Relationship between diabetes and respiratory diseases—Clinical and therapeutic aspects

Accepted Manuscript Title: Relationship between diabetes and respiratory diseases. Clinical and therapeutic aspects Authors: D. Visca, P. Pignatti, A. Spanevello, E. Lucini, E. La Rocca PII: DOI: Reference:

S1043-6618(18)30945-9 https://doi.org/10.1016/j.phrs.2018.10.008 YPHRS 4026

To appear in:

Pharmacological Research

Received date: Revised date: Accepted date:

2-7-2018 28-9-2018 5-10-2018

Please cite this article as: Visca D, Pignatti P, Spanevello A, Lucini E, La Rocca E, Relationship between diabetes and respiratory diseases. Clinical and therapeutic aspects, Pharmacological Research (2018), https://doi.org/10.1016/j.phrs.2018.10.008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Relationship between diabetes and respiratory diseases. Clinical and therapeutic aspects. D.Visca 1, P. Pignatti 2, A. Spanevello 1,3, E. Lucini 1,3, E. La Rocca 4. 1 Division of Pulmonary Rehabilitation, Istituti Clinici Scientifici Maugeri, IRCCS, Italy 2 Allergy and Immunology Unit, Istituti Clinici Scientifici Maugeri, IRCCS, Italy

4 Department of Internal Medicine, Tradate Hospital, Tradate, Italy

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Graphical abstract

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3 Department of Medicine and Surgery, Respiratory Diseases, University of Insubria, Tradate, Varese-Como, Italy

Abstract

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Diabetes is a common metabolic disorder affecting the entire body with high morbidity and mortality worldwide. The major complications related to diabetes are mostly due to the macrovascular and microvascular bed impairment due to metabolic, hemodynamic and inflammatory factors. However, studies over the past decades have added also the lung as a target organ in both type 1 and type 2 diabetes. Diabetes has always been addressed as a major comorbidity conditioning the disease behaviour and the natural history of several respiratory diseases. Increased interest has recently focused on the pathophysiology of the metabolic glycaemic disorder and the respiratory diseases suggesting a similar background shared by the two conditions. The true relationship between pulmonary diseases and diabetes mellitus has not been clarified, this review aims to summarize the link between diabetes and coexisting

respiratory diseases such as asthma, chronic obstructive pulmonary disease, respiratory infections, cystic fibrosis, lung cancer and obstructive sleep apnea from a pathogenetic and therapeutic point of view.

Introduction

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Patients with diabetes mellitus (DM) require ongoing evaluation of diabetes-related complications. A follow up visit should be performed two to three times per year to obtain information regarding management of diabetes and diabetes-related complications, including cardiovascular risk. [1] Morbidity and mortality from diabetes is a consequence of both macrovascular disease (coronary artery disease, cerebrovascular accident) and microvascular disease (retinopathy, nephropathy, and neuropathy). [2] Patients diagnosed with diabetes are at increased risk of asthma, chronic obstructive pulmonary disease (COPD), lung injury and respiratory infections. Furthemore, numerous studies have argued that the same pathophysiological mechanisms that determine the major degenerative complications of diabetic disease may cause pulmonary function deficiency and that patients with obstructive sleep apnea syndrome (OSA) develop various forms of metabolic pathology.

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The aim of this review is to go through the main pulmonary diseases associated with diabetes mellitus, and to evaluate if there is a real similarity between the different etiological causes of degenerative complications due to diabetes mellitus and pulmonary diseases it will also be evaluated the possible effect of new therapies for the treatment of diabetes mellitus in lung diseases.

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Diabetes and Asthma

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Asthma is a chronic inflammatory respiratory disease affecting 1-8% of the population. It is characterized by episodic respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough and by variable expiratory airflow limitation. [3] Obesity is a major comorbid condition among adult asthma patients associated with decreased response to treatment and more frequent asthma exacerbation. Obesity and increased central fat are associated with a higher risk of hypertension, hypercholesterolemia, and diabetes mellitus compared with normal-weight individuals [4] and weight loss is able to improve most of these morbidities. [5] Mechanical effect on the lungs due to central fat distribution, genetic predisposition and systemic pro-inflammatory state may be a link between asthma and obesity, which becomes worse in presence of insulin resistance and diabetes. [6] On the opposite side, several studies suggest that patients with increased body mass index are at higher risk of developing asthma, especially for nonallergic asthma than allergic asthma [7] and patients with diabetes are at high risk of asthma. [8] Epidemiologic studies have indicated that the incidence of type 1 Diabetes has been increasing 3% per year worldwide along with a progressive increase in the prevalence of both type 1Diabetes and asthma in developed countries. A retrospective nationwide population-based cohort study showed a significantly higher incidence of asthma in patients withtype 1 Diabetes than in the general population suggesting that poor glycaemic control might contribute to asthma risk also in childhood. [9] Although the etiological factors explaining the association between these two diseases are currently poorly

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understood, Bjørnvold et al. have noticed a significant correlation between TLR2 rs3804100 T allele and both type 1 diabetes and extrinsic asthma [10] Asthma is a treatable chronic disease and medications are supposed to reduce bronchial inflammation and to provide bronchodilation. However, in poor controlled severe asthma patientstreatment with oral steroids is needed an elevated number of acute exacerbations could lead to impaired glucose intolerance and onset of diabetes. In a retrospective study by Yun et al. asthma status precedes the incidence of diabetes but diseases severity and the influence of body weight were not clear. [11]) However, further studies focusing on methabolic pathways would be useful in order to highlight additional correlation between these two diseases.

Diabetes and COPD

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Chronic obstructive pulmonary disease is defined by fixed airflow limitation associated with abnormal pulmonary and systemic inflammatory response of the lungs to noxious particles. Cardiovascular disease, diabetes, obesity and hypertension are commonly taken into account in clinical practice and treated as comorbidities when associated to COPD. However, all these conditions share common risk factors and pathophysiologic features so that clinicians should take a broad approach to evaluate patients and the term ‘chronic inflammatory syndrome’ should be more appropriate. C-reactive protein (CRP) typically increases in this scenario, suggesting that acute-phase proteins could play a key role in systemic inflammation and lead to simultaneous development of chronic diseases. [12] In a prospective study on women, Rana et al. documented a higher risk of developing type 2 diabetes mellitus (T2DM) in COPD patients than in asthma patients, hypothetically justified by two different inflammatory patterns. [13] Indeed, COPD and diabetes seem to share the same inflammatory condition dominated by neutrophils, macrophages and Th1 cells, whereas in asthma infiltration contains mostly eosinophils and Th2 cells.CRP, IL-6, TNF alfa have been identified as predictors of development of insulin resistance and T2DM in several studies. [14] Over the past decades, it has been speculated that both type 1 diabetes mellitus (T1DM) and T2DM are responsible for the decline in lung function due to collagen and elastin alteration and micrangiopathy damage resulting in thickening of the alveolar wall. In a retrospective longitudinal cohort study by Ehrich et al. it has been documented that patients suffering from diabetes were at higher risk of developing COPD when compared to those without diabetes. These studies are in line with previous literature showing that chronic hyperglicemic status may lead to reduced lung volumes and airflow limitations. [15] Whether there is a common background or a bidirectional interaction between COPD and diabetes it is not completely understood, however the result is a vicious cycle between increased oxidative stress that can exacerbate bronchial inflammation and exacerbation that further increases oxidative stress. Body mass index (BMI) has been shown to be part of the evaluation of COPD and is related to disease progression and severity along with lung function impairment. In addition, COPD patients seem to shift commonly from free mass toward fat mass and low muscle mass. Beijers et al. have recently showed that COPD abdominally obese had glucose and insulin levels lower when compared to those without central obesity. [16] Park et al. have recently focused on the role of physical activity, and found that COPD patients with higher level of activities had lower glucose level in comparison with sedentary COPD patients. [17] Pharmacology therapy for COPD is based on inhaled bronchodilators and inhaled

corticosteroids in selected patients. Whether the use of inhaled corticosteroids leads to higher risk of hyperglycaemia is a mechanism that should be investigated more widely. By contrast, hyperglycaemia and worsening in estabilished diabetes are a major complication of systemic corticorsteroids. [18] So far, the pathogenesis of lung alterations due to diabetes mellitus in COPD subjects is still largely unknown. It may involve multifactorial agents resulting in metabolic disregulation and pro-inflammatory patterns.Additional studies on pathophysiology are needed in this field.

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Diabetes and Lung Injury

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Diabetes implies a chronic hyperglycaemia status that leads to nonenzimatic protein glycosylation responsible for major multi-organ dysfunctions. In addition to atherosclerosis, neuropathy, nephropathy and retinopathy as the most common consequences in diabetic patients, over the last decades also the respiratory system has been addressed as target for diabetes. Most of the studies have focused their attention on the damage of the pulmonary vascular bed and alveolar surface resulting in thickening of the alveolar epithelia, pulmonary capillary basal laminae and pulmonary microangiopathy based on autopsy findings in diabetes patients. [19] Because of the large pulmonary reserve, respiratory dysfunction as described above could remain clinically silent for years, but lung function could mirror systemic microangiopathy and provide useful measures of disease progression. The alveolar-capillary network could be studied through the diffusing capacity of the lung for carbon monoxide (DLCO). [20] It has been noted that patients with diabetes had reduced lung volumes and lung compliance, probably due to increased accumulation of collagen and elastin in connective tissue such as chest wall and lung parenchyma in comparison to controls. [21] By contrast, it has been shown that a low baseline forced vital capacity (FVC) in middle-aged adults without diabetes was independently associated with insulin resistance and predictive of diabetes incidence. [22] Moreover the reduction of DLCO in diabetic subjects has been described as a predictor of pneumonia [23] and heart failure [24] related hospitalization.A study by Dennis et al. documented lower lung function and increased inflammatory markers in patients with inadequate glycaemic control in comparison to patients with adequate control. [25] Despite evidences of lung impairment in diabetic patients, pathogenesis of lung injury is still not completely understood. Zheng et al.have recognized five potential biochemical factors which might contribute to development of pneumologicalcomorbilities of diabetes mellitus. They are oxidative stress, non-enzymatic glycosilation, polyol pathway, NF-kb activity and Protein kinase C (PKC)pathway. They have also suggested that mitochondrial dysfunction might play a role in diabetes related lung impairments, but this aspect has not been sufficiently defined, yet.

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An important cause of tissue damage in diabetic subjects is the increased production of reactive oxygen and nitrogen species promoted by hyperglycaemia. Indeed, it damages several biological structures including DNA. Oxidative stress promotes non-enzymatic protein glycosylation (a process also defined glycation), causing the formation of cross-links and compromising the normal function of macromolecules [26]. Glycation is able to impair the adhesion of endothelial cells to the basal membrane, interfering with the structural configuration of molecules like laminin and type I and type IV collagens. It also modifies the biochemical composition and the physical properties of extracellular matrix, upgrading the production of type III collagen, type V

collagen, type VI collagen, laminin, fibronectin and downgrading both the elongation of polimerical structures and the binding of heparansulfate proteoglycan [27]. The basal lamina in diabetic lung often appears thickened [28]. The advanced glycation end products also activate monocytes and have procoagulant effects. These phenomena may result in pulmonary fibrosis in the long term [27]. Diabetic patients generally recognize an increased activity of poly (ADP-ribose)polymerase (PARP) which determines a reduction of NAD+ reserves. It reduces the cellular ability to control the effects of oxidative damage.

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Chronic hyperglycaemia increasesNF-kB expression in the lungleading to overproduction of cyclooxygenase-2, NO synthase, other pro-inflammatory cytokines and cell adhesion molecules [26]. It is probably associated to intracellular glycation events [27]. Hyperglycaemia increases NADPH activity and PKC levels causing an incremented production of ROS [26].

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Finally, diabetic neuropathy reduces the parasympathetic bronchomotor tone, increases basal airway diameter [29] and impairs the bronchoconstrictory response to irritative stimuli (e.g. methacolin) [30] so that it may be responsible of autonomic ventilation control impairment. These results support a physiopathologic and methabolic correlation between diabetes and COPD.

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Additional studies should further investigate biochemical pathways further in order to provide evidence also for future therapeutic approaches.

Diabetes and Respiratory Infections

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Diabetes is associated with high risk of morbidity and mortality by infectious diseases. It has been seen in vitro that chronic hyperglycaemia could alter innate immune system acting on chemotaxis, phagocytosis and bactericidal activity of neutrophils and macrophages. [31] The glycation of complement proteins and immunoglobulins reduces their biological effectiveness [32]. A prospective study by Benfield et al. documented that hyperglycaemia at baseline was predictive of higher risk of infectious disease hospitalisation also regarding pneumonia. In animal models hyperglycaemia caused inflammation and lung parenchyma and vascular impairment, increasing levels of glucose detected in the airways may lead to increase the growth of the pathogen reducing local immune defence. [33] A prospective study by Jensen et al. observed that also undiagnosed diabetes meatus was prevalent among community-acquired pneumonia with a long term mortality higher in comparison to patients without diabetes mellitus. [34] Although the pathogenic effects of diabetes on the immune system have not been completely studied, these studies highlight the idea that prevention of hyperglycaemia and diabetes should reduce long term incidence of infectious disease. Among lung infection, tuberculosis is the most common associated with diabetes. Globally, 15% of tuberculosis cases are estimated to be attributable to Diabetes Mellitus [35] and it is thought that malfunction of monocytes in patients with diabetes may contribute to the increased susceptibility to tuberculosis and/or a worse prognosis. The predisposition of diabetic patients to lung infections is a consequence of DM induced methabolic disregulation and immunosuppression.

Cystic fibrosis

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Cystic fibrosis (CF) is a genetic disorder that affects lung and differentparenchymatousorgans including the pancreas.Consequently to pancreatic involvement,cystic fibrosis related diabetes mellitus (CFRD)developsearly in children with CF and a continuous increase of CFDR prevalence is observable during the first three decades of life [36]. Since CFRD can induce a rapid involvement of structural lung disease [37] and prediabetic condition may have a potential effect on both nutritional state and lung functionof children, ascreening for CFRD must berecommended annually from the age of 10 years. In order to prevent the decrease of lung function and the nutritional conditions inCFRD patients, subcutaneous insulin therapy bust be startedas soon as possible since, an improvement of weight and lung function can be obtained with an early insulin treatment inpatients. Furthemore, in diabetic CF patientsinsulin therapy can have a positive effect on lung function and infections. Comparing CFRD patients with non CFRD subjects, an improvement of BMI and FVC was observed after three months ofinsulin treatment in CFRD patients, while after two years of treatment no differences were observed in terms of BMI values, forced expiratory volume in 1s (FEV1) and FVC between the two groups. After the beginning of insulin therapy, the percentages of sputum examinations positive for Haemophilusinfluenzae and Streptococcus pneumoniae decreased in the diabetic patients, whereas no differences were observed in terms ofPsedomonas aeruginosa and Staphylococcus aureus. [38]

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As shown by these data, glycomethabolic control in CF patients is very important in order to reduce the damages correlated to this disease.

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Lung Cancer

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Lung cancer is the leading cause of cancer-related deaths worldwide but, despite diagnosis and therapeutic advances, patientssurvival with lung cancer is still unsatisfactory. Among the factors that may influence the prognosisof patients, DMshould be considered. Such as breast, bladder, gastric, prostate, and kidney cancer, epidemiologic studies suggestthat diabetic patients are at a significantly higher risk of cancer incidence or mortality. Even if the correlation between DM and outcome of lung cancer is conflicting and indefinite,recentlyit has been showedthat apre-existing DM might increase the risk of lung cancer, especially among female diabetic patients.

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TGF-β (tumor growth factor-β) expression due to hyperglycaemia is also able to damage fibrotic lung promoting an epithelial-mesenchimal metaplasia. This process might promote the development of high grade malignancy in tumoral cells [39]. On the opposite side glucose restriction is able to partially revert this phenomenon. Moreover a constant hyperglycaemic condition causes cellular proliferation throughthe overexpression of caveolin-1, N-cadherin, SIRT3, SIRT7 and lactate [40]. The levels of insulin-like growth factor 1 and 2 are significantly increased in highly dysplastic tumoral tissues [41]. High glucose level may also increase metastatic risk due to GFAT2 overexpression [39].

Furthemore, in a meta-analysis where 20 studies were included, it was observed an association of DM with the worst prognosis in lung cancer patients, especially in those surgically treated. [42] These results highlight the role played by diabetes and insuline-resistence in influencing solid tumor onset, alongside their prognosis and chemiotherapy response.

Obstructive sleep apnea

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Type 2 diabetes mellitus (T2DM) has shown to be associated with higher incidence of sleep disorders, which may be due to the different typical phatological mechanisms of disease including hypoxia,orto hormonal and glucose/insulin metabolic changes. In particular, shorter sleep duration and erratic sleep behavior itself have been associated with higher incidence of obesity, metabolic syndrome, and T2DM [43] Assessment of sleep quality and sleep disorders must be considered as a part of the comprehensive medical evaluation of patients, considering the close relationship between sleep quality and glycometabolic control in persons with T2DM. Among the numerous metabolic mechanisms associable with bothOSA and T2DMthe development of insulin resistance and the related poor glycometaboliccontrol, play a negative role onmicro- and macrocardiovascular complications. The prevalence of diabetes is closely associated with OSA severity. As reported in the European Sleep Apnea Cohort (ESADA) study [44], in the confrontation of patients without OSA, those with serious OSA have an important increase of T2DM, with a range of prevalence from 6 % to 28 % . In addition, according to the severity of disease, the risk of T2DM as well as the worsening of glucose control,increase compared to patients without OSA. As well known, both poor glycemic control and insulin resistance are associated with debilitating degenerative complications of diabetes, such as retinopathy, nephropathy, neuropathy and macrovascular complications such as coronary artery and cerebrovascular disease. Metabolic syndrome, diabetes mellitus and osas appear to be highly interrelated. It is currently unknown the etiological prevalence of the ipoxical phenomenon or the methabolic disregulation as an initial cause. In these subjects complications might be more severe and pressure control is generally difficult. Their treatment generally needs drug combinations and cpap.

Hypoglicemic therapy and lung disease

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Among the different oral hypoglycemic agents currently on the market, Metformin seems to have the most positive effects on lung disease. In particular, inT2DM patientsaffected by COPD, the use of Metformin may have an important role on inhibition of airway smooth muscle cell proliferation and reduction of pulmonary inflammation.Several studies reported a decrease of Nuclear factor (NF)-kB and different pro-inflammatory cytokines. In both cases the results were associated to glucose/insulin metabolism improvement due to AMP-activated protein kinase (AMPK) activation [45]. In animal models, this medication might decrease allergic eosinophilic airway inflammation, regulating levels of eotaxin and tumor necrosis factor alpha (TNF-a) [46]. A retrospective cohort study by Li et al. documented a clear association between metformin treatment and reduction in asthmarelated hospitalization and asthma exacerbation. [47] However, to better understand pathophysiologic mechanisms and inflammatory pathways and to optimize treatment

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among patients with concurrent asthma and diabetes, further studies are needed in adult and young populations.The association between Metformin and lactic acidosis is a well known problem. Safety of Metformin treatment has been studied in T2DM patients hospitalized for COPD, in hypoxiemic state, respiratory failure or in respiratory acidosis [48]. Despite Metformin therapy, the patients had a lower increase of lactate levels and better survival than patients without metformin treatment. In a retrospective study by Birshwakarma et al. it has been showed that patientsaffected by COPD with DM treated with metformin had fewer emergency room access and hospitalizations related to COPD, in comparison to non-users. [49] It has been shown that metformin increases skeletal muscle function, however its double action on coexisting COPD and DM has not been completely evaluated so far. [50] Finally,the positiveaction of Metformin on autonomic nervous system can induce an improvement of pulmonary function and survival in patients with COPD [51] with a decreasingrisk of respiratory infection and glucose flux through the lung epithelium, [52]. Metformin can play an important rolein diabetic patients with lung cancer with improvement of patients survival. The possible effects of this medicationon cancer, are associated to AMPK activation and inhibition of mTOR with a reduction of translation initiation and inhibition of cancer cell growth [53]. Experimental study showed that Metformin inhibits theneoplastic growth by the action of AMPK and the consequent inhibition of protein synthesis. Furthermore the reduction in gluconeogenesis, the decrease of insulin levels and the inhibition of reactive oxygene species (ROS) can reduce the proliferation of insulin-responsive cancers and the production of somatic cell mutation [54]. Thiazolidinediones (TZDs), medications particularly effective on insulin resistance, seem to have an interesting role onasthma, reducing the incidence of new episodes of disease, preventing its exacerbations and decreasing the use of inhaled and oral steroids [55]. These drugs, agonist of proliferator-activated receptor gamma (PPARg), [56] inhibit the synthesis and release of pro-inflammatory cytokines [57]. Recently, it has been showed an improvement of symptoms, a reduction of asthma exacerbation and oral steroid use, if asthmatic T2DM patients are treated with TZD [58]. In patients treated with inhaled steroids [59], a treatment of asthma with TZDs may hypothetically be useful.Among the new class of glucose-lowering drugs, glucagon-like peptide-1 (GLP-1) agonists seem to have a pleiotropic effect on inflammation and oxidative stress, improving pulmonary function in obstructive pulmonary disease [60]. GLP-1 agonists can have a potential role in the treatment of asthma as well. Results from ex vivo studies using human isolated bronchial rings, showed GLP1-receptor (GLP1-R) expressed in epithelium in airway smooth muscle(ASM) of medium bronchi and a specific action of GLP-1 agonists on bronchial hyperresponsiveness (BHR) [61]. Treatment with GLP-R-1 receptor agonist combined with diet and exercise resulted in significant improvements in OSA and several measures of cardiovascular risk, according to the results of Adam Blackman, GLP-R-1 receptor agonist may be a useful tool in individuals already on continuous positive airway pressure (CPAP)treatment.The trial was limited by its duration, which may not have allowed for maximum weight loss and observation.DPP-4 inhibitor (DPP-4i) may be involved in the pathologic features of asthmatic airway inflammation and cell induced by IL-13, DPP-4i is expressed in stimulated bronchial epithelial cells and in human asthma stimulation of bronchial epithelial cells is induced by IL-13. DPP-4i may be involved in promoting the growth of human bronchial smooth muscle cells (BSMCs) and lung fibroblasts, by enhancing the production of fibronectina. An evaluationwhether DPP-4i treatment may affect asthma control might have an important clinical role,since DPP-4i use

in T2DM management is increasing. At present, as reported by Colice G. et al., no association has been observed between DPP-4i use and asthma control [62]. As shown by these results, hypoglycaemic treatment has a potential positive effect on pulmonary diseases. Further studies are required in order to detect the presence of drug receptors in the lung and to better define the pleiotropic effect of oral hypoglycaemic agents.

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Conclusion

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In order to reduce short and long term complications related to Diabetes mellitus, clinicians need to follow up the patients closely and improve patient self-management of the disease. Diabetes mellitus is a frequent comorbid condition among patients with lung diseases (Fig. 1) with an increased impact on morbidity and mortality of patients. According to different scientific evidences, we can affirm that diabetes and pulmonary disease share a similar pathophysiology background. In addition, it is possible that high glucose blood levels can trigger pulmonary impairment and lead to histopatologic lesions commonly observed in diabetic patients. Indeed, the prevalence of COPD and asthma is higher in diabetic patients and by contrast the prevalence of T2DM is higher in individuals with COPD and asthma. Hyperinsulinemia, hyperglycaemia and chronic pro-inflammatory state can lead to functional pulmonary changes, with an increased risk of developing OSA and lung cancer, especially when associated with overweight/obesity and higher level of insulin resistance. Additional studies are needed to further investigate the role of hypoglycemic drugs on the lung, in order to optimize DM treatment especially in presence of respiratory diseases such as asthma, COPD, OSA, cystic fibrosis and lung cancer.

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Figure 1