Insulin Resistance And Endocannabinoid System In Patients With Obstructive Sleep Apnea-hypopnea Syndrome

Studies showed that compared with control group, patients with obstructive sleep apnea-hypopnea syndrome(OSAHS) were significantly higher in the incidence of glucose metabolism disorders and diabetes. Further research suggested that OSAHS was an independent risk factor for insulin resistance(IR) and diabetes. In addition, IR and diabetes had a close relationship with the endocannabinoid system(ECS). Excessive activation of ECS was an important cause of IR and diabetes, and the inhibition ECS activity can effectively alleviate IR and diabetes mellitus. But there had not been a study of the effects of OSAHS on ECS, and there was no study on whether ECS was involved in the disorder of glucose metabolism induced by OSAHS. Therefore, the main purpose of this study was to answer the above questions. The first part is clinical trials.A total of 64 OSAHS patients(18 cases of mild OSAHS, 24 cases of moderate OSAHS, 22 cases of severe OSAHS) and 24 cases of healthy controls were included in the study. Body mass index(BMI), waist circumference, fasting blood lipids, fasting blood glucose, fasting blood insulin, homeostasis model of assessment for insulin resistance index(HOMA-IR),polysomnography and cannabinoid receptor 1(CB1) protein expression levels in peripheral blood mononuclear cells(PBMC) were measured in participants. The results showed that, compared with the control group, the incidence of glucose metabolism disorder in OSAHS patients was significantly increased. Moreover, HOMA-IR, apnea hypopnea index(AHI) and CB1 protein expression levels of PBMC were significantly positively correlated with each other.In order to further clarify the molecular mechanism of the effect of OSAHS on glucose metabolism and ECS, OSAHS animal model was established and the effects of intermittent hypoxia(IH) on weight gain, glucose metabolism, skeletal muscle cell ultrastructure,expression of GLUT4 and expression of CB1 in skeletal muscle of rats were analyzed in the second part of this study. The results showed that compared with the control group, IH can cause the slowing down of weight gain, increasing of fasting blood insulin level, reduce the insulin sensitivity and damage of mitochondrial in skeletal muscle cells of rats. Meanwhile, the expression of GLUT4 m RNA, total GLUT4 and plasma membrane protein of GLUT4(PM GLUT4) in skeletal muscle were decreased and the expression of CB1 in skeletal muscle was increased. CB1 antagonist rimonabant treatment was demonstrated to improve weight gain, insulin sensitivity and damage of skeletal muscle cell ultrastructure of the rats induced by IH. Simultaneously, rimonabant significantly upregulated expression of GLUT4 m RNA, PM GLUT4, total GLUT4 and downregulated expression of CB1 in the muscle skeletal of the rats induced by IH.The results of this study suggested that OSAHS patients were prone to IR and glucose metabolism disorders, which were closely related to the activation of ECS induced by OSAHS. The decrease of GLUT4 expression and the increased expression of CB1 induced by IH may be an important mechanism of OSAHS induced IR and disorder of glucose metabolism. Due to the effects on the improvement above abnormalities caused by IH, CB1 antagonists is expected to play a role in the treatment of disorder of glucose metabolism induced by OSAHS.