Effects Of Flavonoids From Psidium Guajava Leaves On The Hepatic Insulin Signaling Pathway And Hepatic Gluconeogenesis In Streptozotocin(STZ) Induced Diabetic Mice

Background: With the development of social economy and the changes of lifestyle, the number of people with diabetes(DM) is increasing. According to latest data of the 2011 International Diabetes Federation(IDF), at the end of 2011, the number of DM patients has reached 366 million. By 2030, the DM adult patients of the global will grow to 522 million[1]. DM is caused by a variety of reasons with the character of chronic hyperglycemia and metabolic disorders, accompanied by the defects of insulin secretion. Because of this, the metabolism disorder of sugar, fat and protein is caused. Type 1 diabetes mellitus(T1DM) is based on the absolute lack of insulin secretion. Type 2 diabetes mellitus(T2DM) is mainly caused by insulin resistance associated with insulin secretion. If the patients have a long-term high blood sugar, tissues and organs are damaged extensively[2]. Fllowing after cancer and cardiovascular disease, DM has become the third largest chronic disease threatening the humans health seriously. Until now, although the western medicine and insulin therapy are the main approches to defer the process of DM, these drugs still can not achieve the desired therapeutic effect sometimes, what’s worse, they often cause much side effects and can not protect islets. Therefore, it is very important and urgent to find a reliable and secure method to the DM of prevetion and treatment. Psidium guajava L is a kind of plant of Myrtaceae Guava. Studies have shown that it has a good anti-diabetic effect in recent years, but its mechanism is still not entirely clear. In this paper, we investigate the mechanisms of flavonoids from Psidium guajava Leaves on treating DM. So we can provide a reference for the development of new antidiabetic drugs.Objective: To investigate the effects of flavonoids from Psidium guajava Leaves on the hepatic glucose metabolism, insulin signaling pathway and hepatic gluconeogenesis in streptozotocin(STZ) induced diabetic mice. Methods: Male BALB/c mice were injected with streptozotocin STZ(60mg.kg-1, i.p.) for 5 consecutive days to generate diabetic model, as indicated by fasting blood glucose concentration ≥11.1 mmol.l-1 for 3 consecutive days. Diabetic mice were randomly divided into model group and guava leaves flavonoids treatment group, every group has 10 mice, and a separate 10 normal mice as control group. Flavonoids from Psidium guajava Leaves was administered intragastrically at a dose of 16.5 g crude drug kg-1.d-1. After 2 weeks of administration, the fasting blood glucose level and fasting weight were measured. The method of Elisa was used to measure the insulin levels of serum. Immunohistochemistry was used to observe the insulin secretion of islets. In addition, the mice were euthanized and then the number of islets, pathological changes were observed. Real time fluorescence PCR was used to investigate the m RNA expression of hepatic glucokinase(GK), glucokinase regulatory protein(GKRP), glucose transporter protein 2(GLUT2), insulin growth factor(IGF-1), insulin receptor substrate-1(IRS-1), insulin receptor substrate-2(IRS-2),glucose-6-phosphatase(G-6-pase)and phosphoenolpyruvate carboxykinase(PEPCK); The hepatic of glucose transporter protein 2 was tested by Western blot.Results: Compared with the normal mice, the blood glucose level of diabetic mice increased significantly(p<0.05).The insulin level of serum is decreased and the islets of insulin secretion is reduced; The hepatic m RNA expression of GK, GLUT2, IGF-1, IRS-1 and IRS-2 were decreased; GKRP, G-6-pase and PEPCK were increased significantly(p<0.01) and the Glut2 of hepatic tissue which was tested by western blot is decreased(p<0.01). Compared with the diabetic mice, the blood glucose of treatment group was significantly decreased and the serum insulin levels was significantly increased; The number of islets, the hepatic m RNA expression of GK, GLUT2, IGF-1, IRS-1 and IRS-1 were significantly increased(p<0.01) and the hepatic m RNA expression of GKRP, G-6-pase and PEPCK is decreased(p<0.01); GLUT2 which was tested by western blot is increased(p<0.01).Conclusions: Flavonoids from Psidium guajava Leaves has marked hypoglycemic effect, and is likely through the regulation of the insulin secretion, hepatic glucose metabolic molecular, gluconeogenesis and insulin signaling pathway, and also the islet regenerating effects.