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

• Published in: Diabetologia 2013-06, Vol.56 (6), p.1350-1355
• Main Authors: Jain, R., Jain, D., Liu, Q., Bartosinska, B., Wang, J., Schumann, D., Kauschke, S. G., Eickelmann, P., Piemonti, L., Gray, N. S., Lammert, E.
• Format: Article
• Language: English
• Subjects: Animals; Benzamides - pharmacology; Biological and medical sciences; Cell Line; Cell Survival; Diabetes; Diabetes Mellitus, Type 2 - metabolism; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Erythropoietin - metabolism; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glucose; Glucose - metabolism; Human Physiology; Humans; Imatinib Mesylate; Insulin; Insulin - blood; Insulin - metabolism; Insulin Secretion; Insulinoma - metabolism; Internal Medicine; Islets of Langerhans - metabolism; Kinases; Ligands; Magnetic Resonance Spectroscopy; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Mice, Transgenic; NMR; Nuclear magnetic resonance; Pharmacokinetics; Phosphorylation; Piperazines - pharmacology; Plasma; Protein Kinase Inhibitors - pharmacology; Pyrimidines - pharmacology; Receptor, EphA5 - metabolism; Receptors, Eph Family - antagonists & inhibitors; Receptors, Eph Family - metabolism
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-013-2877-1

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.