Protective Effect of Vanillic Acid against Hyperinsulinemia, Hyperglycemia and Hyperlipidemia via Alleviating Hepatic Insulin Resistance and Inflammation in High-Fat Diet (HFD)-Fed Rats.

Wen-Chang Chang,Yuh-Tai Wang,James Wu,Szu-Chuan Shen,Chen-Wen Chen,Po-Ling Kuo,Hsu-Min Chien

doi:10.3390/nu7125514

Wen-Chang Chang, Yuh-Tai Wang + Show 5 more

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https://doi.org/10.3390/nu7125514

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Abstract

Excess free fatty acid accumulation from abnormal lipid metabolism results in the insulin resistance in peripheral cells, subsequently causing hyperinsulinemia, hyperglycemia and/or hyperlipidemia in diabetes mellitus (DM) patients. Herein, we investigated the effect of phenolic acids on glucose uptake in an insulin-resistant cell-culture model and on hepatic insulin resistance and inflammation in rats fed a high-fat diet (HFD). The results show that vanillic acid (VA) demonstrated the highest glucose uptake ability among all tested phenolic acids in insulin-resistant FL83B mouse hepatocytes. Furthermore, rats fed HFD for 16 weeks were orally administered with VA daily (30 mg/kg body weight) at weeks 13–16. The results show that levels of serum insulin, glucose, triglyceride, and free fatty acid were significantly decreased in VA-treated HFD rats (p < 0.05), indicating the protective effects of VA against hyperinsulinemia, hyperglycemia and hyperlipidemia in HFD rats. Moreover, VA significantly reduced values of area under the curve for glucose (AUCglucose) in oral glucose tolerance test and homeostasis model assessment-insulin resistance (HOMA-IR) index, suggesting the improving effect on glucose tolerance and insulin resistance in HFD rats. The Western blot analysis revealed that VA significantly up-regulated expression of hepatic insulin-signaling and lipid metabolism-related protein, including insulin receptor, phosphatidylinositol-3 kinase, glucose transporter 2, and phosphorylated acetyl CoA carboxylase in HFD rats. VA also significantly down-regulated hepatic inflammation-related proteins, including cyclooxygenase-2 and monocyte chemoattractant protein-1 expressions in HFD rats. These results indicate that VA might ameliorate insulin resistance via improving hepatic insulin signaling and alleviating inflammation pathways in HFD rats. These findings also suggest the potential of VA in preventing the progression of DM.

Highlights

As advanced medical technology and improved living standards extend the expectancy of human life, chronic diseases have become a major threat to the health of people
After a 4-week administration of vanillic acid (VA), a down-regulation of hepatic insulin signaling-related proteins, such as insulin receptor (IR), phosphatidylinositol-3 kinase (PI3K), and glucose transporter 2 (GLUT-2), was found in high-fat diet (HFD) group rats as compared with the control group (Figure 2). These results suggested that VA normalizes hepatic insulin signaling and alleviates hepatic insulin resistance in the liver of HFD-fed rats
The current study suggests that VA may reduce hepatic non-esterified free fatty acid (NEFA) accumulation via promoting the phosphorylation of acetyl CoA carboxylase (ACC) protein expression in liver of HFD rats

Summary

Introduction

As advanced medical technology and improved living standards extend the expectancy of human life, chronic diseases have become a major threat to the health of people. After consuming high-calorie foods, the body is in a hyperglycemic state with an increased insulin secretion, reducing serum glucose to maintain a steady level of serum glucose. Long-term excess intake of high-calorie or high-fat diet (HFD) resulted in increasing blood glucose level and free fatty acid content and induced metabolic related diseases, such as obesity, dyslipidemia, type 2 diabetes mellitus (T2DM), and fatty liver disease [2,3,4]. The increased blood glucose level caused islet cells to continuously secrete insulin, while the increased free fatty acid content caused an increased lipid synthesis, leading to the accumulation of diacylglycerol in the liver and activation of protein kinase Cε (PKCε). Increased release of free fatty acids from adipocytes into blood was reported to activate protein kinases, e.g., protein kinase C, which subsequently affected the expression of inhibitor of kappa β kinase, c-Jun N-terminal kinases (JNK), and p38 mitogen-activated protein kinases, stimulating the release of inflammatory factors such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and causing internal inflammatory responses [8]

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