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

Bleck, Claudia; Wienbergen, Antje; Rustenbeck, Ingo

doi:10.1007/s00125-005-0031-4

Cited by 18 publications

(22 citation statements)

References 41 publications

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“…These compounds were used at a concentration which inhibits B-cell KATP channel activity by about 85% [29], which is comparable to the effect of 100 µM gatifloxacin on reconstituted KATP channels [11]. While tolbutamide closes these channels by binding to the regulatory subunit, SUR1 [12], efaroxan, like the fluoroquinolones, inhibits KATP channels by binding to the pore-forming unit, Kir 6.2 [29].…”

Section: Page 11 Of 30mentioning

confidence: 99%

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The insulinotropic effect of fluoroquinolones

Ghaly¹,

Gunda²,

Sahin³

et al. 2009

Biochemical Pharmacology

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Section: Page 11 Of 30mentioning

confidence: 99%

“…While tolbutamide closes these channels by binding to the regulatory subunit, SUR1 [12], efaroxan, like the fluoroquinolones, inhibits KATP channels by binding to the pore-forming unit, Kir 6.2 [29].…”

Section: Page 11 Of 30mentioning

confidence: 99%

The insulinotropic effect of fluoroquinolones

Ghaly¹,

Gunda²,

Sahin³

et al. 2009

Biochemical Pharmacology

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“…Islets were dissociated into single cells by incubation for 10 min in a Ca 2+ -free medium (135 mmol/l NaCl, 4.8 mmol/l KCl, 1.2 mmol/l KH 2 PO 4 , 1.2 mmol/l MgSO 4 , 25 mmol/l HEPES, 0.5 mmol/l EGTA, 3 mmol/l glucose, 1% BSA, pH 7.4), subsequent vortexmixing for 1 min, centrifugation for 1 min at 200 g and suspension in culture medium. Isolated islets were cultured in the presence of 5 mmol/l glucose (for microfluorimetric measurements) and islet cells in the presence of 10 mmol/l glucose (for patch-clamp experiments) as described previously [23,24].…”

Section: Materials and Mediamentioning

confidence: 99%

“…The loading concentration was 2 μmol/l in basal medium containing 2 mg/ml BSA and 5 mmol/l glucose (45 min at 37°C). As described previously [24], the islets were then perifused at 0.2 ml/min and at 35°C using basal medium (additions as detailed under Results, no BSA) and the epifluorescence was recorded (six islet subregions evaluated per experiment).…”

Section: +mentioning

confidence: 99%

Fuel-induced amplification of insulin secretion in mouse pancreatic islets exposed to a high sulfonylurea concentration: role of the NADPH/NADP+ ratio

Panten

Rustenbeck

2007

Diabetologia

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Aims/hypothesis The aim of this study was to examine whether the cytosolic NADPH/NADP + ratio of beta cells serves as an amplifying signal in fuel-induced insulin secretion and whether such a function is mediated by cytosolic α-ketoglutarate. Methods Pancreatic islets and islet cells were isolated from albino mice by collagenase digestion. Insulin secretion of incubated or perifused islets was measured by ELISA. The NADPH and NADP + content of incubated islets was determined by enzymatic cycling. The cytosolic Ca 2+ concentration ([Ca 2+ ] c ) in islets was measured by microfluorimetry and the activity of ATP-sensitive K + channels in islet cells by patch-clamping. Results Both 30 mmol/l glucose and 10 mmol/l α-ketoisocaproate stimulated insulin secretion and elevated the NADPH/NADP + ratio of islets preincubated in the absence of fuel. The increase in the NADPH/NADP + ratio was abolished in the presence of 2.7 μmol/l glipizide (closing all ATP-sensitive K + channels). However, α-ketoisocaproate, but not glucose, still stimulated insulin secretion. That glipizide did not inhibit α-ketoisocaproate-induced insulin secretion was not the result of elevated [Ca 2+ ] c , as glucose caused a more marked [Ca 2+ ] c increase. Insulin release triggered by glipizide alone was moderately amplified by dimethyl α-ketoglutarate (which is cleaved to produce cytosolic α-ketoglutarate), but there was no indication of a signal function of cytosolic α-ketoglutarate. Conclusions/interpretationThe results strongly suggest that the NADPH/NADP + ratio in the beta cell cytosol does not serve as an amplifying signal in fuel-induced insulin release. The study supports the view that amplification results from the intramitochondrial production of citrate by citrate synthase and from the associated export of citrate into the cytosol.

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“…Thus, the earlier hypothesis that the characteristics of the imidazoline effect are due to a sensitization of the exocytotic machinery to [Ca 2ϩ ] c (Zaitsev et al, 1996) (Liu et al, 1998). Most likely, the [Ca 2ϩ ] c oscillation is the direct consequence of the oscillatory ␤-cell membrane depolarization elicited by efaroxan in the presence of 5 mM glucose (Bleck et al, 2005). The repolarization despite the continuous presence of efaroxan may result from the marked susceptibility of the K ATP channel block by efaroxan to the opening effect of nucleoside diphosphates (Wienbergen et al, 2007).…”

Section: Insulinotropic Effect Of Imidazolinesmentioning

confidence: 98%

Selective Enhancement of Nutrient-Induced Insulin Secretion by ATP-Sensitive K⁺ Channel-Blocking Imidazolines

Hatlapatka

Wienbergen²,

Kühne³

et al. 2009

J Pharmacol Exp Ther

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The contribution of ATP-sensitive K ϩ channel (K ATP channel)-dependent and -independent signaling to the insulinotropic characteristics of imidazolines was explored using perifused mouse islets and ␤-cells. Up to a concentration of 100 M efaroxan had no insulinotropic effect in the presence of a basal glucose concentration, but enhanced the effect of a stimulatory concentration of glucose or nonglucidic nutrients (ketoisocaproate plus glutamine). The secretion by a non-nutrient (40 mM KCl) was not enhanced. At 500 M, efaroxan stimulated insulin secretion when glucose was basal. Likewise, at 0.1 to 10 M RX871024 [2-(imidazolin-2-yl)-1-phenylindole] showed a purely enhancing effect, but at 100 M it elicited a strong KCl-like secretory response in the presence of basal glucose. At 0.1 and 1 M RX871024 did not significantly depolarize the ␤-cell membrane. However, at a purely enhancing drug concentration (10 M RX871024 or 100 M efaroxan) K ATP channel activity was strongly reduced, the membrane was depolarized, and the cytosolic Ca 2ϩ concentration was elevated in the presence of basal glucose. Insulin secretion by sulfonylurea receptor (SUR)1 knockout (KO) islets, which have no functional K ATP channels, was not increased by efaroxan (100 or 500 M) or by 10 M RX871024 but was increased by 100 M RX871024. The imidazolines phentolamine and alinidine (100 M) were also ineffective on SUR1 KO islets. It is concluded that a significant K ATP channel block is compatible with a purely enhancing effect of the imidazolines on nutrient-induced insulin secretion. Only RX871024 has an additional, nondepolarizing effect, which at a high drug concentration is able to elicit a K ATP channel-independent secretion.The insulinotropic effect of the prototypical imidazoline phentolamine was originally believed to be due to an antagonism at ␣ 2 -adrenoceptors of the ␤-cell (Robertson and Porte, 1973; Efendic et al., 1975). The observation that the insulinotropic effect of this compound was not shared by other antagonists at ␣ 2 -adrenoceptors but was shared by other compounds with imidazoline moieties (Ostenson et al., 1988;Schulz and Hasselblatt, 1989) led to the hypothesis that the insulinotropic effect was mediated by a ␤-cell-specific subtype of the imidazoline receptor (Chan et al., 1994). In other tissues, at least two nonadrenergic imidazoline binding sites have been identified, and consequently the hypothetical ␤-cell subtype was named I 3 receptor (Eglen et al., 1998;Morgan, 1999). In contrast to the I 1 and I 2 sites where binding occurs with nanomolar affinity, binding to I 3 sites requires micromolar concentrations of the imidazoline (Rustenbeck et al., 1997).The demonstration that phentolamine and other imidazolines block ATP-sensitive K ϩ channels (K ATP channels) in pancreatic ␤-cells offered an explanation for their insulinotropic property (Plant and Henquin, 1990;Chan and Morgan, 1990). However, it remained unclear how the effect on the K ATP channel was related to the nonadrenergic imidazoline binding sites on...

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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

Cited by 18 publications

References 41 publications

The insulinotropic effect of fluoroquinolones

The insulinotropic effect of fluoroquinolones

Fuel-induced amplification of insulin secretion in mouse pancreatic islets exposed to a high sulfonylurea concentration: role of the NADPH/NADP+ ratio

Selective Enhancement of Nutrient-Induced Insulin Secretion by ATP-Sensitive K⁺ Channel-Blocking Imidazolines

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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

Cited by 18 publications

References 41 publications

The insulinotropic effect of fluoroquinolones

The insulinotropic effect of fluoroquinolones

Fuel-induced amplification of insulin secretion in mouse pancreatic islets exposed to a high sulfonylurea concentration: role of the NADPH/NADP+ ratio

Selective Enhancement of Nutrient-Induced Insulin Secretion by ATP-Sensitive K+ Channel-Blocking Imidazolines

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Selective Enhancement of Nutrient-Induced Insulin Secretion by ATP-Sensitive K⁺ Channel-Blocking Imidazolines