Prevention of Diabetes and Complications

Biography

Biography: Carina Proença

Abstract

Type 2 diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia resulting from inadequate insulin secretion and/or resistance to insulin action. Protein tyrosine phosphatase 1B (PTP1B) is considered a major
negative regulator in the insulin signaling pathway, contributing to insulin resistance. Thus, the discovery and development of selective and effective PTP1B inhibitors is a potential therapeutic target for the management of type 2 DM. Some flavonoids have already been shown to inhibit this enzyme, but the literature still lacks in depth structure-activity relationship studies. The main aim of the present work was to test a diversified panel of known and new flavonoids, with different types of substituents (-OH, -OMe and/or -OBn) in different positions, against the PTP1B inhibitory activity. The evaluation of PTP1B activity was performed in vitro by monitoring PTP1B-catalyzed hydrolysis of the substrate p-nitrophenyl phosphate (pNPP) into the product p-nitrophenolate at 405 nm in a microplate reader. The study of the inhibition type of the most active flavonoid was made using the nonlinear regression Michaelis-Menten enzymatic kinetics and the corresponding Lineweaver-Burk plot. Our results suggest that that the presence of -OMe groups at positions 7 and 8 in A ring, together with the presence of -OBn groups at 3’ and 4’ positions in B ring and a OH group at 3 position in C ring, increases the flavonoids’ ability to inhibit PTP1B. The most active flavonoid was 3’,4’-dimethoxy-7,8-dibenzoxyflavonol, presenting a mixed type inhibition. In conclusion, some of the tested flavonoids seem to be promising PTP1B inhibitors and potential effective drugs in the management of type 2 DM, increasing insulin sensitivity.