Imidazoline Compounds Stimulate Insulin Release by Inhibition of KATP Channels and Interaction With the Exocytotic Machinery

Зайцев, С. В.; Efanov, Alexandre M.; Efanova, Ioulia B.; Larsson, Olof; Östenson, Claes Göran; Gold, Gerald; Berggren, Per Olof; Efendić, Suad

doi:10.2337/diab.45.11.1610

Cited by 75 publications

(37 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2), because in electropermeabilized islets, efaroxan enhanced Ca 2+ -dependent secretion. Similar results have been obtained previously with the imidazoline RX871024 (9).…”

Section: Discussionsupporting

confidence: 91%

“…Like efaroxan, this agent has the ability to induce closure of ␤-cell K ATP channels and to elicit a Ca 2+ -dependent increase in insulin secretion. Surprisingly however, RX871024 also stimulates insulin secretion from electropermeabilized islets, in which the regulation of membrane K + permeability is lost (9). This provides strong evidence that RX871024 must be capable of influencing insulin secretion by interaction with components of the secretory pathway that lie distal to the K ATP channel and are independent of the membrane potential.…”

mentioning

confidence: 89%

“…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.…”

mentioning

confidence: 99%

“…In the case of both of these agents, desensitization results in attenuation of the secretory response to multiple stimuli and is associated with reduced Ca 2+ influx (24)(25)(26)(27). More direct support for the concept that imidazolines can control insulin exocytosis independently of the membrane potential has emerged from studies with RX871024 (9). Like efaroxan, this agent has the ability to induce closure of ␤-cell K ATP channels and to elicit a Ca 2+ -dependent increase in insulin secretion.…”

mentioning

confidence: 99%

See 3 more Smart Citations

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

2001

View full text Add to dashboard Cite

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

show abstract

“…2), because in electropermeabilized islets, efaroxan enhanced Ca 2+ -dependent secretion. Similar results have been obtained previously with the imidazoline RX871024 (9).…”

Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 89%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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

2001

View full text Add to dashboard Cite

show abstract

“…Researchers have been trying to develop pharmacological approaches to inhibit the release of glucagon as a new treatment option. For example, some compounds such as imidazolines26, somatostatin analogues27, amylin and pramlintide2528 have been developed to directly inhibit glucagon secretion but have shown mixed results. Likewise, pramlintide which is an analogue of amylin had a modest effect on reducing glucagon secretion but no reported effect on reducing blood glucose in people with T2D2529.…”

Section: Discussionmentioning

confidence: 99%

Niclosamide reduces glucagon sensitivity via hepatic PKA inhibition in obese mice: Implications for glucose metabolism improvements in type 2 diabetes

Chowdhury

Turner

Bentley

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Type 2 diabetes (T2D) is a global pandemic. Currently, the drugs used to treat T2D improve hyperglycemic symptom of the disease but the underlying mechanism causing the high blood glucose levels have not been fully resolved. Recently published data showed that salt form of niclosamide improved glucose metabolism in high fat fed mice via mitochondrial uncoupling. However, based on our previous work we hypothesised that niclosamide might also improve glucose metabolism via inhibition of the glucagon signalling in liver in vivo. In this study, mice were fed either a chow or high fat diet containing two different formulations of niclosamide (niclosamide ethanolamine salt - NENS or niclosamide - Nic) for 10 weeks. We identified both forms of niclosamide significantly improved whole body glucose metabolism without altering total body weight or body composition, energy expenditure or insulin secretion or sensitivity. Our study provides evidence that inhibition of the glucagon signalling pathway contributes to the beneficial effects of niclosamide (NENS or Nic) on whole body glucose metabolism. In conclusion, our results suggest that the niclosamide could be a useful adjunctive therapeutic strategy to treat T2D, as hepatic glucose output is elevated in people with T2D and current drugs do not redress this adequately.

show abstract

Electrophysiology of the β Cell and Mechanisms of Inhibition of Insulin Release

Dunne

Ämmälä

Straub

et al. 2001

Comprehensive Physiology

View full text Add to dashboard Cite

The sections in this article are: Ion Channels in Insulin‐Secreting Cells Adenosine Triphosphate–Sensitive Potassium Channels Extracellular Control of Adenosine Triphosphate‐Sensitive Potassium Channel Function Therapeutic Manipulation by Modulators of Adenosine Triphosphate‐Sensitive Potassium Channels Architecture of the β‐cell Adenosine Triphosphate‐Sensitive Potassium Channel Calcium‐Selective Ion Channels Voltage‐Gated Sodium Channels Voltage‐Gated Potassium Channels Voltage‐Independent Potassium Channels Nonselective Cation Channels Anion‐Selective Channels Ionic Defects of β‐Cell Function Persistent Hyperinsulinemic Hypoglycemia of Infancy Altered Ionic Control of β Cells and Hypersecretion of Insulin Correlation of Gene Defects in the Adenosine Triphosphate‐Sensitive Potassium Channel with Persistent Hyperinsulinemic Hypoglycemia of Infancy Clinical Therapy for Persistent Hyperinsulinemic Hypoglycemia of Infancy Implications for Diabetes Mellitus Stimulus‐Secretion Coupling Mechanisms Other Than Depolarization Novel Methods for the Measurement of Insulin Secretion Capacitance Amperometry and Voltametry Calcium and Exocytosis Cyclic Adenosine Monophosphate and Exocytosis Effects of Phospholipases and Protein Kinases C and A Sulfonylureas and Exocytosis G Proteins and Exocytosis Other Modulators of Exocytosis Modeling Calcium‐, Cyclic, and Adenosine Monophosphate–, and Guanosine Triphosphate–Dependent Exocytosis Molecular Mechanisms of Exocytosis in the β Cell Receptor‐Mediated Inhibition of Insulin Release: Early and Late Effects Involvement of G Proteins Receptor–G Protein Interactions Inhibitory Mechanisms Adenosine Triphosphate–Sensitive Potassium Channel Activation and Membrane Repolarization Calcium Channel Inhibition Inhibition of Adenylate Cyclase Inhibition at a Distal Site G Protein–Target Interactions Adenosine Triphosphate–Sensitive Potassium Channel L‐Type Calcium Channels Adenylate Cyclase Distal Inhibitory Site Other Possible Mechanisms Inhibition of Glucose Metabolism Inhibition of Fatty Acid Metabolism Stimulation of Calcium–Adenosine Triphosphatase Activity Cyclic Guanosine Monophosphate Cytoskeleton Summary of Inhibitory Mechanisms

show abstract

Imidazoline Compounds Stimulate Insulin Release by Inhibition of KATP Channels and Interaction With the Exocytotic Machinery

Cited by 75 publications

References 0 publications

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

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

Niclosamide reduces glucagon sensitivity via hepatic PKA inhibition in obese mice: Implications for glucose metabolism improvements in type 2 diabetes

Electrophysiology of the β Cell and Mechanisms of Inhibition of Insulin Release

Contact Info

Product

Resources

About