Gabriele Carullo
University of Calabria, Italy
Title: GPR40 as a template for the development of new insulin secretagogues with wound healing properties
Biography
Biography: Gabriele Carullo
Abstract
Free Fatty Acid Receptors, belonging to GPCRs family, are emerging as new targets to treat diabetes or related disorders, representing a versatile family of receptors, activated by fatty acids contained in vegetable oils. In this context, extra-virgin olive oil is a “natural anti-diabetic agent”, favoring GLP-1 secretion from pancreas. Its principal component, olive oil is the endogenous ligand of FFAR1/GPR40. This receptor is highly expressed in pancreatic β-cells, where its activation promotes insulin secretion. Starting from oleic acid, which is able to promote glucose-stimulated insulin secretion (GSIS) at lipo-toxic doses, new hybrid derivatives of oleic acid with quercetin were designed and synthesized. 2-(2,2-diphenylbenzo[d][1,3]dioxol-5-yl)-5,7-dihydroxy-4-oxo-4H-chromen-3-yl oleate (AV1) was synthesized in order to prevent C3-OH auto-oxidation of quercetin and obtained in good yield. Docking simulations demonstrated that AV1 could be accommodated within the long transmembrane crevice of the receptor. These data suggested for the first time that this binding site could recognize exogenous ligands. AV1 was able to evocate insulin release (EC50=5μM) by both pancreatic islets and in vitro β-cells system (INS-1 832- 13). Furthermore, Quercetin-3-oleate (AV2) was synthesized through a green synthesis and was able to favor GSIS at higher concentrations than AV1 (EC50=21μM). Functional assays, conducted by using DC260126 as known antagonist, demonstrated that AV1 is a full GPR40 agonist, whilst AV2 is a partial agonist. AV2 was also assayed for its wound healing properties in HaCaT cell line (stably expressing GPR40). AV2 was able to promote wound healing at very low concentration (10 nM), enhancing the production of TGF-β. Moreover, in THP-1 monocytes, AV2 was able to promote IL-6 production, not affecting IL-1β or TNF-α. These data confirmed that AV2 could be used as a suitable tool in the management of Type 2 Diabetes Mellitus, limiting lipotoxicity due to excessive GPR40 activation and especially in diabetic foot ulcer.