Coronarin A modulated hepatic glycogen synthesis and gluconeogenesis via inhibiting mTORC1/S6K1 signaling and ameliorated glucose homeostasis of diabetic mice

by Selleckchem | May 21 2023

Promotion of hepatic glycogen synthesis and inhibition of hepatic glucose production are effective strategies for controlling hyperglycemia in type 2 diabetes mellitus (T2DM), but agents with both properties were limited. Herein we report coronarin A, a natural compound isolated from rhizomes of Hedychium gardnerianum, which simultaneously stimulates glycogen synthesis and suppresses gluconeogenesis in rat primary hepatocytes. We showed that coronarin A (3, 10 μM) dose-dependently stimulated glycogen synthesis accompanied by increased Akt and GSK3β phosphorylation in rat primary hepatocytes. Pretreatment with Akt inhibitor MK-2206 (2 μM) or PI3K inhibitor LY294002 (10 μM) blocked coronarin A-induced glycogen synthesis. Meanwhile, coronarin A (10 μM) significantly suppressed gluconeogenesis accompanied by increased phosphorylation of MEK, ERK1/2, β-catenin and increased the gene expression of TCF7L2 in rat primary hepatocytes. Pretreatment with β-catenin inhibitor IWR-1-endo (10 μM) or ERK inhibitor SCH772984 (1 μM) abolished the coronarin A-suppressed gluconeogenesis. More importantly, we revealed that coronarin A activated PI3K/Akt/GSK3β and ERK/Wnt/β-catenin signaling via regulation of a key upstream molecule IRS1. Coronarin A (10, 30 μM) decreased the phosphorylation of mTOR and S6K1, the downstream target of mTORC1, which further inhibited the serine phosphorylation of IRS1, and subsequently increased the tyrosine phosphorylation of IRS1. In type 2 diabetic ob/ob mice, chronic administration of coronarin A significantly reduced the non-fasting and fasting blood glucose levels and improved glucose tolerance, accompanied by the inhibited hepatic mTOR/S6K1 signaling and activated IRS1 along with enhanced PI3K/Akt/GSK3β and ERK/Wnt/β-catenin pathways. These results demonstrate the anti-hyperglycemic effect of coronarin A with a novel mechanism by inhibiting mTORC1/S6K1 to increase IRS1 activity, and highlighted coronarin A as a valuable lead compound for the treatment of T2DM.

Comments：

The authors of this study report that coronarin A, a natural compound isolated from the rhizomes of Hedychium gardnerianum, has potential therapeutic effects in the treatment of type 2 diabetes mellitus (T2DM). Specifically, they found that coronarin A stimulates glycogen synthesis and suppresses gluconeogenesis in rat primary hepatocytes, two strategies for controlling hyperglycemia in T2DM. They also found that coronarin A activates the PI3K/Akt/GSK3β and ERK/Wnt/β-catenin signaling pathways, which are involved in regulating these metabolic processes.

The authors further investigated the mechanism of action of coronarin A and found that it regulates a key upstream molecule, IRS1, which is involved in the activation of the PI3K/Akt/GSK3β and ERK/Wnt/β-catenin pathways. They also found that coronarin A inhibits the mTORC1/S6K1 signaling pathway, which leads to increased activity of IRS1.

Finally, the authors tested the therapeutic potential of coronarin A in ob/ob mice, a model of T2DM. They found that chronic administration of coronarin A reduced non-fasting and fasting blood glucose levels and improved glucose tolerance in these mice. These effects were accompanied by the inhibited hepatic mTOR/S6K1 signaling pathway and activated IRS1, along with enhanced PI3K/Akt/GSK3β and ERK/Wnt/β-catenin pathways.

Overall, these findings suggest that coronarin A has potential therapeutic benefits in the treatment of T2DM by regulating multiple metabolic pathways involved in glycogen synthesis and gluconeogenesis. Further studies are needed to explore the safety and efficacy of coronarin A in humans.