanov et al, 2001). The mixed agent moxonidine facilitated glucose induced insulin secretion in isolated rat ␤-cells in a dose-dependent manner (Rosen et al, 1997).…”

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The Role of I₁-Imidazoline and α₂-Adrenergic Receptors in the Modulation of Glucose Metabolism in the Spontaneously Hypertensive Obese Rat Model of Metabolic Syndrome X

Velliquette

Ernsberger

2003

J Pharmacol Exp Ther

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We examined glucose metabolism after I 1 -imidazoline (I 1 R) and ␣ 2 -adrenergic receptor (␣ 2 AR) activation in an animal model of metabolic syndrome X. Fasted spontaneously hypertensive obese rats (SHROB) were given the I 1 R/␣ 2 AR agonists moxonidine and rilmenidine or the ␣ 2 AR agonist guanabenz. Because of the dual specificity of moxonidine, its actions were split into adrenergic and nonadrenergic components by using selective antagonists: rauwolscine (␣ 2 AR) efaroxan (I 1 R/␣ 2 AR), or 2-endo-amino-3-exo-isopropylbicyclo[2.2.1.]heptane (AGN 192403) (I 1 R). Hyperglycemia induced by moxonidine, rilmenidine, and guanabenz resulted from inhibition of insulin secretion. Similar responses were observed after oral dosing and in lean littermates. Glucagon was reduced by the I 1 R agonists (moxonidine, 32 Ϯ 5%; rilmenidine, 24 Ϯ 7%) but elevated by guanabenz (71 Ϯ 32%). The hyperglycemic and hypoinsulinemic responses to moxonidine were blocked by rauwolscine. In contrast, rauwolscine potentiated the reduction in glucagon (39 Ϯ 6%). AGN 193402 blocked the glucagon response without affecting hyperglycemia and hypoinsulinemia. Efaroxan blocked all responses to moxonidine. When SHROB rats were treated with moxonidine 15 min before an oral glucose tolerance test, the glucose area under the curve (AUC) was increased. Antagonizing the ␣ 2 AR component of moxonidine's action with rauwolscine improved glucose AUC 3-fold and facilitated the insulin secretory response and reduced glucagon secretion. Testing fasting glucose and insulin during 3 weeks of oral moxonidine revealed early hyperglycemia that later faded, and a progressive drop in fasting insulin. The acute hyperglycemia and hypoinsulinemia elicited by moxonidine and rilmenidine was mediated by ␣ 2 AR, whereas I 1 R may reduce glucagon and increase insulin, particularly after a glucose load.

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“…The data depicted in Figure 2a show that incubation of pancreatic islets with 10 mM AGN192403 did not affect insulin secretion at 3.3 or 16.7 mM glucose as well as BL11282-stimulated insulin release. In addition, we investigated the involvement of PC-PLC, the enzyme that has been shown to be coupled to the I 1 -receptor, using the inhibitor of PC-PLC, D-609 [19]. The data presented in Figure 2b show that 10 and 100 mM D609 did not modulate the effect of BL11282 on insulin release.…”

Section: Resultsmentioning

confidence: 99%

“…An inhibitor of PC-PLC, D609, blocked moxonidine effect on DAG concentration [29]. To examine whether imidazoline BL11282 is involved in a signaling pathway coupled to I 1 -receptor/PC-PLC, we used a selective I 1 -receptor antagonist AGN192403 [18] and PC-PLC inhibitor D609 [19]. The data obtained show that both blockage of I 1 -receptor with AGN192403 and PC-PLC with D-609 do not affect insulin secretion induced by BL11282.…”

Section: Discussionmentioning

confidence: 99%

Arachidonic acid signaling is involved in the mechanism of imidazoline-induced KATP channel-independent stimulation of insulin secretion

Sharoyko

Zaitseva

Leibiger

et al. 2007

Cell. Mol. Life Sci.

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The mechanism by which the novel, pure glucose-dependent insulinotropic, imidazoline derivative BL11282 promotes insulin secretion in pancreatic islets has been investigated. The roles of KATP channels, alpha2-adrenoreceptors, the I1-receptor-phosphatidylcholine-specific phospholipase (PC-PLC) pathway and arachidonic acid signaling in BL11282 potentiation of insulin secretion in pancreatic islets were studied. Using SUR1(-/-) deficient mice, the previous notion that the insulinotropic activity of BL11282 is not related to its interaction with KATP channels was confirmed. Insulinotropic activity of BL11282 was not related to its effect on alpha2-adrenoreceptors, I1-imidazoline receptors or PC-PLC. BL11282 significantly increased [3H]arachidonic acid production. This effect was abolished in the presence of the iPLA2 inhibitor, bromoenol lactone. The data suggest that potentiation of glucose-induced insulin release by BL11282, which is independent of concomitant changes in cytoplasmic free Ca2+ concentration, involves release of arachidonic acid by iPLA2 and its metabolism to epoxyeicosatrienoic acids through the cytochrome P-450 pathway.

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Imidazoline RX871024 Raises Diacylglycerol Levels in Rat Pancreatic Islets

Cited by 5 publications

References 21 publications

Two Generations of Insulinotropic Imidazoline Compounds

Two Generations of Insulinotropic Imidazoline Compounds

The Role of I₁-Imidazoline and α₂-Adrenergic Receptors in the Modulation of Glucose Metabolism in the Spontaneously Hypertensive Obese Rat Model of Metabolic Syndrome X

Arachidonic acid signaling is involved in the mechanism of imidazoline-induced KATP channel-independent stimulation of insulin secretion

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Imidazoline RX871024 Raises Diacylglycerol Levels in Rat Pancreatic Islets

Cited by 5 publications

References 21 publications

Two Generations of Insulinotropic Imidazoline Compounds

Two Generations of Insulinotropic Imidazoline Compounds

The Role of I1-Imidazoline and α2-Adrenergic Receptors in the Modulation of Glucose Metabolism in the Spontaneously Hypertensive Obese Rat Model of Metabolic Syndrome X

Arachidonic acid signaling is involved in the mechanism of imidazoline-induced KATP channel-independent stimulation of insulin secretion

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The Role of I₁-Imidazoline and α₂-Adrenergic Receptors in the Modulation of Glucose Metabolism in the Spontaneously Hypertensive Obese Rat Model of Metabolic Syndrome X