J Pediatr Endocr Met 2015; 28(1-2): 163–169
María Martín-Frías*, Adelaida Lamas, Emma Lara, Milagros Alonso, Purificación Ros and Raquel Barrio
Pulmonary function in children with type 1 diabetes mellitus Abstract Aim: To assess lung function in children and adolescents with type 1 diabetes mellitus (T1DM). Patients and methods: We conducted a case-control study of 100 patients with T1DM [median age 13 (10.6–14.7), 44% men, 23% prepubertal, and all nonsmokers] and 77 controls. None had evidence of lung disease or any other comorbidity. We performed pulmonary function tests, including spirometry [forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and FEV1/FVC ratio], plethysmography [total lung capacity (TLC), residual volume (RV), RV/TLC ratio, and airway resistance (Raw)], and diffusing capacity of carbon monoxide in the lung (TLCO), alveolar volume (AV), and TLCO/AV ratio. The duration of diabetes, degree of metabolic control, insulin dose, and presence of diabetic complications were registered. The χ2-test and analysis of variance were used to compare categorical and quantitative variables, respectively. Results: The duration of diabetes was 6.2 ± 3.8 years with a median HbA1c of 7.08 ± 0.4%. FEV1/FVC ratio was found to be significantly higher in patients with TIDM than in controls. Patients with diabetes also had a nonsignificant trend towards lower FVC, FEV1, Raw, and TLCO, and higher RV, TLC, and RV/TLC than controls. There were no differences in pulmonary function based on duration of disease or metabolic control. We found differences in pulmonary evaluation when pubertal stage was analyzed. Conclusions: The lung is functionally involved in children with T1DM. Pubertal development stage influences the evaluation of lung function.
*Corresponding author: María Martín-Frías, MD, Pediatric Diabetes and Endocrinology Unit, Hospital Universitario Ramón y Cajal, Carretera Colmenar, Km 9.1, 28034 Madrid, Spain, Phone: +34 913368646, Fax: +34 913368417, E-mail: [email protected] Adelaida Lamas: Pediatric Pneumology Unit, Ramón y Cajal Hospital, Alcalá University, Madrid, Spain Emma Lara, Milagros Alonso, Purificación Ros and Raquel Barrio: Pediatric Diabetes and Endocrinology Unit, Ramón y Cajal Hospital, Alcalá University, Madrid, Spain
Keywords: adolescent; children; pulmonary function; type 1 diabetes mellitus. DOI 10.1515/jpem-2014-0147 Received April 1, 2014; accepted July 14, 2014; previously published online August 7, 2014
Introduction Type 1 diabetes mellitus (T1DM) is one of the most prevalent chronic diseases among children and adolescents (1). In T1DM patients, sustained hyperglycemia determines the development and progression of chronic complications (2). The Diabetes Control and Complications Trial (2) and the Epidemiology of Diabetes Interventions and Complications (3) have demonstrated that adequate glycemic control in T1DM delays the development of chronic complications, highlighting the need for tight glycemic control in these patients, even during childhood. Target tissues of T1DM complications include vessels, which exhibit characteristic microangiopathy (2), and connective tissues, which develop thickened basal membranes and increased extracellular matrix (4). Thus, the lung, with its abundant connective tissue and vascular network, can be a target organ for T1DM complications. Patients also experience chronic systemic inflammation that can contribute to endothelial dysfunction and airway obstruction (5). Furthermore, insulin plays an important role in the lung as it modulates the growth and metabolism of bronchoalveolar epithelium and vascular smooth muscle, inhibits apoptosis, and promotes vasodilation (6). It has been proposed that patients with T1DM could experience pulmonary dysfunction caused by sustained hyperglycemia and nonenzymatic protein glycosylation, with subsequent thickening of the capillary walls and the alveolar basal membrane (7, 8), giving rise to microangiopathy and restrictive lung disease with only slight clinical manifestations. However, pulmonary function in patients with T1DM has not yet been studied in depth, and the few studies on this subject have reported controversial results. The first
Brought to you by | University of California - San Francisco Authenticated Download Date | 2/14/15 2:38 PM
164 Martín-Frías et al.: Pulmonary function in pediatric type 1 DM such studies were performed in an adult population. Schuyler et al. (9) found a decreased total lung capacity (TLC) in patients with T1DM, which was attributed to a loss of lung elastic recoil in the context of chronic hyperglycemia; however, a later study did not confirm these results (10). Asanuma et al. (11) were the first to show decreased forced vital capacity (FVC) and diffusing capacity for CO (DLCO) in T1DM patients, and Schnack et al. (12) reported increased airway resistance (Raw) among these patients; however, these results were not confirmed either in subsequent studies, as in the study by Benbassat et al. (13). Studies investigating pulmonary function in pediatric patients with T1DM have also produced controversial results (Table 1) (14–21). The conflicting results of previous studies could be explained by the methodological differences, the generally small sample sizes, and the heterogeneity of the studied populations with regard to age, race, disease duration, degree of metabolic control, and presence of complications. Some studies have even included patients with smoking history or previous pulmonary conditions (14, 22). Another reason to evaluate pulmonary function in patients with T1DM is that insulin inhalation is being investigated as a potential new method of administration. For inhalation to be considered as an alternative to subcutaneous insulin administration, a patient would have to possess normal lung function and structure to enable adequate drug absorption. Moreover, existing knowledge of lung function in T1DM patients is important to determine whether adverse events can be attributed to the drug or are rather due to lung dysfunction secondary to T1DM. The present study aimed to investigate lung function in children with T1DM. We further assessed whether the degree of metabolic control of diabetes affected the lung function in our pediatric population with T1DM, taking into account the patients’ pubertal stage and duration of diabetes.
Patients and methods We conducted a case-control study of 100 consecutive patients with T1DM seen at our Pediatric Diabetes Clinic at the Ramón y Cajal Hospital, Alcalá University, Madrid, Spain. The included patients were 8–18 years of age and were diagnosed with T1DM based on a positive pancreatic autoimmunity test. Exclusion criteria were history of smoking; chronic respiratory disease; allergies; cardiac, neuromuscular, or connective tissue diseases; obesity; joint movement limitation; or acute respiratory disease in the previous 4 weeks. Control subjects were recruited from general pediatric consultations and included 77 normal individuals within the same age range as the diabetic patients. This study was approved by the ethical committee of our institution, and we obtained informed consent from the children’s parents as well as written assent from mature children who were 12 years of age or older. For each patient, anthropometric data (weight and height) were recorded, and the body mass index (BMI) was calculated as weight (kg)/[height (m)]2. Data were expressed as age- and sexspecific standard deviation (SD) scores according to reference tables and Tanner’s stage of pubertal development. We defined those in Tanner’s stage 1 as prepubescent, those in stages 2–4 as pubescent, and those exceeding stage 5 as postpubertal (23). For diabetic patients, we also recorded their age at diagnosis, duration of disease, insulin dose, and HbA1c level (mean of four to five measurements from the last year) determined by high-performance liquid chromatography (A1C HA-8160 Arkray-2004; Adams, Kyoto, Japan) (normal value: 5.3 ± 0.41%). Chronic diabetes complications, including retinopathy, neuropathy, and nephropathy, were screened via fundoscopy, detailed neurologic examination, and determination of microalbuminuria by turbidimetric immunoassay (Architect ci 16200, Abbott-2008, Chicago, IL, USA) (normal
María Martín-Frías*, Adelaida Lamas, Emma Lara, Milagros Alonso, Purificación Ros and Raquel Barrio
Pulmonary function in children with type 1 diabetes mellitus Abstract Aim: To assess lung function in children and adolescents with type 1 diabetes mellitus (T1DM). Patients and methods: We conducted a case-control study of 100 patients with T1DM [median age 13 (10.6–14.7), 44% men, 23% prepubertal, and all nonsmokers] and 77 controls. None had evidence of lung disease or any other comorbidity. We performed pulmonary function tests, including spirometry [forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and FEV1/FVC ratio], plethysmography [total lung capacity (TLC), residual volume (RV), RV/TLC ratio, and airway resistance (Raw)], and diffusing capacity of carbon monoxide in the lung (TLCO), alveolar volume (AV), and TLCO/AV ratio. The duration of diabetes, degree of metabolic control, insulin dose, and presence of diabetic complications were registered. The χ2-test and analysis of variance were used to compare categorical and quantitative variables, respectively. Results: The duration of diabetes was 6.2 ± 3.8 years with a median HbA1c of 7.08 ± 0.4%. FEV1/FVC ratio was found to be significantly higher in patients with TIDM than in controls. Patients with diabetes also had a nonsignificant trend towards lower FVC, FEV1, Raw, and TLCO, and higher RV, TLC, and RV/TLC than controls. There were no differences in pulmonary function based on duration of disease or metabolic control. We found differences in pulmonary evaluation when pubertal stage was analyzed. Conclusions: The lung is functionally involved in children with T1DM. Pubertal development stage influences the evaluation of lung function.
*Corresponding author: María Martín-Frías, MD, Pediatric Diabetes and Endocrinology Unit, Hospital Universitario Ramón y Cajal, Carretera Colmenar, Km 9.1, 28034 Madrid, Spain, Phone: +34 913368646, Fax: +34 913368417, E-mail: [email protected] Adelaida Lamas: Pediatric Pneumology Unit, Ramón y Cajal Hospital, Alcalá University, Madrid, Spain Emma Lara, Milagros Alonso, Purificación Ros and Raquel Barrio: Pediatric Diabetes and Endocrinology Unit, Ramón y Cajal Hospital, Alcalá University, Madrid, Spain
Keywords: adolescent; children; pulmonary function; type 1 diabetes mellitus. DOI 10.1515/jpem-2014-0147 Received April 1, 2014; accepted July 14, 2014; previously published online August 7, 2014
Introduction Type 1 diabetes mellitus (T1DM) is one of the most prevalent chronic diseases among children and adolescents (1). In T1DM patients, sustained hyperglycemia determines the development and progression of chronic complications (2). The Diabetes Control and Complications Trial (2) and the Epidemiology of Diabetes Interventions and Complications (3) have demonstrated that adequate glycemic control in T1DM delays the development of chronic complications, highlighting the need for tight glycemic control in these patients, even during childhood. Target tissues of T1DM complications include vessels, which exhibit characteristic microangiopathy (2), and connective tissues, which develop thickened basal membranes and increased extracellular matrix (4). Thus, the lung, with its abundant connective tissue and vascular network, can be a target organ for T1DM complications. Patients also experience chronic systemic inflammation that can contribute to endothelial dysfunction and airway obstruction (5). Furthermore, insulin plays an important role in the lung as it modulates the growth and metabolism of bronchoalveolar epithelium and vascular smooth muscle, inhibits apoptosis, and promotes vasodilation (6). It has been proposed that patients with T1DM could experience pulmonary dysfunction caused by sustained hyperglycemia and nonenzymatic protein glycosylation, with subsequent thickening of the capillary walls and the alveolar basal membrane (7, 8), giving rise to microangiopathy and restrictive lung disease with only slight clinical manifestations. However, pulmonary function in patients with T1DM has not yet been studied in depth, and the few studies on this subject have reported controversial results. The first
Brought to you by | University of California - San Francisco Authenticated Download Date | 2/14/15 2:38 PM
164 Martín-Frías et al.: Pulmonary function in pediatric type 1 DM such studies were performed in an adult population. Schuyler et al. (9) found a decreased total lung capacity (TLC) in patients with T1DM, which was attributed to a loss of lung elastic recoil in the context of chronic hyperglycemia; however, a later study did not confirm these results (10). Asanuma et al. (11) were the first to show decreased forced vital capacity (FVC) and diffusing capacity for CO (DLCO) in T1DM patients, and Schnack et al. (12) reported increased airway resistance (Raw) among these patients; however, these results were not confirmed either in subsequent studies, as in the study by Benbassat et al. (13). Studies investigating pulmonary function in pediatric patients with T1DM have also produced controversial results (Table 1) (14–21). The conflicting results of previous studies could be explained by the methodological differences, the generally small sample sizes, and the heterogeneity of the studied populations with regard to age, race, disease duration, degree of metabolic control, and presence of complications. Some studies have even included patients with smoking history or previous pulmonary conditions (14, 22). Another reason to evaluate pulmonary function in patients with T1DM is that insulin inhalation is being investigated as a potential new method of administration. For inhalation to be considered as an alternative to subcutaneous insulin administration, a patient would have to possess normal lung function and structure to enable adequate drug absorption. Moreover, existing knowledge of lung function in T1DM patients is important to determine whether adverse events can be attributed to the drug or are rather due to lung dysfunction secondary to T1DM. The present study aimed to investigate lung function in children with T1DM. We further assessed whether the degree of metabolic control of diabetes affected the lung function in our pediatric population with T1DM, taking into account the patients’ pubertal stage and duration of diabetes.
Patients and methods We conducted a case-control study of 100 consecutive patients with T1DM seen at our Pediatric Diabetes Clinic at the Ramón y Cajal Hospital, Alcalá University, Madrid, Spain. The included patients were 8–18 years of age and were diagnosed with T1DM based on a positive pancreatic autoimmunity test. Exclusion criteria were history of smoking; chronic respiratory disease; allergies; cardiac, neuromuscular, or connective tissue diseases; obesity; joint movement limitation; or acute respiratory disease in the previous 4 weeks. Control subjects were recruited from general pediatric consultations and included 77 normal individuals within the same age range as the diabetic patients. This study was approved by the ethical committee of our institution, and we obtained informed consent from the children’s parents as well as written assent from mature children who were 12 years of age or older. For each patient, anthropometric data (weight and height) were recorded, and the body mass index (BMI) was calculated as weight (kg)/[height (m)]2. Data were expressed as age- and sexspecific standard deviation (SD) scores according to reference tables and Tanner’s stage of pubertal development. We defined those in Tanner’s stage 1 as prepubescent, those in stages 2–4 as pubescent, and those exceeding stage 5 as postpubertal (23). For diabetic patients, we also recorded their age at diagnosis, duration of disease, insulin dose, and HbA1c level (mean of four to five measurements from the last year) determined by high-performance liquid chromatography (A1C HA-8160 Arkray-2004; Adams, Kyoto, Japan) (normal value: 5.3 ± 0.41%). Chronic diabetes complications, including retinopathy, neuropathy, and nephropathy, were screened via fundoscopy, detailed neurologic examination, and determination of microalbuminuria by turbidimetric immunoassay (Architect ci 16200, Abbott-2008, Chicago, IL, USA) (normal
