Anti-diabetic Effects Of Ursolic Acid Derivatives And Mechanism Research

Diabetes is a systemic metabolic disorder disease caused by genetic, inadequate insulin secretion or biological function disorder, is characterized by hyperglycemia. The data form World Health Organization about the total number of people with diabetes is to rise from171million in2000to366million in2030. Expect for injectable drugs insulin and insulin analogues, other oral drugs such as insulin secretagogues, insulin sensitizers, α-glucosidase inhibitors, aldose reductase inhibitors are usually being used to treat diabetes. However, long-term use of these drugs may cause some limitations and side effects, such as hypoglycemia, gastrointestinal tract, liver, kidney effects. Therefore, it is evident that there is an urgent need for more effective and safe therapeutic agents for diabetes mellitus.Ursolic acid, is a kind of pentacyclic triterpenoids. Some experimental studies have proven that UA and its derivatives have anti-diabetic activity, but investigation has not been taken upon the mechanism. Therefore, further research anti-diabetic activity and mechanism of ursolic acid derivatives has great significance for the development of hypoglycemic drugs.The main content and result of this study:(1) The effect of ursolic acid (UA) derivatives on glucose uptake in intestinal tractIn this study, we implemented Caco-2cells to simulate the intestinal epithelial cell, used a glucose analogues2-NBDG as the fluorometric indicator to evaluate the effect of ursolic acid (UA) derivatives on glucose uptake, and then the glucose transporter protein (SGLT-1, GLUT-2) expression were analysis in Caco-2cells. The results of the present study showed that compound10and11were significantly inhibiting on2-NBDG uptake under both Na+-dependent and Na+-independent conditions by decreasing SGLT-1and GLUT-2expressions in Caco-2cells.(2) The effect of ursolic acid (UA) derivatives in streptozocin-induced diabetic ratsSD rats were feed with high caloric diet, and STZ-induce to type2diabetes, and then these diabetic rats were administered with UA derivatives for4weeks. The fasting blood glucose (FBG), insulin levels, biochemical parameters, lipid levels, and oxidative stress markers were finally evaluated.Extended in vivo studies revealed that compound10significantly reduced hyperglycemia by increasing levels of serum insulin, total protein, and albumin while the fasting blood glucose, body weight and food intake were restored much closer to those of normal rats than untreated rats. Compound10and11showed hypolipidemia activity by decreasing total amount of cholesterol (TC) and triglycerides (TG). Compound10confirmed an antioxidant potential by elevating glutathione (GSH) and superoxide dismutase (SOD) and by reducing malondialdehyde (MDA) in the liver and kidney of diabetic rats.We concluded that compound10had an apparent anti-diabetic activity in Caco-2cells and in STZ-induced diabetic rats. The suppress result of compound10on2-NBDG uptake in Caco-2cells was maybe attribute to inhibition on protein expression of SGLT-1and GLUT-2; Compound10showed obvious activity on hypoglycemia, hypolipidemia and augmented oxidative stress in STZ-induced diabetic rats, may be related to the treatment of diabetic.