| Type2diabetes pathogenesis has not been fully elucidated yet. Islet-cell dysfunction isa necessary condition for type2diabetes, and this dysfunction results mainly from increasedapoptosis of islet B cells and decreased B cells. The apoptosis of islet B cells can also impairinsulin signal transduction pathway, which may further accelerate the islet B cell apoptosisand dysfunction to decrease the secretion of insulin. The repair of the islet B cell signalingpathways damaged can protect pancreatic cells, maintain the survival, growth, proliferationand number of islet B cells, and regulate the synthesis and secretion of insulin. Thus,protecting pancreatic B cells, delaying the apoptosis development of them, improving thedecline of their function, and promoting the secretion of insulin is the key to the treatment oftype2diabetes.Glucose toxicity and lipid toxicity are important cause to induce islet B cell apoptosisand decline in its functions. Under a long-term high-sugar and high-fat environment, the ratswith diabetes are in an oxidative stress. It is well known that the resistance of pancreas tooxidation is weakest and pancreas is vulnerable to be attacked and damaged by oxidativestress. While signal transduction pathway of insulin is impaired in islet B cell. IRS-2is thehinge of islet B cell signaling pathway and the defect of it can cause the apoptosis ofpancreatic islet B cells, which is the only way of T2DM. The major role of IRS-2is tostimulate a cascade of the phosphatidylinositol3kinase/protein kinase (phosphatid-ylinositol-3-kinase/protein kinas, PI3K/AKT) to promote cell proliferation and differe-ntiation by activation of AKT phosphorylation. FoxO1is an important target protein of AKTand the phosphorylation of FoxO1through PI3K/AKT cause the loss of its transcriptionalactivity to inhibit the apoptosis of pancreatic B cells. PDX-1is involved in the process ofislet B cell proliferation regulated by FoxO1to induce islet B cell differentiation. PDX-1isthe key transcription factor of the insulin gene expression, which regulates and controlsGLUT-2and GCK by binding to insulin gene promoter to play a regulatory role in glucosetransport. Therefore, proliferation promoting, inhibiting apoptosis, intervention in theimpaired insulin signal transduction system is the goal of diabetes treatment.However, the existing drugs used for the treatment of diabetes are primarily for the purpose to reduce blood sugar. Although they can produce a satisfactory hypoglycemic effect,the side effects induced by them often follow by, and the resistance to them may develop ifthey are used repeatedly for a long time. The active ingredients in natural medicineextraction has better hypoglycemic effect. The main component of schisandrae chinenesis oilis schisandra lignans which can lower the blood sugar, increase the serum insulin secreted,and decrease glucagon. However, the mechanism through which the schisandrae chinenesisoil can be used for the treatment of diabetes is not clear. To our knowledge, whetherschisandrae chinenesis oil exerts its therapeutic effect on diabetes through protectingpancreatic cells from the dysfunction of islet B cells has not been reported.In this study, the high-fat diet combined with the twice injection of low-dose STZ at theideal interval was used to establish the experimental rat model of type2diabetes, and fastingblood glucose, blood lipids, insulin and glucose tolerance in the rats were examined; theMDA content, SOD and CAT activities in pancreatic tissues were measured; pancreatic GSHcontent and GSH-Px activity were determined; effects of schisandrae chinenesis oil onpathological morphological changes of the pancreas was observed with HE staining method;the insulin expression and the intracellular location of FoxO1of rat pancreatic cells wereperformed with immunohis-tochemistry; TUNEL was used to observe the apoptosis of rats'pancreatic cells; RT-PCR assay were used to examine expressions of Bax/bcl-2, Caspase3mRNA, insulin, PDX-1mRNA, IRS-2, GLUT-2, GCK mRNA in rat pancreatic tissues.Western blot analysis was executed to measure expressions of Bax/bcl-2, Caspase3, insulin,PDX-1, IRS-2, AKT, p-AKT, GLUT-2and GCK. The results showed that the successful rateof the established models of type2diabetes was higher (60%), the blood glucose of the ratswith the experimental diabetes was stable, and the high blood sugar, high blood cholesterol,insulin resistance and insulin secretion insufficiency could be seen in them, which could beconsidered as the typical clinical symptoms of type2diabetes; Schisandrae chinenesis oilcould significantly reduce the blood sugar of the rats with type2diabetes, especially in thehigh-dose group it could be restored to the normal blood glucose level, lower TG, TC, NEFA/FFA levels, promote insulin secretion, increase insulin sensitivity index, enhance theamount of the glucose tolerance of the body, and improve the insulin resistance; Schisandraechinenesis oil could reduce the pancreatic MDA, increase SOD and CAT activities, GSHcontent, GSH-Px activity and potentiate the of the body; Schisandrae chinenesis oil couldimprove the pathological changes in the pancreas, induce the enlargement of the islet size, the increase in the number of islet B cells, and decrease the rate of islet cell apoptosis;Schisandrae chinenesis oil could improve insulin expression and induce the phosphorylationof FoxO1protein and its getting out of the nucleus; Schisandrae chinenesis oil could increaseexpressions of Bcl-2mRNA and its protein, decrease Bax/bcl-2ratio, lower levels ofCaspase3mRNA and its protein; Schisandrae chinenesis oil could increase IRS-2mRNAand its protein expression, promote the expression of AKT phosphorylation, improveexpressions of PDX-1, GLUT-2, GCK mRNA and its protein. These results suggest thatschisandrae chinenesis oil can mediate activations of insulin and/or IGF-1/IRS-2/PI3K-AKT/FoxO1/PDX-1signal transduction pathways in rats with diabetes, regulate the apoptoticprotein Caspase-3and anti-apoptotic protein Bcl-2to inhibit the islet cell apoptosis;Schisandrae chinenesis oil can activate AKT through increasing IRS-2expression, therebymaking FoxO1phosphorylation and getting out of the nucleus, inhibit the pancreatic B cellapoptosis, and increase the number of B cells; moreover, it can promote the up-regulation ofGLUT-2and GCK by increasing the expression of specific transcription factor PDX-1ratswith diabetes, regulating the glucose and lipid metabolism and increasing the insulinsecretion to maintain the islet B cell function.In summary, schisandrae chinenesis oil can significantly reduce the blood glucose, lipidlevels of rats with type2diabetes, regulate the glucose and lipid metabolism, and improvethe insulin sensitivity index, and improve the glucose tolerance and insulin resistance. In thebasis of the regulation of glucose and lipid metabolism, schisandrae chinenesis oil canenhance the activity of antioxidant enzymes, reduce the byproducts of lipid peroxide, anddecrease the production of oxygen free radicals to potentiate the antioxidant capacity of thediabetic rats. Schisandrae chinenesis oil can relieve the mitochondrial damage induced byFFA and oxidative stress and inhibit the mitochondrial pathway-induced apoptosis of islet Bcells. Schisandrae chinenesis oil exerts its protective effects on pancreatic B cells of thediabetic rats through the mechanisms in which it mediates the activation of insulin and/orIGF-1/IRS-2/PI3K-AKT/FoxO1/PDX-1signaling pathway to intervene the impaired signal system to delay theprogress of pancreatic B cell apoptosis, increase the number of B cells, improve the B-cellfunction and increase insulin secretion. These findings should provide an importanttheoretical basis for the research and development in the treatment of diabetes. |
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