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Volume 9 Journal of Obesity & Weight Loss Therapy
ISSN: 2165-7904
JOINT EVENT
Childhood Obesity 2019
Diabetes Conference 2019
March 18-19, 2019
&
3rd World Congress on Diabetes and Obesity
12th International Conferences on Childhood Obesity and Nutrition
March 18-19, 2019 | Rome, Italy
GPR40 as a template for the development of new insulin secretagogues with wound healing properties
Gabriele Carullo
University of Calabria, Italy
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.
Biography
Gabriele Carullo has his expertise in green chemistry and development of hybrid compounds for the development of interesting pharmacological tools. In
particular, he is developing new polyphenols-fatty acids hybrids as new GPR40/GPR120 ligands in order to treat type 2 diabetes and its comorbidities. In
addition, he works on the development of new antihypertensive agents starting from flavonoids as a surge of KCa1.1 and Cav1.2 channel modulators. His
pharmacological research is also devoted to the production of new functional foods, for the treatment of hypertension and diabetes, starting from food wastes.
Gabriele Carullo, J Obes Weight Loss Ther 2019, Volume 9
DOI: 10.4172/2165-7904-C1-090