Flavonoids and their metal complexes as potential agents for diabetes mellitus with future perspectives

Type 2 diabetes mellitus (T2DM) is a global health burden, with hyperglycemia as the main hallmark. This review commences with a concise overview of the intricate mechanisms underlying glucose uptake and utilization in organisms. Notably, we emphasize that T2DM management strategies pivot on delaying carbohydrate digestion, augmenting insulin secretion, and enhancing insulin sensitivity in target tissues. Unfortunately, the drugs currently available in the market for the treatment of T2DM have unpleasant side effects, spurring an urgent quest for safer and more efficacious alternatives. Flavonoids, emerging as a promising class of bioactive compounds derived from plants, offer a multi-faceted approach to diabetes treatment. Specifically, they potently inhibit enzymes such as α-amylase, α-glucosidase, dipeptidyl peptidase-4 (DPP-4), glycogen phosphorylase (GP) and protein-tyrosine phosphatase-1B (PTP1B). Through an in-depth analysis, this review not only summarizes these inhibitory actions but also establishes the structure-activity relationship (SAR), providing a blueprint for rational drug design. However, the clinical translation of flavonoids has been hampered by their suboptimal water solubility and bioavailability, attributable to the characteristic carbonyl and hydroxyl groups. Ingeniously, this chemical quirk has been harnessed to engineer metal chelates, which exhibit enhanced pharmacokinetic profiles. Herein, we offer an exhaustive overview of the latest advancements in flavonoid metal complexes research, spotlighting their potential as next-generation diabetes therapeutics. Available data are poised to galvanize the development of novel flavonoid derivatives, be it as potent drugs or functional foods, for combating T2DM.