In vivo and in vitro antidiabetic effects of citrus flavonoids; a study on the mechanism of action

Type 2 diabetes mellitus is a result of hyperglycemia caused by overproduction of glucose at the hepatic level or because of abnormal beta cell function or insulin resistance at target cells. The purpose of this study was to investigate the hypoglycemic effect of hesperidin and naringin and to suggest their probable mechanisms of action in high fat-fed/streptozotocin (STZ)-induced type 2 diabetic rats. Male albino rats were divided into four groups. Group 1 was normal control, and others were induced with diabetes by feeding a high-fat diet for 2 weeks followed by an intraperitoneal injection of streptozotocin (35 mg/kg b.wt.). Group 2 was kept as diabetic control, and groups 3 and 4 were further treated with an oral dose of 50 mg/kg hesperidin and naringin. In the diabetic control group, levels of glucose and glycosylated hemoglobin were significantly increased, while serum insulin level and hepatic and muscle glycogen were decreased. Both hesperidin and naringin supplementation significantly reversed these parameters. The activity of the hepatic key enzyme hexokinase was significantly increased whereas, glucose-6-phosphatase, glycogen phosphorylase, and fructose-1,6-bisphosphatase activities were significantly decreased as a result of treatment. Furthermore, both compounds were found to decrease intestinal glucose absorption in situ and to increase insulin release from isolated islets, peripheral glucose uptake in vitro, and adipose tissue glucose transporter type 4 (GLUT4) messenger RNA (mRNA) and protein expressions. These results showed that hesperidin and naringin have potent antihyperglycemic activity in high fat-fed/STZ-induced diabetic rats.