Comprehensive Mechanistic Characterisation of the Antidiabetic Profile of Sutherlandia frutescens Using Target-Directed In Vitro Assays and Cellomics

Several studies have suggested potential mechanisms through which Sutherlandia frutescens exerts antidiabetic effects, yet much of its therapeutic potential remains unexplored. This study aimed to provide greater insights into the antidiabetic capabilities and limitations of S. frutescens through the use of a comprehensive in vitro screening platform incorporating target-directed assays with automated image cytometry and analysis, where relevant. The antidiabetic effects of a crude hot aqueous extract of S. frutescens were assessed across well-characterised targets representing prominent hallmarks of diabetes: postprandial hyperglycaemia, insulin sensitivity, β-cell dysfunction, chronic inflammation and adipose tissue dysfunction. The findings revealed S. frutescens as a multicomponent therapeutic, with its individual target activities being relatively subtle and a few appearing novel. Notably, however, S. frutescens inhibited multiple targets relevant to postprandial hyperglycaemia—including carbohydrate digestion (29.1% and 26.4% inhibition for sucrose and maltose, respectively, at 500 µg/mL), intestinal glucose uptake in Caco-2 cells (between 9.51% and 20.92% reduction from 100 to 500 µg/mL) and protein glycation (23.2% inhibition at 200 µg/mL)—activities not previously documented in vivo. Glucose consumption in C3A hepatocytes showed a dose-dependent increase in glucose consumption from 12.5 to 100 µg/mL. Glucose consumption was reduced in palmitic acid-induced insulin-resistant L6 skeletal muscle cells from 100% to 69.57%, while 50 µg/mL S. frutescens restored it to 97.84%. S. frutescens also enhanced INS-1 β-cell survival under oxidative stress at concentrations as low as 12.5 µg/mL. The integration of automated image cytometry and analysis provides a novel approach with which to characterise its antidiabetic properties and elucidate its potential molecular mechanisms. Overall, S. frutescens is shown to impact several interrelated mechanisms simultaneously, suggesting that the coordinated modulation of multiple pathways may contribute to its overall biological activity. Whether these effects are additive or synergistic remains to be determined.