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

Pterostilbene Reduces Acetaminophen-Induced Liver Injury by Activating the Nrf2 Antioxidative Defense System via the AMPK/Akt/GSK3β Pathway

“…Indeed, Pts promoted translocation of Nrf2 into the nucleus, which closely related to the increase of nuclear Nrf2 content and Nrf2-target gene transactivation. It has been reported that AMPK induced PI3K/Akt signaling pathway activation [32]. Furthermore, AMPK suppresses the phosphorylation of GSK3β [33], which contributes to mitochondrial defend against iron-induced oxidative stress [33].…”

Salidroside ameliorates diabetic nephropathy in rats by activating renal AMPK/SIRT1 signaling pathway

“…These effects were not investigated in the peripheral tissue of diabetic rats of this study but could be supported by the reported stimulatory effect of Salidroside on AMPK activity in the kidney of these rats as described later. In support, the hypoglycemic effect of Salidroside in db/db and alloxan‐induced T1DM mice was shown to be due to inhibition of hepatic gluconeogenesis and stimulation of GLUT‐4 translocation on peripheral tissues through activating AMPK (Li et al, ; Zheng et al, ). Moreover, Tong et al () have shown a stimulatory effect of Salidroside on glucose uptake in differentiated L6 rat myoblast cells.…”

“…On the contrary, the medical therapeutic potential of Salidroside [(4‐hydroxy‐phenethyl)‐β‐D‐glucopyranoside, a glycosides of Rhodiola rosea (R. rosea L) is well reported in various organs of different animal model with many thanks to antioxidant, anti‐inflammatory, and anti‐apoptotic effects (Chen, Lin, Qi, He, & Zheng, ; Lai et al, ; Lin et al, ; Yin, Yao, Chen, Hu, & Gao, ). Of note, Salidroside attenuated hyperlipidemia, insulin resistance (IR), and renal damage in mice model of T2DM and db/db diabetic mice (Wang et al, ; Wu et al, ; Xue et al, ; Zheng et al, ) and improved kidney function and reduced renal cell apoptosis in streptozotocin (STZ) plus uninephrectomy induced diabetic rats (Guo et al, ).…”

“…Notably, Salidroside improved kidney function, enhanced mitochondria function and reduced renal fibrosis through activation of SIRT1/PGC‐1α in a high‐fat diet (HFD) plus STZ‐induced T2DM mice animal model (Xue et al, ). On the other side, but in extra‐renal tissues including pancreatic β‐cells, muscles, livers, adipocytes, endothelial cells, and kidneys, Salidroside beneficial effect were mediated by activation of AMPK (Ju et al, ; Wang, ; Wu et al, ; Xing et al, ; Zheng et al, ).…”

Phosphatidylinositol 3‑kinase‑mediated HO‑1/CO represses Fis1 levels and alleviates lipopolysaccharide‑induced oxidative injury in alveolar macrophages

“…In addition, as a major survival signaling pathway, activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) resulted in the nuclear translocation of NF-E2 related factor 2 (Nrf2) and subsequently increased the expression of the downstream target gene, HO-1 (14,15). Additionally, phosphorylation of Akt at Ser473 via a PI3K-dependent pathway served a crucial role in regulating mitochondrial oxidative stress-mediated tissue injury (16,17). As described by Wang et al (18), impaired PI3K/Akt signaling may be associated with retinol binding protein 4 (RBP4)-induced imbalance of the fusion and fission cycles in mitochondria.…”