A study of the relationship between pulmonary function tests and both fasting plasma glucose and glycated hemoglobin levels among asymptomatic cigarette smokers

Background Tobacco smoke has been recognized as an independent risk factor for chronic obstructive pulmonary disease and diabetes mellitus type 2. Aim To investigate the association between the presence of airflow obstruction in pulmonary functions and both fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) levels among asymptomatic cigarette smokers. Patients and methods Pulmonary function indices via spirometry and both FPG and HbA1c levels were altogether assessed in 300 apparently healthy participants attending health checkup clinic. Participants were stratified according to their smoking status into group I, which included 150 current and former cigarette smokers (ever smokers), and group II, which included 150 participants with no history of smoking (never smokers). Results FPG and HbA1c% were significantly higher among group I compared with group II (P=0.001 and 0.002, respectively). However, percent of forced expiratory volume in 1 s/forced vital capacity ratio less than 70% was statistically more prevalent among group I compared with group II (17.3, 6.7%, respectively, P=0.042), and the odds ratio (OR) of its occurrence increased with FPG more than or equal to 100 mg/dl [OR=2.91; 95% confidence interval (CI)=1.62–4.01], HbA1c more than or equal to 5.6% (OR=2.07; 95% CI=0.12–0.77), age more than or equal to 50 years (OR=2.85; 95% CI=1.69–3.99), smoking index more than or equal to 25 pack-years (OR=3.11; 95% CI=1.85–3.66), and BMI more than or equal to 25 kg/m2 (OR=2.33; 95% CI=0.06–0.84). Conclusion Risk of chronic obstructive pulmonary disease is increased among asymptomatic current or former cigarette smokers, especially elderly with impaired glucose homeostasis.


Introduction
Tobacco smoke is a major cause of preventable morbidity and mortality worldwide. Nicotine, one of the many components of tobacco smoke, is established to be associated with decrease in the sensitivity of insulin in humans, linking smoking with insulin resistance. However, the mechanisms responsible for this remain unclear, and hence, cigarette smoking has been considered an important risk factor for the development of insulin resistance and ultimately type 2 diabetes mellitus (DM) [1].
Furthermore, tobacco smoke is also the commonest risk factor for chronic obstructive pulmonary disease (COPD) worldwide [2], which is a disease known to affect the quality of life significantly [3] as it increases the annual decline rate in forced expiratory volume in the first second (FEV1) and overall, leading to increased mortality and morbidity compared with nonsmokers [4].
interleukin-1, and interleukin-6, all of which upregulate the activity of neutrophil and macrophage and consequently initiate a cascade of systemic inflammation [5,6]. Strikingly, these mediators have also been postulated to play a role in developing insulin resistance in muscle and liver tissue, which consequently increases the likelihood of future development of DM [7]. Cigarette smoking-related systemic inflammation is therefore hypothesized as the joint etiology independently influencing both lung function and glycemia [8,9]. Several large-scale western studies have linked COPD to DM, an example of which is an American study conducted on 47 million people investigating the prevalence of COPD-associated comorbidities, and it concluded that DM is significantly prevalent in patients with COPD [10].
On the contrary, research into the association between diabetes and pulmonary function in diabetic subpopulation free from overt pulmonary disease has resulted in inconsistent outcomes among studies. A recent meta-analysis on 40 studies attempted to characterize pulmonary function in such population compared with normoglycemic participants and concluded that impaired pulmonary function, but of the restrictive pattern, is the most frequently encountered pattern [11].
However, another study analysis of a large Japanese cohort (follow-up period up to 2 years) suggested that low lung volume might in fact be a risk factor for impaired glucose tolerance rather than impaired fasting glucose (IFG), but an association between prediabetes and early stages of COPD could not be found [12].
The aim of the current study was to investigate the association between prevalence of airflow obstruction as reflected in pulmonary function tests measured via spirometry and two markers that define glycemic status, namely, fasting plasma glucose (FPG) levels and glycated hemoglobin concentration (HbA1c%) among asymptomatic cigarette smokers.

Patients and methods
This is a prospective observational study enrolling 300 participants, aged 40 years or older, attending the health checkup clinic at Nasr City Police Hospital during the period between April 2017 and April 2018. Participants were grouped into two groups based on their smoking status: group I, which included 150 apparently healthy cigarette smokers (whether current or former) (ever smokers group) as the study group, and group II, which included 150 never smokers matched for as a control group (never smokers group). Smoking status is defined by the Centers for Disease Control and Prevention, where current smoker is the one who has smoked 100 cigarettes in his or her lifetime and who currently smokes cigarettes, and former smoker is the one who has smoked 100 cigarettes at least in his or her lifetime but who had quit smoking, whereas a never smoker is the one who has never smoked or has smoked less than 100 cigarettes in his or her lifetime. Cumulative exposure to tobacco smoke was also quantified via calculation of the smoking index (SI) defined as number of cigarette packs smoked a day for a year (pack-years) [13].

Exclusion criteria
Any individual with physician-diagnosed airway disease and patients known to be on antidiabetic medication (insulin and/or oral hypoglycemic therapy) to avoid bias related to drug-induced effects on glycemic markers were excluded.
All enrolled participants were subjected to full history taking (with emphasis on detailed smoking history regarding duration and amount of cigarettes smoked per day) and physical examination, including BMI, which was calculated as person's weight in kilograms/ square the height in meters (kg/m 2 ), where 18.5-24.9 kg/m 2 was considered normal/healthy body weight and 25 kg/m 2 or more was the reference point for overweight according to Centers for Disease Control and Prevention [14].

Laboratory investigations
Venous blood samples were collected after 12 h of fasting and measured via automatic clinical chemistry analyzer. FPG levels were measured by enzymatic methods. High-performance liquid chromatography was used to assess HbA1c following the National Glycohemoglobin Standardization Program protocol [15].
Serum FPG level of 100 mg/dl or more was taken as a cutoff value to indicate IFG, a category of intermediate hyperglycemia, whereas HbA1c concentrations of 5.6% or higher was taken as a cutoff value to reflect chronic hyperglycemia. Both are glycemic markers for prediabetic stage according to the American Diabetes Association [16].

Ethical considerations
Our study gained approval by the ethical committee board. All participants gave informed consent before enrollment. All participants were reassured about the confidentiality of the data, their right to withdraw from the study at any time without giving any reasons, and without effecting their rights to medical care in case of refusal to participate.

Statistical analyses
Analysis of the collected data was done via the 'Statistical Package for the Social Sciences (SPSS, IBM Corp. Armonk, NY, USA) for Windows' program, version 22.0. Mean±SD was calculated for continuous data, whereas number (percentage) was calculated for qualitative data. Analytical statistics was then performed between group I (ever smokers group) and group II (never smokers group) using the following: independent t test to compare between the two groups with normal continuous data distribution, Mann-Whitney test to compare between the two groups with nonnormal continuous data distribution, and χ 2 test or Fisher exact test to compare between two or many categorical groups. Finally, logistic regression analysis was done along with calculation of the odds ratios (ORs) and 95% confidence intervals (CI) to evaluate the probability of an FEV1/FVC, % <70% among different variables considered as potential risk predictors. P value less than 0.05 was considered statistically significant.

Results
Baseline characteristics of all 300 enrolled participants are summarized in Table 1. The two groups (ever versus never smokers) were matched for age, sex, and BMI with no statistically significant differences (P=0.2362 for age, P=0.3463 for sex, and P=0.209 for BMI).
Both indices of glycemic control were higher among participants of group I (ever smokers) compared with those of group II (never smokers), with a highly significant statistical difference between both groups  Table 4).

Discussion
Several epidemiological studies have gathered increasing body of evidence that tobacco smoke is an independent risk factor for COPD, insulin resistance, and type 2 DM [1,2], perhaps through initiation of systemic inflammation, which is common to both [8,9,18].
The presence of a common ground and a joint etiology between both diseases led us to hypothesize that an association between pulmonary function and glycemic status could possibly exist among cigarette smokers even at very early stages before clinical characteristics for either diseases became evident. If such hypothesis is valid and such an association could be established so that the existence of one could be a predictor for the other, this could be of great significance in the context of preventive medicine as early detection is key to disease control, delaying, and decreasing risk of complications as well as reducing medical costs.
In the current work, we aimed to clarify the association between pulmonary function tests, particularly airflow limitation, and two glycemic indices, namely, FPG and HbA1c, among asymptomatic apparently healthy cigarette smokers. concentration is a marker of long-term glucose homeostasis .which reflects average plasma glucose in the past 2-3 months [19].
The main findings of the current work were that FEV1/FVC, % was significantly lower among ever smokers compared with never smokers, and the prevalence of FEV1/FVC less than 70% was higher among group I participants compared with group II (17.3 vs. 6.7%, respectively; P=0.042). Moreover, both FEV1, %pred and FEF 25-75, %pred values were significantly lower in group I versus group II (P=0.001 for the former vs. P=0.003 for the latter).
Both glycemic indices were significantly higher among ever smokers compared with never smokers (P=0.001 for FPG level vs. P=0.002 for HbA1c%), and the mean ±SD of both markers was also significantly higher among smokers with FEV1/FVC less than 70% (26/ 150) than among their counterparts with FEV/FVC more than or equal to 70% (124/150) (P=0.016 for FPG vs. P=0.041 for HbA1c%). These results are in accordance with those of Akpinar et al. [20] who reported that fasting hyperglycemia, one of the components of metabolic syndrome, was significantly prevalent among patients with COPD. Our results also match those of Baba et al. [3] who studied ∼1000 apparently healthy Japanese volunteers and found that HbA1c levels were increased in patients having FEV1/ FVC less than 70% than in patients without an airflow limitation. Moreover, Sato et al. [21] found a greater decline in FEV1 among smokers with metabolic  Logistic regression analysis was conducted to determine the risk of developing airflow obstruction (FEV1/FVC<70%) associated with different potential risk predictors, and our results showed that the risk was highest (three folds) with cumulative smoking exposure more than or equal to 25 pack-years (OR=3.11, 95% CI=1.85-3.66), with FPG more than or equal to 100 mg/dl (OR=2.91, 95% CI=1.62-4.01), and with age more than or equal to 50 years (OR=2.85, 95% CI=1.69-3.99), whereas the risk was less (two folds) with BMI more than or equal to 25 kg/m 2 (OR=2.33, 95% CI=0.06-0.84) and HbA1c more than or equal to 5.6% (OR=2.07, 95% CI=0.12-0.77).
Therefore, according to the results of this study, there was a higher likelihood of FEV1/FVC less than 70% with FPG levels of 100 mg/dl or above than with HbA1c% of 5.6% or more (OR=2.91 vs. 2.07, respectively), which implies a stronger association between the occurrence of airflow limitation and the glucose tolerance status rather than glucose homeostasis. This finding is intriguing and rather difficult to explain because FPG reflects plasma glucose level at a certain point in time, whereas HbA1c gives estimated average plasma glucose levels for the past 2-3 months, which makes it a steadier and more reliable glycemic parameter. A possible explanation might be that elevated FPG and IFG might be transitory and reversible leading to bias in results as they are affected by several factors such as diet, stress [22], as well as the amount of cigarettes smoked at the time of testing because nicotine in tobacco smokers decreases insulin sensitivity by binding to nicotinic acetylcholine a1 receptors in human skeletal muscle, and this effect is proportional to the daily number of cigarettes smoked [23].
Some limitations of the present study should be mentioned: the study population had a small sample size, but we owe this to the relatively small number attending the health checkup clinic, as a relatively small percent of Egyptian population has the culture of doing regular checkups without having any complaints. Moreover, this was an observational study, in which the results reflect a certain point in time, so further longitudinal (follow-up) studies are needed to assess the progress of the findings. Moreover, the possibility of bias in selection cannot be denied, because we collected our data only from patients attending health checkup clinic, and further studies among different population groups are required to prove or disapprove our results. Moreover, we did not assay the oral glucose tolerance test, and therefore, underestimation of cases who have impaired glucose tolerance with fasting normoglycemia is a possibility. Furthermore, inflammatory markers reported to be related to lung dysfunction and the development of diabetes were not assessed. More studies are required to clarify the mechanisms linking risk of diabetes and lung dysfunction. These studies need to focus on data concerning insulin secretion and resistance, and other clinical markers related to diabetes and its development. Finally, our findings suggest association between airflow obstruction and impaired glycemic status, but association does not necessarily mean causation, and further studies are need to tackle this point.

Conclusion
Our results suggest an association and increased risk of COPD among asymptomatic cigarette smokers, current/former, especially elderly with impaired glucose homeostasis. Developing a risk score combining known risk factors for COPD including a measure of blood glucose in screening studies would be recommended.

Financial support and sponsorship
Nil.

Conflicts of interest
There are no conflicts of interest.