Myricitrin Ameliorates Hyperglycemia, Glucose Intolerance, Hepatic Steatosis, and Inflammation in High-Fat Diet/Streptozotocin-Induced Diabetic Mice

Abstract

To test the hypothesis that myricitrin (MYR) improves type 2 diabetes, we examined the effect of MYR on hyperglycemia, glucose intolerance, hepatic steatosis, and inflammation in high-fat diet (HFD) and streptozotocin (STZ)-induced type 2 diabetic mice. Male C57BL/6J mice were randomly divided into three groups: non-diabetic, diabetic control, and MYR (0.005%, w/w)-supplemented diabetic groups. Diabetes was induced by HFD and STZ, and MYR was administered orally for 5 weeks. Myricitrin exerted no significant effects on food intake, body weight, fat weight, or plasma lipids levels. However, MYR significantly decreased fasting blood glucose levels, improved glucose intolerance, and increased pancreatic β-cell mass compared to the diabetic control group. Myricitrin administration also markedly increased glucokinase mRNA expression and activity as well as lowered glucose-6-phosphatase and phosphoenolpyruvate carboxykinase mRNA expression and activity in the liver. In addition, liver weight, hepatic triglyceride content, and lipid droplet accumulation were markedly decreased following MYR administration. These changes were seemingly attributable to the suppression of the hepatic lipogenic enzymes-fatty acid synthase and phosphatidate phosphohydrolase. Myricitrin also significantly lowered plasma MCP-1 and TNF-α levels and the mRNA expression of hepatic pro-inflammatory genes. These results suggest that MYR has anti-diabetic potential.

Keywords: diabetes; glucose intolerance; hepatic steatosis; hyperglycemia; inflammation; myricitrin.

Figure 1

Effects of myricitrin (MYR) on change in body weight (A), body weight gain (B), fat weight (C), food intake (D), food efficiency ratio (FER) (E), and plasma lipids levels (F) in high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice. Values are means ± SE (n = 10). Student’s t-test was used to assess the differences among groups.: * p < 0.05; non-DM group versus DM group. non-DM: non-diabetic group, DM: diabetic control group, MYR: MYR-supplemented diabetic group.

Figure 2

Effects of MYR on fasting blood glucose level (A), IPGTT (B), plasma insulin level (C), pancreas immunohistochemistry (D), and the hepatic glucose-regulating enzymes activities (E) and mRNA expression (F) in HFD/STZ-induced diabetic mice. (A–F): Values are means ± SE (n = 10). Student’s t-test was used to assess the differences among groups.: * p < 0.05, ** p < 0.01, *** p < 0.001; non-DM group versus DM group, # p < 0.05; DM group versus MYR group. (D): Representative images of immunohistochemical staining for insulin in pancreatic sections (arrows). Scale bars represent 19 µm. Magnification is 100×. IPGTT: intraperitoneal glucose tolerance test, GK: glucokinase, G6Pase: glucose-6-phosphatase, PEPCK: phosphoenolpyruvate carboxykinase.

Figure 3

Effects of MYR on liver weight (A), hepatic lipids contents (B), liver morphology (C), and hepatic lipogenic enzymes activities (D) and mRNA expression (E) in HFD/STZ-induced diabetic mice. (A,B,D,E) Values are means ± SE (n = 10). Student’s t-test was used to assess the differences among groups.: * p < 0.05, *** p < 0.001; non-DM group versus DM group, # p < 0.05; DM group versus MYR group. (C) Representative images of hematoxylin and eosin stained liver sections. Arrows indicates lipid droplets. Scale bars represent 19 µm. Magnification is 400×. FAS: fatty acid synthase, PAP: phosphatidate phosphohydrolase.

Figure 4

Effects of MYR on plasma pro-inflammatory MCP-1 and TNF-α levels (A) and hepatic pro-inflammatory genes mRNA expression (B) in HFD/STZ-induced diabetic mice. Values are means ± SE (n = 10). Student’s t-test was used to assess the differences among groups. * p < 0.05, ** p < 0.001, *** p < 0.001; non-DM group versus DM group, # p < 0.05; DM group versus MYR group. MCP-1: monocyte chemoattractant protein-1, TNF-α: tumor necrosis factor-α, TLR: toll-like receptor.