title: Pharmacological inhibition of Eph receptors enhances glucose-stimulated insulin secretion from mouse and human pancreatic islets.
abstract: OBJECTIVE
  Type 2 diabetes is characterised by impaired glucose-stimulated insulin secretion (GSIS) from pancreatic islets. Since erythropoietin-producing hepatoma (Eph)-ephrin bidirectional signalling fine-tunes GSIS from pancreatic beta cells, we investigated Eph receptor tyrosine kinases (RTK) as potential drug targets for selectively increasing GSIS.
  
  
  METHODS
  Insulin secretion assays were carried out using mouse and human pancreatic islets as well as mouse insulinoma (MIN6) cells in the presence or absence of two Eph RTK inhibitors. Furthermore, the most potent inhibitor was injected into mice to evaluate its effects on glucose tolerance and plasma insulin levels.
  
  
  RESULTS
  We showed that the Eph RTK inhibitors selectively increased GSIS from MIN6 cells as well as mouse and human islets. Our results also showed that the insulin secretory effects of these compounds required Eph-ephrin signalling. Finally, pharmacological inhibition of Eph receptor signalling improved glucose tolerance in mice.
  
  
  CONCLUSIONS
  We showed for the first time that Eph RTKs represent targets for small molecules to selectively increase GSIS and improve glucose tolerance.
authors.affiliation: Institute of Metabolic Physiology and German Diabetes Center, Heinrich-Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Jain
authors.forename: D
authors.initials: D
authors.lastname: Jain
authors.forename: Q
authors.initials: Q
authors.lastname: Liu
authors.forename: B
authors.initials: B
authors.lastname: Bartosinska
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: D
authors.initials: D
authors.lastname: Schumann
authors.forename: S G
authors.initials: SG
authors.lastname: Kauschke
authors.forename: P
authors.initials: P
authors.lastname: Eickelmann
authors.forename: L
authors.initials: L
authors.lastname: Piemonti
authors.forename: N S
authors.initials: NS
authors.lastname: Gray
authors.forename: E
authors.initials: E
authors.lastname: Lammert
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004921:Erythropoietin / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D007340:Insulinoma / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D036123:Receptor, EphA5 / Q000378:metabolism; D036081:Receptors, Eph Family / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D001549:Benzamides; D007328:Insulin; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D004921:Erythropoietin; D000068877:Imatinib Mesylate; D036123:Receptor, EphA5; D036081:Receptors, Eph Family; D005947:Glucose