Chemically Synthesized Urolithin-C Regulates Glucose Uptake in HepG2 Cells

Background

In recent years, the prevalence of diabetes has increased dramatically worldwide. Although several drugs are available for its management, their severe cytotoxic effects have created a need for safer and more effective alternatives. Urolithins (A, B, C, D, M5, M6, and M7) have gained attention due to their pharmacological potential; however, Urolithin-C remains the least studied. In our previous study, we reported the anti-inflammatory mechanism of chemically synthesized Urolithin-C.

Objectives

In this current study, the effect of chemically synthesised Urolithin-C on glucose uptake in HepG2 cells was examined.

Materials and Methods

The antidiabetic activity of synthetically synthesised Urolithin-Con was assessed by measuring its inhibitory effects on α-amylase, α-glucosidase, and dipeptidyl Peptidase-IV (DPP-IV), along with glucose uptake studies in HepG2 cells.

Results

The inhibitory effect of Urolithin-C on α-amylase activity was shown by 57.14% (IC₅₀=352.69 μg/mL) and α-glucosidase activity by 64.40% (IC₅₀=296.83 μg/mL) compared with the positive control acarbose. Urolithin-C in a dose-dependent manner inhibited DPP-IV enzyme activity by approximately 68% compared with sitagliptin (72%). Molecular docking analysis of α-amylase and α-glucosidase showed binding energies of -7.7 kcal/mol and −8.2 kcal/mol, respectively with the active sites. Later, Urolithin-C enhanced glucose uptake by 58.24% in HepG2 cells after 4 hr of exposure, measured through 2-NBDG fluorescence intensity. Metformin (100 µM/mL) was used as the standard control and stimulated 64.53% by flow cytometry.

Conclusion

Urolithin-C demonstrates promising antidiabetic potential by enhancing the activity of the antioxidant enzyme G6PD, as indicated by a cellular G6PD assay.