Inadequate glucose control in type 2 diabetes is associated with impaired lung function and systemic inflammation: a cross-sectional study

The association of type 2 diabetes with decreased lung function (measured by known determinants of pulmonary disability and death, such as FEV₁), has received renewed attention [1, 2]. Inflammation, microangiopathy, and alterations in lung matrix proteins may all play a role. The first mechanism tends to unify the impairment seen in patients with emphysema with that seen in diabetes and cardiovascular disease; in this context, both type 2 diabetes and chronic lung disease, such as COPD, have been associated with increased levels of low-grade acute and chronic systemic inflammatory mediators and inflammatory markers [3‐5]. Until recently, however, few studies had explored lung function among subgroups of diabetic subjects. It is likely that persistent inadequate glucose control over time may alter regulation of inflammatory pathways that are involved in the impairment of lung function [2, 6].

It is still unknown if inadequate glucose control in type 2 diabetes is simultaneously associated with a decrease in lung function and increased systemic levels of inflammatory markers. In this study, we compared type 2 diabetes subjects based on their glucose control profile (adequate vs. inadequate) and assessed differences in lung function (spirometry) and blood levels of five known systemic inflammatory markers.

This was a cross-sectional study. The sampling frame from which patients were selected was the Colombian Diabetes Association (ACD), a private institution in Bogota, Colombia, that provides basic and specialized ambulatory care for diabetic patients of all socio-economic strata. Patients need not be referred with any special degree of severity or case-mix. We invited to participate in the study both incident and prevalent diabetes patients of either sex, who were seen at the ACD between July 2005 and September 2007. Inclusion criteria were age between 35 and 65 years, and medical diagnosis of type 2 diabetes confirmed at ACM. The Latin-American Diabetes Association (ALAD) definition for type 2 diabetes (fasting glycemia equal to or greater than 126 mgr/dL, glycemia equal to or greater than 200 mgr/dL after a glucose load during a glucose tolerance test, or casual glucose blood levels of 200 mgr/dL or more), is the standardized definition used in the ACD [7]. We excluded patients that met any of the following criteria: pregnancy, previous diagnosis of rheumatoid arthritis or collagen disease; cystic fibrosis, lung cancer or tuberculosis; thoracic, lung, or heart surgery; or deformities that would preclude conducting a reliable spirometric procedure.

The study protocol was approved by the Clinical Research Ethics Committee at Fundación Cardioinfantil in Bogotá.

Results of this study show that those diabetic subjects with inadequate glucose control over the past several weeks as measured with HBA_1c, have lower pulmonary function than those with adequate control. These differences were not explained by usual determinants of lung function such as age, height, sex, cigarette smoking or other lifetime exposures. Subjects with inadequate control also had significantly higher levels of inflammatory markers (TNF-α, ferritin, fibrinogen, and C-RP), although, there is no clear dose-effect relation. We selected these markers, including IL-6, because increased levels of these inflammatory cytokines (IL-6 and TNF-α), as well as downstream proteins such as C-RP, ferritin and fibrinogen, have been implicated in the inflammatory response seen in COPD and diabetes.

The limitations of our approach should be discussed. Although selection bias is a possibility, we minimized it by selecting all consecutive cases with diabetes with no particular severity of disease, duration, or case-mix. Confounding bias is not likely in our study, as we adjusted the results for known determinants of lung function, such as age, height and sex, as well as smoking history. Persistent confounding by smoking may be possible given that we did not quantify the intensity of lifetime exposure (i.e. pack-years). However, the likelihood of this is low, because the intensity of current cigarette exposure seemed to be lower in those with inadequate control. Although those diabetic subjects with poorer control also had longer disease duration, adjustment for time elapsed from diagnosis did not change results. Given that we assessed diabetes duration by patient history, however, we cannot exclude persistent confounding and non-differential misclassification as a possible explanation for this finding. Finally, by taking both incident and prevalent cases of diabetes, our results may be confounded by the effects of treatment and by survivor bias, but both biases, if present, would have tended to decrease the magnitude of the effect sizes seen in this study. Classification bias is not likely to have altered our results, as all subjects met pre-determined criteria for diabetes, and both the definition of control (HBA_1c) and cut-off point selected to define inadequate control (greater than 7%) were established a priori. Some recall bias may have been possible with respect to past medical history and respiratory exposures, but, even if present, these are more likely to have been non-differential between those with adequate and inadequate glucose control (subjects were not aware of the hypothesis under study).

From a clinical perspective, the importance of changes in lung function has usually been judged as the rate of change over time, derived from observational cohorts or clinical trials. Thus, it is difficult to fairly assess the significance of the magnitude of change observed in this study, given the cross-sectional approach. This study confirms previous findings of decreased lung function in diabetic subjects and in those with insulin resistance [2, 6, 14]. Davis et al and McKeever et al recently reported decreased lung function in diabetic subjects, and convincingly showed that this decrease is associated with inadequate diabetes control, which is consistent with our study results [6, 15]. However, our study goes further to show that some inflammatory markers are elevated in patients with simultaneous inadequate control and decreased lung function, suggesting a potential association. Mechanisms related to chronic hyperglycemia may involve both the formation of oxygen radicals and their effect on pulmonary vasculature or the alveolar-capillary membrane, and the secondary effect of systemic inflammation seen in diabetic patients [16‐19]; both mechanisms need not be mutually exclusive. The second mechanism tends to equate the impairment seen in patients with emphysema with that seen in diabetes and cardiovascular disease, through inflammatory mediators [20]. In addition to the wealth of literature available on endothelial damage and cardiovascular events, recent studies have shown that systemic inflammation markers such as ferritin [3], fibrinogen [21, 22], and C-RP are increased in subjects with type 2 diabetes as indicators of prognosis, as well as inflammation mediators associated with insulin resistance such as IL-1, IL-6, and TNF-α [23].

It should be highlighted that the impairment seen in our study is more consistent with a restrictive lung disorder. Although not a uniform finding, this has been previously described in other studies [1, 24, 25]. This suggests a causal pathway (or pathways) for inflammation different from that in emphysema and COPD. Alteration of matrix proteins seen in DM due to the formation of advanced glycosylation end products and subsequent inflammation in the lungs [26] has been suggested, and may provide such a pathway.

Diabetic subjects with inadequate glucose control have lower pulmonary function than those with adequate control, a difference not explained by usual determinants of lung function. Similarly, those subjects with inadequate control also had significantly higher levels of inflammation markers (TNF-α, Ferritin, Fibrinogen, and C-RP), suggesting a potential association. Our results need to be confirmed by longitudinal studies (given that diabetic control is a time-dependent variable). Hopefully, it can also be shown that better glucose control can result not only in no further decrease in lung function but also in attenuation of the inflammatory response. Our findings, however, should make clinicians more aware of this association and add to the necessity of advising diabetic patients of the need for adequate glucose control.