A comprehensive review on the antidiabetic activity of flavonoids targeting PTP1B and DPP-4: a structure-activity relationship analysis

Abstract

Type 2 diabetes (T2D) is an expanding global health problem, resulting from defects in insulin secretion and/or insulin resistance. In the past few years, both protein tyrosine phosphatase 1B (PTP1B) and dipeptidyl peptidase-4 (DPP-4), as well as their role in T2D, have attracted the attention of the scientific community. PTP1B plays an important role in insulin resistance and is currently one of the most promising targets for the treatment of T2D, since no available PTP1B inhibitors were still approved. DPP-4 inhibitors are among the most recent agents used in the treatment of T2D (although its use has been associated with possible cardiovascular adverse events). The antidiabetic properties of flavonoids are well-recognized, and include inhibitory effects on the above enzymes, although hitherto not therapeutically explored. In the present study, a comprehensive review of the literature of both synthetic and natural isolated flavonoids as inhibitors of PTP1B and DPP-4 activities is made, including their type of inhibition and experimental conditions, and structure-activity relationship, covering a total of 351 compounds. We intend to provide the most favorable chemical features of flavonoids for the inhibition of PTP1B and DPP-4, gathering information for the future development of compounds with improved potential as T2D therapeutic agents.

Keywords:

• Diabetes
• protein tyrosine phosphatase 1B
• dipeptidyl peptidase-4
• inhibitory activity
• phenolic compounds
• flavonoids
• antidiabetic agents

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The work was supported by UIDB/50006/2020 with funding from Fundação para a Ciência e Tecnologia (FCT)/Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) through national funds, and “Programa Operacional Competitividade e Internacionalização” (COMPETE) (POCI-01-0145-FEDER-029241). CP acknowledges FCT the financial support for the PhD grant (SFRH/BD/116005/2016), in the ambit of "QREN - POPH - Tipologia 4.1 - Formação Avançada", co-sponsored by Fundo Social Europeu (FSE) and by national funds of MCTES. DR and MF acknowledge the financial support from the European Union (FEDER funds through COMPETE) (POCI-01-0145-FEDER-029253 and POCI-01-0145-FEDER-029248, respectively).