[HTML][HTML] Pharmacological inhibition of Eph receptors enhances glucose-stimulated insulin secretion from mouse and human pancreatic islets
Diabetologia, 2013•Springer
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 …
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 …
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.
Springer