Improvement of Glucose Metabolism by Pennogenin 3-O-β-Chacotrioside via Activation of IRS/PI3K/Akt Signaling and Mitochondrial Respiration in Insulin-Resistant Hepatocytes

Scope: Insulin resistance (IR), which causes chronic hyperglycemia, has been one of the most prevalent components of metabolic syndrome over the centuries. Pennogenin 3-O-β-chacotrioside (P3C), the main steroid glycoside derived from Paris polyphylla, has been found to exert various biological activities. However, the exact role of P3C on glucose metabolism in the IR state remains unexplored. Methods and results: To induce IR, AML12 cells were exposed to glucose (27 mM) and insulin (10 µg/mL) and then incubated with P3C (0.25 or 0.5 µM) for 24 h. The effects of P3C on glucose metabolism in insulin-resistant AML12 cells were evaluated through glucose consumption assays, real-time quantitative polymerase chain reaction (qPCR), Western blotting, and metabolic analysis for extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Our data showed that P3C significantly improved insulin sensitivity in AML12 hepatocytes with high glucose-induced IR. P3C stimulated insulin sensitivity and glucose uptake by activating the IRS/PI3K/Akt signaling pathway, which enhances glycogen synthesis and suppresses gluconeogenesis in insulin-resistant AML12 cells. In addition, P3C treatment increased the protein expression of p-AMPK and PGC1α, as well as the expression of oxidative phosphorylation complex proteins, potentially enhancing mitochondrial oxidative respiration. Conclusions: Our findings imply that P3C could be a therapeutic option for improving metabolic abnormalities associated with IR.