Editorial Page 1 of 4 Looking for solutions to lung dysfunction in type 2 diabetes Rafael Simó1,2, Albert Lecube2,3 1 Endocrinology and Nutrition Department, Hospital Universitari Vall d’Hebron, Diabetes and Metabolism Research Unit, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain; 2Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; 3Endocrinology and Nutrition Department, Hospital Universitari Arnau de Vilanova, Obesity, Diabetes and Metabolism Research Group (ODIM), Institut de Recerca Biomèdica de Lleida (IRBLleida), Universitat de Lleida, Lleida, Spain Correspondence to: Rafael Simó, MD, PhD. Endocrinology and Nutrition Department, Hospital Universitari Vall d’Hebron, Diabetes and Metabolism Research Unit, Vall d’Hebron Institut de Recerca, Pg. Vall d’Hebron 119-129. 08024-Barcelona, Spain. Email: rafael.simo@vhir.org. Provenance and Peer Review: This article was commissioned and reviewed by the Academic Editor Dr. Jiewen Jin (Department of Endocrinology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China). Comment on: Kim JM, Kim MK, Joung KH, et al. Association between glycemic state and pulmonary function and effect of walking as a protective factor in subjects with diabetes mellitus. Ann Transl Med 2019;7:530. Submitted Mar 16, 2020. Accepted for publication Mar 30, 2020. doi: 10.21037/atm.2020.03.225 View this article at: http://dx.doi.org/10.21037/atm.2020.03.225 Diabetes-induced pulmonary dysfunction is an emerging and forced vital capacity (FVC) than control subjects, but topic within the “new” complications of diabetes and in also that the impaired pulmonary function also exists in the particular in type 2 diabetes (1). The lungs show a huge prediabetes stage. Overall, data from Kim et al. confirm vascularization and are rich in proteins with an elevated previous information in Caucasian population and reinforce turnover such as elastin and collagen, pointing this organ the notion that lung dysfunction is a progressive defect as a potential target to the harmful effects of chronic across glucose abnormalities, beginning in the prediabetes hyperglycaemia (1). In fact, an inverse association between stage and expanding when type 2 diabetes appears (5). metabolic control and spirometric values has been observed (2). Notably, after adjustment for potential confounding factors In addition, positive changes in spirometric maneuvers after (age, sex, body mass index, waist circumference and smoking of 3-months of improvement in glycemic control has also status) an increase of 1% in the HbA1c level was associated been reported (3). The mechanisms to explain the cluster of with a −1.20% difference in FVC and a −0.77% difference pulmonary dysfunctions associated with type 2 diabetes are in FEV1, with similar results when a 10 mg/dL increase not yet fully understood. However, it has been argued that in fasting plasma glucose was considered. As prevalence of the most suitable explanations could be related with insulin prediabetes and undiagnosed diabetes are both increasing, a resistance, nonenzymatic glycosylation of lung proteins, closer relationship between endocrinologists, pneumologists low-grade chronic inflammation state, microvascular and primary care physicians is needed not only to better damage, autonomic neuropathy and defects in the understand the deleterious effects of type 2 diabetes on bronchiolar surfactant layer (1) (Figure 1). The manuscript of lung parenchyma but to successfully target pulmonary Kim et al. sheds light on this issue, exploring the connection dysfunction (6). between prediabetes, type 2 diabetes and pulmonary The potential advantageous role of physical activity on function in the Korea National Health and Nutrition the respiratory muscles’ strength and function has been Examination Survey (KNHANES) (4). Their data confirm reported in patients with lung diseases (7). Our group not only that patients with type 2 diabetes exhibits lower has also assessed the benefit from heart-healthy lifestyle values of forced expiratory volume in one second (FEV1) behaviors on lung mechanics in a cross-sectional study © Annals of Translational Medicine. All rights reserved. Ann Transl Med 2020;8(8):521 | http://dx.doi.org/10.21037/atm.2020.03.225 Page 2 of 4 Simó and Lecube. Lung and diabetes Insulin resistance Microvascular Increase physical activity Low-grade chronic damage inflammation Improve metabolic control Defects in Decreased muscle Impaired strength surfactant layer pulmonary Give up smoking function Deficit in GLP-1 Autonomic concentrations Raise insulin sensitivity neuropathy Non-enzymatic Leptin Therapy with incretin mimetics glycosylation of resistance lung proteins Therapeutic options TYPE 2 DIABETES Potential ethiopathogenic mechanisms Figure 1 Suggested mechanisms to explain the involvement of pulmonary function and therapeutic options in patients with type 2 diabetes. conducted in 3,020 Spanish middle-aged subjects free of control were peak expiratory flow (PEF) and FEV1, the lung disease (8). In this population, low physical activity former related with neuromuscular integrity. This relation was significant and independently associated with the between muscle strength and pulmonary function also presence of pulmonary impairment assessed by FEV1 reinforce the relevance to prescribe physical activity to <80% only in men (8). Kim et al. go one step further to patients with type to diabetes more vulnerable to develop explore the therapeutic implications of walking exercise in lung involvement. And it is also another reason to insist preventing a decreased pulmonary function in subjects with on patients with diabetes about the need to achieve good diabetes (4). Their results show that walking more than 300 glycemic control and thus prevent the development of late minutes per week has a significant effect avoiding FVC and complications. FEV1 decline. However, this beneficial effect disappeared The glucagon like peptide 1 (GLP-1) receptor is after correction for smoking status, pointing to smoking expressed by alveolar type 2 cells, and its activation have cessation as a fundamental pillar among the strategies aimed been shown to stimulate the production of pulmonary at improving lung function of patients with diabetes. surfactant in experimental studies (9). In fact, serum Other possibilities that can be added to physical activity surfactant protein D (SP-D) has been proposed as a serum to treat or prevent lung dysfunction in patients with type 2 biomarker useful to identify patients with type 2 diabetes diabetes should be considered. The first option to consider with defects in their bronchiolar surfactant layer (10). In this would be the improvement of glycemic control. In this way, way, SP-D serum concentrations were inversely correlated Gutiérrez-Carrasquilla et al. have recently communicated with FEV1 and the stepwise multivariate regression analysis results from a prospective and interventional study to showed that a serum SP-D value equal or higher than determine whether ameliorating metabolic control in 32.3 ng/mL was independently associated with a FEV1 patients with type 2 diabetes without known pulmonary <80% of predicted (10). Therefore, the underlying deficit disease during a three-month period produce significant of GLP-1 in type 2 diabetes could also be involved in changes in respiratory function (3). Therefore, in the the impairment of airway caliber. This hypothesis is now Sweet Breath Study a favorable change in the spirometric been testing in the LIRALUNG study (ClinicalTrials.gov parameters was just observed in the subgroup of participants Identifier: NCT02889510), a randomized double blind, who reached a reduction of their HbA1c higher than 0.5%, crossover, placebo controlled clinical trial to evaluate the and this result was not related with weight reduction (3). effect of liraglutide, a GLP-1 analogue, on lung function in More interesting, the spirometric parameters that appeared patients with type 2 diabetes. On the other hand, worthy of to be most sensitive to this rapid improvement of metabolic additional attention is whether preventing the inactivation © Annals of Translational Medicine. All rights reserved. Ann Transl Med 2020;8(8):521 | http://dx.doi.org/10.21037/atm.2020.03.225 Annals of Translational Medicine, Vol 8, No 8 April 2020 Page 3 of 4 of the endogenous GLP-1 through the pharmacological Open Access Statement: This is an Open Access article inhibition of the dipeptidyl peptidase-4 applies any effect distributed in accordance with the Creative Commons on pulmonary function (1). On a similar level remains the Attribution-NonCommercial-NoDerivs 4.0 International possibility to enhance pulmonary function rising insulin License (CC BY-NC-ND 4.0), which permits the non- sensitivity in patients with type 2 diabetes. Although commercial replication and distribution of the article with there are no prospective studies addressing this option, a the strict proviso that no changes or edits are made and the little retrospective study also in Korean patients showed original work is properly cited (including links to both the how treatment with insulin sensitizers was independently formal publication through the relevant DOI and the license). associated with improvements in FVC compared with See: https://creativecommons.org/licenses/by-nc-nd/4.0/. insulin therapy (11). And similarly, after adjustment for glycemic control and the known duration of type 2 diabetes, References Colombian patients under treatment with metformine 1. Lecube A, Simó R, Pallayova M, et al. Pulmonary showed significantly lower differences from the expected Function and Sleep Breathing: Two New Targets for Type values in FVC measures in comparison with patients 2 Diabetes Care. Endocr Rev 2017;38:550-73. receiving a secretagogue therapy (12). 2. Lecube A, Sampol G, Muñoz X, et al. Type 2 diabetes To sum up, we hope that health professionals who take impairs pulmonary function in morbidly obese women: a care of patients with type 2 diabetes begin to consider case-control study. Diabetologia 2010;53:1210-6. them as a vulnerable group for pulmonary dysfunction. 3. Gutiérrez-Carrasquilla L, Sánchez E, Barbé F, et al. Effect Although clinical relevance of such changes has to date of Glucose Improvement on Spirometric Maneuvers in been little, we cannot forget that a 10% decrease in FEV1 Patients With Type 2 Diabetes: The Sweet Breath Study. is an independent predictor of all-cause mortality in type 2 Diabetes Care 2019;42:617-24. diabetes (13). In this context, and while we find therapeutic 4. Kim JM, Kim MK, Joung KH, et al. Association between targets capable of reversing this situation, investment in a glycemic state and pulmonary function and effect of healthy lifestyle that includes high physical activity, give walking as a protective factor in subjects with diabetes up smoking and selected antidiabetic therapies to improve mellitus. Ann Transl Med 2019;7:530. metabolic control should be recommended to patients with 5. Sánchez E, Gutiérrez-Carrasquilla L, Barbé F, et al. Lung diabetes. function measurements in the prediabetes stage: data from the ILERVAS Project. Acta Diabetol 2019;56:1005-12. Acknowledgments 6. Mirahmadizadeh A, Fathalipour M, Mokhtari AM, et al. The prevalence of undiagnosed type 2 diabetes and Funding: This research was supported by grants from the prediabetes in Eastern Mediterranean region (EMRO): Instituto de Salud Carlos III (Fondo de Investigación A systematic review and meta-analysis. Diabetes Res Clin sanitaria, PI 15/00260 and PI 18/00964) and the European Pract 2020;160:107931. Union (European Regional Development Fund). 7. Salcedo PA, Lindheimer JB, Klein-Adams JC, et al. Effects of Exercise Training on Pulmonary Function in Adults With Chronic Lung Disease: A Meta-Analysis of Footnote Randomized Controlled Trials. Arch Phys Med Rehabil Conflicts of Interest: All authors have completed the ICMJE 2018;99:2561-9.e7. uniform disclosure form (available at http://dx.doi. 8. Gutiérrez-Carrasquilla L, Sánchez E, Hernández M, et org/10.21037/atm.2020.03.225). The authors have no al. Effects of Mediterranean Diet and Physical Activity conflicts of interest to declare. on Pulmonary Function: A Cross-Sectional Analysis in the ILERVAS Project. Nutrients 2019. doi: 10.3390/ Ethical Statement: The authors are accountable for all nu11020329. aspects of the work in ensuring that questions related 9. Romaní-Pérez M, Outeiriño-Iglesias V, Moya CM, et al. to the accuracy or integrity of any part of the work are Activation of the GLP-1 Receptor by Liraglutide Increases appropriately investigated and resolved. ACE2 Expression, Reversing Right Ventricle Hypertrophy, © Annals of Translational Medicine. All rights reserved. Ann Transl Med 2020;8(8):521 | http://dx.doi.org/10.21037/atm.2020.03.225 Page 4 of 4 Simó and Lecube. Lung and diabetes and Improving the Production of SP-A and SP-B in Lung Dis 2010;14:362-7. the Lungs of Type 1 Diabetes Rats. Endocrinology 12. Vargas HA, Rondón M, Dennis R. Pharmacological 2015;156:3559-69. treatment and impairment of pulmonary function in 10. López-Cano C, Lecube A, García-Ramírez M, et al. patients with type 2 diabetes: a cross-sectional study. Serum surfactant protein D as a biomarker for measuring Biomedica 2016;36:276-84. lung involvement in obese patients with type 2 diabetes. J 13. Davis WA, Knuiman M, Kendall P, et al. Glycemic Clin Endocrinol Metab 2017;102:4109-16. exposure is associated with reduced pulmonary function in 11. Kim HJ, Lee JY, Jung HS, et al. The impact of insulin type 2 diabetes: the Fremantle Diabetes Study. Diabetes sensitisers on lung function in patients with chronic Care 2004;27:752-7. obstructive pulmonary disease and diabetes. Int J Tuberc Cite this article as: Simó R, Lecube A. Looking for solutions to lung dysfunction in type 2 diabetes. Ann Transl Med 2020;8(8):521. doi: 10.21037/atm.2020.03.225 © Annals of Translational Medicine. All rights reserved. Ann Transl Med 2020;8(8):521 | http://dx.doi.org/10.21037/atm.2020.03.225