Shengdihuang Xiyangshen Zhimu Cangzhu Formula Improves Hepatic Glycogen Synthesis via the JNK/c-Jun/IRS1/GSK3β...

Diabetes mellitus (DM) is one of the major chronic diseases endangering human health worldwide, and disorders of hepatic glucose metabolism are its main feature. Glucose homeostasis is maintained by hepatic glycogen synthesis and catabolism, glycolysis, and gluconeogenesis. Inflammation can inhibit glycogen synthesis and cause persistent hyperglycemia via the c-Jun N-terminal kinase (JNK) signaling pathway. Shengdihuang Xiyangshen Zhimu Cangzhu (SXZC) formula is a botanical medicine complex with hypoglycemic effects, and it is not clear whether the SXZC formula could improve glucose metabolism in the liver. In this study, we are aimed at investigating the effect of the SXZC formula on hepatic glucose metabolism. The SXZC formula was administered to db/db mice for 4 weeks. Three concentration gradients of the SXZC formula were administered: a high-dose group (5.96 g·kg^-1·d^-1), a medium-dose group (2.98 g·kg^-1·d^-1), and a low-dose group (1.49 g·kg^-1·d^-1). The potential signaling pathways were identified by network pharmacology, subsequently validated via molecular docking and kinetic simulations, as well as molecular experiments. It was found that the SXZC formula reduced blood glucose levels, inflammatory and phosphorylation levels of JNK, c-Jun, and insulin receptor substrate 1 (IRS1), and promoted glycogen synthase kinase-3 β (GSK3β) phosphorylation and hepatic glycogen synthesis. We indicated that the SXZC formula alleviates hepatic inflammation and promotes hepatic glycogen synthesis by the JNK/c-Jun/IRS1/GSK3β signaling pathway.