Ferulic Acid from Beta vulgaris subsp. vulgaris Altissima Group Pulp Targets the CaMKKβ/SIRT-1/AMPK Pathway To Combat Hyperglycemia

Hyperglycemia exacerbates type 2 diabetes (T2D), and metformin regulates glucose metabolism via the AMPK signaling pathway. Ferulic acid, a natural antioxidant from Beta vulgaris subsp. vulgaris Altissima Group (sugar beet) pulp (SBP), an agri-processing byproduct, has unclear antidiabetic mechanisms. Our previous study showed that SBP extract improves obesity-induced T2D via the SIRT-1/AMPK pathway in C57BL/6J mice. In this study, we purified ferulic acid from SBP (FA-SBPE) and evaluated its effects on hyperglycemia-induced HepG2 cells. FA-SBPE activated AMPKα/β via its upstream kinase CaMKKβ, upregulated GLUT2 through the SIRT-1/AMPK axis, and modulated the PI3K/Akt pathway by regulating INSR, PIP4K2A, and B gene expression. It enhanced insulin sensitivity, mitochondrial function, and lipid metabolism via PGC-1α and PPARα independently of AMPK. FA-SBPE also inhibited gluconeogenesis, GSK3β, and mTOR signaling. These findings suggest that FA-SBPE modulates glucose metabolism through CaMKKβ/SIRT-1/AMPK and PI3K/Akt/mTOR/GSK3β signaling pathways, making it a potential therapeutic agent for managing hyperglycemia in T2D.