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Kim, Park, Kyung, An, Lee, Park, Chung, and Jeong: Association of Diabetes Mellitus and Metabolic Syndrome with Idiopathic Pulmonary Fibrosis
Original Article
Tuberculosis and Respiratory Diseases

Tuberculosis and Respiratory Diseases 2009; 67(2): 113-120.

Published online: 31 August 2009

DOI: https://doi.org/10.4046/trd.2009.67.2.113

Association of Diabetes Mellitus and Metabolic Syndrome with Idiopathic Pulmonary Fibrosis

Yu Jin Kim, M.D.1, Jeong-Woong Park, M.D.1, Sun Young Kyung, M.D.1, Chang Hyeok An, M.D.1, Sang Pyo Lee, M.D.1, Hye Yun Park, M.D.2, Man Pyo Chung, M.D.2, Sung Hwan Jeong, M.D.1

1Division of Pulmonology, Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Korea.

2Division of Pulmonology, Department of Internal Medicine, Sungkyunkwan University Samsung Medical Center, College of Medicine, Seoul, Korea.

Address for correspondence: Sung Hwan Jeong, M.D. Division of Pulmonology, Department of Internal Medicine, Gachon University Gil Medical Center, 1198, Guwol 1-dong, Namdong-gu, Incheon 405-760, Korea. Phone: 82-32-460-3200, Fax: 82-32-469-4320, jsw@gilhospital.com

Received 29 May 2009       Accepted 13 July 2009

Copyright©2009. The Korean Academy of Tuberculosis and Respiratory Diseases. All rights reserved.

Abstract

Background

Reactive oxygen species (ROS) by oxidative stress may play an important role in the pathogenesis of various chronic diseases such as diabetes mellitus, obesity, hyperlipidemia, hypertension and malignancy that are linked to metabolic syndrome. Oxidative stress has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). We examined the relationship between IPF and presenting factors associated with metabolic disorders.

Methods

One hundred fourteen patients who met the current consensus of IPF definition were enrolled from March 2000 to April 2006 in Gil Hospital and Samsung Medical Center in Korea. One hundred thirty-four control subjects without pulmonary diseases were selected from subjects who visited Gil hospital for routine medical examinations, including low-dose chest computed tomography from January 2002 to July 2006. Retrospectively, we analyzed the clinical characteristics, the results of blood examinations, and lung function tests from medical records of both groups.

Results

IPF patients and control subjects differed in the prevalence of diabetes mellitus as assessed by univariate analysis. Multivariate analysis demonstrated that diabetes mellitus and obesity were associated with IPF. The adjusted odds ratios for diabetes mellitus were 2.733 (95% confidence interval [CI], 1.282~5.827) and 2.001 (95% [CI], 1.063~3.766) for obesity. The remaining factors tested showed no differences between the patient group and the control.

Conclusion

Diabetes mellitus and obesity may be associated with IPF development.

Keywords: Diabetes mellitus, Idiopathic pulmonary fibrosis, Metabolic syndrome, Oxidative stress

Introduction

Idiopathic pulmonary fibrosis (IPF) is characterized by irreversible, heterogenous inflammation and fibrosis of lung parenchyma. It is an age-related, chronic, and fatal disease. Various epidemiologic studies had reported risk factors of IPF, including wood dust, metal dust, cigarette smoking, gastroesophageal reflux, viruses such as adenovirus, cytomegalovirus, hepatitis C, Epstein-Barr virus (EBV), Herpes virus and some metabolic diseases1-4. Recently, It is widely accepted that oxidative stress, generated by imbalance between oxidants and antioxidants, may be associated with IPF1. Oxidative stress may affect on epithelial layer, growth factors, inflammatory cells, proteases, proteases inhibitors, and the extracellular matrix and initiate to develop end-stage fibrosis of major organs5-7. Other investigators suggested that reactive oxygen species (ROS) by oxidative stress may play an important role in the pathogenesis of various chronic diseases such as diabetes mellitus (DM), obesity, hyperlipidemia, and hypertension that are linked to metabolic syndrome8-10. Recent report suggested the association of DM with IPF4. We performed the present study, using a case-control approach, to determine whether other metabolic disorders may be relevant to development of IPF.

Materials and Methods

1. Study design

IPF patients were admitted to Gachon University Gil Hospital and Sungkyunkwan University Samsung Medical Center from 1 March 2000 to 30 April 2006. IPF was diagnosed by respiratory specialist based on clinical history, clinical examination, high resolution CT (HRCT). Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) and open lung biopsy were performed in all patients to confirm the diagnosis. All patients had progressive dyspnea or exertional dyspnea. They had basal fine crakles on auscultation and predominantly peripheral, subpleural, bibasal fine reticular shadows and/or honeycombing, occasionally with traction bronchiectasis and bronchioloectasis on HRCT. There was no evidence of either a history of occupational dust exposure or coexisting collagen - vascular disease in any of the patients. One hundred thirtyfour control subjects visited to Gachon University Gil Hospital for routine medical examination from 1 January 2000 to 30 July 2006. All control subjects was performed low dose chest computed tomography (CT). There was no evidence of lung disease on clinical history and low dose CT in control subjects. We analyzed medical records of IPF patients and control subjects, retrospectively, including sex, age, past history, smoking history, DM, hypertension, hyperlipidemia, laboratory data, pulmonary function test, body weight, height. If IPF patients had steroid therapy, the levels of factors were affected. Thus, We excluded IPF patients that had received steroid therapy.
The diagnosis of IPF is, corresponding to the international consensus statement of American Thoracic Society and European Respiratory Society 2002, as follows: (1) exclusion of other known causes of interstitial lung disease such as certain drug toxicities, environmental exposures, and connective tissue disease (2) abnormal pulmonary function studies that include evidence of restriction (3) bibasal reticular abnormalities with minimal ground glass opacities on HRCT (4) result of open lung biopsy was IPF, pathologically11.
The diagnosis of DM was established by satisfying one of the following criteria: (1) known DM patient with treatment including hypoglycemic agent, diet, exercise et al. (2) fasting glucose ≥126 mg/dL and/or HbA1C>6.0%12. The hypertension was diagnosed by satisfying one of the following criteria: (1) Known hypertension patients with treatment including antihypertensive agent, diet, exercise et al. (2) Systolic blood pressure ≥140 mmHg, or diastolic blood pressure ≥90 mmHg based on The Seventh Report of the Joint National Committee13. Obesity was considered when body mass index (BMI) was ≥2514. The diagnosis of hyperlipidemia was established by satisfying one of the following criteria: (1) Known hyperlipidemia with treatment with any medication for hyperlipidemia (2) Total cholesterol ≥200 mg/dL and/or triglyceride ≥150 mg/dL and/or LDL cholesterol ≥100 mg/dL based on Adult Treatment Panel III classification15. The definition of smoker was current smoker and non-smoker (cessation of less than1 year). The non-smoker was associated with never smoker and ex-smoker (cessation of over 1 year). The study was approved by the Institutional Research Board of Gachon University Gil Hospital for human study.

2. Statistical analysis

Data were expressed mean±standard deviation. Continuous data were done by the Student t-test and categorical data were compared by the Pearson's chi-square test. Multiple logistic regression analysis was performed to assess the role of several variables as risk factors for the IPF. Differences were considered significant when the p value was less than 0.05. Statistical analyzed were performed by version 13.0 of SPSS for Windows (SPSS, Inc., Chicago, IL, USA).

Results

1. Clinical characteristics, blood tests and pulmonary function tests between two groups

One hundred fourteen patients with IPF and 134 control subjects were enrolled. About 70% of both IPF patients and control subjects were male (69.3% and 70.9%). The mean age of each group was 60.1±7.9 years in IPF patients and 59.8±4.5 years in control subjects. The two groups have no significant difference in other clinical features; smoking history (18.8±25.4 pack-year vs. 19.4±21.2 pack-year), body weight (63.4±13.7 kg vs. 59.5±22.7 kg), height (151.6±42.6 cm vs. 145.7±49.3 cm), BMI (22.9±6.9 kg/m2 vs. 21.9±7.8 kg/m2), systolic blood pressure (119.6±30.9 mmHg vs. 121.9±35.2 mmHg), diastolic blood pressure (74.1±18.3 mmHg vs. 75.2±21.7 mmHg). The level of serum fasting glucose was significantly higher (114.3±61.1 mg/dL) in IPF patients than in control subjects (99.8±34.7 mg/dL). IPF patients have significantly high level of total white blood cell (WBC) (8,060.4±2,948.2/µL vs. 6,277.3±2,488.2/µL), segmented neutrophil (59.8±40.4% vs. 51.0±15.5%), and erythrocyte sediment rate (ESR) (31.6±40.4 mm/h vs. 9.9±11.8 mm/h). Total cholesterol, triglyceride, HDL cholesterol and LDL cholesterol were lower in IPF patients than in control subjects (154.2±76.3 mg/dL vs. 177.8±7.3 mg/dL; 78.9±115.5 mg/dL vs. 135.5±106.7 mg/dL; 20.1±23.0 mg/dL vs. 45.0±21.0 mg/dL; 53.1±62.4 mg/dL vs. 103.2±48.8 mg/dL) respectively. The level of FEV1 (L), FEV1 (%), and FVC (%) in IPF patients was significantly lower than in control subjects (1.9±1.0 L vs. 2.2±1.3 L; 71.4±38.2% vs. 85.7±49.4%; 63.4±34.0% vs. 80.6±45.1%) respectively (Table 1).

2. Association of metabolic disorders with IPF

Univariate analysis was performed to evaluate nonadjusted odds ratio about risk factor between IPF patients and control subjects. Odds ratio (OR) of DM was statistically different between IPF patients and control subjects. OR of DM was 2.199 (95% CI, 1.146~4.217, p=0.016). The prevalence of DM was 25.4% (n=25) for IPF and 13.4% (n=18) for control subjects. The OR of other factors were not significant different; obesity, 1.093; smoking status, 0.661; hypertension, 0.669; hyperlipidemia, 0.663 (Table 2). We analyzed each risk factor by multivariate analysis in which DM and obesity were significantly associated with IPF. The adjusted OR of DM and obesity was 2.733 (95% CI, 1.282~5.827) and 2.001 (95% CI, 1.063~3.766). The adjusted OR of smoking status was 0.694 (95% CI, 0.395~1.219). Hypertension (adjusted OR, 0.675; 95% CI, 0.352~1.294) and hyperlipidemia (adjusted OR, 0.593; 95% CI, 0.326~1.078) were not statistically significant (Table 2).

3. Differences between IPF patients with DM or without DM, and patients with obesity or without obesity

We analyzed IPF patients with DM or without (Table 3). Smoking history, height, triglyceride, HDL, LDL, FEV1 and FEV1/FVC were significantly higher in IPF patients with DM than in IPF without DM. We also evaluated IPF patients with obesity or without obesity (Table 4). Glucose were significantly higher in IPF patients with obesity.

Discussion

We showed that the prevalence of DM in IPF patients was significantly higher than in control subjects (25.4% vs. 13.4%). The level of fasting glucose in IPF patients was also significantly higher than in control subjects (114.3±61.1 mg/dL vs. 99.8±34.7 mg/dL), and the adjusted OR of DM by multivariate analysis was 2.733 (95% CI, 1.282~5.827). These results supported a previous report that the prevalence of DM was higher in patients with IPF than in control subjects4. On the other hand, there was a conflicting report that DM was not associated with IPF3. In that report, investigators had collected data by self-administered questionnaires and defined individuals who were only being in dietary or drug treatment as DM patients. They did not include latent or untreated DM. So they might have underestimated true association3. In this current study, obesity (OR 2.001) is also significantly associated with IPF using multivariate analysis. As the prevalence of obesity is getting increased in general, many investigators have been interested in chronic diseases which might be associated with obesity. Obesity was known to be one of important risk factors in the metabolic syndrome, and associated with an increased risk of DM and heart diseases15,16. There have been conflict reports about relationship between obesity and IPF3,4. One had reported that BMI of IPF patients was higher than in control subject3. On the contrary, the other investigation showed that BMI and obesity, which was defined as BMI of >25, were not related to IPF. They showed the prevalence of obesity was not statistically different between IPF patients and control subjects4. In our study, more patients were analyzed than in study of previous studies4. Accordingly our study might have stronger statistical power than previous studies4. Although definition of obesity in metabolic syndrome has been identified as abdominal obesity17, we used BMI as a parameter for obesity. There are some reports that measurement of BMI as well as waist circumference has been used to identify insulin resistance and cardiovascular risk factors18,19. It is still cautious to analyze obesity-related data due to different definition of obesity. Hyperlipidemia and hypertension were not associated with IPF in this current study like previous studies. Smoking status was not significant related to the risk of IPF, which was inconsistent with previous investigations that smoking history was associated with an increased risk for the development of IPF3,4,20. Pack-years of smoking was not statistically associated with IPF in our study. Baumgartner et al. showed that current smoking and more than 40 pack-years of smoking in IPF patients were not significantly related to a risk of IPF3,20. Similar result was reported in the study of Yoshihiro et al. that there was no association with dose-response of cigarette smoking and IPF statistically3,20. We enrolled control subjects without lung diseases and abnormalities in low-dose CT. Because low-dose CT was performed to detect early lung cancer, most of control subjects had a smoking history so that smoking status was not so different from patients. It might be one reason that pack-years of smoking was not associated with IPF compared to control subjects in our study.
Recent studies have suggested that exogenous, endogenous multiple, microscopic stimuli may injure the alveolar epithelial cells, followed by an abnormal wound healing in the pathogenesis of IPF5-7. On the molecular level, a number of studies have reported that the imbalance of oxidants/antioxidants may play a significant role in the progression of pulmonary fibrosis1,2. The excess formation of reactive oxygen species (ROS) may cause tissue injuries including those involving the lung and leading to pulmonary fibrosis1,2,5-7. Many studies suggested that diabetes was involved by high level of free radicals or oxidant/antioxidant imbalance and oxidative stress may play a major role in the development and progression of DM and its complication8-10,21. Oxidative stress might be produced by advanced glycation end products (AGE) under hyperglycemia9,22. AGEs may inactivate enzymes and alter their structures and functions, promote free radical formation. AGEs may be linked to influence the expression of growth factors, cytokines and transcription factors that are believed in mediating the differentiation of epithelial cells to form myofibroblasts, such as TGF-β1, CTGF and NF-kβ23-26. AGE may activate TGF-β-Smad signaling and influence mesangial cell hypertrophy and fibronectin synthesis22. AGEs can accumulate in alveolar macrophages and bronchial epithelial cells in idiopathic pulmonary fibrosis27.
In the obese patients, adipose cells may play a role in endothelial dysfunction by pro-inflammatory cytokines, such as IL-6, TNF-α. In cultured adipocytes, elevated levels of fatty acids increased oxidative stress via NADPH oxidase activation16.
The lung has developed antioxidant defense mechanism against oxidants1. This defense mechanism may be contributed to protect against pulmonary complication by oxidative stress and show less manifestation than other organs. Many results have reported that oxidative stress induced not only IPF but also DM, including obesity. The present study appears to support previous findings that DM may be associated with increased IPF. Moreover, our result provides an opportunity to raise interest about obesity as a risk factor of IPF. In conclusion, we demonstrate that DM and obesity are associated with IPF. Based on these results, we need to investigate more the relation between metabolic disorders such as DM, and obesity and IPF in perspective of molecular basis.

Figures and Tables

Table 1
Comparison of clinical characteristics, blood tests and pulmonary function tests between patients with IPF and control subjects
trd-67-113-i001

IPF: idiopathic pulmonary fibrosis.

*Total cholesterol, †Triglyceride.

Table 2
Risk factors for IPF in relation to metabolic disorders and smoking
trd-67-113-i002

IPF: idiopathic pulmonary fibrosis.

*Diabetes mellitus, †Adjusted for age, sex.

Table 3
Clinical characteristics, the results of blood and pulmonary function tests in IPF patients with or without diabetes mellitus
trd-67-113-i003

IPF: idiopathic pulmonary fibrosis.

*Total cholesterol, †Triglyceride.

Table 4
Clinical characteristics, the results of blood and pulmonary function tests in IPF patients with or without obesity
trd-67-113-i004

IPF: idiopathic pulmonary fibrosis.

*Total cholesterol, †Triglyceride.

Acknowledgements

I would like to thank the authors in Gachon University Gil Hospital and Sungkyunkwan University Samsung Medical Center for help in recruiting patients and collecting data.

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