Advances in Small Molecules of Flavonoids for the Regulation of Gluconeogenesis

Hyperglycemia resulting from over-gluconeogenesis is a prominent feature of type 2 diabetes mellitus (T2DM). Therefore, it is very important to reduce glucose output, especially liver glucose output, and maintain blood glucose homeostasis in the treatment of T2DM. It has been found that small molecules of natural flavonoids are able to act on various targets in the gluconeogenic pathways, interfering with rate-limiting enzyme activity or regulating the cascade of hormonal signaling and affecting all levels of transcription factors by limiting the transport of non-sugar substrates. As a result, gluconeogenesis is inhibited. Literature indicated that gluconeogenesis regulated by flavonoids could be divided into two pathways, namely the pre-translational pathway and the pro-translational pathway. The pre-translational pathway mainly interferes with the signaling pathway and transcription factors in gluconeogenesis and inhibits RNA transcription and the expression of gluconeogenic genes, while the post-translational pathway mainly regulates the transport of nonglucose substrates and directly inhibits four rate-limiting enzymes. This review describes the effects of small flavonoid molecules on different targets and signaling pathways during gluconeogenesis, as well as relevant validation methods, in the hope of providing references for similar studies and promoting the development of anti-diabetic drugs.