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Pathophysiology of Clinical Studies in Gestational Impaired Glucose Tolerance with Sleep Apnea Syndrome of Pregnant Women

Author: ShiZhiMin
Tutor: LiTaoPing
School: Southern Medical University,
Course: Internal Medicine
Keywords: Sleep apnea-hypopnea syndrome Impaired glucose tolerance Inflammatory factors Interleukin-6 Tumor necrosis factor-α
CLC: R714.2
Type: PhD thesis
Year: 2011
Downloads: 52
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Abstract


Obstructive sleep apnea in type 2 diabetes patients are common, both in clinical and epidemiological and pathogenesis, and independent of obesity. Currently type 2 diabetes as harmful to health has been recognized, and OSA brought by healthy harm and medical burden is far from understanding by people. The international diabetes federation epidemic and prevention panel in 2008 published consensus suggest the global interdisciplinary personnel common efforts, make everyone fully realize the OSA and type 2 diabetes relationships.In the 1960s, apnea/hypopnea syndrome officially became a separate disease. Sleep-related breathing disorder becomes a common disease. Obstructive sleep apnea/hypopnea syndrome (OSAHS) is a syndrome that has sleep apnea and snoring, breathe shallow slow, serious daytime sleepiness. Refers to 7 hours nightly during sleep apnea repeated attacks on 30 times above, or sleep apnea hypoventilation index is equal to or greater than 5 times/hour. Among, hypoventilation refers to breath pressure strength during sleep than basic level (range) and is accompanied by reduced by 50% above and SaO2 a basic level is equal to or greater than the 4% decline. Many domestic provinces epidemiological surveys showed that the prevalence of adults OSA about 4 per cent. Despite the current domestic obesity rate is not high, but the OSA is high, this may morbidity with compatriots and maxillofacial structure characteristics related. Research results show that OSA is independent risk factor for the variety of systemic disease. But now the medical staff lack of knowledge about this disease, especially seriousness and universality, and clinical diagnosis and treatment conventions also exists many problems need to be settled as soon as possible. OSAHS patients appeared repeatedly sleep apnea, cause intermittent hypoxia, sleep fragment and hypercapnia, these stress influence sugar metabolism, lead to insulin resistance; and stimulate catecholamine, renin and angiotensin etc released, this can cause autonomic function and endocrine metabolic disorder, cause increased blood pressure, and then cause the heart, lungs, brain, kidney and other organs changed. Because sleep repeatedly of hypoxemia and sleep structure disorder, OSAHS patients experienced sleep disorders, memory loss and daytime sleepiness, combined with cardiopulmonary cerebrovascular disease risk bigger, the quality of life have been seriously affected. OSAHS is a serious disease, can involvement every system, a significant increase incidence and mortality. According to statistics, normal adult OSAHS prealence was 2-4%. Pregnancy greatly increased OSAS’s prevalence. Young etc by polysomnography found that the prevalence in middle-aged male and women has 24% and 9%, respectively.OSA patients on health resources consumption twice for healthy people, so right evaluation of OSA patients’ symptoms, correct diagnosis and timely treatment can reduce related health resources consumption. In addition, sleepiness cause less productive, traffic accidents, production accidents and therefore the disability, the impact on the economy of the OSA far higher than the direct medical expenses.Diabetes mellitus is the metabolic diseases characterized by a group of chronic blood glucose (sugar) increased. Diabetes is caused by the insulin absolute or relative lack and also insulin resistance caused by chronic high blood glucose syndrome, serious even can cause diabetes complications, and long-term hyperglycemia can lead to tissue organ damage, cause microvascular and macrovascular lesions. High blood glucose is due to insulin secretion defects and (or) insulin action caused by defects. Besides carbohydrates, protein, fat exist metabolism disorders. Prolonged illness can cause many system chronic progressive lesions, such as the eyes, kidneys and nerves, heart, blood vessels, make functional defects and failure. Diabetes is common and frequently-occurring diseases. With the development of economy, lifestyle changes, prolonging and raise the level of understanding of disease, diabetes cases increases year by year. The world health organization (WHO) 1997 report about 135 million people with diabetes, and by 2025 will rise to 3 billion. The prevalence of diabetes grows fast in developing countries, and also growth quite amazing in China in the past 30 years. In developed countries, diabetes has become the third largest non-communicable diseases, followed by cardiovascular and tumor, the harm of diabetes and its complications cause the more and more people’s attention. Diabetes etiology is not at all clear. Currently accepted diabetes is not a single cause of disease, but by composite causes of syndrome, and related genetic, autoimmune and environmental factors. In 1999 the WTO divided diabetes into four types, namely type 1 diabetes, type 2 diabetes and other special type and the gestational diabetes.Nationwide survey in 2007-2008 show that our country diabetes prevalence was 9.7%, pre-diabetes, sugar (IGT) and impaired fasting glucose (IFG) prealence of 15.5% to calculate that the national diabetes cases about 90 million. Diabetes caused 208 billion yuan RMB medical expenses,4.38% in total medical expenses in 2003. In recent years, there many researches about OSA and diabetes, insulin resistance. OSA and glucose metabolic abnormalitiesCorrelation OSA and type 2 diabetesType 2 diabetes OSAHS and are vulnerable to concurrent cardiovascular disease, and more and more studies show that type 2 diabetes and OSAHS closely related, often merger exists. According to reports, diabetes prevalence averaged 12.3%~48.0 % in OSAHS patients. More than half of OSA in diabetes patients, and there are one-third of need treatment; Studies have reported diabetes mellitus merger sleep problems can get 58 percent. Einhorn D etc show that if sleep apnea hypoventilation index (AHI) than 10 times/hours to define sleep apnea (SA), incidence of SA in adult type 2 diabetes patients was 48 percent; If AHI than 15 times/hours to define, with an incidence of 36%; If AHI than 20 times/hours to define, with an incidence of 29 percent. Meslier studied the incidence of type 2 diabetes and abnormal glucose tolerance is 30%,20%, respectively, in 494 cases male OSAHS and blood sugar level positively correlated with OSAHS severity. This suggested OSAHS is related to glucose metabolic abnormalities and type 2 diabetes, however it independent of age, obesity.Linear regression analysis found that OSAHS, fasting insulin, blood glucose and glycated hemoglobin significant correlation. The results of the study show that, OSA diagnoses by polysomnography when AHI above 10 easily happen glucose tolerance damaged and diabetes than non-OSA. OSAHS mainly related with type 2 diabetes, and has been listed as the clinical risk factors in type 2 diabetes. Patients with OSAHS get type 2 diabetes will spend pre-diabetes which including glucose tolerance damage, an oral glucose tolerance test after 2 h damaged and fasting glucose damaged.Foster GD etc research shows in diabetic patients with obese the prevalence of OSAHS get to 86%. Shiba T research found that diabetic retinopathy patients have 42% sleep-disordered breathing, the incidence of men with 50 percent rate,27% for female. Based on a male population clinical research by Meslier N, the results showed that sleep apnea severity and insulin resistance positively correlated. Sleep-disordered breathing related to insulin sensitivity damaged, glucose effectiveness and beta cell in pancreas function by Punjabi NM’s research. With mild, moderate, and severe sleep disorder breathing patients compared to normal people, Insulin sensitivity decline 36.5% and 26.7% and 4.37%, respectively. But Lam DC’s research shows that adipose cell type fatty acid-binding protein is associated with insulin resistance, and is independent of obesity, this correlation is more significant in severe OSAHS. OSAHS not only increases the occurrence of type 2 diabetes, but also can aggravating type 2 diabetes symptoms, and even cause death. Sleep disordered breathings can also lead to diabetes rapid progress and the incidence of cardiovascular disease and mortality rate increases. Lavie P found diabetes cause mortality rate only after COPD and chronic heart failure in OSAHS’s patients. Research shows that blood oxygen desaturation associated with fasting blood glucose and 2h blood glucose in oral glucose tolerance test (OGTT), the severe OSA parameters related with the degree of insulin resistance. Wisconsin found that different degree of OSA (through the calibration obesity parameters) was associated with type 2 diabetes. Two large studies found, snoring is independent risk factors for diabetes after 10 years. Sleep clips and sleep quality in diabetes patients is the important predictor glycated hemoglobin. Continuous positive airway pressure can improve insulin sensitivity, help control blood glucose and reduce HbAlc.Interactional mechanism in OSA and type 2 diabetesGenerally, pathogenesis of diabetes is mainly insulin resistance and B cell function defects. OSAHS leads to insulin resistance and pancreatic hyperglycemia disease, there may be the following ways:OSAHS-insulin resistance, pancreatic hyperglycemia disease-X syndrome-ischemic heart disease. That is many pathogenic factors may interact by leads to insulin resistance, this common link lead to high blood pressure, glucose metabolic abnormalities, lipid metabolic abnormalities and arterial sclerosis consequences. In recent years the mechanism about the correlation OSA and type 2 diabetes as well as the possible intervention treatment methods are studied, the OSA can cause and aggravating the mechanism of type 2 diabetes are mainly:(1) the sympathetic nervous activity enhanced; (2) intermittent hypoxia; (3) HPA dysfunction; (4) systemic inflammation; (5) adipose cell factors changed, such as leptin levels increases and adiponectin decreased; (6) sleep deprivation. Above factors can lead to insulin resistance. In addition, the autonomic nerve dysfunction caused by diabetes can increase the dangerous of OSA, forming a vicious cycle. Diabetes has high genetic susceptibility, exists insulin resistance in early stage, there are influence by adverse environmental factors or the evolution of the disease itself, insulin resistance progressive, insulin compensatory secretion increases, causing pancreatic hyperglycemia, cause abnormal glucose tolerance. When B cell function is reduced to cannot produce enough insulin to maintain normal blood glucose, namely appear high blood glucose and eventually lead to diabetes. The incidence of OSAHS in diabetes patients increased significantly. The possible mechanism of OSAHS trigger type 2 diabetes still include low oxygen state, aerobic anaerobic glycolysis decrease, so that some of the ferment without oxidation and reduction of pyruvic into lactic acid, the latter into liver changed to glucose; Repeated hypoxia and hypercapnia activate sympathetic nerve, stimulate secretion of endocrine organs catecholamine, thus make glycogen release increase glycogen, causing blood glucose increased, etc. OSA patients sympathetic nervous activity increases, glucose metabolism balance can be damaged by adding glycogen decomposition and caused insulin resistance; HPA elevated cause serum cortisol increased, causing insulin secretion decline; OSA patients night repeatedly apnea can cause airframe anoxia, etc. Diabetes patients than non-diabetic patients breathe periodically more common. In addition a study found that people with diabetes autonomic dysfunction and central chemical sensors for CO2 sensitivity rising and peripheral chemical sensors reduced. This may occur in 30% patients, but without the OSA periodic breathing and central sleep apnea, apparently still need further study of the role of autonomic dysfunction during sleep. Research results show that after CPAP treatment 3 months can significantly improve insulin sensitivity, CPAP therapy can make the HbAlc is decreased obviously. Obese OSA patients undergoing 12 weeks of CPAP therapy, the visceral fat reduction, leptin levels reduce, but blood glucose or insulin resistance did not improve. Every night the CPAP treatment time above 4h has obvious effect, but less than 4h effect is not obvious. Although pregnancy is a normal physiological processes, but its obvious abdomen circumference increase thus promote OSAS occurs.Gestational diabetes mellitus refer to the first discovery or happened glucose metabolic abnormalities, including not diagnosed type 2 diabetes. The incidence is 1%~14% in pregnancy. Gestational blood volume increased, blood diluted, insulin relative deficiency; the hormone secreted by placenta has insulin resistance in the surrounding tissue, and this make demand of insulin almost twice than nonpregnant. Gestational diabetes the damage degree closely related with blood glucose levels, may cause fetal congenital malformation, neonatal blood sugar is too low and acute respiratory distress syndrome, stillbirth, premature birth, pregnant women hydramnios, urinary tract infection, such as headaches, not only influence fetal development, also harm to maternal health. Early diagnosis and prompt, reasonable treatment will greatly reduce maternal complications and adverse pregnancy occurs Plenty of evidence suggests that, for pregnant women increased the incidence of snoring and made its original apnea and hypoxia increasing. For pregnant women, the research of sleep disordered breathings is relatively small, mainly with pregnant women is difficult to accept the check on polysomnography. Co-exist for pregnant women with abnormal glucose tolerance in patients with OSAHS, we conducted some studies to explore the possible pathophysiological mechanisms, and provide a non-intervention treatment. For the current research status, we believe that gestational diabetes, as diabetes early stage may be related to obstructive sleep apnea syndrome similar relationship also exists, this study reveals this relationship and may be provide a new way of the treatment of gestational diabetesStudies have demonstrated obstructive sleep apnea hypopnea syndrome (OSAHS) is an independent risk factor for diabetes. It is noteworthy that, OSAHS is also gestational diabetes and impaired glucose tolerance during pregnancy is an independent risk factor? Abroad in recent years researchers have found that pregnant women who snore increased risk of diabetes, hypertension and fetal growth restriction. Research has shown that the incidence of OSA in diabetes was 23%, it is likely that covert development of sleep-disordered breathing is a risk factor for diabetes. At present, for OSAHS studies in pregnant populations form the majority of the survey and carried out by PSG is only individual cases, for which we will have the option of pregnant women are carried out into the whole night of polysomnography, and analysis apnea-hypopnea index and lowest oxygen saturation and degree of impaired glucose tolerance and related clinical parameters, further studies in which the possible pathogenesis by detecting the hormone in serum, IL-6 and TNF-α.Many studies have found the level of inflammatory factors in impaired glucose tolerance and gestational diabetes was significantly higher than normal pregnant women, but the causes of elevated inflammatory cytokines is not clear, more research studies tend to vascular endothelial injury theory. Vascular endothelial injury is what causes it? Our study suggests that may be overlooked sleep problems caused.Part one Pulse blood oxygen desaturation index for the diagnosis of sleep apnea syndromeObjective To study the diagnosis value of pulse oxygen desaturation index (PODI) in patients with sleep apnea/hypopnea syndrome (SAS). Methods 178 randomly selected patients with suspected SAS has to be overnight polysomnography monitoring and pulse oxygen saturation monitoring at the same time, and statistics sleep apnea/hypopnea index(AHI)、the mean time for sleep apnea/hypopnea(TIME-mean)、the longest time for sleep apnea/hypopnea(TIME-max)、the mean Spo2(Spo2-Mean)、the lowest Spo2(Spo2-Min)and PODI were calculated. Results There were a significant correlation (rs=0.959, p=0.000) between PODI and AHI. Multiple stepwise regression analysis found that the impact factor PODI are AHI, Spo2-min, BMI, and standard regression coefficients were 0.79,-0.188,0.053,respectively. ROC analysis of the PODI,4.75 is the best standard to judge whether or not patients with SAS (sensitivity of 97.4% and specificity was 100%), divided into mild and moderate SAS value of 14 (sensitivity of 92.0%, specificity was 90.3%), classified as moderate to severe 25.6 (sensitivity of 89.4% and specificity was 90.3%). PODI values smaller than AHI in criteria for the classification of SAS, therefore relatively more sensitive. Conclusion PODI is an objective ideal target for the diagnosis of SAS.Part two Association of progestogen in IGT patients with pregnancy combined with obstructive sleep apnea hypopnea syndromeObjective To investigate the possible pathogenesis and the correlation of progestogen in patients with impaired glucose tolerance (IGT) pregnancy combined with obstructive sleep apnea hypopnea syndrome (OSAHS). Methods Twenty-five impaired glucose tolerance pregnancy women combined with OSAHS and thirty-five IGT pregnancy women were randomly selected to record all night polysomnography(PSG), and record apnea hypopnea index(AHI).We measured the estriol levels(E3) and progesterone(P) level, and also recorded age, gestational age, body mass index (BMI). Results AHI is 1.48±1.34 times/hour in simple group, and 8.23±2.78 times/hour in the combined OSAHS group; LSpO2 is 94.63±1.94% in simple group, and 88.40±2.80% in the combined OSAHS group; E3 is 21.83±2.15nmol/L in simple group, and 21.87±2.11nmol/L in the combined OSAHS group; P is 526.91±59.13nmol/L in simple group, and 528.94±63.44nmol/L in the combined OSAHS group. AHI, LSpO2 significantly was higher (p are 0.000) in the combined OSAHS group than the simple group.The E3 (P=0.934) and P (P=0.899) in patients with IGT pregnancy combined with OSAHS were not significantly different with those of the controls (all P>0.05). Conclusions The progestogen condition of IGT patients with pregnancy combined with OSAHS is not different with IGT patients pregnancy. IGT pregnancy combined with OSAHS may not be due to different levels of sex hormones and may not be take part in the pathology process of progestogen.Part three Inflammation factors in IGT patients with pregnancy combined sleep apnea/hypopnea syndrome and the possible pathogenesis of IGT patients with pregnancyObjective To investigate the possible pathogenesis and the correlation of inflammatory cytokines (IL-6 and TNF-a) in patients with impaired glucose tolerance (IGT) pregnancy combined with obstructive sleep apnea hypopnea syndrome (OSAHS). Methods Twenty-five impaired glucose tolerance pregnancy women combined with OSAHS and thirty-five IGT pregnancy women were randomly selected to record all night polysomnography(PSG), and record apnea hypopnea index(AHI),the lowest pulse oxygen saturation (LSpO2), age, gestational age, body mass index and glucose serum protein, also IL-6 and TNF-αwere measured. Results GSP in a simple group was 1.44±0.15mmol/L, in the combined OSAHS group was 1.68±0.24mmol/L; TNF-αin simple group was 8.77±2.61pg/ml, in the combined group was 22.70 OSAHS±5.65 pg/ml; IL-6 in a simple group was 99.29±8.83 pg/ ml, in combination OSAHS group was 146.65±22.65pg/ml. AHI, LSpO2 significantly were higher (p are 0.000) than control; GSP, IL-6 and TNF-αalso increased (p are 0.000). Significant positive correlations of AHI to GSP、IL-6 and TNF-α; LSpO2 was found to inversely correlate to GSP、IL-6 and TNF-a.There were a significant correlation (rs=0.510, P=0.000) between IL-6 and GSP., and also correlation (rs=0.476,P=0.000) between TNF-αand GSP. Conclusions The inflammatory cytokines of IGT patients with pregnancy combined with OSAHS is higher than IGT pregnancy. The level of IL-6 and TNF-αis relevant to GSP、AHI、LSpO2, respectively. The inflammatory factors may have very important role in this process, and OSAHS may induce or aggravate IGT.Part four nCPAP therapy on glucose metabolism in IGT with sleep apnea syndrome pregnant womenObjective Continuous positive airway pressure therapy on glucose metabolism in IGT pregnant with sleep apnea syndrome women, further study of the correlation between sleep apnea hypopnea syndrome (OSAHS) and abnormal glucose tolerance during pregnancy and its possible pathogenesis.Methods Through continuous positive airway pressure treatment of 15 IGT with sleep apnea syndrome pregnant women 1 week, fasting blood glucose, FINS were measured before and after treatment, respectively. Results 12 subjects successfully completed the study. Before and after the CPAP, AHI were 12.03±0.96times/hour,1.94±1.06 times/hour; before and after the CPAP, LSpO2 were 86.92±2.31%,94.75±1.36%; FBG were 4.78±0.22mmol/L,4.73±0.27mmol/L before and after the CPAP; before and after the CPAP, FINS were 13.09±1.15mIU/L,12.49±0.93mIU/L; HOMA were 2.78±0.23,2.62±0.15 before and after CPAP. FBG, FINS were not statistically significant (P=0.131,0.069) before and after treatment, HOMA-IR was statistically significant (P=0.03). After treatment, AHI and LSpO2 returned to normal condition, and insulin sensitivity improved.Conclusions Continuous positive airway pressure on impaired glucose tolerance with sleep apnea syndrome pregnant women is a safe and effective treatment, further support for OSAHS is a risk factor for development of gestational impaired glucose tolerance.

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