Salidroside ameliorates insulin resistance through activation of a mitochondria-associated AMPK/PI3K/Akt/GSK3β pathway.

Abstract

BACKGROUND AND PURPOSE:

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.

EXPERIMENTAL APPROACH:

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.

KEY 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 AND IMPLICATIONS:

Salidroside exerts an antidiabetic effect by improving the cellular metabolic flux through the activation of a mitochondria-related AMPK/PI3K/Akt/GSK3β pathway.

• Authors: Tao Zheng, Xiaoyan Yang, Dan Wu, Shasha Xing, Fang Bian, Wenjing Li, Jiangyang Chi, Xiangli Bai, Guangjie Wu, Xiaoqian Chen, Yonghui Zhang, Si Jin
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 172 Issue 13 Pg. 3284-301 (Jul 2015) ISSN: 1476-5381 [Electronic] England
• PMID: 25754463 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The British Pharmacological Society.

Chemical References

• Glucosides
• Hypoglycemic Agents
• Insulin
• Phenols
• Phosphatidylinositol 3-Kinases
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3
• AMP-Activated Protein Kinases
• Glucose
• rhodioloside

Topics

• AMP-Activated Protein Kinases (metabolism)
• Adipose Tissue (drug effects, pathology)
• Animals
• Cells, Cultured
• Diabetes Mellitus, Experimental (drug therapy, metabolism)
• Diabetes Mellitus, Type 2 (drug therapy, metabolism)
• Glucose (metabolism)
• Glucosides (pharmacology, therapeutic use)
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Hepatocytes (drug effects, metabolism)
• Hypoglycemic Agents (pharmacology, therapeutic use)
• Insulin (blood)
• Insulin Resistance
• Lipid Metabolism (drug effects)
• Liver (drug effects, metabolism)
• Male
• Mice, Inbred C57BL
• Mice, Transgenic
• Mitochondria (drug effects, metabolism, physiology)
• Oxygen Consumption
• Pancreas (drug effects, pathology)
• Phenols (pharmacology, therapeutic use)
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)