PMID- 36085523 OWN - NLM STAT- MEDLINE DCOM- 20230228 LR - 20240302 IS - 1745-7254 (Electronic) IS - 1671-4083 (Print) IS - 1671-4083 (Linking) VI - 44 IP - 3 DP - 2023 Mar TI - Coronarin A modulated hepatic glycogen synthesis and gluconeogenesis via inhibiting mTORC1/S6K1 signaling and ameliorated glucose homeostasis of diabetic mice. PG - 596-609 LID - 10.1038/s41401-022-00985-5 [doi] AB - 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 muM) dose-dependently stimulated glycogen synthesis accompanied by increased Akt and GSK3beta phosphorylation in rat primary hepatocytes. Pretreatment with Akt inhibitor MK-2206 (2 muM) or PI3K inhibitor LY294002 (10 muM) blocked coronarin A-induced glycogen synthesis. Meanwhile, coronarin A (10 muM) significantly suppressed gluconeogenesis accompanied by increased phosphorylation of MEK, ERK1/2, beta-catenin and increased the gene expression of TCF7L2 in rat primary hepatocytes. Pretreatment with beta-catenin inhibitor IWR-1-endo (10 muM) or ERK inhibitor SCH772984 (1 muM) abolished the coronarin A-suppressed gluconeogenesis. More importantly, we revealed that coronarin A activated PI3K/Akt/GSK3beta and ERK/Wnt/beta-catenin signaling via regulation of a key upstream molecule IRS1. Coronarin A (10, 30 muM) 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/GSK3beta and ERK/Wnt/beta-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. CI - (c) 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society. FAU - Huang, Su-Ling AU - Huang SL AD - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. FAU - Xie, Wei AU - Xie W AD - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. AD - University of Chinese Academy of Sciences, Beijing, 100049, China. FAU - Ye, Yang-Liang AU - Ye YL AD - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. FAU - Liu, Jia AU - Liu J AD - Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. FAU - Qu, Hui AU - Qu H AD - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. FAU - Shen, Yu AU - Shen Y AD - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. FAU - Xu, Ti-Fei AU - Xu TF AD - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. FAU - Zhao, Zhuo-Hui AU - Zhao ZH AD - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. AD - University of Chinese Academy of Sciences, Beijing, 100049, China. FAU - Shi, Yu AU - Shi Y AD - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. AD - University of Chinese Academy of Sciences, Beijing, 100049, China. FAU - Shen, Jian-Hua AU - Shen JH AD - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. jhshen@simm.ac.cn. FAU - Leng, Ying AU - Leng Y AD - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. yleng@simm.ac.cn. AD - University of Chinese Academy of Sciences, Beijing, 100049, China. yleng@simm.ac.cn. LA - eng PT - Journal Article DEP - 20220909 PL - United States TA - Acta Pharmacol Sin JT - Acta pharmacologica Sinica JID - 100956087 RN - 0 (Liver Glycogen) RN - 0 (beta Catenin) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - 0 (coronarin A) RN - 0 (Insulin) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - IY9XDZ35W2 (Glucose) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) SB - IM MH - Mice MH - Rats MH - Animals MH - Gluconeogenesis MH - Liver Glycogen/metabolism MH - beta Catenin/metabolism MH - Glycogen Synthase Kinase 3 beta/metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - *Diabetes Mellitus, Type 2/metabolism MH - Phosphatidylinositol 3-Kinases/metabolism MH - *Diabetes Mellitus, Experimental MH - Insulin/metabolism MH - TOR Serine-Threonine Kinases/metabolism MH - Glucose/metabolism MH - Mechanistic Target of Rapamycin Complex 1/metabolism MH - Homeostasis MH - Phosphorylation PMC - PMC9958036 OTO - NOTNLM OT - IRS1 OT - coronarin A OT - gluconeogenesis OT - glycogen synthesis OT - mTORC1/S6K1 pathway OT - type 2 diabetes mellitus COIS- The authors declare no competing interests. EDAT- 2022/09/11 06:00 MHDA- 2023/03/03 06:00 PMCR- 2024/03/01 CRDT- 2022/09/10 00:06 PHST- 2021/12/20 00:00 [received] PHST- 2022/08/18 00:00 [accepted] PHST- 2022/09/11 06:00 [pubmed] PHST- 2023/03/03 06:00 [medline] PHST- 2022/09/10 00:06 [entrez] PHST- 2024/03/01 00:00 [pmc-release] AID - 10.1038/s41401-022-00985-5 [pii] AID - 985 [pii] AID - 10.1038/s41401-022-00985-5 [doi] PST - ppublish SO - Acta Pharmacol Sin. 2023 Mar;44(3):596-609. doi: 10.1038/s41401-022-00985-5. Epub 2022 Sep 9.