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American Journal of Respiratory and Critical Care Medicine Vol 167. pp. 911-916, (2003)
© 2003 American Thoracic Society

Original Article

Association between Glycemic State and Lung Function

The Framingham Heart Study

Robert E. Walter, Alexa Beiser, Rachel J. Givelber, George T. O'Connor and Daniel J. Gottlieb

The Pulmonary Center, Boston University School of Medicine; Veteran's Administration Boston Health Care System; Boston University School of Public Health, Boston; National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts; and the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Correspondence and requests for reprints should be addressed to Robert Walter, M.D., M.P.H., The Pulmonary Center, R304, 715 Albany Street, Boston, MA 02118. E-mail: bwalter{at}lung.bumc.bu.edu


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Diabetes mellitus has been inconsistently associated with a reduced level of pulmonary function. To elucidate this association further, we analyzed the relationship of diabetes and of fasting blood glucose to the level of pulmonary function assessed by spirometry in the 3,254 members of the Framingham Offspring Cohort. Diabetes was defined as a fasting blood glucose of 126 mg/dl or more or pharmacologic treatment. Subjects were classified as current, former, or never smokers based on questionnaire responses. Predicted pulmonary function was determined from the coefficients of a regression of pulmonary function on age, sex, and body habitus in the 1,110 never smokers. Both the diagnosis of diabetes and a higher level of fasting blood glucose were associated with lower than predicted levels of pulmonary function. The adverse effect of diabetes and glycemic level on pulmonary function was stronger among ever smokers than never smokers, suggesting an interaction between the level of fasting glycemia and tobacco smoking.

Key Words: lung diseases, obstructive • diabetes mellitus • blood glucose • epidemiology • lung diseases

The current model for the pathogenesis of chronic obstructive pulmonary disease (COPD) involves upregulated inflammation in response to tobacco smoking in the majority of cases; this inflammation results in parenchymal destruction and narrowing of the airways (1). As only a minority of smokers develops clinically significant COPD (2), other factors likely influence the risk of developing disease. Diabetes mellitus (DM) has been associated with markers of systemic inflammation and with increased risk of other diseases in which inflammation plays a role, such as cardiovascular disease. Several studies have suggested that diabetes is associated with impaired pulmonary function (3–9), but this relationship has been inconsistent (10–14). Using the Offspring Cohort of the Framingham Heart Study, we examined the cross-sectional relationship of diabetes and the level of fasting blood glucose to pulmonary function.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
Recruitment of the Offspring Cohort of the Framingham Heart Study has been previously described (15); this cohort was recruited from 1971 to 1975, enrolling 3,544 children of the Framingham Heart Study Original Cohort and 1,580 spouses of these offspring. Informed consent for participation was obtained from all participants, in accordance with the protocol approved by the institutional review board. The subjects included in this analysis are Offspring Cohort participants who had measurements of the variables of interest at examination 5 (1991–1994).

Blood Glucose, Smoking Status, and Body Habitus
Blood glucose was measured after an overnight fast (A-gent glucose test; Abbott, South Pasadena, CA), assays were run in duplicate, and the intra-assay coefficient of variation was less than 3% (16). DM was defined as a fasting blood glucose of 126 mg/dl or more or treatment with either insulin or an oral hypoglycemic agent (17, 18). Subjects were asked at their initial visit if they had ever smoked cigarettes, and at each subsequent visit they were asked to quantify their smoking if they had smoked regularly in the previous 12 months. Subjects reporting no cigarette use at every visit were classified as never smokers. Those not currently smoking but reporting smoking at any time before examination 5 were classified as former smokers, and those smoking at examination 5 were classified as current smokers. Participants undergo physician examination at each cycle and examiners review symptoms, medications, and medical problems. Based on these data, the physician is asked whether a subject has asthma; subjects classified by the examining physician as "yes" were considered to have asthma, and those classified as "maybe" or "no" were considered not to have asthma. Chronic obstructive lung disease was defined by a FEV1 to FVC ratio of 0.70 or less (19), in accordance with the recommendations of Global Initiative for Chronic Obstructive Lung Disease. Weight and standing height were measured without shoes. Waist and hip girths were measured standing, at the level of the umbilicus and the level of maximal gluteal protrusion, respectively.

Spirometry
Spirometric data were obtained using a Collins Survey II spirometer, interfaced to pulmonary function data acquisition and quality control software (SandM Instruments, Doylestown, PA), and calibrated daily. Spirometric maneuvers were performed according to American Thoracic Society standards (20, 21). The largest FEV1 and FVC of acceptable maneuvers were used in this analysis; the FEV1/FVC ratio was obtained from the maneuver with the largest sum of FEV1 plus FVC.

Statistical Analyses
All statistical analyses were performed using SAS software (SAS Institute, Cary, NC). Predicted lung function was obtained using the coefficients obtained from regression models in which each of the three spirometric measures (FEV1, FVC, and FEV1/FVC ratio) was individually regressed on age, sex, and body habitus in the 1,100 nonsmokers for whom spirometric information was available. Multiple prediction models, with clinical measures known to be associated with level of pulmonary function, were tested, including all combinations of age, height, height2 (to test for a quadratic relationship to the variable of interest), weight, sex, and first-order interaction terms (to test for effect modification). Interaction terms were included when appropriate. The most parsimonious models for FEV1 (R2 = 0.73) and FVC (R2 = 0.77) included sex, age, height, weight, and age x height, and for FEV1/FVC ratio (R2 = 0.09) included sex, age, height, and weight. The waist/hip ratio was included in a second model but did not improve the predictive value of the model. Residual pulmonary function was determined by subtracting the predicted from the measured value; negative values thus reflect pulmonary function less than expected.

Using linear regression, residual pulmonary function was adjusted for sex and smoking history (pack-years). Exclusion of patients with asthma and further adjustment for body mass index or waist/hip ratio did not change the model. Patients with diabetes were compared with those without diabetes for all subjects (without adjustment for smoking status) and for strata of smoking status using analysis of covariance. Restricting analysis to the subjects not on pharmacologic therapy for diabetes, the mean residual pulmonary function level was compared across quartiles of fasting blood glucose (first quartile, 48–88 mg/dl; second quartile, 89–94 mg/dl; third quartile, 95–101 mg/dl; and fourth quartile, 102–305 mg/dl) using analysis of covariance to adjust for sex and pack-years of tobacco smoking. This analysis was done for all subjects combined and was also stratified by smoking status. Finally, logistic regression was used examine the relationship between the diagnosis of diabetes to COPD, adjusting for sex and pack-years of cigarette smoking.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Subject Characteristics
Of the 3,799 subjects attending examination 5, 3,261 had acceptable spirometric data. Seven participants were excluded because of a lack of information on smoking status, anthropomorphic measurements, or blood glucose levels. The characteristics of the remaining 3,254 subjects are described in Table 1 . Men were 46.5% of the subjects without diabetes and 60% of the subjects with diabetes; 280 of the subjects were classified as having DM (fasting blood glucose of 126 mg/dl or more or pharmacologic treatment for DM). Those with diabetes were slightly older than those without diabetes (59.6 versus 53.9 years) and were heavier (87.6 versus 77.0 kg). Although subjects with diabetes were no more likely to have been smokers, they had longer pack-years exposure to tobacco smoke.


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  		TABLE 1. Subject characteristics

 
Relationship of DM to Pulmonary Function
Among current smokers, mean residual FEV1 was 139 ml lower among individuals with diabetes (p = 0.04) than among individuals without (Table 2) . Compared with individuals without diabetes, the diagnosis of DM was associated with a mean residual FEV1 that was 64 ml lower in former smokers and 27 ml lower in never smokers, although these differences did not achieve statistical significance.


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  		TABLE 2. Mean residual pulmonary function, adjusted for sex and pack-years

 
The diagnosis of diabetes was also associated with a lower level of FVC, adjusted for sex and pack-years, across all strata of smoking status. Compared with those without diabetes of corresponding smoking status, individuals with diabetes who smoked had a lower mean residual FVC by 251 ml (p < 0.001); those with diabetes who were former smokers had a lower mean residual FVC by 163 ml (p < 0.001), and those with diabetes who were smokers a lower mean residual FVC by 109 ml (p = 0.047). The adjusted residual FEV1/FVC ratio was approximately 1.5% higher in individuals with than without diabetes, a small but statistically significant (p < 0.001) difference. This small effect was seen in each stratum of smoking status.

Relationship of Fasting Blood Glucose to Pulmonary Function
Inclusion of treated individuals with diabetes, with consequent improved glycemic control, may have mitigated some of the relationship between lung function and blood sugar. To assess directly the relationship of pulmonary function to fasting blood sugar across a broad range of blood glucose values, we examined this relationship excluding only those subjects on either insulin or oral hypoglycemic agents. For this analysis, mean residual pulmonary function, adjusted for sex and pack-years, was compared across quartiles of fasting blood glucose.

The mean residual FEV1 decreased (Figure 1) with increasing quartile of blood glucose, regardless of smoking status. In each stratum of smoking status, there was a negative linear association between quartile of fasting blood glucose and level of residual FEV1 (for linear trend, p < 0.001 for all subjects, p = 0.03 for current smokers, p < 0.001 for former smokers, p = 0.03 for never smokers). Compared with subjects in the lowest quartile of fasting blood glucose, subjects in the highest quartile of fasting blood glucose had a residual FEV1 that was on average 98 ml lower among current smokers, 104 ml lower among former smokers, and 82 ml lower among never smokers. When all strata of smoking status were combined, subjects in the highest quartile of fasting blood glucose had a residual FEV1 that was on average 85 ml lower than subjects in the lowest quartile.



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  		Figure 1. Relationship of residual FEV1 to level of fasting glucose. Quartiles of blood glucose: first quartile, 48–88 mg/dl; second quartile, 89–94 mg/dl; third quartile, 95–101 mg/dl; and fourth quartile, 102–305 mg/dl; p values are for linear trend across quartiles. Error bars are SDs.

 
Similarly, there were negative linear associations (Figure 2) between quartile of fasting blood glucose and level of residual FVC (for linear trend, p = 0.18 for current smokers, p < 0.001 for former smokers, and p = 0.04 for never smokers). Current smokers in the highest quartile of fasting blood glucose had a mean adjusted residual FVC that was 69 ml lower than the lowest quartile. Former smokers in the highest quartile of fasting blood glucose had an average adjusted FVC that was 125 ml less than those in the lowest quartile, and never smokers in the highest quartile of fasting blood glucose had an average adjusted FVC that was 90 ml less than those in the lowest quartile. When all strata of smoking status were combined, subjects in the highest quartile of fasting blood glucose had a mean residual FVC that was 94 ml lower than those in the lowest quartile.



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  		Figure 2. Relationship of residual FVC to level of fasting glucose. Quartiles of blood glucose: first quartile, 48–88 mg/dl; second quartile, 89–94 mg/dl; third quartile, 95–101 mg/dl; and fourth quartile, 102–305 mg/dl; p values are for linear trend across quartiles. Error bars are SDs.

 
Although higher levels of fasting blood glucose were associated with reductions in both residual FEV1 and residual FVC, among the individual strata of smoking status, higher levels of fasting blood glucose were associated with significantly lower mean residual FEV1/FVC ratios (Figure 3) only among current smokers (lowest quartile to highest quartile difference = 1.8%, test for linear trend, p = 0.012). A similar effect was seen when the subgroups were combined; the residual ratio was 1% lower in the highest quartile compared with the lowest quartile of fasting blood glucose (test of linear trend, p = 0.04).



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  		Figure 3. Relationship of residual FEV1/FVC to level of fasting glucose. Quartiles of blood glucose: first quartile, 48–88 mg/dl; second quartile, 89–94 mg/dl; third quartile, 95–101 mg/dl; and fourth quartile, 102–305 mg/dl; p values are for linear trend across quartiles. Error bars are SDs.

 
Finally, we investigated whether the diagnosis of DM was associated with the diagnosis of COPD. More subjects with diabetes than without diabetes had COPD (see Table 1; 21 versus 26%, p = 0.07); however, after adjustment for sex and tobacco consumption, there was no significant association between the diagnosis of DM and COPD. Exclusion of individuals with asthma from the analysis did not significantly alter the results.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The current paradigm for the pathogenesis of COPD involves the upregulation of neutrophil and macrophage activity with consequent connective tissue degradation, usually in response to smoking (1, 22). The FEV1 of cigarette smokers declines approximately 15–30 ml per year faster than that of nonsmokers, but there is a spectrum of sensitivity to tobacco smoke (23–31). Markers of systemic inflammation (32–34) and levels of cytokines that regulate neutrophil function, including interleukin (IL)-1 (35), IL-4 (36), IL-6 (37), IL-8 (38), and tumor necrosis factor (35, 38–41), have been associated with COPD, and heterogeneity in expression of inflammatory mediators may affect the risk of developing COPD (42).

Although our understanding of the pathogenesis of type I diabetes has long included a significant role for inflammation and other immune mechanisms (43), recent epidemiologic studies have also demonstrated an association between type II diabetes and higher levels of markers of systemic inflammation. Elevated serum ferritin (44) and other inflammatory markers (45–47) have been associated with an increased risk for the development of diabetes. A variety of mediators of inflammation, including IL-1, IL-6, and tumor necrosis factor, that have also been implicated in the pathogenesis of COPD have been associated with insulin resistance (48, 49). Systemic inflammation related to cigarette smoking might therefore independently influence both lung function and glycemia (50, 51).

Arnalich and colleagues (52) observed a reduction in serum markers of inflammation with the treatment of diabetes, however, suggesting that diabetes may itself be a cause of systemic inflammation. This could be due to the proinflammatory effects of advanced glycation end-points (AGEs). Advanced glycation end-points, the result of interaction of intracellular proteins and decomposing saccharides and polysaccharides, can alter matrix proteins, affect the expression of cytokines and growth by macrophages and mesangial cells, alter expression of inflammatory mediators by endothelial cells (53), and induce apoptosis (54). In addition, expression of the transmembrane receptor for advanced glycation end-points is seen in the lung, preferentially localized to the basal face of type I pneumocytes (55). If DM and hyperglycemia are themselves proinflammatory, impaired glycemic control may cause ventilatory impairment in either an independent or synergistic manner with tobacco smoke.

We have demonstrated an association between glycemic state and reduced lung function. The diagnosis of DM was associated with a lower mean adjusted residual FEV1 and FVC. This effect was greater in ever smokers than never smokers and was greatest among current smokers, even after adjusting for pack-years of smoking. Overall, after adjusting for sex and pack-years of smoking, there was a progressive fall in residual pulmonary function across quartiles of fasting blood glucose, with a difference of approximately 85 ml in residual FEV1 and 94 ml in residual FVC from highest to lowest quartile of fasting blood glucose. Although the effect was slightly greater in ever smokers than never smokers, there was no clear difference in the effect of fasting blood glucose across strata of smoking status. Although the diagnosis of diabetes was associated with a slightly increased FEV1/FVC ratio, suggesting a restrictive pattern of ventilatory impairment, the residual FEV1/FVC ratio of subjects not on therapy for diabetes fell with the increasing serum glucose concentration. This effect varied between strata of smoking status, with the most striking association among current smokers.

Diabetes has previously been inconsistently associated with spirometric abnormalities in a number of small retrospective cross-sectional studies. Several studies of fewer than 50 subjects with diabetes reported no differences in spirometric measures between type I (10–12), type II (13), or a mixed population of subjects (14) and controls. In contrast, Bell and colleagues (3) observed proportional reductions in FEV1 and FVC in 28 young individuals with diabetes compared with age- and height-matched control subjects; these changes were more pronounced among those with diabetes who smoked tobacco. Schnack and colleagues (4) compared 31 individuals with type I diabetes who were never smokers to healthy control subjects and found significant reductions in lung function among those with diabetes, especially among those with microalbuminuria; this relationship was stronger for FEV1 than for FVC. However, Innocenti and colleagues (5) demonstrated nearly equal reductions in FEV1 and FVC in 24 insulin-dependent nonsmokers compared with control subjects. Primhak and colleagues (6) observed a reduction in FVC among 88 pediatric individuals with diabetes compared with control subjects that did not correlate with duration of DM.

In these small studies, attempts to characterize the nature of the pulmonary function abnormalities of various groups of individuals with diabetes have produced inconsistent results. Most studies have reported a reduction in diffusion (3, 4, 7, 12, 14, 56) or FVC, either with concomitantly reduced FEV1 (3, 4) or in isolation (4, 6, 7, 9, 12, 56, 57). Innocenti and colleagues (5) reported an isolated reduction in diffusion among only those with renal dysfunction.

Few larger studies have examined the impact of diabetes on pulmonary function. Cross-sectional analysis of participants in the Copenhagen City Heart Study (58), including 284 subjects with diabetes among 11,763 subjects, demonstrated some impairment of pulmonary function among subjects with diabetes, more pronounced in those treated with insulin. The average FEV1 and FVC among insulin-treated patients with diabetes were 239 and 334 ml lower than control subjects, respectively, and 122 and 150 ml lower than individuals with diabetes treated with oral agents. In addition, among participants not known to have DM, there was a significant association between elevated plasma glucose and a reduction in lung function. Longitudinal analysis (59) of participants in the Copenhagen City Heart Study, including 326 subjects with diabetes and 9,051 control subjects, demonstrated an association between the new diagnosis of diabetes and impaired pulmonary function; after adjusting for confounders, those individuals who were newly diagnosed with diabetes annually lost 29 ml of FVC and 25 ml of FEV1 more than control subjects. The Cardiovascular Health Study, in determining reference standards for a healthy population, found diabetes to be significantly associated with a decreased FEV1 (60). These observations were not duplicated in the analysis of the Rancho Bernardo cohort, in which measures of lung function were not associated with fasting blood glucose (61). However, age differences between these studies and the younger Framingham Offspring Cohort may limit comparison.

Among the subjects included in our analysis, diagnosis of DM was associated with a larger reduction in residual FVC than FEV1. The consequent larger residual FEV1/FVC ratio in subjects with diabetes suggests restrictive physiology. In contrast, when those with diabetes on therapy were excluded, higher levels of fasting blood glucose were associated with larger reduction in FEV1 than FVC. The resulting progressive decrement in level of residual FEV1/FVC ratio with increasing level of blood sugar suggests that higher fasting blood sugar is associated with more obstructive physiology. When we explored the relationship of the diagnosis of DM to COPD, we found no significant association after adjusting for confounders. The relatively small number of participants with an abnormally low FEV1/FVC ratio may limit the ability to demonstrate such an association. As described previously here, the existing literature provides an inconsistent picture of the overall nature of the impairment of pulmonary function among those with diabetes, and this study does not provide a definitive answer.

Our observation that decreased lung function is associated with diabetes and level of fasting blood glucose and that this effect appears greater in smokers than nonsmokers adds to a growing body of evidence that diabetes may increase susceptibility to the adverse pulmonary effects of tobacco smoking. This association may offer clues into the pathogenesis of both COPD and DM. It may be that host factors, presumably genetically determined, confer common susceptibility to both impaired glucose tolerance and ventilatory impairment. Alternatively, diabetes or subclinical hyperglycemia may alter the regulation of inflammatory pathways, augmenting inflammatory response in the lung with consequent development of chronic ventilatory impairment. Inflammatory mediators implicated in the pathogenesis of both COPD and diabetes, such as IL-1, IL-6, and tumor necrosis factor, represent the most promising candidates for future investigations.

Our understanding of the pathogenesis of COPD, especially as it relates to the variable risk of disease among those exposed, remains quite limited. Risk factors other than tobacco smoking likely contribute to the pathogenesis of COPD, although little is known about these. Improved understanding of the epidemiology of cardiovascular disease has improved understanding of its pathogenesis; interventions that improve mortality and even reverse the course of the disease have been developed as a consequence. At least in part due to these advances, a decline in the age-adjusted rates of cardiovascular disease has occurred (62). The exploitation of the potential for similar interventions in COPD will require a better understanding of the relationship of COPD to novel risk factors, such as hyperglycemia and diabetes.


   FOOTNOTES
 
Supported by National Institutes of Health/National Heart, Lung, and Blood Institute grants 1 R03 HL 70289–01, 1 R01 HL 49869–01, and T32 HL 07,035.

No part of the research presented has been funded by tobacco industry sources.

Received in original form March 15, 2002; accepted in final form December 5, 2002


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