title: Salidroside ameliorates insulin resistance through activation of a mitochondria-associated AMPK/PI3K/Akt/GSK3β pathway.
abstract: OBJECTIVE
  Recent reports have suggested that salidroside could protect cardiomyocytes from oxidative injury and stimulate glucose uptake in skeletal muscle cells by activating AMP-activated protein kinase (AMPK). The aim of this study was to evaluate the therapeutic effects of salidroside on diabetic mice and to explore the underlying mechanisms.
  
  
  METHODS
  The therapeutic effects of salidroside on type 2 diabetes were investigated. Increasing doses of salidroside (25, 50 and 100 mg·kg(-1) ·day(-1)) were administered p.o. to db/db mice for 8 weeks. Biochemical analysis and histopathological examinations were conducted to evaluate the therapeutic effects of salidroside. Primary cultured mouse hepatocytes were used to further explore the underlying mechanisms in vitro.
  
  
  RESULTS
  Salidroside dramatically reduced blood glucose and serum insulin levels and alleviated insulin resistance. Hypolipidaemic effects and amelioration of liver steatosis were observed after salidroside administration. In vitro, salidroside dose-dependently induced an increase in the phosphorylations of AMPK and PI3K/Akt, as well as glycogen synthase kinase 3β (GSK3β) in hepatocytes. Furthermore, salidroside-stimulated AMPK activation was found to suppress the expression of PEPCK and glucose-6-phosphatase. Salidroside-induced AMPK activation also resulted in phosphorylation of acetyl CoA carboxylase, which can reduce lipid accumulation in peripheral tissues. In isolated mitochondria, salidroside inhibited respiratory chain complex I and disturbed oxidation/phosphorylation coupling and moderately depolarized the mitochondrial membrane potential, resulting in a transient increase in the AMP/ATP ratio.
  
  
  CONCLUSIONS
  Salidroside exerts an antidiabetic effect by improving the cellular metabolic flux through the activation of a mitochondria-related AMPK/PI3K/Akt/GSK3β pathway.
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|The Key Laboratory of Natural Medicinal Chemistry, Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|The Key Laboratory of Natural Medicinal Chemistry, Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|The Key Laboratory of Natural Medicinal Chemistry, Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|The Key Laboratory of Natural Medicinal Chemistry, Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China.
authors.forename: Shasha
authors.initials: S
authors.lastname: Xing
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|The Key Laboratory of Natural Medicinal Chemistry, Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Bian
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|The Key Laboratory of Natural Medicinal Chemistry, Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|The Key Laboratory of Natural Medicinal Chemistry, Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China.
authors.forename: Jiangyang
authors.initials: J
authors.lastname: Chi
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|The Key Laboratory of Natural Medicinal Chemistry, Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China.
authors.forename: Xiangli
authors.initials: X
authors.lastname: Bai
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|The Key Laboratory of Natural Medicinal Chemistry, Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China.
authors.forename: Guangjie
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|The Key Laboratory of Natural Medicinal Chemistry, Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China.
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|The Key Laboratory of Natural Medicinal Chemistry, Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|The Key Laboratory of Natural Medicinal Chemistry, Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China.|Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Si
authors.initials: S
authors.lastname: Jin
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D005960:Glucosides / Q000494:pharmacology* / Q000627:therapeutic use; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010101:Oxygen Consumption; D010179:Pancreas / Q000187:drug effects / Q000473:pathology; D010636:Phenols / Q000494:pharmacology* / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D005960:Glucosides; D007004:Hypoglycemic Agents; D007328:Insulin; D010636:Phenols; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D055372:AMP-Activated Protein Kinases; D005947:Glucose; C009172:rhodioloside