Procyanidin A2, a polyphenol autophagy-enhancer, ameliorates hyperglycemia through multifaceted insulin-related mechanisms

Procyanidin A2 (PCA2), a flavonoid from cranberries and lingonberries, has shown various bioactivities, but its antidiabetic effects remain largely under-investigated. This study assessed PCA2's glucose-lowering potential through in silico, in vitro, and in vivo analyses. Molecular docking revealed strong binding of PCA2 to α-glucosidase (PDB: 3TOP), with competitive inhibition (IC₅₀ = 3.62 ± 0.841 µM). PCA2 was non-toxic up to 100 µM in C2C12 and INS-1 cells and enhanced glucose uptake via AMPK/AKT phosphorylation and GLUT4 expression. It also reduced oxidative stress and modulated autophagy-related proteins, increasing Beclin1, LC3-II, and Atg5 while decreasing p62. In diabetic mice, PCA2 improved glucose tolerance, protected β-cells, and restored hepatic and muscular glycogen levels, as confirmed by H&E and PAS staining. Western blotting supported modulation of insulin signaling and autophagy. These findings suggest PCA2 as a promising candidate for functional foods targeting glucose regulation and metabolic dysfunctions.