# α‐Glucosidase Inhibitory Potential of Citrus reticulata Peel‐Derived Flavonoids—A Prelude for the Management of Type 2 Diabetes

## TL;DR

Citrus peel flavonoids may help manage type 2 diabetes by inhibiting α-glucosidase, reducing glucose absorption with fewer side effects.

## Contribution

The study identifies citrus-derived flavonoids as effective and less harmful α-glucosidase inhibitors for diabetes treatment.

## Key findings

- Quercetin and rutin from citrus peels showed strong α-glucosidase inhibition comparable to acarbose.
- Flavonoids exhibited low cytotoxicity on Caco-2 cells, suggesting safety for use.
- In silico and in vitro results aligned, confirming the compounds' inhibitory potential.

## Abstract

α‐Glucosidase inhibitors (AGIs) are compounds used to treat type 2 diabetes (T2D) by preventing the breakdown of dietary starch into monosaccharides, which reduces their absorption by the body and lowers blood glucose levels. AGIs often cause gastrointestinal issues such as diarrhea and flatulence due to excessive α‐amylase inhibition, leading to excess residual starch reaching the colon and being fermented by microbes. There is a need to prospect for novel AGIs that are effective and have fewer adverse effects. This study investigated the potential of citrus‐derived flavonoids as AGIs targeting amylolytic enzymes: α‐amylase and α‐glucosidase. Firstly, flavonoids were extracted from
Citrus reticulata
(tangerines) peels using an ultrasound‐assisted methanolic procedure, followed by C18 column‐purification and profiling with liquid chromatography‐mass spectrometry. Select citrus peel‐derived flavonoids, quercetin (−9.2 kcal/mol) and rutin (−10.8 kcal/mol), and the commercial AGI, acarbose (−8.7 kcal/mol), showed strong binding affinities against α‐glucosidase. Molecular dynamics simulations of the compounds were also assessed, revealing flexibility and stability in response to ligand interactions with the α‐glucosidase. The in silico data correlated positively with the results from the in vitro inhibition assays; acarbose (Ki = 0.14 mg/mL), quercetin (Ki = 0.12 mg/mL) and rutin (Ki = 0.19 mg/mL) recorded low inhibition constant values. The cytotoxicity profile of the selected compounds was also conducted on Caco‐2 cells, with flavonoids showing no significant cytotoxic effects. Flavonoids could be used as AGIs with minimal gastrointestinal impacts, reducing residual starch entering the colon and decreasing glucose uptake.

Flavonoids derived from Citrus reticulate peel inhibit α‐glucosidase activity, delaying carbohydrate digestion and reducing glucose absorption, thereby indicating their potential as functional food components for type 2 diabetes management.