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

R. Jain, D. Jain, Q. Liu, B. Bartosinska, J. Wang, D. Schumann, S. G. Kauschke, P. Eickelmann, L. Piemonti, N. S. Gray, E. Lammert

Research output: Contribution to journalArticlepeer-review

Abstract

Aims/hypothesis: 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/interpretation: We showed for the first time that Eph RTKs represent targets for small molecules to selectively increase GSIS and improve glucose tolerance.

Original languageEnglish
Pages (from-to)1350-1355
Number of pages6
JournalDiabetologia
Volume56
Issue number6
DOIs
Publication statusPublished - Jun 2013

Keywords

  • Compound
  • Eph
  • Ephrin
  • Glucose tolerance
  • Insulin secretion
  • Pancreatic islets

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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