Heterogeneous characteristics of imidazoline-induced insulin secretion

Rustenbeck, Ingo; Leupolt, Lars; Kowalewski, Roland; Hasselblatt, A.

doi:10.1007/pl00005347

Cited by 11 publications

(10 citation statements)

References 38 publications

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“…Our conclusion, therefore, is that the greater glucose dependence of efaroxan effects on insulin secretion is not simply a function of a less complete K ATP channel closure. This view is supported by previous observations that phentolamine also exerts an enhancing effect on secretion in the presence of 5 mmol/l glucose, when used at the lower concentration of 32 mol/l (16).…”

Section: Discussionsupporting

confidence: 84%

“…In this context, it should be kept in mind that the term "imidazolines" covers a rather heterogeneous group. We have shown earlier that phentol-amine does in fact stimulate secretion also at basal glucose (16), whereas efaroxan has been described to exhibit a practically ideal glucose sensitivity in that it fails to increase insulin secretion at subthreshold glucose concentrations (17). The glucose dependence of the insulinotropic effect of RX 871024 decreased in a concentrationdependent manner between 10 and 100 mol/l (9,14).…”

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confidence: 91%

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Glucose Dependence of Imidazoline-Induced Insulin Secretion

2004

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The glucose dependence of the insulinotropic action of K ATP channel-blocking imidazoline compounds was investigated. Administration of 100 mol/l phentolamine, but not 100 mol/l efaroxan, markedly increased insulin secretion of freshly isolated mouse islets when the perifusion medium contained 5 mmol/l glucose. When the glucose concentration was raised to 10 mmol/l in the continued presence of either imidazoline, a clear potentiation of secretion occurred as compared with 10 mmol/l glucose alone. In the presence of efaroxan, a brisk first-phase-like increase was followed by a sustained phase, whereas a more gradual increase resulted in the presence of phentolamine. Administration of 100 mol/l phentolamine was somewhat more effective than 100 mol/l efaroxan to inhibit K ATP channel activity in intact cultured ␤-cells (reduction by 96 vs. 83%). Both compounds were similarly effective to depolarize the ␤-cells. When measured by the perforated patch-technique, the depolarization by efaroxan was often oscillatory, whereas that by phentolamine was sustained. In perifused cultured islets, both compounds increased the cytosolic calcium concentration ( I midazolines are a group of investigational antidiabetic drugs. Originally, an antagonism at ␣-adrenoceptors was believed to be the mechanism of action of the prototypical imidazoline, phentolamine (1,2). When it became clear that the insulinotropic effect of this compound was not due to an ␣-antagonism but was related to its imidazoline moiety (3,4), it was hypothesized that this effect was mediated by a ␤-cell imidazoline receptor, as had been described previously for other pharmacological actions of imidazoline compounds (5).The demonstration that phentolamine and other imidazolines block K ATP channels in pancreatic ␤-cells (6,7) offered an explanation for their insulinotropic property. However, it remained unclear how the effect on the K ATP channel was related to the hypothetical ␤-cell imidazoline receptor (8). The demonstration that the imidazoline RX 871024 increased insulin secretion not only by blocking K ATP channels, but also by acting at a site distal to calcium influx, led to the alternative hypothesis that imidazolines have effects at multiple independent sites of the pancreatic ␤-cell (9). The concept of a ␤-cell imidazoline receptor mediating a multitude of effects was rendered less likely by the observation that the K ATP channel block by imidazolines was exerted directly at Kir6.2, the pore-forming subunit of the channel (10,11).Thus, it could be expected that by structural modification it should be possible to separate the blocking effect of the imidazolines on K ATP channels from their more direct effect on exocytosis. An imidazoline devoid of a K ATP channel-blocking activity was expected to stimulate secretion only in the presence of high but not basal glucose concentrations. In fact, several newly synthesized imidazoline compounds were shown to stimulate insulin secretion at concentrations at which they did not affect K ATP channel activity (12,13...

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Section: Discussionsupporting

confidence: 84%

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confidence: 91%

Glucose Dependence of Imidazoline-Induced Insulin Secretion

2004

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“…This has led to the implicit assumption that these insulin secretagogues have a homogeneous pharmacological profile, which is not the case [2,3]. Also, it remained unclear whether the imidazoline moiety was essential for the insulinotropic characteristics.…”

Section: Discussionmentioning

confidence: 99%

“…Their insulinotropic effect differs from that of sulfonylureas in two respects: (1) insulin secretion is increased only in the presence of stimulatory glucose concentrations; and (2) insulin secretion is increased beyond the extent achieved by sulfonylureas [1]. However, these characteristics do not apply equally to each insulinotropic imidazoline compound [2,3].…”

Section: Introductionmentioning

confidence: 99%

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

Bleck¹,

Wienbergen²,

Rustenbeck

2005

Diabetologia

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Essential role of the imidazoline moiety in the insulinotropic effect but not the K ATP channel-blocking effect of imidazolines; a comparison of the effects of efaroxan and its imidazole analogue, KU14R Abstract Aims/hypothesis: Imidazolines are a class of investigational antidiabetic drugs. It is still unclear whether the imidazoline ring is decisive for insulinotropic characteristics. Materials and methods: We studied the imidazoline efaroxan and its imidazole analogue, KU14R, which is currently classified as an imidazoline antagonist. The effects of both on stimulus secretion-coupling in normal mouse islets and beta cells were compared by measuring K ATP channel activity, plasma membrane potential, cytosolic calcium concentration ([Ca 2+ ] c ) and dynamic insulin secretion. Results: In the presence of 10 mmol/l but not of 5 mmol/l glucose, efaroxan (100 μmol/l) strongly enhanced insulin secretion by freshly isolated perifused islets, whereas KU14R (30, 100 or 300 μmol/l) was ineffective at both glucose concentrations. Surprisingly, the insulinotropic effect of efaroxan was not antagonised by KU14R. K ATP channels were blocked by efaroxan (IC 50 8.8 μmol/l, Hill slope −1.1) and by KU14R (IC 50 31.9 μmol/l, Hill slope −1.5). Neither the K ATP channelblocking effect nor the depolarising effect of efaroxan was antagonised by KU14R. Rather, both compounds strongly depolarised the beta cell membrane potential and induced action potential spiking. However, KU14R was clearly less efficient than efaroxan in raising [Ca 2+ ] c in single beta cells and whole islets at 5 mmol/l glucose. The increase in [Ca 2+ ] c induced by 10 mmol/l glucose was affected neither by efaroxan nor by KU14R. Again, KU14R did not antagonise the effects of efaroxan. Conclusions/interpretation:The presence of an imidazole instead of an imidazoline ring leads to virtually complete loss of the insulinotropic effect in spite of a preserved ability to block K ATP channels. The imidazole compound is less efficient in raising [Ca 2+ ] c ; in particular, it lacks the ability of the imidazoline to potentiate the enhancing effect of energy metabolism on Ca 2+ -induced insulin secretion.

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“…midazoline reagents, such as efaroxan (1)(2)(3)(4)(5), phentolamine (6)(7)(8), and RX871024 (9)(10)(11)(12)(13)(14), can stimulate insulin secretion both in vivo and in vitro, and a number of structurally related compounds are currently under development as novel oral antihyperglycemic agents. Despite this, the mechanism of action of imidazoline insulinsecretagogues has not been fully established, and their principal molecular target has not been defined at the level of the ␤-cell.…”

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confidence: 99%

Characterization of a KATP Channel—Independent Pathway Involved in Potentiation of Insulin Secretion by Efaroxan

2001

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Efaroxan, like several other imidazoline reagents, elicits a glucose-dependent increase in insulin secretion from pancreatic ␤-cells. This response has been attributed to efaroxan-mediated blockade of K ATP channels, with the subsequent gating of voltage-sensitive calcium channels. However, increasing evidence suggests that, at best, this mechanism can account for only part of the secretory response to the imidazoline. In support of this, we now show that efaroxan can induce functional changes in the secretory pathway of pancreatic ␤-cells that are independent of K ATP channel blockade. In particular, efaroxan was found to promote a sustained sensitization of glucose-induced insulin release that persisted after removal of the drug and to potentiate Ca 2+ -induced insulin secretion from electropermeabilized islets. To investigate the mechanisms involved, we studied the effects of the efaroxan antagonist KU14R. This agent is known to selectively inhibit insulin secretion induced by efaroxan, without altering the secretory response to glucose or KCl. Surprisingly, however, KU14R markedly impaired the potentiation of insulin secretion mediated by agents that raise cAMP, including the adenylate cyclase activator, forskolin, and the phosphodiesterase inhibitor isobutylmethyl xanthine (IBMX). These effects were not accompanied by any reduction in cAMP levels, suggesting an antagonistic action of KU14R at a more distal point in the pathway of potentiation. In accord with our previous work, islets that were exposed to efaroxan for 24 h became selectively desensitized to this agent, but they still responded normally to glucose. Unexpectedly, however, the ability of either forskolin or IBMX to potentiate glucose-induced insulin secretion was severely impaired in these islets. By contrast, the elevation of cAMP was unaffected by culture of islets with efaroxan. Taken together, the data suggest that, in addition to effects on the K ATP channel, imidazolines also interact with a more distal component that is crucial to the potentiation of insulin secretion. This component is not required for Ca 2+ -dependent secretion per se but is essential to the mechanism by which cAMP potentiates insulin release. Overall, the results indicate that the actions of efaroxan at this distal site may be more important for control of insulin secretion than its effects on the K ATP channel. Diabetes 50:340-347, 2001

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Heterogeneous characteristics of imidazoline-induced insulin secretion

Cited by 11 publications

References 38 publications

Glucose Dependence of Imidazoline-Induced Insulin Secretion

Glucose Dependence of Imidazoline-Induced Insulin Secretion

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

Characterization of a KATP Channel—Independent Pathway Involved in Potentiation of Insulin Secretion by Efaroxan

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