State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Acta Pharmacol Sin. 2023 Mar;44(3):596-609. doi: 10.1038/s41401-022-00985-5. Epub 2022 Sep 9.
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.
促进肝糖原合成和抑制肝葡萄糖生成是控制 2 型糖尿病（T2DM）高血糖的有效策略，但同时具有这两种特性的药物有限。本文报道了一种从益智属植物根茎中分离得到的天然化合物冠状 A，它可同时刺激大鼠原代肝细胞的糖原合成和抑制糖异生。结果表明，冠状 A（3、10 μM）剂量依赖性地刺激糖原合成，同时增加大鼠原代肝细胞中 Akt 和 GSK3β磷酸化。用 Akt 抑制剂 MK-2206（2 μM）或 PI3K 抑制剂 LY294002（10 μM）预处理可阻断冠状 A 诱导的糖原合成。同时，冠状 A（10 μM）显著抑制糖异生，同时增加 MEK、ERK1/2、β-catenin 的磷酸化，并增加大鼠原代肝细胞中 TCF7L2 的基因表达。用 β-catenin 抑制剂 IWR-1-endo（10 μM）或 ERK 抑制剂 SCH772984（1 μM）预处理可消除冠状 A 抑制的糖异生。更重要的是，我们揭示了冠状 A 通过调节关键上游分子 IRS1 激活 PI3K/Akt/GSK3β 和 ERK/Wnt/β-catenin 信号通路。冠状 A（10、30 μM）降低了 mTOR 和 S6K1 的磷酸化，mTORC1 的下游靶标，这进一步抑制了 IRS1 的丝氨酸磷酸化，随后增加了 IRS1 的酪氨酸磷酸化。在 2 型糖尿病 ob/ob 小鼠中，冠状 A 的慢性给药显著降低了非空腹和空腹血糖水平，并改善了葡萄糖耐量，同时抑制了肝 mTOR/S6K1 信号通路，激活了 IRS1，并增强了 PI3K/Akt/GSK3β 和 ERK/Wnt/β-catenin 通路。这些结果表明，冠状 A 通过抑制 mTORC1/S6K1 来增加 IRS1 活性，从而发挥抗高血糖作用，具有新的作用机制，并强调冠状 A 是治疗 2 型糖尿病的有价值的先导化合物。
