| Objective1. To study the effect of mifepristone on glycolipid metabolism disorders in chronic stress rats fed with high-fat diet.2. To investigate the possible mechanism of mifepristone on glycolipid metabolism disorders in chronic stress rats fed with high-fat diet.3. To study the effect of mifepristone on glycolipid metabolism disorders in type2diabetic rats induced by high-fat diet combined with low dose of streptozotocin (STZ).4. To investigate the possible mechanism of mifepristone on glycolipid metabolism disorders in type2diabetic rats induced by high-fat diet combined with low dose of streptozotocin (STZ).Methods1. Impaired glucose tolerance male rats was induced by high-fat diet plus one of four different stress mode(absorbent gauze wrap secured with tape, restraint in a polyvinyl chloride tube (L=25cm, ID=5cm) closed at either end, immobilization on a board with tape, tail suspension), the long-term effects of chronic stress plus high-fat diet on glycolipid metabolism in male rats were researched. Male rats were separated into control group, model group (impaired glucose tolerance group), positive control fluoxetine (FLU)(10mg·kg-1·d-1) group, low dose of mifepristone (MIF-L)(10mg·kg-1·d-1) group, medium dose of mifepristone (MIF-M)(25mg·kg-1·d-1) group, high dose of mifepristone (MIF-H)(50mg·kg-1·d-1) group, all groups were given intragastric administration. Control group and model group were given distilled water. Intraperitoneal injection glucose tolerance test (IPGTT) was used to tested, comprehensive study of the glycolipid metabolism of MIF on impaired glucose tolerance male rats was obtained from determining level of TC, TG, HDL-C, LDL-C in plasma, content of glycogen in liver and muscle, and so on.2. Impaired glucose tolerance female rats was induced by high-fat diet plus one of four different stress mode (absorbent gauze wrap secured with tape, restraint in a polyvinyl chloride tube (L=25cm, ID=5cm) closed at either end, immobilization on a board with tape, tail suspension), the long-term effects of chronic stress plus high-fat diet on glycolipid metabolism in female rats was investigated. Female rats were separated into control group, model group (impaired glucose tolerance group), positive control fluoxetine (FLU)(10mg·kg-1·d-1) group, low dose of mifepristone (MIF-L)(10mg·kg-1·d-1) group, medium dose of mifepristone (MIF-M)(25mg·kg-1·d-1) group, high dose of mifepristone (MIF-H)(50mg·kg-1·d-1) group, all groups were given intragastric administration. Control group and model group were given distilled water. Intraperitoneal injection glucose tolerance test (PGTT) was used to tested impaired glucose tolerance. The TC, TG, HDL-C, LDL-C level in plasma, content of glycogen in liver and muscle were measured in impaired glucose tolerance female rats for comprehensive study of the glycolipid metabolism of MIF, and so on.3. Male rats were divided into control group, model group (impaired glucose tolerance group), low dose of mifepristone (MIF-L)(10mg·kg-1·d-1) group, medium dose of mifepristone (MIF-M)(25mg·kg-1·d-1) group, high dose of mifepristone (MIF-H)(50mg·kg-1·d-1) group and positive control fluoxetine (FLU)(10mg·kg-1·d-1) group, all groups were given intragastric administration. Control group and model group were given distilled water. CRH, ACTH in plasma were measured after7,21,28days’ adminstration, CORT, INS in plasma were measured; the rats were sacrificed after4weeks, hippocampus, liver, muscle and adipose tissues of rat were collected, the expression of GR mRNA,11β-HSD1mRNA in hippocampus, the expression of GR mRNA, PPAR-γ mRNA in liver, GLUT-4mRNA in muscle tissue, PPAR-y mRNA in adipose tissue were assayed, expression of GR protein in hippocampus and liver were detected. The possible mechanism of MIF on improving glycolipid metabolism of impaired glucose tolerance rats were studied.4. Type2diabetic rats were induced by high-fat diet plus a dose of STZ (30mg.kg-1). Rats were divided into control group, type2diabetic model group, positive control metformin (MET)(200mg·kg-1·d-1) group, low dose of mifepristone (MIF-L)(10mg·kg-1·d-1) group, medium dose of mifepristone (MIF-M)(25mg·kg-1·d-1) group, high dose of mifepristone (MIF-H)(50mg·kg-1·d-1) group, all groups were given intragastric administration. Control group and model group were given distilled water. The TC, TG, HDL-C, LDL-C level in plasma, content of glycogen in liver and muscle were measured in impaired glucose tolerance female rats for comprehensive study of the glycolipid metabolism of MIF, and so on.5. Rats were divided into control group, type2diabetic model group, positive control metformin (MET)(200mg·kg-1·d-1) group, low dose of mifepristone (MIF-L)(10mg·kg-1·d-1) group, medium dose of mifepristone (MIF-M)(25mg·kg-1·d-1) group, high dose of mifepristone (MIF-H)(50mg·kg-1·d-1) group, all groups were given intragastric administration. Control group and model group were given distilled water. Level of CRH, ACTH, CORT, INS and ALD in plasma were measured, the rats were sacrificed after5weeks; Hippocampus, liver, muscle and adipose tissues of rat were collected, the expression of GR mRNA,11β-HSD1mRNA in hippocampus, the expression of GR mRNA, PPAR-γ mRNA in liver, GLUT-4mRNA in muscle were measured, the possible mechanism of MIF on regulating glycolipid metabolism in type2diabetic rats were studied.Results1. Compared with control group, in model group, fasting blood glucose was increased by24.7%(P<0.01) after21days, blood glucose level was increased by34.4%(P<0.01),33.8%(P<0.05) at30min after7,21days; TG, TC, LDL-C was increased by170.6%(P<0.01),11.4%(P<0.01),29.7%(P<0.05), HDL-C was reduced by25.2%(P<0.05); there is a reduction tendancy of glycogen content. Compared with model group, fasting blood glucose was reduced by10.4%(P<0.05),15.3%(P<0.01) after14and21days in MIF-M group; TC was decreased by11.2%,20.9%(P<0.01) in MIF-M, MIF-H group, TG was decreased by33.9%(P<0.05),40.4%(P<0.01) in MIF-M, MIF-H group, LDL-C was decreased by16.9%(P<0.05) in MIF-M group, HDL-C was increased by25.5%,25.5%,25.2%respectively in each MIF group (P<0.01); liver glycogen was decreased by24.1%,26.5%,24.1%(P<0.01) respectively in each MIF group; Muscle glycogen was decreased by25.0%(P<0.01),25.0%(P<0.05) in MIF-M, MIF-H group. There was an improving effect of MIF-M (25mg·kg-1·d-1), MIF-H (50mg·kg-1·d-1) on glucose and lipid metabolism in impaired glucose tolerance male rats, and it was better in MIF-M group.2. Compared with control group, TC, TG and LDL-C in impaired glucose tolerance female rats was increased by16.0%,30.7%,27.7%respectively, HDL-C was decreased by25.6%(P<0.05). Compared with model group, TG was decreased by34.1%,52.3%,43.2%(P<0.01).in MIF group, respectively, HDL-C was increased by39.7%,56.9%(P<0.01) in MIF-M, MIF-H group.3. Compared with control group, in impaired glucose tolerance male rats, there is an increasing tendancy of CRH, ACTH, CORT level was increased by93.7%,140.6%(P<0.01) after7,14days; the expression of GR mRNA in liver tissue was decreased by64.0%(P<0.01), PPAR-y mRNA in liver and adipose was decreased by48.0%,45.0%(P<0.01), GLUT-4mRNA was decreased by62.0%(P<0.01); Expression of GR protein was decreased in hippocampus and liver tissue. Compared with model group, CRH was decreased by8.9%(P<0.05),11.9%(P<0.01) in MIF-M, MIF-H group after7days, level of CORT was decreased by54.0%(P<0.01),14.4%(P<0.05) in MIF-L, MIF-M group after14days, but in MIF-H group was increased by135.1%(P<0.01) after28days; the expression of GR mRNA in liver tissue was increased by50.0%(P<0.05),36.1%(P<0.01),44.4%(P<0.01), expression of PPAR-γ mRNA in liver was increased by332.7%(P<0.01),309.6%(P<0.05),348.1%(P<0.05), PPAR-γ mRNA in adipose was increased by49.1%.161.8%(P<0.05),72.7%(P<0.05) in each MIF group, respectively; Expression of GLUT-4mRNA in muscle was increased by76.3%(P<0.05) in MIF-M group; Expression of GR protein in hippocampus and liver was improved by MIF-M.4. Compared with control group, food intake, water intake were significantly increased, body weight was significantly decreased, fasting blood glucose was significantly increased (P<0.01); TC, TG and LDL-C was increased by111.5%,124.9%(P<0.01),98.8%(P<0.05) in type2diabetic rats. Compared with model group, food intake was reduced by16.1%(P<0.05),12.5%(P<0.01) in MIF-M group and reduced by18.2%,20.8%(P<0.01) in MIF-H group after7and28days, water intake was reduced by21.0%(P<0.05) in MIF-H group after7days, while it was reduced by29.9%(P<0.05) in MIF-M group after28days, there is an increasing tendancy of body weight with MET administration, body weight can be improved by MIF; Level of FBG was reduced by9.4%(P<0.01) in MIF-M group after28days; TC was decreased by24.7%,26.9%,31.5%(P<0.01), TG was decreased by36.6%,33.9%(P<0.05),56.6%(P<0.01) in each MIF group, respectively.5. Compared with control group, in type2diabetic rats, there is an elevating trend of CORT, INS, ALD, the expression of GR mRNA was significantly reduced by20.6%(P<0.01) in hippocampus, PPAR-y mRNA was decreased by61.8%; The expression of GR mRNA was significantly reduced by57.8%(P<0.01) in liver, expression of11β-HSD1mRNA was increased by93.5%. Compared with model group, CRH, ACTH, CORT was reduced by19.6%,5.3%,13.7%in MIF-M group, there is a lower tendency in secretion of ACTH, CORT, INS in MET group, while the secretion of ALD is lower in each MIF group; The expression of GR mRNA in the hippocampus, PPAR-y mRNA in liver and adipose was increased in each MIF group, the expression of GR mRNA in liver tissue was increased by89.1%,71.7%(P<0.05) in MIF-M, MIF-H group, the expression of11β-HSD1mRNA was decreased by38.6%(P<0.05),46.9%(P<0.01), expression of GLUT-4mRNA was increased by168.6%(P<0.05),117.1%(P<0.01) in MIF-M, MIF-H group. Conclusion1. The higher fasting blood glucose may be improved by MIF administration and there is a trend to improve impaired glucose tolerance in impaired glucose tolerance male rats.2. Lipid metabolism disorders may be improved by MIF administration in impaired glucose tolerance female rats.3. The level of CORT is related with HPA axis, the expression of GR mRNA in hippocampus, PPAR-y mRNA in liver; expression of GR protein in hippocampus and liver may be increased by MIF-M administration, thereby impaired glucose tolerance and glycolipid disorders in impaired glucose tolerance male rats maybe improved by MIF administration based on the regulation of above hormones, genes and proteins.4. The higher fasting blood glucose in type2diabetic rats can be improved by MIF administration, the large amount of food and water intake can be reduced.5. There is a tendancy to decreasing the secretion of CRH, ACTH and CORT by MIF administration; Expression of GR mRNA, PPAR-y mRNA can be increased in hippocampus and liver, expression of11β-HSD1mRNA can be decreased in hippocampus by MIF, thereby glycolipid metabolism disorders in type2diabetic rats may be improved by MIF based on the regulation of above gene expressions. |
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