| ObjectiveThis thesis focuses on the establishment and evaluation of the best method for inducing rat model of insulin resistance by chronic psychological stress,and the investigation of the ameliorative effects of Rehmannia glutinosa oligosaccharide(ROS)on insulin resistance and its mechanism in rats.MethodsRats were exposed to four stressors that restraint with absorbent gauze,PVC tube,frisket and hang tail to investigate the change of glucose metabolism.Insulin resistance rat model was induced by chronic stress and fed high lipid food simultaneously,and evaluated by oral glucose tolerance test and insulin tolerance test,especially plasma glucose,glucogen and hormones.All rats were divided into control group,insulin resistance model group,ROS(100, 200 mg·kg-1·d-1)treated group and total saponins of Panax Ginsen(200 mg·kg-1·d-1treated group.All drugs were adiministered by intragastric administration(i.g.).ResultsGlucose metabolism was significantly affected by long-term chronic psychological stress, chronic hyperglycemia,impaired glucose tolerance and impaired insulin tolerance were induced.At the fifth week,fasting plasma glucose level of stress group(7.2±0.8 mmol·L-1) was raised 18%compared with that of control group(6.1±0.4mmol·L-1)(P＜0.05).In oral glucose test,plasma glucose level of stress group(18.1±3.5 mmol·L-1)at the time of 30 min was raised 39%compared with that of control group(13.0±3.5 mmol·L-1)(P＜0.01).In addition,lipid metabolism was disordered and frequently plasma free fatty acids level in stress group(367.19±115.85 mmol·L-1)was increased 69.6%compared with that of control group(216.45±83.78 mmol·L-1).Thymus and spleen were also impaired,but the influence of stress was decreased after 5 weeks.Insulin resistance was simultaneously induced by chronic psychological stress and fed high lipid food.High lipid food magnified the influence of stress and aggravated the metabolism disorders.The insulin resistance model induced by chronic psychological stress and fed high lipid food represented severe impaired oral glucose tolerance and impaired insulin tolerance. The result showed that in oral glucose test insulin resistance was induced at the fifth week. Plasma glucose level at the time of 30 min in stress and fed high lipid food group(22.3±4.8 mmol·L-1)was raised 71%(P＜0.01),23%and 21%(P＜0.05),respectively,compared with thats of control group(13.0±3.5 mmol·L-1),stress group(18.1±4.5 mmol·L-1)and high lipid food group(18.4±3.2 mmol·L-1).The pancreatic islets were destroyed by STZ with insulin-ins -ufficiency,plasma insulin levels of STZ group(8.11±4.78μIU·ml-1)and STZ plus stress group(7.50±4.13μIU·ml-1)were decreased 67.5%and 70%,respectively,compared with that of control group(24.94±7.11μIU·ml-1).The rats showed impaired glucose tolerance,but the insulin tolerance test indicated that insulin sensitivity to extrinsic source insulin was not impaired.Thus,the rat model induced by stress and high lipid food was suitable to be used in the study of pharmacological mechanism of ROS.The results showed that insulin resistance in ROS-treated groups was decreased compared with that of insulin resistance model group,especially in high dose(200 mg·kg-1·d-1,i.g.) treated group.After treated with ROS for four weeks,plasma glucose levels(16.6±3.1 mmol·L-1,17.8±3.0 mmol·L-1)of ROS treated groups(200 mg·kg-1·d-1and 100 mg·kg-1·d-1)at the time of 30 min in the oral glucose test were decreased 16.5%(P＜0.05)and 11.3% (P＜0.05),respectively,compared with that of insulin resistance model group(22.6±4.6 mmol·L-1).The results suggested that ROS treatment improved the disordered hypothalamic-pituitary -adrenal axis and decreased plasma corticosterone level.Corticosterone level of ROS treated groups(1.17±0.20 ng·ml-1,1.24±0.31 ng·ml-1)were decreased 26.9%(P＜0.05)and 21.5% (P＜0.05),respectively,compared with that of insulin resistance model group(1.60±0.27 ng·ml-1).In addition,ROS treatment decreased plasma FFA level,which was decreased 35.19%in the high dose of ROS(273.15±85.06 mmol·L-1)compared with that of the insulin resistance model group(421.41±104.16 mmol·L-1).Plasma insulin level of the ROS treated groups of high dose(20.20±2.67μIU·ml-1)was raised 17.4%compared with that of the insulin resistance model group(17.20±4.25μIU·ml-1).ConclusionLong-term chronic psychological stress can induce the activation of hypothalamic-pituitary -adrenal axis,increase corticosterone level,and induce a serious of metabolism abnormality, including chronic hyperglycemia and insulin resistance.Fed high lipid food can magnify the influence of stress and aggravate the metabolism disorder.The pathogenesis of insulin resistance in the model induced by stress and fed high lipid food is similar to human being. The function of neuroendocrine immuno-modulation network of the model rats was disordere -d because hypothalamic-pituitary-adrenal axis was activated,with the characteristics of insuli -n resistance,chronic hyperglycemia,lipid metabolic disorder and impaired immune function. This model was suitable to be used in the study of pharmacological experiments of insulin resistance and diabetes mellitus.ROS treatment can improve insulin resistance and the disorder of glucose metabolism.The ameliorative effects may be mediated through adjusting the function of hypothalamic-pituitary-adrenal axis and improving neuroendocrine immuno-modulation network.
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