Antidiabetic and Antiobesity Effects of Artemether in db/db Mice

Abstract

This study is designed to investigate the effect of artemether on type 2 diabetic db/db mice. The experiments consisted of three groups: normal control (NC, db/+, 1% methylcellulose, intragastric administration), diabetic control (DM, db/db, 1% methylcellulose, intragastric administration), and artemether treated (artemether, db/db, 200 mg/kg of artemether, intragastric administration). The treatment lasted for two weeks. The food intake, body weight, and fasting blood glucose of mice were measured every three days. At the start and end of the experiment, the intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (IPITT) were performed. We determined the serum insulin and glucagon levels by ELISA kits and calculated insulin resistance index (HOME-IR). HE staining was used to observe the morphologies of pancreas and liver in mice. The damage of pancreatic beta cells was evaluated by TUNEL staining and immunofluorescence. We found the following: (1) compared with the DM group, the food intake and weight increase rate of artemether group significantly reduced (P < 0.05); (2) compared with pretreatment, artemether significantly reduced the fasting blood glucose levels, and the areas under the curves (AUCs) of IPGTT were decreased significantly, increasing the tolerance to glucose of db/db mice. (P < 0.05); (3) artemether improved hyperinsulinemia and decreased the AUCs of IPITT and HOME-IR, increasing the insulin sensitivity of db/db mice. (4) Artemether significantly ameliorated islet vacuolar degeneration and hepatic steatosis in db/db mice. (5) Artemether reduced the apoptosis of pancreatic beta cells and increased insulin secretion in db/db mice compared with DM group (P < 0.05). Our results indicated that artemether significantly improved glucose homeostasis and insulin resistance and had the potential activity to prevent obesity, reduced the severity of fatty liver, and protected pancreatic beta cells, promising to treat type 2 diabetes.

Antidiabetic Effect of Artemether in Db/Db Mice Involves Regulation of AMPK and PI3K/Akt Pathways

“…To test this possibility, we checked the protein expression level of glucokinase (GK) and phosphoenolpyruvate carboxykinase (PEPCK), two critical rate-limiting enzymes individually controlling hepatic glycolysis and gluconeogenesis (17,18), by Western blotting analysis using the liver samples obtained from db/+ mice in the negative control (NC) group and DM group administrated with or without artemether. These db/db mice naturally showed typical diabetic characteristics, like significant changes in food intake, body weight, and fasting blood glucose (FBG), which were dose-dependently reversed to some extent by artemether treatment (Figures 1A-C), as similarly reported by a previous study (14). More importantly, as shown in…”

“…Artemether, a derivative of artemisinin, has been previously demonstrated to possess antidiabetic activities in db/db mice, such as improving glucose homeostasis and insulin resistance, preventing obesity and reducing the severity of fatty liver, and protecting pancreatic beta cells (14). Based on these observations, we proposed that artemether might serve as a promising and effective medicine for the treatment of T2DM (14). However, the underlying molecular mechanisms by which artemether exerts these antidiabetic activities are unclear, which could dismay the rational application of artemether against T2DM in the future.…”

“…Artemether decreases fasting blood glucose (FBG) level and improves glucose tolerance in db/db mice (diabetes mellitus, DM) (14). We wondered whether this effect of artemether is associated with altered glucose metabolism in the liver.…”

“…Artemether has been shown to exhibit anti-obesity function (14,21), but whether it affects the level of plasma lipid is not investigated yet. We show here that both the levels of triglyceride (TG) and total cholesterol (TC) in the plasma were increased in DM mice compared with those of NC group, whereas, artemether treatment significantly reduced them in DM mice (Figures 3A,B), which indicates a beneficial role of artemether in preventing the increase of plasma lipid level in diabetic mice.…”

“…For example, artemisinin and its derivatives exhibit certain anti-obesity and anti-fatty activities both in vitro and in animal models (13). Moreover, a previous study has shown that artemether has antidiabetic effects in db/db mice (14). However, the underlying mechanisms are still largely unclear.…”