Association of Habitual Snoring with Glucose and Insulin Metabolism in Nonobese Korean Adult Men
http://www.100md.com
美国呼吸和危急护理医学 2005年第2期
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Institute of Human Genomic Study, Ansan Hospital, Department of Internal Medicine, Anam Hospital, Korea University
Department of Preventive Medicine, Ajou University, Gyeonggi-do, Korea
National Genome Research Institute, National Institute of Health, Korea Center for Disease Control and Prevention, Seoul, Korea
ABSTRACT
Habitual snoring is associated with cardiovascular morbidity and mortality, and metabolic abnormalities such as impaired glucose homeostasis. Many studies were performed in obese Western populations. The purpose of this study was to examine the association of habitual snoring with glucose and insulin metabolism in nonobese Korean men who were free of diabetes and hypertension. A total of 2,719 men ages 40eC69 years from the Korean Health and Genome Study participated in this study. Information of snoring frequency was obtained by a questionnaire and glucose and insulin levels during oral glucose tolerance test were measured. Repeated measures analysis of variance detected significant differences in the changing patterns of glucose and insulin levels at 1 hour and 2 hours between habitual snorers and nonhabitual snorers, whereas there were no significant differences in fasting blood glucose and insulin levels. Multivariate logistic regression analyses revealed that habitual snoring was independently associated with elevated 1-hour and 2-hour glucose levels and a 2-hour insulin level, respectively. The present data suggest that habitual snoring may affect glucose-insulin metabolism, independent of diabetes and hypertension, even in nonobese Korean middle-age men. Further prospective studies are needed to examine the causal relationship between habitual snoring and insulin resistance or glucose intolerance.
Key Words: epidemiology glucose tolerance insulin resistance sleep-disordered breathing
Habitual snoring is one of the most common symptoms of sleep-disordered breathing (SDB), which causes hypoxemia and hypercapnia from the partial obstruction of the upper airway during sleep. There has been increasing evidence that SDB may be associated with impaired glucose homeostasis or insulin resistance (1eC7). In a population-based study, Jennum and associates (1) reported that snoring was independently associated with a 2-hour blood glucose level, but not fasting glucose level, despite controlling for body mass index (BMI), physical activity, alcohol consumption, and smoking history. In a clinic-based study, Ip and coworkers (4) found that subjects with obstructive sleep apnea, defined as an apneaeChypopnea index (AHI) 5, were more insulin resistant than those without obstructive sleep apnea, and obesity was the major determinant of insulin resistance. They have shown that SDB parameters such as AHI and minimum oxygen saturation were also independent determinants after adjustment for obesity and other important confounding factors of insulin resistance. Elmasry and colleagues (7) also indicated that patients with obesity and obstructive sleep apnea had significantly higher levels of fasting blood glucose and fasting serum insulin compared with patients without obstructive sleep apnea.
Although most of studies on the association between SDB and impaired glucose tolerance or insulin resistance were adjusted for obesity, a confounding effect may still remain because of the high predictability of obesity for these two disorders. Moreover, biological consequences of SDB on glucose metabolism may differ depending on obesity status. However, few studies have been conducted in nonobese subjects. If the association between SDB and impaired glucose metabolism may be indeed shown to persist among nonobese subjects, it would strengthen independent relation of SDB to glucose metabolism. The purpose of this study, therefore, was to examine the association between habitual snoring and glucose metabolism in nonobese, middle-age Korean men. Specifically, time-dependent variations in glucose and insulin levels during oral glucose tolerance test were evaluated in relation to the presence of habitual snoring.
Some of the results of this study have been previously reported in the form of an abstract (38).
METHODS
Sample
The study sample was drawn from the Korean Health and Genome Study, which began in 2001 as an ongoing population-based study of Korean adults aged 40eC69 years to describe the frequency and determinants of chronic diseases in Korea (8). Participants included residents of an industrialized community 32 kilometers southwest of Seoul, South Korea (Ansan), and in a rural setting 100 kilometers south of Seoul (Ansung). A total of 2,523 men and 2,497 women in Ansan and 2,239 men and 2,779 women in Ansung agreed to participate in a baseline physical examination. In both Ansan and Ansung, the age and sex distributions of those examined were similar to those who were not examined. In this report, the study sample included 2,719 nonobese male participants who were free of diabetes and severe hypertension.
Measurements
Study participants were asked by a trained interviewer about frequency of snoring that occurred during a typical week. In this report, habitual snoring was defined as a snoring frequency 4 days or more per week, and, if otherwise, nonhabitual snoring was defined. Snoring responses were also confirmed by a bed partner or a member of the family. To examine the test-retest reliability of the snoring questionnaire, 200 adults aged 40eC69 years were queried about their snoring habits 2 weeks after the first test. Agreement between the two episodes was good with a Kappa statistic value of 0.73. Among the sample, 83% replied with the same answer on both occasions.
After an overnight fasting, blood was drawn for determinations of fasting glucose and insulin levels along with total cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol concentration. In addition to fasting glucose and insulin, glucose and insulin levels were also measured 1 hour and 2 hours after the ingestion of 75 grams of glucose. A diagnosis of diabetes was made if a fasting glucose level was greater than or equal to 126 mg/dl or when postchallenge levels were greater than or equal to 200 mg/dl (9). Diabetes was also defined when participants were receiving oral hypoglycemic agents or insulin therapy.
Severe hypertension was defined when either a systolic or diastolic blood pressure was greater than or equal to 160 and 100 mm Hg, respectively, or when participants were taking antihypertensive medication (10). Obesity was defined as waist circumference greater than 90 centimeters (11) or BMI greater than or equal to 27.5 kg/m2 (12).
Statistical Analysis
Descriptive statistics between habitual snorers and nonhabitual snorers were compared by Mann-Whitney U test and independent samples t test; categorical variables were compared by chi-squared test. Repeated-measures analysis of variance was employed to examine the differences in changing patterns of glucose and insulin levels over time (at fasting, 1 hour, and 2 hours) after loading a 75 grams of glucose within and between the two groups. Point estimates were presented as least-square means. Multiple logistic regression models were used to estimate the odds ratios and 95% confidence interval of elevated blood glucose and insulin levels for habitual snorers versus nonhabitual snorers. The elevated blood glucose and insulin levels were defined as the top quartile of corresponding values. All analysis was performed using SPSS for Windows software (Version 10.0, SPSS, Inc., Chicago, IL).
RESULTS
Characteristics of Study Sample
Among the 4,762 male participants in the Korean Health and Genome Study, 619 (13.0%) with diabetes mellitus and 507 (10.6%) with severe hypertension were excluded. Moreover, 621 (13.0%) obese men with a waist circumference more than 90 centimeters or BMI greater than or equal to 27.5 kg/m2 were also excluded. Insufficient information regarding sociodemographic and sleep-related characteristics was collected in 296 (6.2%) other men. After excluding those individuals, data from 2,719 men (385 habitual snorers and 2,334 nonhabitual snorers) were included in this report.
Table 1 shows the comparison of sociodemographic and clinical characteristics between habitual snorers and nonhabitual snorers. Mean age was 50.9 years for both habitual snorers and nonhabitual snorers. Even after excluding obese subjects with waist circumference more than 90 centimeters or BMI greater than or equal to 27.5 kg/m2, habitual snorers had significantly (p < 0.001) higher mean BMI (23.7 kg/m2) and waist circumference (81.6 centimeters) than did nonhabitual snorers (23.0 kg/m2 and 80.2 centimeters). Habitual snorers had a significantly lower (p < 0.001) level of HDL cholesterol, whereas there was no significant difference in total cholesterol between habitual snorers and nonhabitual snorers level of HDL cholesteroleCdeleted). There were no significant differences in the proportions of subjects reporting alcohol consumption, being a current smoker, and subjects with impaired fasting glucose or family history of diabetes between the two groups. Moreover, no significant differences were found in mean systolic and diastolic blood pressure and serum triglycerides levels between habitual snorers and nonhabitual snorers.
Table 2 and Figures 1 and 2 show the changes in blood glucose and blood insulin levels by the time course after loading 75 grams of glucose within and between habitual snorers and nonhabitual snorers. A fasting blood glucose level of habitual snorers (88.6 mg/dl) was not significantly different from that of nonhabitual snorers (88.3 mg/dl), whereas 1-hour and 2-hour glucose levels of habitual snorers (156.9 and l17.0 mg/dl, respectively) during the oral glucose tolerance test were significantly (p < 0.01) greater than those of nonhabitual snorers (149.2 and 112.6 mg/dl) in nondiabetic men. With regard to insulin secretion, there was no significant difference in fasting insulin levels between habitual and nonhabitual snoring groups (6.4 and 6.5 e蘄U/ml, respectively). In addition, the 1-hour insulin level was the same between the two groups. However, the mean 2-hour insulin level was significantly (p < 0.01) greater in habitual snorers (24.2 e蘄U/ml) than in nonhabitual snorers (21.0 e蘄U/ml). The repeated measures analysis of variance detected significantly (p < 0.01) different changing patterns by time course in both glucose and insulin levels between the two groups. In Table 2, the p values of time indicate the significance of changes with time course in each parameter, and the p values of interaction mean whether the changes in glucose and insulin levels at each time points were significantly different between habitual snoring and nonhabitual snoring.
Table 3 shows the estimated odds ratios of elevated glucose and insulin levels for habitual snorers versus nonhabitual snorers at fasting, 1 hour, and 2 hours during an oral glucose tolerance test. Adjusting for age, current alcohol consumption, current smoking, BMI, systolic blood pressure, serum HDL cholesterol, and family history of diabetes, the odds of elevated glucose levels at 1 hour and 2 hours among habitual snorers were 1.33 and 1.32 times greater, respectively, than those among nonhabitual snorers. In addition, the odds of an elevated 2-hour insulin level were 31% higher among habitual snorers than among nonhabitual snorers.
DISCUSSION
The results of this study demonstrate that in nonhypertensive, nondiabetic, and nonobese Korean men aged 40 to 69 years, the changing patterns of glucose and insulin levels at 1 hour and 2 hours after an ingestion of 75 grams of glucose were significantly different between habitual snorers and nonhabitual snorers, whereas there were no significant differences in fasting blood glucose and insulin levels between these two groups. Our data also show that habitual snoring was independently associated with the elevated 1-hour and 2-hour glucose levels and a 2-hour insulin level even after adjusting for age and other risk factors, including current alcohol consumption, current smoking, BMI, systolic blood pressure, serum HDL cholesterol, and family history of diabetes.
Previous studies that used self-reported symptoms, such as snoring and witnessed apnea, demonstrated the relationship between SDB and metabolic abnormalities (1, 2, 7, 13, 14). Grunstein and coworkers (2) showed that snoring and witnessed apnea was positively associated with a fasting insulin level after controlling for body fat distribution and other potential confounders, including age, smoking, alcohol consumption, medication use, and sagittal diameter. More recent investigations based on larger clinical samples revealed the relationship between SDB and impaired glucoseeCinsulin metabolism independent of obesity. Vgontzas and colleagues (15) found that fasting blood insulin and glucose levels of obese subjects with obstructive sleep apnea were significantly higher than BMI-matched controls without obstructive sleep apnea, suggesting that SDB is an independent risk factor for hyperinsulinemia. In a clinic-based study with 595 male patients (494 obstructive sleep apnea syndrome patients and 101 nonapneic snorers), Meslier and colleagues (6) reported that fasting and 2-hour blood glucose levels increased with severity of sleep apnea, whereas insulin sensitivity decreased with increasing severity of sleep apnea. Among community-dwelling participants in the Sleep Heart Health Study (1994eC1999) (16), subjects with mild SDB (a respiratory disturbance index of 5.0eC14.9 events/hour) and moderate to severe SDB ( 15 events/hour) had adjusted odds ratios of 1.27 (95% CI: 0.98eC1.64) and 1.46 (95% CI: 1.09eC1.97), respectively, for fasting glucose intolerance (p for trend < 0.01) compared with subjects with reference category (< 5.0 events/hour). Although these studies are not completely comparable because of differences in subjects' characteristics and methodology, the findings consistently showed that SDB may cause abnormal glucose and insulin metabolism independent of age and BMI. In the present study, habitual snorers had significantly higher 1-hour and 2 hour glucose levels and a 2-hour insulin level compared with those of nonhabitual snorers, despite there being no significant differences in fasting blood glucose and insulin concentrations between these two groups, which confirms earlier results.
With regard to the incidence of type II diabetes, a cross-sectional study of 5,201 adults older than age 65 years indicated that snoring in women was independently related to diabetes (odds ratio: 1.34; 95% confidence interval: 1.1eC1.7) after adjusted for BMI (17). In addition, prospective data from two population-based cohort studies in men ages 30eC69 years (14) and women aged 40 to 65 years (18) showed that snoring was associated with an increased incidence of diabetes mellitus over a 10-year period after adjusted for BMI and other confounding variables.
On the other hand, several studies reported no correlation between SDB and metabolic abnormalities. Davies and coworkers (19) found that fasting insulin levels of patients with SDB were not significantly different from those of controls matched on age, BMI, smoking history, and alcohol use. Therefore, they concluded that SDB may not contribute to an increased risk of metabolic dysfunction. Stoohs and colleagues (20) also demonstrated that there was no correlation between SDB and insulin resistance after adjusting for BMI in a sleep study of 50 healthy subjects. The lack of independent association in these studies, however, may reflect insufficient power given the small number of patients studied.
Although the causal relationships have not been established, some studies demonstrated the possibility that SDB results in insulin resistance and glucose intolerance independent of obesity. Punjabi and colleagues (5) observed a twofold increase in insulin resistance with an AHI 5 events/h and every 4% decrease in oxygen saturation in healthy men who were mildly obese (mean BMI = 30.5 ± 2.9 [SD] kg/m2). Furthermore, it was shown that AHI and minimum oxygen saturation were independent determinants of insulin resistance after adjusting for obesity in nondiabetic patients (4). On the other hand, it was shown that the prevalence of obstructive sleep apnea was much higher in women with polycystic ovary syndrome than in premenopausal normal women (21, 22). Moreover, Vgontzas and colleagues (21) found that insulin resistance was a stronger risk factor than BMI or testosterone for SDB in women with polycystic ovary syndrome. They suggested that SDB may be a manifestation of a metabolic abnormality in which insulin resistance plays an important role, implicating that the association between SDB and insulin resistance may be bidirectional. Therefore, a prospective study is still needed to further investigate the causal association between SDB and the future risk of insulin resistance or type II diabetes.
Although the findings from majority of earlier studies showed a consistent association between SDB and impaired insulineCglucose metabolism independent of BMI, the mechanism underlying this relationship has not been elucidated. It is known that hypoxia and hypercapnia that occur in SDB provoke sympathetic nervous activity (23eC25) and catecholamine, epinephrine and norepinephrine, and cortisol are released by triggering the physiologic stress response (26, 27). The systemic effect of sympathetic hyperactivity and increased catecholamines can impair glucose homeostasis by increasing glycogenolysis and gluconeogenesis (28, 29), which can result in increased circulating insulin levels (hyperinsulinemia) and increased risk of insulin resistance, which may result in type II diabetes mellitus (28). Moreover, hypoxia could lead to impaired glucose tolerance and insulin resistance by promoting the release of proinflammatory cytokines, such as interleukin-6 and tumor necrosis factor- (16, 30). In clinic-based studies (15, 31), patients with SDB had higher plasma levels of interleukin-6 and tumor necrosis factor- when compared with control subjects. There are increasing data that interleukin-6 is positively correlated with indices of insulin resistance (32eC34), and tumor necrosis factor- has a potential role in the development of insulin resistance (35, 36). SDB also leads to elevations of other mediators of inflammation, including intercellular adhesion molecule-1 and C-reactive protein (30).
As expected, our data showed that habitual snorers had a significantly lower level of HDL cholesterol and a higher level of triglycerides compared with nonhabitual snorers. Consistent with our results, it has also demonstrated that relevant metabolic markers of insulin resistance include a decreased HDL cholesterol concentration and an increased plasma triglyceride concentration (37).
Although earlier studies have shown that SDB is independently associated with metabolic dysfunction, including glucose intolerance and insulin resistance, many of these studies have several methodologic limitations, including limited sample sizes, lack of objective data on sleep and predictable laboratory parameters, and the use of clinic-based patients, Western populations, or a selective subject group (e.g., Nurses' Health Study). In this respect, the strong point of the current study is that the independent association of SDB with impaired glucose tolerance and insulin resistance was found in a large, nonobese Asian population. Thus this report adds to a growing body of literature that suggests that habitual snoring is associated with insulin resistance and glucose intolerance independent of obesity and ethnic background. Several limitations, however, must be considered in the interpretation of our results. First, our data on habitual snoring were collected from a questionnaire, which is a typical limitation of most epidemiologic studies. To compensate for this limitation, we examined the test-retest reliability of the question responses on snoring, and the results show that their reproducibility was high. Moreover, question responses on snoring were confirmed by a bed partner or family member. Therefore, our data on self-reported snoring are likely to be reasonably reliable. Second, the present report is based on a cross-sectional data, which indicates that causal relationship may not be addressed. Third, although the exclusion of women decreased the potential of confounding, it limits the generalizability of our results.
In conclusion, our findings from the Korean Health and Genome Study show that 1-hour and 2-hour blood glucose and 2-hour insulin levels of habitual snorers were significantly higher than those of nonhabitual snorers, even though postload blood glucose and insulin levels in both groups were within their normal ranges. Thus our results may suggest that habitual snorers tend to be more glucose intolerant and insulin resistant compared with nonhabitual snorers, further implying control of SDB could have important effects on the development of the metabolic disorders. A prospective study is needed to confirm the association between SDB and the future risk of impaired glucose and insulin metabolism in a healthy population without diabetes, hypertension, and obesity.
Acknowledgments
The authors thank JungBok Lee from the Institute of Statistics at Korea University for his valuable statistical advice.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
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Joo SJ, Shin C, Kim JY, Kim JK, Lee JB, Kim JH, Lee SY, Kang KH, Yoo SH, Shim JJ, et al. Impact of habitual snoring on time-dependent variations of glucose and insulin levels in normoglycemic middle-aged men: the Korean Health and Genome Study . 2004 International Conference. Am J Respir Crit Care Med 2004;169:A758.(Chol Shin, JinYoung Kim, )
Department of Preventive Medicine, Ajou University, Gyeonggi-do, Korea
National Genome Research Institute, National Institute of Health, Korea Center for Disease Control and Prevention, Seoul, Korea
ABSTRACT
Habitual snoring is associated with cardiovascular morbidity and mortality, and metabolic abnormalities such as impaired glucose homeostasis. Many studies were performed in obese Western populations. The purpose of this study was to examine the association of habitual snoring with glucose and insulin metabolism in nonobese Korean men who were free of diabetes and hypertension. A total of 2,719 men ages 40eC69 years from the Korean Health and Genome Study participated in this study. Information of snoring frequency was obtained by a questionnaire and glucose and insulin levels during oral glucose tolerance test were measured. Repeated measures analysis of variance detected significant differences in the changing patterns of glucose and insulin levels at 1 hour and 2 hours between habitual snorers and nonhabitual snorers, whereas there were no significant differences in fasting blood glucose and insulin levels. Multivariate logistic regression analyses revealed that habitual snoring was independently associated with elevated 1-hour and 2-hour glucose levels and a 2-hour insulin level, respectively. The present data suggest that habitual snoring may affect glucose-insulin metabolism, independent of diabetes and hypertension, even in nonobese Korean middle-age men. Further prospective studies are needed to examine the causal relationship between habitual snoring and insulin resistance or glucose intolerance.
Key Words: epidemiology glucose tolerance insulin resistance sleep-disordered breathing
Habitual snoring is one of the most common symptoms of sleep-disordered breathing (SDB), which causes hypoxemia and hypercapnia from the partial obstruction of the upper airway during sleep. There has been increasing evidence that SDB may be associated with impaired glucose homeostasis or insulin resistance (1eC7). In a population-based study, Jennum and associates (1) reported that snoring was independently associated with a 2-hour blood glucose level, but not fasting glucose level, despite controlling for body mass index (BMI), physical activity, alcohol consumption, and smoking history. In a clinic-based study, Ip and coworkers (4) found that subjects with obstructive sleep apnea, defined as an apneaeChypopnea index (AHI) 5, were more insulin resistant than those without obstructive sleep apnea, and obesity was the major determinant of insulin resistance. They have shown that SDB parameters such as AHI and minimum oxygen saturation were also independent determinants after adjustment for obesity and other important confounding factors of insulin resistance. Elmasry and colleagues (7) also indicated that patients with obesity and obstructive sleep apnea had significantly higher levels of fasting blood glucose and fasting serum insulin compared with patients without obstructive sleep apnea.
Although most of studies on the association between SDB and impaired glucose tolerance or insulin resistance were adjusted for obesity, a confounding effect may still remain because of the high predictability of obesity for these two disorders. Moreover, biological consequences of SDB on glucose metabolism may differ depending on obesity status. However, few studies have been conducted in nonobese subjects. If the association between SDB and impaired glucose metabolism may be indeed shown to persist among nonobese subjects, it would strengthen independent relation of SDB to glucose metabolism. The purpose of this study, therefore, was to examine the association between habitual snoring and glucose metabolism in nonobese, middle-age Korean men. Specifically, time-dependent variations in glucose and insulin levels during oral glucose tolerance test were evaluated in relation to the presence of habitual snoring.
Some of the results of this study have been previously reported in the form of an abstract (38).
METHODS
Sample
The study sample was drawn from the Korean Health and Genome Study, which began in 2001 as an ongoing population-based study of Korean adults aged 40eC69 years to describe the frequency and determinants of chronic diseases in Korea (8). Participants included residents of an industrialized community 32 kilometers southwest of Seoul, South Korea (Ansan), and in a rural setting 100 kilometers south of Seoul (Ansung). A total of 2,523 men and 2,497 women in Ansan and 2,239 men and 2,779 women in Ansung agreed to participate in a baseline physical examination. In both Ansan and Ansung, the age and sex distributions of those examined were similar to those who were not examined. In this report, the study sample included 2,719 nonobese male participants who were free of diabetes and severe hypertension.
Measurements
Study participants were asked by a trained interviewer about frequency of snoring that occurred during a typical week. In this report, habitual snoring was defined as a snoring frequency 4 days or more per week, and, if otherwise, nonhabitual snoring was defined. Snoring responses were also confirmed by a bed partner or a member of the family. To examine the test-retest reliability of the snoring questionnaire, 200 adults aged 40eC69 years were queried about their snoring habits 2 weeks after the first test. Agreement between the two episodes was good with a Kappa statistic value of 0.73. Among the sample, 83% replied with the same answer on both occasions.
After an overnight fasting, blood was drawn for determinations of fasting glucose and insulin levels along with total cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol concentration. In addition to fasting glucose and insulin, glucose and insulin levels were also measured 1 hour and 2 hours after the ingestion of 75 grams of glucose. A diagnosis of diabetes was made if a fasting glucose level was greater than or equal to 126 mg/dl or when postchallenge levels were greater than or equal to 200 mg/dl (9). Diabetes was also defined when participants were receiving oral hypoglycemic agents or insulin therapy.
Severe hypertension was defined when either a systolic or diastolic blood pressure was greater than or equal to 160 and 100 mm Hg, respectively, or when participants were taking antihypertensive medication (10). Obesity was defined as waist circumference greater than 90 centimeters (11) or BMI greater than or equal to 27.5 kg/m2 (12).
Statistical Analysis
Descriptive statistics between habitual snorers and nonhabitual snorers were compared by Mann-Whitney U test and independent samples t test; categorical variables were compared by chi-squared test. Repeated-measures analysis of variance was employed to examine the differences in changing patterns of glucose and insulin levels over time (at fasting, 1 hour, and 2 hours) after loading a 75 grams of glucose within and between the two groups. Point estimates were presented as least-square means. Multiple logistic regression models were used to estimate the odds ratios and 95% confidence interval of elevated blood glucose and insulin levels for habitual snorers versus nonhabitual snorers. The elevated blood glucose and insulin levels were defined as the top quartile of corresponding values. All analysis was performed using SPSS for Windows software (Version 10.0, SPSS, Inc., Chicago, IL).
RESULTS
Characteristics of Study Sample
Among the 4,762 male participants in the Korean Health and Genome Study, 619 (13.0%) with diabetes mellitus and 507 (10.6%) with severe hypertension were excluded. Moreover, 621 (13.0%) obese men with a waist circumference more than 90 centimeters or BMI greater than or equal to 27.5 kg/m2 were also excluded. Insufficient information regarding sociodemographic and sleep-related characteristics was collected in 296 (6.2%) other men. After excluding those individuals, data from 2,719 men (385 habitual snorers and 2,334 nonhabitual snorers) were included in this report.
Table 1 shows the comparison of sociodemographic and clinical characteristics between habitual snorers and nonhabitual snorers. Mean age was 50.9 years for both habitual snorers and nonhabitual snorers. Even after excluding obese subjects with waist circumference more than 90 centimeters or BMI greater than or equal to 27.5 kg/m2, habitual snorers had significantly (p < 0.001) higher mean BMI (23.7 kg/m2) and waist circumference (81.6 centimeters) than did nonhabitual snorers (23.0 kg/m2 and 80.2 centimeters). Habitual snorers had a significantly lower (p < 0.001) level of HDL cholesterol, whereas there was no significant difference in total cholesterol between habitual snorers and nonhabitual snorers level of HDL cholesteroleCdeleted). There were no significant differences in the proportions of subjects reporting alcohol consumption, being a current smoker, and subjects with impaired fasting glucose or family history of diabetes between the two groups. Moreover, no significant differences were found in mean systolic and diastolic blood pressure and serum triglycerides levels between habitual snorers and nonhabitual snorers.
Table 2 and Figures 1 and 2 show the changes in blood glucose and blood insulin levels by the time course after loading 75 grams of glucose within and between habitual snorers and nonhabitual snorers. A fasting blood glucose level of habitual snorers (88.6 mg/dl) was not significantly different from that of nonhabitual snorers (88.3 mg/dl), whereas 1-hour and 2-hour glucose levels of habitual snorers (156.9 and l17.0 mg/dl, respectively) during the oral glucose tolerance test were significantly (p < 0.01) greater than those of nonhabitual snorers (149.2 and 112.6 mg/dl) in nondiabetic men. With regard to insulin secretion, there was no significant difference in fasting insulin levels between habitual and nonhabitual snoring groups (6.4 and 6.5 e蘄U/ml, respectively). In addition, the 1-hour insulin level was the same between the two groups. However, the mean 2-hour insulin level was significantly (p < 0.01) greater in habitual snorers (24.2 e蘄U/ml) than in nonhabitual snorers (21.0 e蘄U/ml). The repeated measures analysis of variance detected significantly (p < 0.01) different changing patterns by time course in both glucose and insulin levels between the two groups. In Table 2, the p values of time indicate the significance of changes with time course in each parameter, and the p values of interaction mean whether the changes in glucose and insulin levels at each time points were significantly different between habitual snoring and nonhabitual snoring.
Table 3 shows the estimated odds ratios of elevated glucose and insulin levels for habitual snorers versus nonhabitual snorers at fasting, 1 hour, and 2 hours during an oral glucose tolerance test. Adjusting for age, current alcohol consumption, current smoking, BMI, systolic blood pressure, serum HDL cholesterol, and family history of diabetes, the odds of elevated glucose levels at 1 hour and 2 hours among habitual snorers were 1.33 and 1.32 times greater, respectively, than those among nonhabitual snorers. In addition, the odds of an elevated 2-hour insulin level were 31% higher among habitual snorers than among nonhabitual snorers.
DISCUSSION
The results of this study demonstrate that in nonhypertensive, nondiabetic, and nonobese Korean men aged 40 to 69 years, the changing patterns of glucose and insulin levels at 1 hour and 2 hours after an ingestion of 75 grams of glucose were significantly different between habitual snorers and nonhabitual snorers, whereas there were no significant differences in fasting blood glucose and insulin levels between these two groups. Our data also show that habitual snoring was independently associated with the elevated 1-hour and 2-hour glucose levels and a 2-hour insulin level even after adjusting for age and other risk factors, including current alcohol consumption, current smoking, BMI, systolic blood pressure, serum HDL cholesterol, and family history of diabetes.
Previous studies that used self-reported symptoms, such as snoring and witnessed apnea, demonstrated the relationship between SDB and metabolic abnormalities (1, 2, 7, 13, 14). Grunstein and coworkers (2) showed that snoring and witnessed apnea was positively associated with a fasting insulin level after controlling for body fat distribution and other potential confounders, including age, smoking, alcohol consumption, medication use, and sagittal diameter. More recent investigations based on larger clinical samples revealed the relationship between SDB and impaired glucoseeCinsulin metabolism independent of obesity. Vgontzas and colleagues (15) found that fasting blood insulin and glucose levels of obese subjects with obstructive sleep apnea were significantly higher than BMI-matched controls without obstructive sleep apnea, suggesting that SDB is an independent risk factor for hyperinsulinemia. In a clinic-based study with 595 male patients (494 obstructive sleep apnea syndrome patients and 101 nonapneic snorers), Meslier and colleagues (6) reported that fasting and 2-hour blood glucose levels increased with severity of sleep apnea, whereas insulin sensitivity decreased with increasing severity of sleep apnea. Among community-dwelling participants in the Sleep Heart Health Study (1994eC1999) (16), subjects with mild SDB (a respiratory disturbance index of 5.0eC14.9 events/hour) and moderate to severe SDB ( 15 events/hour) had adjusted odds ratios of 1.27 (95% CI: 0.98eC1.64) and 1.46 (95% CI: 1.09eC1.97), respectively, for fasting glucose intolerance (p for trend < 0.01) compared with subjects with reference category (< 5.0 events/hour). Although these studies are not completely comparable because of differences in subjects' characteristics and methodology, the findings consistently showed that SDB may cause abnormal glucose and insulin metabolism independent of age and BMI. In the present study, habitual snorers had significantly higher 1-hour and 2 hour glucose levels and a 2-hour insulin level compared with those of nonhabitual snorers, despite there being no significant differences in fasting blood glucose and insulin concentrations between these two groups, which confirms earlier results.
With regard to the incidence of type II diabetes, a cross-sectional study of 5,201 adults older than age 65 years indicated that snoring in women was independently related to diabetes (odds ratio: 1.34; 95% confidence interval: 1.1eC1.7) after adjusted for BMI (17). In addition, prospective data from two population-based cohort studies in men ages 30eC69 years (14) and women aged 40 to 65 years (18) showed that snoring was associated with an increased incidence of diabetes mellitus over a 10-year period after adjusted for BMI and other confounding variables.
On the other hand, several studies reported no correlation between SDB and metabolic abnormalities. Davies and coworkers (19) found that fasting insulin levels of patients with SDB were not significantly different from those of controls matched on age, BMI, smoking history, and alcohol use. Therefore, they concluded that SDB may not contribute to an increased risk of metabolic dysfunction. Stoohs and colleagues (20) also demonstrated that there was no correlation between SDB and insulin resistance after adjusting for BMI in a sleep study of 50 healthy subjects. The lack of independent association in these studies, however, may reflect insufficient power given the small number of patients studied.
Although the causal relationships have not been established, some studies demonstrated the possibility that SDB results in insulin resistance and glucose intolerance independent of obesity. Punjabi and colleagues (5) observed a twofold increase in insulin resistance with an AHI 5 events/h and every 4% decrease in oxygen saturation in healthy men who were mildly obese (mean BMI = 30.5 ± 2.9 [SD] kg/m2). Furthermore, it was shown that AHI and minimum oxygen saturation were independent determinants of insulin resistance after adjusting for obesity in nondiabetic patients (4). On the other hand, it was shown that the prevalence of obstructive sleep apnea was much higher in women with polycystic ovary syndrome than in premenopausal normal women (21, 22). Moreover, Vgontzas and colleagues (21) found that insulin resistance was a stronger risk factor than BMI or testosterone for SDB in women with polycystic ovary syndrome. They suggested that SDB may be a manifestation of a metabolic abnormality in which insulin resistance plays an important role, implicating that the association between SDB and insulin resistance may be bidirectional. Therefore, a prospective study is still needed to further investigate the causal association between SDB and the future risk of insulin resistance or type II diabetes.
Although the findings from majority of earlier studies showed a consistent association between SDB and impaired insulineCglucose metabolism independent of BMI, the mechanism underlying this relationship has not been elucidated. It is known that hypoxia and hypercapnia that occur in SDB provoke sympathetic nervous activity (23eC25) and catecholamine, epinephrine and norepinephrine, and cortisol are released by triggering the physiologic stress response (26, 27). The systemic effect of sympathetic hyperactivity and increased catecholamines can impair glucose homeostasis by increasing glycogenolysis and gluconeogenesis (28, 29), which can result in increased circulating insulin levels (hyperinsulinemia) and increased risk of insulin resistance, which may result in type II diabetes mellitus (28). Moreover, hypoxia could lead to impaired glucose tolerance and insulin resistance by promoting the release of proinflammatory cytokines, such as interleukin-6 and tumor necrosis factor- (16, 30). In clinic-based studies (15, 31), patients with SDB had higher plasma levels of interleukin-6 and tumor necrosis factor- when compared with control subjects. There are increasing data that interleukin-6 is positively correlated with indices of insulin resistance (32eC34), and tumor necrosis factor- has a potential role in the development of insulin resistance (35, 36). SDB also leads to elevations of other mediators of inflammation, including intercellular adhesion molecule-1 and C-reactive protein (30).
As expected, our data showed that habitual snorers had a significantly lower level of HDL cholesterol and a higher level of triglycerides compared with nonhabitual snorers. Consistent with our results, it has also demonstrated that relevant metabolic markers of insulin resistance include a decreased HDL cholesterol concentration and an increased plasma triglyceride concentration (37).
Although earlier studies have shown that SDB is independently associated with metabolic dysfunction, including glucose intolerance and insulin resistance, many of these studies have several methodologic limitations, including limited sample sizes, lack of objective data on sleep and predictable laboratory parameters, and the use of clinic-based patients, Western populations, or a selective subject group (e.g., Nurses' Health Study). In this respect, the strong point of the current study is that the independent association of SDB with impaired glucose tolerance and insulin resistance was found in a large, nonobese Asian population. Thus this report adds to a growing body of literature that suggests that habitual snoring is associated with insulin resistance and glucose intolerance independent of obesity and ethnic background. Several limitations, however, must be considered in the interpretation of our results. First, our data on habitual snoring were collected from a questionnaire, which is a typical limitation of most epidemiologic studies. To compensate for this limitation, we examined the test-retest reliability of the question responses on snoring, and the results show that their reproducibility was high. Moreover, question responses on snoring were confirmed by a bed partner or family member. Therefore, our data on self-reported snoring are likely to be reasonably reliable. Second, the present report is based on a cross-sectional data, which indicates that causal relationship may not be addressed. Third, although the exclusion of women decreased the potential of confounding, it limits the generalizability of our results.
In conclusion, our findings from the Korean Health and Genome Study show that 1-hour and 2-hour blood glucose and 2-hour insulin levels of habitual snorers were significantly higher than those of nonhabitual snorers, even though postload blood glucose and insulin levels in both groups were within their normal ranges. Thus our results may suggest that habitual snorers tend to be more glucose intolerant and insulin resistant compared with nonhabitual snorers, further implying control of SDB could have important effects on the development of the metabolic disorders. A prospective study is needed to confirm the association between SDB and the future risk of impaired glucose and insulin metabolism in a healthy population without diabetes, hypertension, and obesity.
Acknowledgments
The authors thank JungBok Lee from the Institute of Statistics at Korea University for his valuable statistical advice.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
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