Lung Function and Glucose Metabolism: An Analysis of Data from the Third National Health and Nutrition Examination Survey
Tricia M. McKeever1,
Philip J. Weston2,
Richard Hubbard1 and
Andrew Fogarty1
1 Division of Respiratory Medicine, City Hospital, Nottingham, United Kingdom
2 Department of Diabetes, Royal Liverpool University Hospital, Liverpool, United Kingdom
Correspondence to Dr. Tricia McKeever, Division of Respiratory Medicine, Clinical Science Building, City Hospital, Hucknall Road, Nottingham NG5 1PB, United Kingdom (e-mail: Tricia.McKeever{at}Nottingham.ac.uk).
Received for publication May 13, 2004.
Accepted for publication December 12, 2004.
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ABSTRACT
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Although people with diabetes have decreased lung function, the dose-response relation between measures of glucose control and lung function in nondiabetic people is not known. The authors used data from the Third National Health and Nutrition Examination Survey (19881994) to investigate the relation between glucose tolerance test response and other measures of glucose homeostasis and lung function in an adult population without a clinical diagnosis of diabetes. Plasma glucose level 2 hours after oral administration of 75 g of glucose was inversely related to forced expiratory volume in 1 second (FEV1), with a difference of 144.7 ml (95% confidence interval: 231.9, 57.4) for persons in the highest quintile of postchallenge glucose compared with the lowest. Similar inverse associations with FEV1 were found for other measures of glucose autoregulation. Lung function did not appear to be related to fasting glucose level. Similar associations were seen for forced vital capacity (FVC) but not for the FEV1:FVC ratio. In the total study population, persons with previously diagnosed diabetes had an FEV1 119.1 ml (95% confidence interval: 161.5, 76.6) lower than persons without diabetes. This effect was greater in those with poorly controlled diabetes. These findings suggest that impaired glucose autoregulation is associated with impaired lung function.
glucose; hemoglobin A, glycosylated; insulin; lung; respiratory function tests
Abbreviations:
CI confidence interval; FEV1 forced expiratory volume in 1 second; FVC forced vital capacity; NHANES III Third National Health and Nutrition Examination Survey
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INTRODUCTION
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Chronic obstructive pulmonary disease affects up to 24 million people in the United States and is a major cause of morbidity and mortality (1
). Chronic obstructive pulmonary disease is characterized by increased respiratory symptoms such as cough and phlegm and obstructive airways disease, as defined by reduced forced expiratory volume in 1 second (FEV1) and a reduced ratio between FEV1 and forced vital capacity (FVC) (2
). Cigarette smoking is the main risk factor for chronic obstructive pulmonary disease, but other nutritional and environmental factors may be important, including those acting early in life, such as low birth weight. Diabetes mellitus and insulin resistance (3
17
) have been independently associated with impaired lung function, but what is not known is the dose-response relation between lung function and response to an oral glucose load in persons with no clinical diagnosis of diabetes.
The prevalence of smoking is declining and that of diabetes is increasing, so it is important to understand the effects of other exposures that may negatively affect lung function. For this reason, we used data from the Third National Health and Nutrition Examination Survey (NHANES III) in a population without a diagnosis of diabetes to investigate the relation between response to a glucose tolerance test and lung function as measured by FEV1 and the FEV1:FVC ratio. We hypothesized that an increase in markers of impaired glycemic control would be associated with a reduction in both FEV1 and FEV1:FVC ratio.
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MATERIALS AND METHODS
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We used data from NHANES III, a survey designed to examine the health and nutrition of a randomly selected sample of the noninstitutionalized US population. The survey was conducted between 1988 and 1994. Full details on the survey design and examination procedure have been published by the National Center for Health Statistics (18
). All adults aged 2060 years were eligible for inclusion in the analyses. In the main analysis, persons with a known diagnosis of diabetes (defined as a physician's diagnosis or the regular use of diabetic medications) were excluded, as were those with missing data for lung function, plasma glycemic markers, and potentially confounding variables (figure 1). However, persons who had undiagnosed diabetes, as demonstrated by their fasting plasma glucose level or glucose tolerance test response, were included in the study population. In addition, to comply with standardized procedures for the measurement of fasting plasma glucose level and glucose tolerance testing (19
), we included in these analyses only those participants who had undergone examination in the morning and had fasted for 8 hours or more.

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FIGURE 1. Flow diagram for selection of study subjects, Third National Health and Nutrition Examination Survey, 19881994. Of the 7,045 subjects excluded to meet World Health Organization (WHO) criteria for glucose tolerance testing, 79% of those who did not meet the WHO criteria were excluded for having an afternoon or evening examination, and the remaining 21% were excluded because of missing data on the time of examination or the period of fasting. FEV1, forced expiratory volume in 1 second.
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Data collection
Blood samples were obtained for biochemical assays, and anthropometric measurements were taken, including measurement of height and weight and spirometric factors (including FEV1 and FVC), using standardized techniques. We extracted data on various markers of glucose regulation, including levels of fasting glucose, glycosylated hemoglobin (hemoglobin A1c), insulin, and C-peptide and, for people over age 40 years, results of oral glucose tolerance testing, in which the subject's initial plasma glucose level was measured at baseline and 2 hours after oral administration of 75 g of glucose (DextolTM or TrutolTM). Insulin resistance was calculated from the measurements by means of a formula devised for use in epidemiologic studies: fasting glucose (mmol/liter) x fasting insulin (µU/ml)/25 (20
). A detailed description of laboratory methods has been published elsewhere (21
).
Statistical analyses
The main population studied was persons with no clinical diagnosis of diabetes. We also studied a larger population including persons with a clinical diagnosis of diabetes to assess the impact of diabetes on lung function. Using self-reported information on smoking history, we classified subjects as never smokers, ex-smokers, or current smokers and quantified total cigarette smoking in pack-years. We modeled measures of lung function with adjustment for age, sex, height, smoking (status and pack-years), and race/ethnicity to derive the most parsimonious model that minimized variance. We examined a variety of more complex models for lung function that included higher-order variables for age, height, pack-years of smoking, and body mass index (weight (kg)/height (m)2), including interaction terms, but these did not improve the fit of the model; therefore, we chose the simplest model.
Glycemic markers were arbitrarily categorized into quintiles, and the relations between measures of glycemic status and lung function were explored using multiple linear regression. We fitted the models with quintiles of glycemic markers as both ordered and unordered factors and compared the two models for evidence of departure from linearity. The p value for linear trend is presented where there was no departure from linearity, and the p value from a test of heterogeneity is presented where the data demonstrated evidence of departure from linearity. Many of the markers demonstrated nonlinear relations; therefore, the results are presented in quintiles. We also divided the fasting blood glucose values according to the World Health Organization definitions of normal glucose tolerance, impaired glucose tolerance, and diabetes (19
). Normal values for fasting plasma glucose are those less than 110 mg/dl; impaired fasting glucose values are 110125.99 mg/dl; and values equal to or above 126 mg/dl indicate diabetes. The normal values for plasma glucose 2 hours after a 75-g oral glucose challenge are those less than 140 mg/dl; values for impaired glucose tolerance are 140199.99 mg/dl; and values equal to or above 200 mg/dl indicate diabetes. The impact of these clinical definitions of impaired glycemic control on FEV1, FVC, and FEV1:FVC ratio was examined. We examined a number of confounding factors, such as body mass index, waist:hip ratio, poverty index ratio, and levels of serum triglycerides, serum antioxidants, and C-reactive protein (fitted as continuous or categorical variables as appropriate), to determine whether they altered the regression coefficients.
To obtain additional data, we also used the same modeling strategies to study the effect of a known diagnosis of diabetes on lung function using all persons with and without diagnosed diabetes who had data available. In addition, we examined the impact of the degree of glucose regulation in persons with known diabetes by stratifying these persons into two groups defined by a glycosylated hemoglobin concentration of <7 percent versus
7 percent. A factor was considered a confounding factor if its addition to the model changed the size of the effect by 15 percent or more. Because of the complex, multistage probability sample design of NHANES III, we accounted for the survey design in calculating estimates, using the specialized survey command within Stata/SE 8.0 (Stata Corporation, College Station, Texas). Because certain age groups and ethnic groups were oversampled in the NHANES III study population, we also repeated the analyses using weighting variables to establish the descriptive population corrected to be representative of the general US population.
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RESULTS
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A total of 12,496 adults were eligible for the initial analyses. Reasons for exclusion are outlined in figure 1. Six hundred and eighteen (5 percent) of those excluded from the initial analysis had a clinical diagnosis of diabetes, and 7,045 subjects (56 percent) were excluded because they failed to meet World Health Organization criteria for glucose testing. Our study population was similar to the excluded population in terms of demographic characteristics (table 1). A total of 4,257 participants (34 percent) had data on serum measures of glucose control, and 1,612 (13 percent) had data on serum glucose level 2 hours after a glucose load. The mean age of the population was 37 years; 54 percent were female. The mean levels and distributions of the various glycemic markers are presented in table 2.
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TABLE 1. Demographic characteristics of the study population and of subjects excluded from the study, Third National Health and Nutrition Examination Survey, 19881994
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TABLE 2. Mean levels of various markers of glycemic status, Third National Health and Nutrition Examination Survey, 19881994
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For the 1,612 participants who had data on glucose tolerance testing, an inverse dose-response relation with FEV1 was found, such that those in the highest quintile of plasma glucose after oral glucose loading had a decrease of 144.7 ml (95 percent confidence interval (CI): 231.9, 57.4) compared with those in the lowest quintile (table 3). A similar relation was seen with increasing fasting insulin, plasma C-peptide, insulin resistance, and glycosylated hemoglobin, although there was no clear association between fasting plasma glucose and FEV1.
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TABLE 3. Association between various markers of glycemic status and forced expiratory volume in 1 second, Third National Health and Nutrition Examination Survey, 19881994
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Adjusting the above associations for body mass index (in categories) and waist:hip ratio slightly decreased these associations between measures of glucose control and FEV1. Adjusting for other possible confounders, such as plasma antioxidants, vitamins A, C, and E, poverty index ratio, C-reactive protein, and triglycerides, did not appreciably alter these associations (data not shown). Stratifying the results according to age did not produce any noticeable difference in effect across the age categories, and there were no significant interactions between smoking and glycemic markers. Restricting the analysis to persons who had never smoked did not significantly alter these associations.
The relation between glycemic markers and FVC was similar to the results shown for FEV1, although the size of the effect was greater for FVC (table 4). However, no consistent association was seen between the different glycemic markers and the FEV1:FVC ratio (table 5).
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TABLE 4. Association between various markers of glycemic status and forced vital capacity, Third National Health and Nutrition Examination Survey, 19881994
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TABLE 5. Association between various markers of glycemic status and the ratio of forced expiratory volume in 1 second to forced vital capacity, Third National Health and Nutrition Examination Survey, 19881994
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When we compared persons with impaired glucose tolerance and persons who had clinical diabetes defined by glucose tolerance testing with persons whose values fell within the normal range, the differences in FEV1 were 34.3 ml (95 percent CI: 114.5, 45.9) and 108.8 ml (95 percent CI: 217.3, 0.3), respectively (table 6). Impaired fasting glucose and diabetes as defined by fasting glucose level were associated with decreases in FEV1 of 60.8 ml (95 percent CI: 95.7, 25.8) and 93.8 ml (95 percent CI: 127.4, 60.2), respectively. Persons with an elevated hemoglobin A1c concentration had an associated decrease in FEV1 of 75.0 ml (95 percent CI: 231.0, 80.9).
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TABLE 6. Association between various clinical definitions of diabetes* and forced expiratory volume in 1 second, Third National Health and Nutrition Examination Survey, 19881994
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In examining the effect of diagnosed diabetes on lung function, we found that persons with diabetes had a 119.1 ml (95 percent CI: 161.5, 76.6) reduction in FEV1 in comparison with the rest of the population (table 7). Persons with suboptimal diabetic control, as determined by a glycosylated hemoglobin concentration of
7 percent, had lower lung function than persons with well-controlled diabetes.
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TABLE 7. Association between known diagnosis of diabetes and forced expiratory volume in 1 second, Third National Health and Nutrition Examination Survey, 19881994
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Correction for the selective oversampling of certain age and ethnic groups in NHANES III using models that included the weighting variables did not change the qualitative nature of the results. Correction for weighting did increase the effect size of the association between measures of glycemic control and lung function, and it also increased the confidence intervals in the analyses of a smaller sample population, as shown in tables 6 and 7. We thus elected to present the data using the more conservative regression models derived from the data available for each eligible individual.
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DISCUSSION
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We have demonstrated that in adults without a diagnosis of diabetes, impaired glucose regulation as indicated by glucose tolerance testing, higher levels of glycosylated hemoglobin, plasma insulin (a marker of insulin resistance (22
)), and C-peptide (a by-product of insulin production), and an epidemiologic measure of insulin resistance are associated with impaired lung function in a dose-response manner. However, fasting plasma glucose was not associated with lung function. We have also demonstrated that persons with a clinical diagnosis of diabetes have impaired lung function, a finding that is consistent with previous work in this area (3
17
). These findings were not explained by obesity or increasing age. This relation was seen throughout the nondiabetic values of these markers of glucose autoregulation, which suggests that the relation between glucose and lung function is not just an association seen in persons with overt diabetes. A similar association was also seen between glycemic markers and FVC but was not seen consistently with the FEV1:FVC ratio; this suggests that the effect is primarily an effect on lung function and does not influence the development of obstructive lung disease (as seen in chronic obstructive pulmonary disease).
The strength of this study was the use of biologic markers of glycemic control and physiologic measurements of lung function in a well-defined population with no clinical diagnosis of diabetes and no knowledge of the hypothesis being tested. NHANES III had a high participation rate, with 86 percent and 78 percent of those invited to participate in the questionnaire survey and the medical examination, respectively, taking part (18
). However, the population studied for the effect of fasting glucose, C-peptide, insulin resistance, and response to glucose tolerance testing was a subsample of the original NHANES III population, since we excluded some participants in order to comply with standardized conditions for collecting the samples (19
) (including only those who had attended a morning examination and had fasted for 8 hours or more). It is unlikely that those who were included in this group had lower lung function than those who did not fast for 8 hours or underwent examination in the afternoon. We do have to consider the potential for confounding, especially by smoking, antioxidants, and early life development. Because an association between smoking and diabetes has been demonstrated (23
, 24
), smoking status may confound the relation between impaired glycemic control and lung function (25
). However, we rigorously adjusted for self-reported smoking history using both current smoking status and total pack-years of smoking, additionally restricting our analysis to persons who had never smoked, and this did not alter our findings. Another risk factor that is associated with both diabetes (26
) and reduced lung function (27
) is antioxidant status, although adjustment for serum vitamin C and vitamin E levels did not alter our findings.
One potentially confounding factor, which we are unable to exclude, is growth in early life. An association has been demonstrated between low body weight in early life and impaired glucose control, insulin resistance (28
, 29
), and decreased lung function (30
). It is thus possible that our apparent association between poor glucose regulation and reduced lung function is a consequence of confounding by growth in early life, although no effect of birth weight on lung function was reported in a recent study (9
). Alternatively, it may be that poor glycemic control lies within the causal pathway explaining the association between low birth weight and decreased lung function. The use of data from a cross-sectional study such as NHANES III does not permit temporal relations to be considered; therefore, we cannot exclude the possibility of reverse causalitythat is, lower lung function's leading to impaired glucose regulation.
The absence of an effect of fasting plasma glucose on FEV1 in the presence of a negative effect of increasing levels of other markers of poor glycemic control is anomalous and difficult to explain. Over 95 percent of our study population was in the nondiabetic ranges for fasting plasma glucose, and we theorize that there may be greater random variation of fasting plasma glucose within these levels, while the other measures of glycemic control provide a more consistent measure of glycemic control. Although we have been unable to find data in the literature to substantiate this, the association of a gradient of decreasing FEV1 among persons with fasting plasma glucose levels in the "impaired" or diabetic ranges (table 4) demonstrates a consistency with the rest of the data, suggesting that this may be the case. The mechanism by which impaired glycemic control may lead to a reduction in lung function is uncertain, though it has been suggested that the increased systemic inflammation associated with diabetes (31
) may result in pulmonary inflammation (4
) and hence airway damage (32
). Alternatively, a reduction in antioxidant defenses resulting from increased oxidative activity associated with diabetes (26
) may lead to a secondary reduction in the antioxidant defenses of the lung and hence increased susceptibility to environmental oxidative insults, resulting in subsequent loss of lung function. In addition to an increase in intracellular oxidative stress, increased nuclear factor-
B, and inflammatory mediator expression, long-term hyperglycemia causes an increase in collagen molecule synthesis and cross-linking via the accumulation of advanced glycosylation end products, which may also adversely influence lung function (33
). The observation that increasing insulin level and insulin resistance is associated with loss of lung function suggests that insulin may have a direct negative effect on airway function (34
).
The initial studies of diabetes and lung function were small and had little statistical power, which may explain why the results were inconsistent (6
8
, 35
42
). The subsequent larger population-based studies have been more coherent, demonstrating reduced pulmonary function in persons with an elevated plasma glucose level and a diagnosis of diabetes. Enright et al. (43
) reported a small reduction in FEV1 of 23 ml among persons with diabetes in the Cardiovascular Health Study. Analysis of 3,254 members of the Framingham Offspring Cohort showed associations of both diagnosed diabetes and elevated plasma glucose with reduced FEV1 (4
). The results demonstrated that persons with diabetes had an FEV1 61 ml lower than that of persons without diabetes and that persons in the highest quartile of plasma glucose had an FEV1 85 ml lower than that of persons in the lowest quartile (4
). The cross-sectional data from the Copenhagen City Heart Study demonstrated a reduction in FEV1 of 239 ml among diabetics who required insulin and a reduction of 117 ml among diabetics treated with oral hypoglycemic agents (3
) in comparison with nondiabetics. In an analysis of persons without diagnosed diabetes, an inverse association was observed between an elevated nonfasting plasma glucose level (
200 mg/dl) and lung function; there was a difference in FEV1 of 218 ml in comparison with persons with normal fasting plasma glucose levels (3
). The longitudinal analyses of the same population demonstrated an association between a new diagnosis of diabetes and impaired pulmonary function, with the newly diagnosed diabetics having an annual decrease in FEV1 of 25 ml more than control subjects (44
). A similar increased decline in lung function among persons with poor diabetic control has been reported elsewhere (45
), although follow-up at 15 years demonstrated that the decline in FEV1 among those with diabetes was the same as that among those without the disease. Similarly, in the Normative Aging Study, Lazarus et al. (10
) demonstrated an association between decreased FEV1 and increased insulin resistance, although persons with lower baseline lung function were observed to be more likely to develop insulin resistance 20 years later (11
)a result that was also seen for the development of diabetes elsewhere (46
). However, these relations were not seen in analysis of adults aged 5195 years in the Rancho Bernardo Study (47
), where lung function was not associated with fasting blood glucose level; this may have been a consequence of studying an older population. Interestingly, a small cohort study of 18 subjects with type I diabetes who were using an insulin pump to achieve normoglycemia in comparison with conventional therapy suggested that intensive insulin treatment, and hence better glycemic control, may preserve pulmonary function, although the absence of baseline pulmonary function measurements limited the interpretation of these data (48
).
We have demonstrated that increases in the glucose response to a glucose tolerance test, glycosylated hemoglobin, serum insulin, and a marker of insulin resistance are all associated with a reduction in lung function as assessed by FEV1 (and FVC). This effect is not explained by confounding due to obesity. The observation that persons with diagnosed diabetes that is poorly controlled have worse lung function than persons with diagnosed diabetes who have good glucose control is consistent with the hypothesis that good control of diabetes is associated with preserved lung function. Further understanding of the effect of glucose regulation on the lungs would be obtained by assessing lung function in participants from a trial of intensive glucose regulation, such as the Diabetes Control and Complications Trial, where beneficial effects on diabetic nephropathy are seen 78 years after the end of the intervention (49
). Although smoking is the main risk factor for loss of lung function, there is an urgent need to understand other factors that contribute to a reduction in lung function, as demonstrated by the 95 percent excess mortality among persons who have never smoked but have reduced lung function in comparison with those with normal lung function (50
). In addition, the emergence of novel risk factors such as hyperglycemia will lead to increased understanding of the pathogenesis of worse lung function and hence new possibilities for intervention. In view of the public health importance of lung function in health and the increasing prevalence of diabetes, this is a subject that warrants further investigation.
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ACKNOWLEDGMENTS
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This research was funded by the Wellcome Trust (London, United Kingdom).
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