Type 2 diabetes impairs pulmonary function in morbidly obese women: a case–control study
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To determine whether the presence of type 2 diabetes and the degree of metabolic control are related to reduced pulmonary function in obese individuals.
Seventy-five morbidly obese women (25 with type 2 diabetes [cases]—and 50 without diabetes [controls]) with a history of non-smoking and without prior cardiovascular or respiratory disease were prospective recruited for a case–control study in the outpatient obesity unit of a referral centre. Both groups were closely matched by age, BMI and waist circumference. Pulmonary function test included forced spirometry and static pulmonary volume measurements.
Type 2 diabetic patients showed lower forced expiratory volume at 1 s (FEV1) (mean difference −11.6% of predicted [95% CI −20.4 to −2.8]; p = 0.011), and FEV1/forced vital capacity (FEV1/FVC) ratio (mean difference −4.4% [95% CI −8.1 to −0.7]; p = 0.049), but a greater residual volume (RV) (mean difference 19.5% of predicted [95% CI 10.8–28.3]; p < 0.001). In addition, an obstructive ventilatory pattern was more frequent in diabetic patients. Significant negative correlations between FEV1 and fasting glucose, HbA1c and HOMA insulin resistance (HOMA-IR) were detected. By contrast, RV was positively correlated with fasting glucose, HbA1c and HOMA-IR. Multiple linear regression analyses showed that fasting glucose and HbA1c independently predicted FEV1 and RV.
The presence of diabetes and the degree of glycaemic control are related to respiratory function impairment in morbidly obese women. Therefore, the impact of type 2 diabetes on pulmonary function should be taken into consideration by those providing care for obese people.
KeywordsObesity Pulmonary function Type 2 diabetes
Maximum mid-expiratory flow
Forced expiratory volume in 1 s
Forced vital capacity
Global Initiative for Chronic Obstructive Lung Disease
Insulin resistance measured by HOMA
The rapid increase of obesity prevalence during the last two decades has become one of the main threats to public health in the Western world. WHO predicts that by 2015 at least 10% of the projected global population will be obese . This will constitute a significant health and economic burden, with associated increases in cardiovascular and metabolic disturbances, musculoskeletal disease and malignancy . In addition, although there has been little focus on the impact of obesity on respiratory disease, there are clear effects on pulmonary function [3, 4]. Cross-sectional studies have demonstrated an inverse relationship between forced expiratory volume in 1 s (FEV1) and both BMI and waist circumference [5, 6]. This is of particular importance because FEV1 is an independent predictor of all-cause mortality and a strong risk factor for cardiovascular disease, stroke and lung cancer . The mechanical effects of truncal obesity and the metabolic effects of adipose tissue partly explain the impairment of pulmonary function in obese individuals .
Type 2 diabetes is another epidemic disease strongly associated with obesity. The relationship between both disorders is of such interdependence that the term ‘diabesity’ has been coined. Although the lung is not considered a target organ in type 2 diabetes, increasing evidence through cross-sectional studies has appeared showing the opposite [8, 9]. In fact, diabetes is frequently co-morbid with chronic obstructive pulmonary disease , and data from the Atherosclerosis Risk in Communities Study showed a faster pulmonary function decline in type 2 diabetic patients than in other participants . This is undeniably significant, because airflow limitation is an independent predictor of death in type 2 diabetes . The available data suggest that the appearance of structural changes in respiratory muscle associated with insulin resistance [13, 14], non-enzymatic glycosylation of the connective tissue [15, 16], defects in the stimulation of pulmonary surfactant production  and the presence of a low-grade chronic inflammation state  should be considered among the possible mechanisms involved in this relationship. In support of these findings, thickening of the alveolar epithelia and pulmonary capillary basal lamina, fibrosis, centrilobular emphysema and pulmonary microangiopathy have been described in autopsy findings from diabetic individuals . In addition, we have recently shown that type 2 diabetes is an independent risk factor for severe nocturnal hypoxaemia in obese patients . However, there are no studies designed to investigate whether diabetes and the degree of glycaemic control are independent determinants of reduced pulmonary function in obese patients. For this purpose we designed a case-control study comparing respiratory function variables between diabetic and non-diabetic morbidly obese participants closely matched by the most important variables that could affect lung function. In addition, a multivariate regression analysis taking into account the potential confounders was also performed.
Design of the study and description of study population
In this study we have investigated the effect of type 2 diabetes and the degree of glycaemic control on the lung function of morbidly obese participants following the Strengthening the Reporting of Observational Studies in Epidemiology guidelines for reporting case–control studies .
On this basis, a total of 25 consecutive morbidly obese type 2 diabetic women without associated complications attending the outpatient obesity unit of a university hospital (Hospital Universitari Vall d’Hebrón, Barcelona, Spain) were recruited for the study over a 12-month period (cases). Women were selected for several reasons: (1) women represent 70–80% of patients attending our obesity unit; (2) men attending our obesity unit are generally older and have higher rates of co-morbidities (i.e. active smoking and coronary heart disease) that were exclusion criteria in the present study (see below); (3) hormonal status could affect susceptibility to lung dysfunction [22, 23].
Main clinical characteristics of participants included in the study
Type 2 diabetes
Non-type 2 diabetes
Mean difference (95% CI)
44.0 ± 8.7
44.0 ± 7.8
0.0 (−4.0 to 3.9)
49.2 ± 6.6
49.0 ± 5.1
0.1 (−2.8 to 3.2)
Waist circumference (cm)
130.0 ± 10.8
129.6 ± 9.6
0.3 (−4.5 to 5.2)
Fasting glucose (mmol/l)
8.6 ± 2.7
5.6 ± 0.6
2.9 (1.8 to 4.1)
7.5 ± 1.4
5.8 ± 0.4
1.7 (1.1 to 2.2)
8.7 ± 4.7
5.3 ± 3.6
3.4 (1.1 to 5.6)
2.5 ± 0.7
2.6 ± 0.6
−0.1 (−0.6 to 0.3)
1.2 ± 0.2
1.3 ± 0.5
−0.1 (−0.3 to 0.1)
2.0 ± 0.9
1.5 ± 0.4
0.5 (0.1 to 0.9)
Systolic blood pressure (mmHg)
139.4 ± 22.3
3.5 (−6.5 to 13.7)
Diastolic blood pressure (mmHg)
87.5 ± 15.2
−3.7 (−10.1 to 2.5)
Insulin treatment, n (%)
Oral hypoglycaemic agents, n (%)
Microangiopathy, n (%)a
The exclusion criteria included history of smoking habit, chronic respiratory disease, asthma, cardiovascular disease, hearth failure, stroke and chest wall disease. A complete physical examination and chest radiography were performed on all patients included in the study.
Type 2 diabetes was defined according to the criteria recommended by the Expert Committee on the Diagnosis and Classification of Diabetes. On this basis, all type 2 diabetic cases were diagnosed by two fasting plasma glucose values equal or higher than 7.0 mmol/l. Insulin resistance was determined by the HOMA (HOMA-IR) .
Informed written consent was obtained from all participants and the study was approved by the hospital’s human ethics committee.
Measurement of respiratory function data
Forced spirometry and static pulmonary volume measurements were performed using MasterLab apparatus (MasterLab; Jaeger; Würzburg, Germany). All tests were performed following guidelines proposed by the European Respiratory Society . Static pulmonary volumes were measured using the plethysmography method. The theoretical values proposed by Roca et al.  were applied for spirometry, and values proposed by the European Respiratory Society for static volumes . According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), an obstructive ventilatory pattern was established by the presence of an FEV1 <80% of predicted, and FEV1/forced vital capacity (FVC) ratio <70% (GOLD guideline criteria for stage 2) . The definition of a restrictive lung disease was an FVC <80% of predicted, with an FEV1/FVC ratio >70% .
Room air arterial blood gas sampling was performed according to standard guidelines. Briefly, after patients had been sitting for at least 10 min samples were anaerobically drawn into preheparinised syringes following the administration of local anaesthesia in the area of the radial artery. Air bubbles were removed and each sample was taken immediately for analysis using an IL 682 Co-oximeter (Instrumentation Laboratories, Lexington, MA, USA).
Normal distribution of the variables was evaluated using the Kolmogorov–Smirnov test. Data were expressed as the means ± SD. Comparisons between groups were made using the Student’s t test for continuous variables and the χ2 test for categorical variables. The relationship between the continuous variables was examined by the Pearson linear correlation test.
In addition, stepwise multiple linear regression analyses were performed. FEV1 and residual volume (RV) were considered as dependent variables, and the independent variables were: baseline clinical variables that could affect pulmonary function (BMI, waist circumference and age), along with variables associated with lung volumes in univariate analysis (fasting glucose and HbA1c and HOMA-IR). Because a strong correlation between fasting blood glucose and HbA1c was observed, two regression models taking separately into account each one of these variables were performed.
All p values were based on a two-sided test of statistical significance. Significance was accepted at the level of p < 0.05. Statistical analyses were performed using the SSPS statistical package (SPSS, Chicago, IL, USA).
Main pulmonary variables and arterial blood values of the participants included in the study
Type 2 diabetes (n = 25)
Non-type 2 diabetes (n = 50)
Mean difference (95% CI)
Pulmonary function test
88.4 ± 19.7
100.1 ± 12.4
−11.6 (−20.4 to −2.8)
72.5 ± 40.7
97.8 ± 24.4
−25.3 (−45.0 to −5.6)
85.1 ± 17.2
93.3 ± 20.1
−8.2 (−13.1 to 0.5)
FEV1/FVC ratio (%)
81.4 ± 10.1
85.8 ± 5.2
−4.4 (−8.1 to −0.7)
96.9 ± 13.2
94.4 ± 9.4
2.4 (−2.8 to 7.7)
99.8 ± 22.3
80.3 ± 15.2
19.5 (10.8 to 28.3)
Arterial blood samples
80.4 ± 11.0
82.1 ± 8.7
−1.6 (−6.6 to 3.3)
40.2 ± 5.5
38.3 ± 4.0
1.8 (−0.5 to 4.2)
In addition, clinically significant obstructive ventilatory pattern (FEV1 < 80% and FEV1/FVC ratio < 70%) was more frequent in diabetic patients than in non-diabetic patients (12.0% vs 0%; p = 0.012). In this regard a higher proportion of participants with FEV1 <80% (36.0% vs 10.0%; p = 0.007), FEF25–75 <65% (32.0% vs 4.0%; p = 0.001) and FEV1/FVC ratio < 70% (16.0% vs 0%, p = 0.004) were identified among diabetic patients in comparison with non-diabetic patients. However, although the presence of a restrictive lung disease (FVC < 80% and FEV1/FVC ratio > 70%) was higher than the obstructive pattern, no differences between groups were detected. In addition, in diabetic patients a greater RV (99.8 ± 22.4% vs 80.3 ± 15.3% of predicted; mean difference 19.5 [95% CI 10.8–28.3]; p < 0.001) was observed. No significant differences in arterial blood analyses (PaO2 and PaCO2) were observed between groups.
Multiple linear regression analyses showed that both fasting blood glucose and HbA1c were independently related to FEV1 (see Electronic supplementary material [ESM] Table 1) and RV (ESM Table 2). In addition, HOMA-IR was also independently related to RV. Blood glucose levels and HbA1c explained 7.6% and 8.5% of FEV1 variation, respectively. Regarding RV, fasting glucose and HbA1c explained 17.6% and 6.2% of variation, respectively. Finally, HOMA-IR explained 12.0% of RV variation.
In the present study we provide, for the first time, evidence that diabetes is a risk factor for respiratory function impairment in morbidly obese women. The two main abnormalities detected were an obstructive ventilatory pattern and an increase in RV. As in diabetic patients a 10% decrease in FEV1 has been associated with a 12% increase in all-cause mortality , our results have serious implications for patients suffering from obesity and diabetes. Notably, we have found a relationship between the degree of blood glucose control (fasting glucose and HbA1c) and the impairment of pulmonary function tests. In addition, fasting glucose and HbA1c contribute independently to lung volumes in multiple linear regression analysis. This finding strongly suggests that metabolic pathways related to hyperglycaemia are the main factor accounting for this impairment and points to the lung as a new target of long-term diabetic complications.
As expected, a restrictive rather than obstructive pattern was more frequent in obese patients, but no significant differences were observed between diabetic and non-diabetic participants. Autopsy findings and some cross-sectional studies have suggested an association between type 2 diabetes and lung damage [8, 9, 12, 19], but very little is known about the implications of diabetes for pulmonary function in obesity. Among the possible mechanisms involved in our results are: (1) the relation between type 2 diabetes and muscle strength; (2) the impairment in lung elastic properties; (3) defects in pulmonary surfactant; and (4) the presence of a low-grade chronic inflammation state.
Ventilatory function is partially determined by respiratory muscle strength. In this way, structural changes associated with muscle atrophy, augmented lipid deposition and decreased mitochondria as well as muscle fibre transformation have been described in type 2 diabetic patients . In addition, in cross-sectional data collected from 655 men from the Normative Aging Study, skeletal muscle strength (as measured by handgrip dynamometry) was negatively associated with fasting insulin levels after adjustment for potential confounders , thus pointing to insulin resistance as a main factor involved in this impairment. Interestingly, we found a significant negative correlation between HOMA-IR and both FEV1 and RV. Furthermore, alterations in bronchial activity and respiratory muscle may be also related with autonomic and/or phrenic neuropathy .
Regarding the impairment of pulmonary elastic properties, there is little information, and what there is mostly refers to type 1 diabetic patients. Non-enzymatic glycosylation of collagen and elastin, which are essential components of the connective tissue, have been proposed as the main contributors to the impairment of pulmonary elastic properties that occurs in diabetes. In this regard, it has been reported that diabetic patients with severe limited joint mobility presented a significant decrease in FVC and FEV1, thus suggesting that altered respiratory mechanics could be a manifestation of a generalised disturbance in collagen metabolism . In addition, it has been shown that type 1 diabetic patients treated with a standard twice-daily insulin injection regimen for 6 years presented a significant decrease in FVC in comparison with those who achieved near normoglycaemia treated with subcutaneous insulin infusion . Consequently, diabetic microangiopathy has also been linked with altered lung volume, suggesting a relationship between alveolar and systemic microangiopathy . Our findings reinforce the theory that poorly controlled diabetes is associated with an obstructive pattern of pulmonary abnormalities. Therefore, it is possible that type 2 diabetic patients exhale less air from the lungs at a slower rate than non-diabetic individuals and that this is associated with an increase in RV. In addition, these abnormalities could be involved in the propensity of diabetic patients to acquire lung infections.
Defects in the bronchiolar surfactant layer, which is involved in maintaining airway stability and diameter, may be also considered a contributing factor to the impairment of calibre regulation in type 2 diabetes. When the alveolocapillary barrier is damaged, surfactant proteins leak into the bloodstream. A recent population-based random sample has described how increased circulating levels of surfactant protein A, the major surfactant-associated protein, were associated with altered glucose tolerance and insulin resistance . Therefore, surfactant defects in diabetic individuals may also lead to an increase in airway resistance and to a reduction in FEV1, FEF25–75 and FEV1/FVC ratio, as observed in our patients. In addition, as glucagon-like peptide 1 has been shown to play a role in the stimulation of surfactant production , its underlying deficit in type 2 diabetes could also enhance the airway resistance observed in these patients. However, the beneficial effects on pulmonary function using incretin-based therapies remain to be elucidated.
Finally, the presence of low-grade chronic inflammation could also be considered as a contributing factor to pulmonary abnormalities detected in morbidly obese diabetic patients. Similarly to the active implication of proinflammatory adipokines in the development of insulin resistance associated with obesity, a potential interaction between abnormal adipose tissue activity, systemic inflammation and pulmonary function has been suggested . In this regard, data from the Third National Health and Nutrition Examination Survey showed how participants with chronic airflow obstruction had higher circulating levels of leucocytes, C-reactive protein and fibrinogen than those without airflow obstruction . Given that proinflammatory cytokine levels have been reported to be higher in morbidly obese type 2 diabetic individuals compared with those without diabetes , it is possible that this could be a contributing factor to the impairment of respiratory function detected in type 2 diabetes.
There are some potential limitations that should be taken into account in evaluating the results of our study. First, this was a cross-sectional study and, therefore, a causal link between type 2 diabetes and impaired pulmonary function cannot be drawn. However, the lack of differences in arterial blood gas sampling between groups and the significant correlation between lung volume and metabolic variables point to diabetes as the primary event. In this regard, studies aimed at determining whether the normalisation of blood glucose levels could improve functional lung variables are warranted. Second, we have not excluded autonomic neuropathy in diabetic patients, and therefore alterations in bronchial activity and respiratory muscle attributable to its presence cannot be ruled out. Third, recent data suggest that obesity is often associated with asthma . However, although we have not specifically evaluated the presence of bronchial hyperreactivity in our patients, the exclusion of participants with self-reported asthma makes this potential bias very unlikely. Finally, in the present study only a selected population of morbidly obese women was included. Although our results and the possible mechanisms involved in the negative effect of type 2 diabetes on pulmonary function might also be transferable to men and less obese individuals, further studies in these populations are required.
In conclusion, the presence of type 2 diabetes and the degree of glycaemic control are related to respiratory function impairment, at least in morbidly obese women. Therefore, the impact of type 2 diabetes on pulmonary function should be considered by those providing care for obese people. Future studies to define not only the mechanisms involved in the pulmonary dysfunction associated with type 2 diabetes, but also to determine whether blood glucose control could prevent lung injury, are needed.
This study was supported by a grant from the Instituto de Salud Carlos III (Fondo de Investigación Sanitaria, PI060476). CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) and CIBER de Enfermedades Respiratorias (CIBERES) are an initiative of the Instituto Carlos III.
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
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