Significance of spirometry in diabetic patients

1. Diabetes mellitus 

Diabetes mellitus is a major, rapidly growing public health care problem. It is increasing in incidence, and brings with it long term complications [1]. Chronic hyperglycemia of diabetes mellitus is associated with continuing damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, lungs and blood vessels. Diabetes mellitus is an incurable life-long disease, involving multiple systems, and with devastating complications which end up in severe disability and death [2]. Diabetes mellitus is associated with the ongoing malfunction of various organs and its complications are mainly a consequence of macro-vascular and micro-vascular damage [3]. 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 [3] may result in pulmonary inflammation [4] as well, and hence, it can cause air way damage [5]. Moreover, secondary reduction in the antioxidant defense of lung and increased susceptibility to environmental oxidative insults results in the subsequent loss of lung function [6] and ultimately, lung damage. It has been demonstrated that pulmonary complications in diabetes mellitus are due to a thickening of the walls of alveoli, alveolar capillaries and pulmonary arterioles, and these changes cause pulmonary dysfunction [7], [8]. Diabetes mellitus can cause pulmonary complications due to collagen and elastin changes, as well as micro-angiopathy [9]. Furthermore, pulmonary function impairment and lung dysfunction in diabetic patients is secondary, due to immune function impairment [10].

2. Spirometry and diabetes mellitus 

Cardio-respiratory clinical features in diabetic patients, such as shortness of breath, dysponea, wheezing and easy fatigability make physicians more alert to coronary artery disease (CAD). No one can deny that diabetes mellitus is a major risk factor of coronary artery disease, but it must be borne in mind that the lung is also a target organ in diabetic patients, and such clinical features might be due to pulmonary complications than CAD alone. A substantial number of patients who present with dysponea shows normal coronary arteries, and even normal cardiac perfusion and systolic function. Within this clinical scenario, patients’ complaints of shortness of breath, dysponea and easy fatigability might need further investigation. In this situation, the application of spirometry must be fully utilized to rule out pulmonary problems. The basic concepts of normal pulmonary physiology that are involved in spirometry/pulmonary function testing include mechanics (airflows and lung volumes), ventilation–perfusion interrelationship, diffusion and gas exchange, as well as respiratory muscle strength [11] (see Table 1).

Table 1. Indications of spirometry in diabetic patients.

	Diagnostic indications
	•Mandatory monitoring of lung functions in diabetic individuals every two years •Diabetic patients with history of cigarette smoking, tobacco chewing, cough, phlegm production, chest pain, dyspnea or wheezing •Diabetic patients with abnormal laboratory tests such as blood gases and chest radiograph •Evaluate the effect of diabetes mellitus on pulmonary function •Screen all diabetic patients during their initial visits to ascertain the status of lungs •Screen all the diabetic patients with abnormal HBA1C and fasting blood glucose •Assessment of pre-operative risk in those diabetic who need to undertake any surgical process •When decision is needed for the diabetic patient who underwent an amputation
	Monitoring indications
	•Assess the therapeutic intervention related to respiratory illness in diabetic patients •Describe the course of diseases that affect lung function and associated structures •Monitor diabetic patients who are exposed to occupational/industrial hazardous agents
	Disability/impairment evaluations
	•Assess diabetic patients as a part of a rehabilitation program •Assess diabetic patients as part of an insurance evaluation •Assess diabetic patients for social security and legal reasons

Spirometry is a powerful tool that can be used to detect, differentiate, follow and manage patients with pulmonary disorders. Advances in science and technology have made spirometry a much more reliable, valid and relatively simple tool to incorporate into routine clinical visits. Spirometry is a basic, widely used pulmonary function test (PFT). It typically assesses the lung volumes and flows, and is ideally suited to describing the effects of obstruction or restriction on lung function [12]. It is now regarded as an integral component of any respiratory medical surveillance program. PFT has assumed a key role in epidemiological studies investigating the incidence, natural history and causality of lung disease [13]. Although there is no substitute for spirometry, and even in countries where it is not widely available as a standardized clinical algorithm or diagnostic pathway, yet, it can greatly assist in the diagnosis of common airway diseases. Spirometry is essential for diagnosing respiratory illnesses, assessing their severity, determining response to treatment and tracking patients’ progress over time [14]. The utility of spirometry was further recognized when its applications were highlighted in diabetic patients [15] inhaled insulin was introduced for the treatment of diabetes mellitus and researchers discussed its applications in association with inhaled insulin at various scientific gatherings [16] (see Table 2, Table 3).

Table 2. Contraindications of Spirometry in diabetic patients.

	•Nausea, vomiting, headache, dizziness (these disorders affect the test performance) •Hemoptysis of unknown origin •Current history of any abdominal or thoracic surgery •Current history of any limb amputation •Current history of glaucoma or any eye surgery •Recent history of severe chest pain, unstable angina or myocardial infarction •Thoracic aneurysms/pneumothorax •Diabetic patients with a history of HIV/hepatitis B/hepatitis C (because of high risk of transmission of infection. However, spirometry can be performed after taking high standard sterilizing measures)

Table 3. Patho-physiological factors affecting the lung functions.

	Physiological factors:
	•Age, gender, height, weight, BMI, ethnicity, pregnancy, posture, exercise •Customary activity, time of day, season, climate and geographical location •Diet (malnutrition)
	Environmental factors:
	•Air pollution (occupational/environmental exposure) •Smoking
	Pathological conditions:
	•Chronic obstructive pulmonary disease (COPD), interstitial lung disease •Coronary artery disease •Diabetes mellitus/impaired glucose tolerance/hormonal disorders •Neuromuscular disorders (Guillain barre syndrome, Myasthenia gravis) etc.

3. Diabetes mellitus and lung function 

Diabetic mellitus targets lungs and its associated structures, as it does other organs. Electron microscopic study has shown that in diabetic patients, all parts of the lung are equally affected, and the thickening of the basal lamina is of the same order of magnitude in both the lung and the kidney [10]. Pulmonary damage at an early stage in most patients with diabetes mellitus is subclinical, and rarely present with complaints [17]. Spirometry noninvasively quantifies the physiological reserves in a large micro-vascular bed that is not clinically affected by diabetes. Lung function may provide useful measures of the progression of systemic micro-angiopathy in diabetic patients [17].

In normal healthy non smokers after the age of 35, the expected decline in lung function (FEV1) is 25–30ml/year. However, the average rate of decline of lung function in diabetic patients, as measured by Forced Expiratory Volume in 1 s (FEV1), is 71ml/year. [18] McKeever et al. [19] have observed that an increase in mean HbA1c is associated with a decrease in the lung function parameters FVC and FEV1. They hypothesize that impaired glucose auto-regulation is associated with impaired lung function. Asanuma et al. [20], Lange et al. [21] and Boulbou et al. [22], have reported that FVC and FEV1 are reduced in diabetic subjects, as compared to the control subjects. Similarly, Cazzato et al. [23], conducted a cross-sectional study to assess pulmonary function in children with insulin-dependent diabetes mellitus (IDDM), and reported that FVC and FEV1 were significantly lower in diabetics than in controls. Similarly, Makkar et al. [24], performed spirometry on patients with IDDM, and reported that the IDDM patients had reduced FVC, FEV1 and MEF 25–75%, as compared to their matched control. Moreover, Rosenecker et al. [25] demonstrated that in patients with diabetes, FVC and FEV1 declined significantly over the five year study period, whereas patients without diabetes did not show a significant decline during this period. Davis et al. [26] have reported that the Forced Vital Capacity (FVC), Forced Expiratory Volume in 1 s (FEV1), Vital Capacity (VC) and Peak Expiratory Flow (PEF) were reduced in diabetic patients. Similarly, Meo et al. [15], [27] reported that lung function parameters Forced Vital Capacity (FVC) and Forced Expiratory Volume in 1 s (FEV1), and Peak Expiratory Flow (PEF) in type 1 and type 2 diabetic patients were impaired, as compared to their matched controls. Stratification of results by years of disease showed a duration of disease-response effect on lung function.

4. Impaired lung function can cause diabetes mellitus 

Diabetes mellitus and lung function have a two way cause effect relationship. It is pertinent to assess respiratory dysfunction caused by diabetes mellitus, and it is even more pertinent, in non-diabetic subjects, to assess the risk of diabetes mellitus. The impaired lung function may be forecast quite reliably many years before the actual diagnosis of diabetes mellitus. Subjects with reduced lung function are at a higher risk of developing insulin resistance and hyperinsulinemia. Impaired pulmonary function may increase the risk of developing diabetes mellitus. Subjects who are predisposed to developing diabetes have decreased spirometric indices many years prior to the diagnosis, compared with those who do not develop diabetes. This decrement in spirometric parameters remains after the development of diabetes; however, the mechanism involved is most probably that of insulin resistance [28], [29], [30], [31].

5. Impaired lung function is emerging risk factor for type 2 diabetes mellitus 

Impaired lung function, especially FVC and FEV1, has attracted mounting attention as a potentially novel risk factor for glucose intolerance [32], insulin resistance 33 and type 2 diabetes mellitus [28], [29], [30], [31]. The most probable mechanisms include effects of hypoxemia on glucose and insulin regulation [33], lung-related inflammatory mediators and their effects on insulin signaling [32]. Yeh et al. [34] analyzed longitudinal data of a large sample of middle-aged adults from a community-based study, and tested the hypothesis that decreased lung function (FVC and FEV1) is cross-sectionally associated with features of insulin resistance, and is an independent predictor of the incidence of type 2 diabetes mellitus. Moreover, they also reported that adults with impaired FVC (% predicted) had various features of insulin resistance, including higher levels of blood glucose, insulin, triglycerides, lower HDL cholesterol and higher systolic blood pressure.

Lazarus et al. [33] found that the decrease in FVC, FEV1 and maximal midexpiratory flow rate at the baseline forecast hyperinsulinemia and estimated insulin resistance over 20years of follow-up, independent of age, adiposity and cigarette smoking. Similarly, Eriksson and Lindgarde [35] found that non-diabetic middle-aged subjects with a 10% decrease in mean vital capacity developed diabetes mellitus during a 6-year follow-up. Engstrom and Janzon [28] demonstrated that decreased FVC and FEV1 predicted the presence of diabetes. Ford and Mannino [30] reported that FVC and FEV1 were significantly and inversely associated with the prevalence of diabetes. They also found that restrictive lung disease was significantly associated with the incidence of diabetes; however, this association was not observed in subjects with obstructive lung disease.

The most credible explanation for the link between low FVC and FEV1 and diabetes risk is related to hypoxemia-induced insulin resistance. The animal model studies also reported that experimental hypoxia produces insulin resistance and hyperinsulinemia in animals [36]. Moreover, exposure to high altitude hypoxia [32] or hypobaric hypoxia can reduce insulin sensitivity and lead to a predisposition for the development of type 2 diabetes. Impaired vital capacity and the risk of diabetes are partially determined by adverse fetal or early-life conditions, and inflammatory precursors may also favor resistance to insulin action [37]. The main suggestion of the study by Yeh et al. is that impaired lung function (FVC and FEV1) deserves high attention as an emerging novel risk factor for type 2 diabetes mellitus. FVC might still be a useful risk predictor, and the FVC-diabetes link could suggest explanations for other phenomena such as an increased risk of coronary artery disease, along with impaired lung function.

6. Diabetes mellitus and alveolar gas exchange 

Diabetic patients showed impaired alveolar gas exchange capacity and reduced pulmonary elastic recoil, as compared with healthy controls [38]. It has also been found that the impairment of the pulmonary diffusion capacity for carbon monoxide was common in type 2 diabetes mellitus in Asian Indian patients [39]. The normal physiological reserves that allow alveolar oxygen uptake to increase in accordance with metabolic demand and exertional dyspnea may not develop until 40–50% of alveolar gas exchange capacity is lost. Diabetic lung involvement is best characterized as a loss of physiological reserves, and it become a cause of exertional dyspnea in diabetic patients [9].

7. Diabetes mellitus and respiratory muscles strength 

Respiratory muscle endurance is of interest in pulmonary critical care and many other areas of medicine. Reduced muscle strength has been reported in diabetic patients. Bilateral or unilateral diaphragmatic paralysis has been observed in diabetic patients [40]. In addition [41] conducted a study, and determined respiratory muscles endurance by means of a direct MVV test during the inspiratory and expiratory phases of respiration, by using a MP-100 student Bio Pac system. They reported that the respiratory muscles endurance was impaired, and a greater perception of respiratory exertion was noticed in diabetic patients relative to their matched controls. Moreover, breathlessness on exertion and orthopnea in association with type 2 diabetes mellitus has been also reported. Investigation showed that bilateral diaphragmatic paralysis due to phrenic neuropathy may be an important, if rare complication of diabetes, and diaphragmatic function should be considered in any patient with unexplained breathlessness and orthopnoea [40].

8. Diabetes mellitus and pulmonary infection 

The frequency and enhanced severity of pulmonary tract infections in uncontrolled diabetes have been well known for a long time. The availability of antibiotics has made a significant difference, but infection is probably a more serious threat to life in a diabetic than in a non-diabetic individual. Diabetes mellitus is recognized as an independent risk factor for developing lower respiratory tract infections [42], [43]. The mechanism for increased susceptibility to infection is due to an alteration in the chemotactic, phagocytic and bactericidal activity of polymorphonuclear leukocytes [44]. The impaired phagocytic function is also one of the major causes of pulmonary infection in diabetic patients.

9. Diabetes mellitus and pulmonary tuberculosis 

The association between diabetes mellitus and tuberculosis (TB) has been discussed in the literature for a long time. Pulmonary tuberculosis and diabetes mellitus frequently coexist [45]. It has been also reported that there is a high prevalence of TB disease in diabetic children and adolescents [46]. The frequency of tuberculosis was 4–5 times more than in non-diabetics. The disease was more aggressive in poorly controlled diabetics, and is significantly associated with the development of pleural effusion [47]. Increased reactivation of tuberculosis lesions has also been recorded in diabetics. It has also been reported that the development of tuberculosis occurred more frequently in juvenile diabetes and the occurrence of tuberculosis increased with the duration of diabetes, causing a significantly greater mortality rate. In various infectious conditions of the lung, along with other related investigations, spirometry may also provide reliable information about the health of the lung.

10. Conclusion 

Spirometry is a simple, reliable, valid and powerful tool that can be used to assess, differentiate, follow-up and manage patients with pulmonary disorders. Diabetes mellitus is a major public health care problem with increasing incidence and long term complications and is a leading cause of illness and death across the world. Diabetes mellitus is associated with continuing damage, dysfunction and failure of various organs, including the lungs. Therefore, when the question of the management of diabetes mellitus arises, physicians should be aware of the size of the problem of pulmonary complications, and must consider the lung as being as serious as other complications of diabetes mellitus. The impaired lung functions (FVC and FEV1) reflects a causative role played by the lungs in developing diabetes, then optimizing the health of the lung through cessation of smoking habits, avoidance of irritants and toxic exposure, control of underlying airway inflammation and the promotion of physical activity seem warranted. Indeed, it seems time to add the spirometer to the tools available for monitoring diabetes mellitus and its important sequelae. Moreover, physicians must fully utilize Spirometry in the management of diabetes mellitus.

Conflict of interest statement 

None declared.