Inhibition of Eph/ephrin interaction with the small molecule UniPR500 improves glucose tolerance in healthy and insulin-resistant mice

C. Giorgio, M. Incerti, D. Pala, S. Russo, P. Chiodelli, M. Rusnati, A. M. Cantoni, R. Di Lecce, E. Barocelli, S. Bertoni, P. Ravassard, F. Manenti, L. Piemonti, F. Ferlenghi, A. Lodola, M. Tognolini

Research output: Contribution to journalArticlepeer-review

Abstract

Eph/ephrin interactions and their bidirectional signaling are integral part of the complex communication system between β-cells, essential for glucose homeostasis. Indeed, Eph/ephrin system was shown to be directly involved in the glucose-stimulated insulin secretion (GSIS) process occurring in the pancreatic islets. Here we tested the Eph antagonist UniPR500 as GSIS enhancer. UniPR500 was validated as EphA5-ephrin-A5 inhibitor in vitro and its efficacy as GSIS enhancer was assessed on EndoC-βH1 cells. The selectivity of UniPR500 was evaluated by testing this compound on a panel of well-known molecular targets responsible for the regulation of glucose homeostasis. Plasmatic levels of UniPR500 were measured by HPLC/MS approach after oral administration. Finally, UniPR500 was tested as hypoglycemic agent in healthy mice, in a non-genetic mouse model of insulin resistance (IR) and in a non-genetic mouse model of type 1 diabetes (T1D). The compound is an orally bioavailable and selective Eph antagonist, able to increase GSIS from EndoC-βH1 cells. When tested in vivo UniPR500 showed to improve glucose tolerance in healthy and IR mice. As expected by a GSIS enhancer acting on healthy β-cells, UniPR500 was ineffective when tested on a non-genetic mouse model of type 1 diabetes, where pancreatic function was severely compromised. In conclusion our findings suggest that Eph targeting is a new and valuable pharmacological strategy in the search of new hypoglycemic agents.

Original languageEnglish
Pages (from-to)319-330
Number of pages12
JournalPharmacological Research
Volume141
DOIs
Publication statusPublished - Mar 2019

Keywords

  • Diabetes
  • Eph/ephrins
  • Insulin

ASJC Scopus subject areas

  • Pharmacology

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