Pharmacological inhibition of Eph receptors enhances glucose-stimulated insulin secretion from mouse and human pancreatic islets

Jain, Ruchi; Jain, Deepak; Liu, Q; Bartosinska, Barbara; Wang, J; Schumann, Desiree M.; Kauschke, Stefan G.; Eickelmann, Peter; Piemonti, Lorenzo; Gray, Nathanael S.; Lammert, Eckhard

doi:10.1007/s00125-013-2877-1

Cited by 26 publications

(18 citation statements)

References 20 publications

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“…Interestingly, EphA forward signaling induced by ephrin-A5 also plays a complementary role in the glucose-sensing hypothalamic region of the brain, where it promotes the release of hormones that correct hypoglycemia (118). Consistent with these findings, mouse preclinical studies show that pharmacological Eph kinase inhibition can enhance glucose-stimulated insulin secretion, suggesting its potential use for diabetes treatment (119). …”

Section: Other Diseasesmentioning

confidence: 70%

“…Surprisingly, dasatinib was recently reported to also inhibit kinase-independent EphA2 oncogenic signaling in cells through an indirect mechanism (149). Various types of screens to identify Eph kinase inhibitors have also yielded some promising compounds, with mouse preclinical studies showing the potential usefulness of several of them for inhibition of angiogenesis (150; 151) or the treatment of diabetes (119). …”

Section: Strategies For Targeting the Eph/ephrin Systemmentioning

confidence: 99%

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Eph Receptors and Ephrins: Therapeutic Opportunities

Barquilla

Pasquale

2015

Annu. Rev. Pharmacol. Toxicol.

247

287

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The Eph receptor tyrosine kinase family plays important roles in developmental processes, adult tissue homeostasis and various diseases. Interaction with ephrin ligands on the surface of neighboring cells triggers Eph receptor kinase-dependent signaling. The ephrins can also transmit signals, leading to bidirectional cell contact-dependent communication. Moreover, Eph receptors and ephrins can function independently of each other, through interplay with other signaling systems. Given their involvement in many pathological conditions ranging from neurological disorders to cancer and viral infections, Eph receptors and ephrins are increasingly recognized as attractive therapeutic targets and a variety of strategies are being explored to modulate their expression and function. Eph receptor/ephrin upregulation in cancer cells, the angiogenic vasculature, and injured or diseased tissues also offers opportunities for Eph/ephrin-based targeted drug delivery and imaging. Thus, despite the challenges presented by the complex biology of the Eph receptor/ephrin system, exciting possibilities exist for therapies exploiting these molecules.

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Section: Other Diseasesmentioning

confidence: 70%

Section: Strategies For Targeting the Eph/ephrin Systemmentioning

confidence: 99%

Eph Receptors and Ephrins: Therapeutic Opportunities

Barquilla

Pasquale

2015

Annu. Rev. Pharmacol. Toxicol.

247

287

View full text Add to dashboard Cite

show abstract

“…Recently we started to explore neuronal receptors as new targets for selectively increasing GSIS in mouse and human islets 13 , as islets are innervated 14,15 and beta cells and neurons share many features 16,17 . Islets express components of the glutamate signaling system, such as vesicular glutamate transporters, excitatory amino acid transporters (EAATs), AMPA and kainate receptors, and NMDA receptors (NMDARs) [18][19][20][21][22] .…”

mentioning

confidence: 99%

Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment

Marquard

Otter

Welters

et al. 2015

Nat Med

129

192

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In the nervous system, NMDA receptors (NMDARs) participate in neurotransmission and modulate the viability of neurons. In contrast, little is known about the role of NMDARs in pancreatic islets and the insulin-secreting beta cells whose functional impairment contributes to diabetes mellitus. Here we found that inhibition of NMDARs in mouse and human islets enhanced their glucose-stimulated insulin secretion (GSIS) and survival of islet cells. Further, NMDAR inhibition prolonged the amount of time that glucose-stimulated beta cells spent in a depolarized state with high cytosolic Ca(2+) concentrations. We also noticed that, in vivo, the NMDAR antagonist dextromethorphan (DXM) enhanced glucose tolerance in mice, and that in vitro dextrorphan, the main metabolite of DXM, amplified the stimulatory effect of exendin-4 on GSIS. In a mouse model of type 2 diabetes mellitus (T2DM), long-term treatment with DXM improved islet insulin content, islet cell mass and blood glucose control. Further, in a small clinical trial we found that individuals with T2DM treated with DXM showed enhanced serum insulin concentrations and glucose tolerance. Our data highlight the possibility that antagonists of NMDARs may provide a useful adjunct treatment for diabetes.

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“…However in another study performed on human and rat pancreatic islets imatinib did not affect insulin secretion10. The latter observation is supported by other findings obtained with MIN6 mouse beta cells, mouse and human islets11. In contrast to imatinib, sunitinib was able to increase insulin level and decrease blood glucose level in a non-obese, spontaneously diabetic Torii rats animal model3.…”

mentioning

confidence: 54%

Novel members of quinoline compound family enhance insulin secretion in RIN-5AH beta cells and in rat pancreatic islet microtissue

Őrfi

Wáczek

Baska

et al. 2017

Sci Rep

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According to clinical data, some tyrosine kinase inhibitors (TKIs) possess antidiabetic effects. Several proposed mechanisms were assigned to them, however their mode of action is not clear. Our hypothesis was that they directly stimulate insulin release in beta cells. In our screening approach we demonstrated that some commercially available TKIs and many novel synthesized analogues were able to induce insulin secretion in RIN-5AH beta cells. Our aim was to find efficient, more selective and less toxic compounds. Out of several hits, we chose members from a compound family with quinoline core structure for further investigation. Here we present the studies done with these novel compounds and reveal structure activity relationships and mechanism of action. One of the most potent compounds (compound 9) lost its affinity to kinases, but efficiently increased calcium influx. In the presence of calcium channel inhibitors, the insulinotropic effect was attenuated or completely abrogated. While the quinoline TKI, bosutinib substantially inhibited tyrosine phosphorylation, compound 9 had no such effect. Molecular docking studies further supported our data. We confirmed that some TKIs possess antidiabetic effects, moreover, we present a novel compound family developed from the TKI, bosutinib and optimized for the modulation of insulin secretion.

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Pharmacological inhibition of Eph receptors enhances glucose-stimulated insulin secretion from mouse and human pancreatic islets

Cited by 26 publications

References 20 publications

Eph Receptors and Ephrins: Therapeutic Opportunities

Eph Receptors and Ephrins: Therapeutic Opportunities

Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment

Novel members of quinoline compound family enhance insulin secretion in RIN-5AH beta cells and in rat pancreatic islet microtissue

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