Abstract
Aim: It is not clear whether the restrictive or obstructive pattern of spirometry is associated with metabolic syndrome. We investigated the associations between restrictive and obstructive spirometric patterns and metabolic risk factors using data from the Korea National Health and Nutrition Examination Survey (KNHANES). Additionally, we investigated whether sarcopenia is associated with metabolic syndrome in patients with chronic obstructive pulmonary disease (COPD). Methods: Using data from KNHANES between 2008 and 2011, we enrolled 8,145 subjects (normal lung function: 6,077, obstructive spirometric pattern: 1,039, restrictive pattern: 1,029) aged ≥40 years who underwent anthropometric measurement, laboratory tests, spirometry and estimation of appendicular muscle mass. Sarcopenia was defined as an appendicular skeletal muscle mass divided by body weight squared <2 SD below the sex-specific mean for the young reference group. Results: Sarcopenia was found in 32.8% of male and 12.2% of female patients with COPD. The odds ratio (OR) of metabolic syndrome for the restrictive spirometric pattern in male was 1.29 (95% confidence interval [CI], 1.02–1.65), and that for obstructive pattern in males was 0.99 (95% CI, 0.79–1.26) after adjustments for covariables (female restrictive pattern (ORs, 1,45; 95% CI, 1.09–1.91) and female obstructive pattern (ORs 0.73; 95% CI, 0.49–1.09). After adjustment for other confounding factors, the risk of metabolic syndrome was higher in sarcopenic male (OR, 1.88; 95% CI, 1.27–2.77) with COPD than in those without sarcopenia. Conclusions: The restrictive spirometric pattern is associated with metabolic syndrome, and sarcopenia may contribute to the risk of metabolic syndrome in male patients with COPD.
Keywords:
Introduction
Individuals with chronic obstructive pulmonary disease (COPD) are at higher risk of cardiovascular disease and may die from cardiovascular causes (Citation1). Metabolic syndrome presents multiple risks for the development of cardiovascular disease. The estimated prevalence of metabolic syndrome in people with COPD is 21–53% (Citation2, 3).
The association between metabolic syndrome and the restrictive and obstructive patterns of spirometry is controversial. Previous cross-sectional studies have found that the restrictive spirometric pattern defined as a predicted forced vital capacity (FVC) less than 80% and forced expiratory volume in 1 s (FEV1)/FVC greater than 0.7 was associated with metabolic syndrome (Citation4, 5); however, other studies showed that an obstructive spirometric pattern defined as FEV1/FVC less than 0.7 was not associated with metabolic syndrome (Citation6, 7).
Sarcopenia is characterized by progressive and generalized loss of skeletal muscle mass and strength with a risk of adverse outcomes such as physical disability, poor quality of life, and death (Citation8). Malnutrition and weight loss are common among patients with COPD caused by a negative energy balance as the result of low dietary intake and a higher than normal energy expenditure (Citation9). Moreover, sarcopenia is related to metabolic disorders including obesity, insulin resistance, and diabetes (Citation10).
Because skeletal muscle is the primary site of glucose uptake and deposition, sarcopenia promotes insulin resistance (Citation10), leading to the development of metabolic syndrome and diabetes (Citation11). An increase in whole-body lean mass in elderly subjects with sarcopenia has been reported to increase insulin sensitivity (Citation12). Insulin resistance is an underlying factor for type 2 diabetes and metabolic syndrome, which is characterized by a constellation of cardiovascular risk factors including obesity, hypertension, dyslipidemia, and dysglycemia (Citation13). Thus, it may be inferred that sarcopenia induces type 2 diabetes or metabolic syndrome through an increase in insulin resistance without obesity. Several previous studies have shown an association between impaired pulmonary function and insulin resistance (Citation7, Citation14). Fimognari et al. (Citation7) reported that insulin resistance was significantly higher in patients with the restrictive pattern than in those in the obstruction and normal groups.
Although sarcopenia is an emerging risk factor for metabolic disorders, no previous studies have investigated the association between sarcopenia and metabolic syndrome in people with COPD. Our cross-sectional study investigated the association between metabolic risk factors assessed using data from the Korea National Health and Nutrition Examination Survey (KNHANES) and the restrictive and obstructive patterns of spirometry measured using FVC or FEV1. We also evaluated whether sarcopenia is associated with metabolic syndrome in patients with COPD. To our knowledge, our study is the first to investigate the association of sarcopenia and metabolic syndrome in COPD.
Methods
Study participants
Our study used data acquired in the second and third years (2008–2009) of KNHANES IV and the first and second years (2010–2011) of KNHANES V. KNHANES has been conducted periodically since 1998 to assess the health and nutritional status of the non-institutionalized civilian population of South Korea. Annually, 10,000–12,000 individuals in 4,600 households are selected from a panel to represent the Koreans aged 18 years or older using the multistage clustered and stratified random sampling method based on National Census Data. The sampling frame was developed based on the 2,005 population and housing census in Korea. Household units were selected by a stratified multistage probability sampling design for the South Korean population. Approximately 260,000 primary sampling units, each of which contained ∼60 households. KNHANES IV and V were cross-sectional, nationally representative surveys conducted by the Division of Chronic Disease Surveillance, Korea Centers for Disease Control and Prevention. Of the 18,198 participants, our study included 8,145 subjects aged ≥40 years, who underwent anthropometric measurements, laboratory tests, dual energy X-ray absorptiometry, and spirometry.
Dual energy X-ray absorptiometry measurement and definition of sarcopenia
Healthy young volunteers (aged 18–39; 2,680 males and 3,520 females) who underwent a body composition test using dual energy X-ray absorptiometry (DXA; Discovery-W, Hologic Inc., Waltham, MA, USA) were recruited as a sex-specific young reference group. The DXA was used to measure whole and regional body composition. Appendicular skeletal muscle mass (ASM) was calculated as the sum of skeletal muscle in the arms and legs, assuming that all non-fat and non-bone tissue was skeletal muscle. Sarcopenia was defined as ASM divided by height squared (ASM/Ht2) < 2 SD below the sex-specific mean of the young reference group (Citation15). The cutoff value for sarcopenia was 6.95 kg/m2 for males and 4.94 kg/m2 for females.
Measurements
We measured height, weight, and blood pressure. Body mass index (BMI) was calculated by dividing weight (kilograms) by height squared (square meters). Waist circumference measurements were taken at the end of normal expiration to the nearest 0.1 cm, measuring from the middle point between the lower border of the rib cage and the iliac crest at the mid-axillary line.
Self-reported smoking, alcohol intake, and physical activity were estimated from questionnaire responses. Individuals were classified as never, former, or current smokers. Alcohol consumption was indicated as ‘yes’ for participants who consumed at least two units of alcohol every week over the last year. Household income was categorized according to quartile of total income of each member in the household. Regular exercise was indicated as ‘yes’ when the participants performed moderate or strenuous exercise on a regular basis (>30 min at a time more than five times per week for moderate exercise; >20 min at a time for strenuous exercise) or when the subject walked >30 min at a time more than five times per week. Daily energy and nutrient intake were assessed using the 24-h recall method, which provides reliable and valid nutrient information and has been used worldwide (Citation16). Daily intake of total energy, fat, carbohydrate, and protein were calculated based on the food items consumed.
A venous blood sample was collected from each subject after a 12-h fast. The sample was centrifuged and refrigerated at the examination site and then transported in an icebox to a central laboratory on the same day. Plasma glucose, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels were measured using an auto-analyzer (Hitachi automatic analyzer 7600 Hitachi, Tokyo, Japan). Fasting insulin levels were measured by immunoradiometric assay using a 1470 WIZARD gamma counter (PerkinElmer Oy, Turku, Finland). Insulin resistance status was calculated using homeostatic model assessment-insulin resistance (HOMA-IR) using the following formula:
Metabolic syndrome was defined according to The National Cholesterol Education Program's Adult Treatment Panel III revised guidelines (Citation17). This definition was satisfied if a subject met three or more of the following five criteria: (1) abdominal waist circumference ≥90 cm in males or ≥80 cm in females, (2) serum TG ≥150 mg/dL (1.7 mmol/L), (3) serum HDL-C <40 mg/dL (1.03 mmol/L) in males or <50 mg/dL (1.3 mmol/L) in females, (4) average blood pressure ≥130/85 mmHg, and (5) fasting serum glucose ≥100 mg/dL (5.6 mmol/L). Individuals who reported taking antihypertensive medication currently were classified as having high blood pressure, and individuals currently taking insulin or an oral hypoglycemic medication were classified as having impaired fasting glucose.
Lung function measurement
Spirometry was performed by trained technicians according to the 1994 American Thoracic Society recommendations using the same type of dry rolling-seal spirometer (Model 2130; SensoMedics, Yorba Linda, CA, USA) for all subjects.
Airway obstruction was defined according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria (GOLD Stage I) as FEV1/FVC <70%. The severity of airway obstruction was based on the percentage predicted FEV1 in accordance with the GOLD criteria (FEV1 ≥80% predicted, mild; FEV1 = 50–79% predicted, moderate; FEV1 = 30–49% predicted, severe; FEV1 <30% predicted, very severe). The restrictive spirometric pattern was defined as FEV1/FVC > 70% and FVC <80% predicted.
Ethical issues
All KNHANES IV and V participants signed an informed consent form. Thus, because our study used data from those surveys, ethical approval was not required.
Data analysis
Clinical characteristics were compared among participants with normal, restrictive, and obstructive lung function using an analysis of variance (ANOVA) for continuous variables and the chi-squared test or Fisher's exact test for categorical variables. Multiple logistic regressions were used to examine adjusted odds ratios (ORs) for restrictive lung disease in metabolic syndrome and for sarcopenia in patients with COPD. The logistic regression model was adjusted for age, BMI, smoking, alcohol, personal income, physical activity, education, and carbohydrate intake. Statistical analyses were conducted using the Statistical Package for the Social Sciences for Windows, version 20.0 (SPSS Inc., Chicago, IL, USA).
Results
Clinical characteristics of the study population according to spirometric patterns are shown in Table . We found the obstructive pattern of spirometry in 760 males and 279 females, the restrictive pattern in 511 males and 518 females, and 2346 males and 3731 females had normal lung function. The prevalence of metabolic syndrome was 29.5% in males with the obstructive pattern and 41.7% in those with the restrictive pattern. The prevalence of sarcopenia was 32.8% for males with the obstructive pattern and 21.5% for those with the restrictive pattern. Table shows the prevalence of metabolic syndrome and its components according to sarcopenic status in patients with COPD. Abdominal obesity was more common among non-sarcopenic patients than those with sarcopenia. The crude odds ratio (OR) for metabolic syndrome in males with the restrictive pattern was 1.99 (95% confidence interval [CI], 1.64–2.43) and the OR for males with the obstructive pattern was 1.17 (95% CI, 0.97–1.39).
Table 1. Clinical characteristics of study participants
Table 2. Comparison of cardiovascular risk factors in patients with COPD
Following adjustment for age, BMI, smoking, alcohol intake, education, personal income, and physical activity, the OR for metabolic syndrome in males with the restrictive spirometric pattern was 1.29 (95% CI, 1.02–1.65) and 1.45 (ORs, 1.45; 95% CI, 1.09–1.91) for females. The OR of metabolic syndrome for the obstructive pattern was 0.99 (95% CI, 0.79–1.26) for males and 0.73 (ORs 0.73; 95% CI, 0.49–1.09) for females (Table ). Table shows the results of the logistic regression analysis according to sarcopenic status in patients with COPD. The odds of abdominal obesity and metabolic syndrome were higher for male patients with sarcopenia than for those without the condition. Sarcopenia increases the risk of metabolic syndrome (OR 1.88; 95% CI, 1.27–2.77) in males with COPD.
Table 3. Odds ratios for the restrictive and obstructive spirometric patterns and metabolic syndrome
Table 4. Adjusted odds ratios for metabolic abnormalities in patients with COPD according to sarcopenic status
Discussion
Sarcopenia is related to metabolic disorders including obesity, insulin resistance, and diabetes (Citation10). Obesity is believed to be the most important underlying cause of insulin resistance (Citation18), and insulin resistance is a likely pathogenetic mechanism underlying sarcopenia; inversely, sarcopenia may cause an increase in insulin resistance without obesity.
Reduced free fat mass is a characteristic of patients with COPD, particularly in the peripheral skeletal muscles (Citation19). Age-related muscle loss is accelerated by COPD, particularly in the acute phase when high levels of circulating pro-inflammatory cytokines cause high protein turnover, hypoxemia, and acidosis further restrict physical activity (Citation20). In the inflammatory state of chronic lung disease, body metabolism shifts toward net protein catabolism, which depletes the muscle mass and is accompanied by an increase in the systemic markers of inflammation (Citation21). Thus, muscle loss and a decrease in fat oxidative capacity along with low levels of physical activity cause further muscle loss and fat gain. Fat gain, in turn, elevates circulating tumor necrosis factor-α concentration, which escalates insulin resistance and muscle loss (Citation22).
Our findings suggest that the pulmonary consequences of metabolic syndrome lead to a restrictive spirometric pattern with significantly lower FEV1 and FVC values after adjustment for age, sex, BMI, and smoking status. Abdominal obesity played a dominant role, and subcutaneous and intra-abdominal adipose tissue was positively correlated with circulating levels of IL-6 and TNF-α, but was negatively correlated with adiponectin, which is involved in insulin sensitivity. Several factors may underlie lung volume restriction including a combination of abdominal obesity, reduced pulmonary elasticity through non-enzymatic glycosylation of tissue proteins, loss of inspiratory muscle strength, and/or diaphragmatic compromise due to diabetic neuropathy. Previous studies of the association between metabolic syndrome and restrictive or obstructive lung patterns have yielded conflicting results.
Two previous cross-sectional studies found that restrictive disease defined as predicted FVC less than 80% and FEV1/FVC greater than 0.7 was associated with metabolic syndrome (Citation4, 5), whereas investigations defining obstructive disease as FEV1/FVC less than 0.7 found no relationship with metabolic syndrome (Citation6, 7).
Two population-based studies conducted in Asia (6), (23) and a social center-based study of elderly people in Italy (7) found an association between metabolic syndrome and the restrictive, but not obstructive, spirometric pattern. Obese subjects generally present with restrictive spirometric patterns. Leone et al. (Citation4) reported that abdominal obesity was the most powerful predictor of poor pulmonary function and also found that abdominal obesity was positively related to both obstructive and restrictive lung function impairment.
Our findings are consistent with recent reports that restrictive abnormality, but not airflow obstruction, is associated with metabolic syndrome. However, the population-based studies conducted in Taiwan (18) and Japan (6) included subjects < 40 years of age. As demonstrated by the lower prevalence of metabolic syndrome in Taiwan (5.8%), COPD and metabolic syndrome are relatively uncommon among subjects aged <40 years. Thus, it is possible that including younger subjects lowered the prevalence of the diseases, thereby affecting the statistical significance of the true relationship. Furthermore, the Japanese study (6) did not control for BMI, and smoking was not adjusted for in the statistical model of the Italian study (7). The subjects in our study were 40 years of age or older, and we adjusted for BMI and smoking status. Recent population-based studies have combined both sexes in the statistical analysis (5, 6). However, as in other Confucian societies where the majority of females are non-smokers, the frequency of female smokers was low in our sample. Thus, we analyzed the sexes separately.
Several studies have shown body weight had an independent effect on survival in patients with COPD (Citation20) (Citation24) (Citation25). Moreover, these authors reported that the negative effect of low body weight could be reversed by appropriate therapy. We found that sarcopenia was common in patients with COPD that the condition was associated with metabolic syndrome in this population. Thus, preventive strategies for sarcopenia, such as proper exercise and nutritional support, may be helpful for patients with COPD.
Our study had several limitations. First, its cross-sectional nature precluded our ability to identify cause-effect relationships. Second, all participants were relatively healthy because individuals who were admitted to hospital or nursing homes were not included in KNHANES IV and V. Thus, we may have underestimated the prevalence of sarcopenia. Third, at the time our data were collected, the clinically relevant threshold for muscle mass loss had not been established because of the associated higher risk of disability, morbidity, or mortality. Several methods in addition to ASM/ht2 have been used to determine a clinically relevant threshold for muscle mass loss; thus, the results are inconsistent (Citation8, Citation15, Citation26, 27).
Recently, the European Working Group on Sarcopenia in Older People (EWGSOP) developed a practical clinical definition and consensus diagnostic criteria for age-related sarcopenia (Citation28). Fourth, the definition of sarcopenia was based on data pertaining to a population aged 18–39 years whereas the studied population was over 40. As a consequence, the prevalence of sarcopenia could be overestimated in this study. For the diagnosis of sarcopenia, EWGSOP recommends using the presence of low muscle mass + low muscle function (strength or performance). We could not use the EWGSOP definition because we did not have data on muscle function. Finally, the presence of the restrictive pattern should be assessed as a reduction in total lung capacity rather than a decrease in FVC.
The restrictive pattern is identified on the basis of the simple spirometry which is not an accurate diagnostic tool. However, measuring total lung capacity is not feasible in large studies because it is time consuming, expensive, and requires special facilities. Nonetheless, the strengths of our study include the Korea national-based sample, standardized spirometric techniques, extensive data on potential confounders, and a large sample size that increased precision and permitted multiple statistical adjustments.
In conclusion, our nationally representative, cross-sectional study demonstrated that the restrictive spirometric pattern was more prevalent in subjects with metabolic syndrome after adjusting for other variables. Moreover, the prevalence of sarcopenia was greater in patients with COPD than in those with normal lung function, and sarcopenia was associated with metabolic syndrome in male patients with COPD.
Acknowledgment
This study was supported by the Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital.
Declaration of Interest Statement
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
All authors contributed conception, analysis, interpretation, revising, and final approval of the manuscript. JH Chung served as a principal investigator and had full access to all of the data in the study. DH Kim and MS Park take responsibility as co-corresponding authors for the integrity of the data and the accuracy of the data analysis. HJ Hwang, CH Han, BS Son provided study management.
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