Inhibition of Eph/ephrin interaction with the small molecule UniPR500 improves glucose tolerance in healthy and insulin-resistant mice. (March 2019)

• Record Type: Journal Article
• Authors: Giorgio, C.; Incerti, M.; Pala, D.; Russo, S.; Chiodelli, P.; Rusnati, M.; Cantoni, A.M.; Di Lecce, R.; Barocelli, E.; Bertoni, S.; Ravassard, P.; Manenti, F.; Piemonti, L.; Ferlenghi, F.; Lodola, A.; Tognolini, M.
• Is Part Of: Pharmacological research. Volume 141(2019)
• Page Start: 319
• Page End: 330
• Publication Date: 2019-03
• Subjects: Eph/ephrins -- Diabetes -- Insulin; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2019.01.011
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: 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.