PMID- 37495090 OWN - NLM STAT- MEDLINE DCOM- 20231009 LR - 20231011 IS - 1872-8057 (Electronic) IS - 0303-7207 (Linking) VI - 577 DP - 2023 Nov 1 TI - Schisandrin B, a potential GLP-1R agonist, exerts anti-diabetic effects by stimulating insulin secretion. PG - 112029 LID - S0303-7207(23)00180-6 [pii] LID - 10.1016/j.mce.2023.112029 [doi] AB - Diabetes mellitus is a metabolic disease that is characterized by elevated blood sugar. Although glucagon-like peptide-1 receptor agonists (GLP-1RA) lower blood glucose in a glucose-dependent manner, most of them are macromolecule polypeptides. Macromolecular peptides are relatively expensive and inconvenient compared with small molecules. Therefore, this study sought to identify the small molecules binding to GLP-1R via cell membrane chromatography (CMC), confirm their agonistic activity, and further study its beneficial effects in a mouse model of type 2 diabetes mellitus (T2DM) induced by a combination of high-fat diet and streptozotocin. We used CMC, calcium imaging and molecular docking techniques to screen and identify the potential small molecule Schisandrin B (Sch B), which exhibits a strong binding effect to GLP-1R, from the small molecule library of traditional Chinese medicine. Through in-vitro experiments, we found that Sch B stimulated insulin secretion in beta-TC-6 cells, while GLP-1R antagonist Exendin9-39, adenylate cyclase inhibitor SQ22536, and protein kinase A (PKA) inhibitor H89 could significantly inhibit the insulin secretion induced by Sch B. In vivo, Sch B significantly improved fasting blood glucose levels, intraperitoneal glucose tolerance test damage, and the status of pancreatic tissue damage, and reduced serum insulin levels, total cholesterol, triglyceride and low density lipoprotein in T2DM mice. These results indicate that Sch B alleviates T2DM by promoting insulin release through the GLP-1R/cAMP/PKA signaling pathway, suggesting that Sch B may be a potential GLP-1RA, which is expected to provide a new therapeutic strategy for the prevention and treatment of T2DM. CI - Copyright (c) 2023 Elsevier B.V. All rights reserved. FAU - Shang, Jia AU - Shang J AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University, Xi'an, 710061, China. FAU - Yan, Wenhui AU - Yan W AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University, Xi'an, 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, 710061, China. FAU - Cui, Xin AU - Cui X AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University, Xi'an, 710061, China. FAU - Ma, Weina AU - Ma W AD - School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China. FAU - Wang, Zhuanzhuan AU - Wang Z AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University, Xi'an, 710061, China. FAU - Liu, Na AU - Liu N AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University, Xi'an, 710061, China. FAU - Yi, Xinyao AU - Yi X AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University, Xi'an, 710061, China. FAU - Guo, Tingli AU - Guo T AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University, Xi'an, 710061, China. FAU - Wei, Xiaotong AU - Wei X AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University, Xi'an, 710061, China. FAU - Sun, Yuzhuo AU - Sun Y AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University, Xi'an, 710061, China. FAU - Hu, Hao AU - Hu H AD - Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University, Xi'an, 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, 710061, China. FAU - Cui, Wei AU - Cui W AD - Department of Endocrinology and Second Department of Geriatrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China; International Obesity and Metabolic Disease Research Center (IOMC), Xi'an Jiaotong University, Xi'an, 710061, China. Electronic address: wwei.mc@xjtu.edu.cn. FAU - Chen, Lina AU - Chen L AD - Department of Endocrinology and Second Department of Geriatrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China; Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University, Xi'an, 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, 710061, China; International Obesity and Metabolic Disease Research Center (IOMC), Xi'an Jiaotong University, Xi'an, 710061, China; Cardiometabolic Innovation Center, Ministry of Education, Xi'an, 710061, China. Electronic address: chenlin@xjtu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230724 PL - Ireland TA - Mol Cell Endocrinol JT - Molecular and cellular endocrinology JID - 7500844 RN - 02XA4X3KZW (schizandrin B) RN - 0 (Blood Glucose) RN - 0 (Receptors, Glucagon) RN - 0 (Insulin) RN - 0 (Peptides) RN - 0 (Glucagon-Like Peptide-1 Receptor) SB - IM MH - Mice MH - Animals MH - Insulin Secretion MH - *Diabetes Mellitus, Type 2/drug therapy MH - Blood Glucose MH - Molecular Docking Simulation MH - Receptors, Glucagon/metabolism MH - Insulin/metabolism MH - Peptides/pharmacology MH - Glucagon-Like Peptide-1 Receptor/metabolism OTO - NOTNLM OT - Cell membrance chromatography OT - Diabetes OT - GLP-1R OT - Schisandrin B COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/07/27 01:09 MHDA- 2023/10/09 06:41 CRDT- 2023/07/26 19:22 PHST- 2023/05/23 00:00 [received] PHST- 2023/07/21 00:00 [revised] PHST- 2023/07/23 00:00 [accepted] PHST- 2023/10/09 06:41 [medline] PHST- 2023/07/27 01:09 [pubmed] PHST- 2023/07/26 19:22 [entrez] AID - S0303-7207(23)00180-6 [pii] AID - 10.1016/j.mce.2023.112029 [doi] PST - ppublish SO - Mol Cell Endocrinol. 2023 Nov 1;577:112029. doi: 10.1016/j.mce.2023.112029. Epub 2023 Jul 24.