Abstract
The flower of Edgeworthia gardneri (Wall.) Meisn is commonly used in beverage products in Tibet and has potential health benefits for diabetes. However, the mechanisms underlying anti-insulin resistance (IR) action of the flower of E. gardneri are not fully understood. This study aims to investigate the effects of the water extract of the flower of E. gardneri (WEE) on IR in palmitate (PA)-exposed HepG2 hepatocytes. WEE was characterized by UPLC analysis. PA-treated HepG2 cells were selected as the IR cell model. The cell viability was determined using MTT assay. Moreover, the glucose consumption and production were measured by glucose oxidase method. The glucose uptake and glycogen content were determined by the 2-NBDG (2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl) amino]-D-glucose) glucose uptake assay and anthrone-sulfuric acid assay, respectively. The intracellular triglyceride content was detected by oxidative enzymic method. Protein levels were examined by Western blotting. Nuclear localization of FoxO1 was detected using immunofluorescence analyses and Western blotting. The expression of FoxO1 target genes was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The viability of PA-treated HepG2 cells was concentration-dependently increased by incubation with WEE for 24 h. WEE treatment remarkably increased the consumption and uptake of glucose in PA-exposed HepG2 cells. Moreover, treatment with WEE significantly decreased the PA-induced over-production of glucose in HepG2 cells. After exposure of HepG2 cells with PA and WEE, the glycogen content was significantly elevated. The phosphorylation and total levels of IRβ, IRS1, and Akt were upregulated by WEE treatment in PA-exposed HepG2 cells. The phosphorylation of GSK3β was elevated after WEE treatment in PA-treated cells. WEE treatment also concentration-dependently downregulated the phosphorylated CREB, ERK, c-Jun, p38 and JNK in PA-exposed HepG2 cells. Furthermore, the nuclear protein level and nuclear translocation of FoxO1 were also suppressed by WEE. Additionally, PA-induced changes of FoxO1 targeted genes were also attenuated by WEE treatment. The GLUT2 and GLUT4 translocation were also promoted by WEE treatment in PA-treated HepG2 cells. Taken together, WEE has potential anti-IR effect in PA-exposed HepG2 cells; the underlying mechanism of this action may be associated with the regulation of IRS1/GSK3β/FoxO1 signaling pathway. This study provides a pharmacological basis for the application of WEE in the treatment of metabolic diseases such as type 2 diabetes mellitus.
Highlights
Type 2 diabetes mellitus (T2DM) is one of the most prevalent metabolic diseases worldwide and characterized by hyperglycemia accompanied by progressive and irreversible loss of pancreatic insulin secretion (Ashcroft and Rorsman, 2012)
The ultra-performance liquid chromatography (UPLC) chromatogram showed that rutin, chlorogenic acid, and tiliroside were present in WEE powder
We found that the phosphorylation of IRb, insulin receptor substrate (IRS)-1, and Akt were downregulated during PA treatment, and WEE treatment concentration-dependently upregulated the phosphorylated IRb, IRS-1, and Akt, suggesting that WEE prevented the impairment of insulin-stimulated phosphorylation caused by PA treatment
Summary
Type 2 diabetes mellitus (T2DM) is one of the most prevalent metabolic diseases worldwide and characterized by hyperglycemia accompanied by progressive and irreversible loss of pancreatic insulin secretion (Ashcroft and Rorsman, 2012). Insulin resistance (IR), a subnormal biological response to normal insulin concentrations in target cells (e.g., hepatocytes, skeletal muscle cells, and adipocytes), plays a pivotal role in the development of several metabolic diseases including T2DM, hypertension, and hyperlipidemia (Reaven, 1991; Lillioja et al, 1993; Veerkamp et al, 2005). In patients with T2DM, circulating FFAs directly enter into the liver; increased levels of hepatic FFAs can induce IR in the liver and activate some serine kinases, such as c-Jun-N-terminal kinase, p38, and ERK (Bi et al, 2013; Gao et al, 2018), leading to dephosphorylation of insulin receptor and its substrate 1/2 (IRS-1/2), thereby inhibiting Akt activity (Nakamura et al, 2009a). Targeting the IRS1/GSK3b/FoxO1 signaling is one of the focuses in developing effective anti-IR agents for T2DM
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