**1. Introduction**

238 Chronic Obstructive Pulmonary Disease – Current Concepts and Practice

[28] Ghanei M, Fathi H, Mohammad MM, et al.Long-term respiratory disorders of claimers with subclinical exposure to chemical warfare agents. *Inhal Toxicol* 2004; 16: 491-5. [29] Ghanei M, Hosseini AR, Arabbaferani Z,ShahKarami E. Evaluation of Chronic Cough in

[30] Hefazi M, Attaran D, Mahmoudi M, Balali-Mood M. Late respiratory complications of mustard gas poisoning in Iranian veterans.*Inhal Toxicol* 2005; 17: 587-92. [31] Ghanei M, Fathi H, Mohammad MM, et al.Long-term respiratory disorders of claimers with subclinical exposure to chemical warfare agents. *Inhal Toxicol* 2004; 16: 491-5. [32] Attaran D, Khajedaloui M, Jafarzadeh R, Mazloomi M. Health related quality of life in

[33] Heidarnejad H, Zendehdel N, Dastgiri S.Temporal trend of clinical and spirometric parameters in mustard gas victims: A ten year study. *Arch Iran Med* 1988; 1: 13-6. [34] Beheshti J, Mark EJ, Hosein Akbaei HM,et al. Mustard Lung Secrets: Long Term

[35] Bagheri M H, Hosseini S K, Mostafavi SH,Alavi SA. High-resolution CT in chronic pulmonary changes after mustard gas exposure.*Acta Radiol* 2003; 44: 241-5. [36] Ghanei M, Mokhtari M, Mohammad MM,Aslani J. Bronchiolitis obliterans following

[37] Emad AF, Rezaian GR, Hosseini K, Ghayyoomi SMA. Chronic pulmonary sequelaeof sulfur mustard gas exposure in man: A report of 36 Cases. *Irn J Med Sci* 1995; 20:1-4. [38] 65 Sohrabpour H, Roshan-Zamir F, Aminorroya AP. Comparison of acute

[39] Ghanei M, Shohrati M, Harandi AA, et al.Inhaled corticosteroids and long-acting beta 2-

[40] Shohrati M, Aslani J, Eshraghi m, et al.Therapeutics effect of N-acetyl cysteine on

2005; 20: 6-10.

2006;9:359–363.

202: 739-44.

*JRadiol* 2004; 52: 164-9.

victims. *Iran J Med Sci* 1996; 21: 34.

sulfur mustard. *Inhal Toxicol* 2007; 19:889-94.

pulmonary function test. *Respir Med* 2008;102: 443-8.

Chemical Chronic Bronchitis Patients.*Environmental Toxicology & Pharmacology*

patients with chemical warfare induced COPD.*Archives of Iranian Medicine*.

Clinicopathological Study Following Mustard Gas Exposure. *Pathol Res Pract* 2006;

exposure to sulfur mustard: chest high resolution computed tomography. *Eur* 

bronchodilatory effects of inhaled Sulbotamol and Combivent in mustard gas

agonists in treatment of patients with chronic bronchiolitis following exposure to

mustard gas exposed patients: Evaluating clinical aspect in patients with impaired

The progressive increase in the average age of the population leads to chronic diseases that are increasingly important. Chronic conditions are large in number, the prevalence of each one is high and so does the annual cost of their care. Moreover, clinicians alert about the impact of one disease on the development and severity of others. Among chronic morbidities the most prevalent are cardiovascular disease (CV), cancer, diabetes *mellitus* (DM) and chronic obstructive pulmonary disease (COPD) (Chillón et al., 2009). Noticeably, a 25% of patients older than 65 years have two chronic conditions and this figure rises to 40% in population over 75 years old (Chatila et al., 2008).

The following text focuses on two of these pathologies: COPD and DM. Our group provided data on COPD pathophysiology, particularly about hypoxia and related oxidative stress, the effect of nutritional status, physical exercise and sleep disorders (Álvarez-Sala R, 2010; García-Río et al., 2009, 2011; Braghiroli & Álvarez-Sala, 2010; Alcolea et al., 2007). In addition, the sleep apnea hypopnea syndrome (SAHS), its association with metabolic syndrome (MS) constituents and the sum of SAHS plus COPD in the so called "overlap syndrome" were studied (Santiago-Recuerda et al., 2007; De Miguel et al., 2002). We made a search in PubMed including articles published during the last ten years about COPD and DM, in order to review how one disease influences the onset, evolution, treatment and prognosis of the other one.

### **2. Chronic obstructive pulmonar disease and diabetes** *mellitus* **definitions, epidemiology and comorbidities**

COPD is defined as a preventable and treatable entity caused by toxic gases, mainly tobacco. Its main feature is poorly reversible obstruction of airflow that is progressive and is associated with a systemic inflammatory response (Álvarez-Sala, 2010). This proinflammatory state may lead to extrapulmonary manifestations (Global initiative for obstructive lung disease [GOLD], 2008) in the majority of patients have a negative effect on the overall prognosis of the disease (Peces Barba et al., 2008). Its prevalence sharply

Chronic Obstructive Pulmonary Disease and Diabetes *Mellitus* 241

among patients with DM. COPD predisposes to pulmonary hypertension, right ventricular dysfunction and arrhythmias. DM is often accompanied by systemic hypertension, left ventricular dysfunction and congestive heart failure. Carotid and peripheral atherosclerosis are also macrovascular complications of DM. Finally, both COPD and DM converge in a

Probably all these comorbidities are influenced by the inflammatory and oxidative stress in these patients after exposure to tobacco (Lavi S et al., 2007). One hundred million people will be affected by tobacco during the XXI century. The tobacco is currently responsible for five million and six hundred thousand deaths each year worldwide. It acts synergistically with other risk factors and may increase cardiovascular mortality by 20, but after leaving

The prognostic significance of hyperglycemia in these patients has been evaluated in several studies, especially during exacerbations. It seems that the poor glycemic control increases hospital stay, the isolation of gram-negative bacteria in sputum, increased pulmonary artery pressure and the risk of death (Archer & Baker, 2009; Gudmundsson et al., 2006; Makarevich et al., 2007; Sicras et al., 2007; Parappil et al., 2010). Moreover, it seems that sustained hyperglycemia may have other effects that worsen the prognosis. The vascular damage should be highlighted in the first place. Microvascular diabetic disease may affect the alveolus-capillary barrier. Pulmonary microvascular involvement may worsen respiratory function in patients with COPD and DM. Pulmonary diffusing capacity in patients with type 1 or type 2 DM is decreased and this decrease may be more pronounced in those with

It is known that early diagnosis and treatment of COPD and its comorbidities, including DM, have prognostic implications. However, the association and interactions between COPD and DM are not completely understood. Under the current evidence, coincidence is more plausible than a causative connection. Whether causality exists or not, the high rate of simultaneity in general population will give ground for concern. We consider that DM affects 1.6 to 16% among subjects with COPD. DM prevalence increases in relation with

Pathogenic links between COPD and DM have been hypothesized in the setting of population-based and clinical observational studies. The Atherosclerosis Risk Assessment in Communities (ARIC) and the Fremantle Diabetes Study (FDS) found a lung vital capacity declining in persons with type 2 diabetes (Yeh et al., 2008; Davis et al., 2004). Lung dysfunction was predominantly restrictive, while COPD is an obstructive disorder. Excessive weight could be an explanation as mean BMI of diabetic patients (30.9 ± 5.7 kg/m2) significantly exceeded BMI of the non diabetic group (27.2 ± 4.8 kg/m2) in the ARIC study. DM patients who subsequently developed COPD also had a higher BMI in data by Ehrlich et al. (Ehrlich et al., 2010). A theoretical risk for COPD in a diabetic environment is based on several mechanisms: glycation of proteins of lung parenchyma and bronchial tree, thickening of basal lamina, increased susceptibility to infections and a modified sarcolema with subsequent skeletal muscle weakness (Weynand et al., 1999; Dalquen, 1999). Nevertheless, hyperglycemia has mostly been associated with a modest restrictive defect due to diabetic microangiopathy that thickens the epithelial and capillary basement membrane. The result is an increased extracellular matrix and connective tissue and an

higher occurrence of coronary events and sudden death (Falk et al., 2008).

tobacco for two or three years, the risk is superimposed to non-smokers.

pulmonary impairment, older age and BMI of 30 kg/m2 (Lavi et al, 2007).

altered alveolar diffusion capacity of the lungs (Popov & Simioescu, 1997).

other microvascular complications.

increases with age and tobacco consumption, and is estimated at around 4-10% globally (Mathers, 2008). Nowadays this disease is considered the fourth leading cause of death and the WHO assessed that in 2020 ranked third in terms of mortality and the fourth in prevalence. In Spain there have been two major studies on the prevalence of COPD. On the one hand we have the IBERPOC study that estimated a 9.1% in patients aged between 40 and 70 years. Most recently EPI-SCAN obtained a 10.2% in subjects between 40 and 80 years (Álvarez-Sala, 2010). In recent years, COPD is considered a disease that goes beyond the lungs involvement. The high morbidity associated with this condition makes some authors (Álvarez- Sala,2010; Sevenoaks et al., 2006; Oudijk et al., 2003) think that pulmonary disease is just an expression of a multisystemic inflamatory disease. The main comorbidities associated with COPD are diabetes, hypertension, ischemic heart disease and heart failure. In addition, other illnesses converge such as malnutrition, osteoporosis, anemia, endocrine disorders, depression or anxiety (Moussas et al., 2008). Most of the comorbidities influence prognosis and length of hospital stay for these patients. One example is low weight, defined as a body mass index *(*BMI) below 18.5 kg/m2, and considered a predictor of poor prognosis in patients with COPD. In particular, loss of muscle compartment is the most affected in the body and its measurement is a better predictor of mortality than total body weight. Another important aspect is osteoporosis, which is present in up to 68% of patients with severe COPD, with a consequent increase in fracture risk. There are several risk factors that may influence the development of osteoporosis in these patients: age, malnutrition, weight loss, smoking, hypogonadism, sedentary lifestyle or the use of glucocorticoids.

In addition, patients with more severe lung disease, have endocrine alterations, the most frequent is exogenous hypercorticism that associated with hyperglycemia, infections and cardiovascular complications (Chillón et al., 2009).

With reference to DM, it is a frequent consequence of corticosteroid therapy in individuals with advanced COPD and those receiving high and continued doses. However, coincidence with primary diabetes predominates in COPD patients, even if we assume there is no linkage between both diseases. There are two types of primary diabetes, type 1 is characterized by absolute insulin deficiency secondary to an autoimmune cause in 90% of cases or idiopathic destruction of pancreatic beta cells. These patients require insulin to survive. Type 2 DM is far more frequent in COPD. The natural history of type 2 begins with insulin resistance with a compensatory hyperinsulinemia that maintains normal glucose tolerance at the outset. Persistent insulin resistance facilitates the final expression of a latent β cell dysfunction thus resulting in hyperglycemia and frank diabetes. Diabetes has become one of the most prevalent health problems in recent years, according to some authors, affect over 366 million people worldwide in 2030 (Wild et al., 2004).

### **3. Links between chronic obstructive pulmonary disease and diabetes**  *mellitus*

At this point, the question arises about the relationship between both disorders. To answer this question, we will refer to the so called cardiovascular risk of COPD. COPD and DM are associated with an enhanced cardiovascular risk profile. COPD patients have a two to threefold cardiovascular related mortality when compared to the general population rates. Cardiovascular disease is the second cause of death among COPD patients and the first one

increases with age and tobacco consumption, and is estimated at around 4-10% globally (Mathers, 2008). Nowadays this disease is considered the fourth leading cause of death and the WHO assessed that in 2020 ranked third in terms of mortality and the fourth in prevalence. In Spain there have been two major studies on the prevalence of COPD. On the one hand we have the IBERPOC study that estimated a 9.1% in patients aged between 40 and 70 years. Most recently EPI-SCAN obtained a 10.2% in subjects between 40 and 80 years (Álvarez-Sala, 2010). In recent years, COPD is considered a disease that goes beyond the lungs involvement. The high morbidity associated with this condition makes some authors (Álvarez- Sala,2010; Sevenoaks et al., 2006; Oudijk et al., 2003) think that pulmonary disease is just an expression of a multisystemic inflamatory disease. The main comorbidities associated with COPD are diabetes, hypertension, ischemic heart disease and heart failure. In addition, other illnesses converge such as malnutrition, osteoporosis, anemia, endocrine disorders, depression or anxiety (Moussas et al., 2008). Most of the comorbidities influence prognosis and length of hospital stay for these patients. One example is low weight, defined as a body mass index *(*BMI) below 18.5 kg/m2, and considered a predictor of poor prognosis in patients with COPD. In particular, loss of muscle compartment is the most affected in the body and its measurement is a better predictor of mortality than total body weight. Another important aspect is osteoporosis, which is present in up to 68% of patients with severe COPD, with a consequent increase in fracture risk. There are several risk factors that may influence the development of osteoporosis in these patients: age, malnutrition, weight loss, smoking, hypogonadism,

In addition, patients with more severe lung disease, have endocrine alterations, the most frequent is exogenous hypercorticism that associated with hyperglycemia, infections and

With reference to DM, it is a frequent consequence of corticosteroid therapy in individuals with advanced COPD and those receiving high and continued doses. However, coincidence with primary diabetes predominates in COPD patients, even if we assume there is no linkage between both diseases. There are two types of primary diabetes, type 1 is characterized by absolute insulin deficiency secondary to an autoimmune cause in 90% of cases or idiopathic destruction of pancreatic beta cells. These patients require insulin to survive. Type 2 DM is far more frequent in COPD. The natural history of type 2 begins with insulin resistance with a compensatory hyperinsulinemia that maintains normal glucose tolerance at the outset. Persistent insulin resistance facilitates the final expression of a latent β cell dysfunction thus resulting in hyperglycemia and frank diabetes. Diabetes has become one of the most prevalent health problems in recent years, according to some authors, affect

**3. Links between chronic obstructive pulmonary disease and diabetes** 

At this point, the question arises about the relationship between both disorders. To answer this question, we will refer to the so called cardiovascular risk of COPD. COPD and DM are associated with an enhanced cardiovascular risk profile. COPD patients have a two to threefold cardiovascular related mortality when compared to the general population rates. Cardiovascular disease is the second cause of death among COPD patients and the first one

sedentary lifestyle or the use of glucocorticoids.

cardiovascular complications (Chillón et al., 2009).

over 366 million people worldwide in 2030 (Wild et al., 2004).

*mellitus*

among patients with DM. COPD predisposes to pulmonary hypertension, right ventricular dysfunction and arrhythmias. DM is often accompanied by systemic hypertension, left ventricular dysfunction and congestive heart failure. Carotid and peripheral atherosclerosis are also macrovascular complications of DM. Finally, both COPD and DM converge in a higher occurrence of coronary events and sudden death (Falk et al., 2008).

Probably all these comorbidities are influenced by the inflammatory and oxidative stress in these patients after exposure to tobacco (Lavi S et al., 2007). One hundred million people will be affected by tobacco during the XXI century. The tobacco is currently responsible for five million and six hundred thousand deaths each year worldwide. It acts synergistically with other risk factors and may increase cardiovascular mortality by 20, but after leaving tobacco for two or three years, the risk is superimposed to non-smokers.

The prognostic significance of hyperglycemia in these patients has been evaluated in several studies, especially during exacerbations. It seems that the poor glycemic control increases hospital stay, the isolation of gram-negative bacteria in sputum, increased pulmonary artery pressure and the risk of death (Archer & Baker, 2009; Gudmundsson et al., 2006; Makarevich et al., 2007; Sicras et al., 2007; Parappil et al., 2010). Moreover, it seems that sustained hyperglycemia may have other effects that worsen the prognosis. The vascular damage should be highlighted in the first place. Microvascular diabetic disease may affect the alveolus-capillary barrier. Pulmonary microvascular involvement may worsen respiratory function in patients with COPD and DM. Pulmonary diffusing capacity in patients with type 1 or type 2 DM is decreased and this decrease may be more pronounced in those with other microvascular complications.

It is known that early diagnosis and treatment of COPD and its comorbidities, including DM, have prognostic implications. However, the association and interactions between COPD and DM are not completely understood. Under the current evidence, coincidence is more plausible than a causative connection. Whether causality exists or not, the high rate of simultaneity in general population will give ground for concern. We consider that DM affects 1.6 to 16% among subjects with COPD. DM prevalence increases in relation with pulmonary impairment, older age and BMI of 30 kg/m2 (Lavi et al, 2007).

Pathogenic links between COPD and DM have been hypothesized in the setting of population-based and clinical observational studies. The Atherosclerosis Risk Assessment in Communities (ARIC) and the Fremantle Diabetes Study (FDS) found a lung vital capacity declining in persons with type 2 diabetes (Yeh et al., 2008; Davis et al., 2004). Lung dysfunction was predominantly restrictive, while COPD is an obstructive disorder. Excessive weight could be an explanation as mean BMI of diabetic patients (30.9 ± 5.7 kg/m2) significantly exceeded BMI of the non diabetic group (27.2 ± 4.8 kg/m2) in the ARIC study. DM patients who subsequently developed COPD also had a higher BMI in data by Ehrlich et al. (Ehrlich et al., 2010). A theoretical risk for COPD in a diabetic environment is based on several mechanisms: glycation of proteins of lung parenchyma and bronchial tree, thickening of basal lamina, increased susceptibility to infections and a modified sarcolema with subsequent skeletal muscle weakness (Weynand et al., 1999; Dalquen, 1999). Nevertheless, hyperglycemia has mostly been associated with a modest restrictive defect due to diabetic microangiopathy that thickens the epithelial and capillary basement membrane. The result is an increased extracellular matrix and connective tissue and an altered alveolar diffusion capacity of the lungs (Popov & Simioescu, 1997).

Chronic Obstructive Pulmonary Disease and Diabetes *Mellitus* 243

(hazard ratio: 1.43 [1.10 to 1.86], adjusted for age, gender, race, fasting glucose, BMI and

A further step would be the association of COPD and SAHS in the same individual or "overlap syndrome". The prevalence of overlap varies depending on SAHS clinical or subclinical definition. The latter identifies individuals with at least 5 hypopneas or apneas per hour during a polysomnography or polygraphy whom diurnal sleepiness does not necessarily occur. The prevalence of SAHS is estimated to be 1-4% in general population. The percentage of overlap is 3-11% among subjects with SAHS and 16-20% among COPD patients (Owens & Malhotra, 2010; Zamarrón et al., 2008). COPD clinics is characterized by cough, sputum production and dyspnea. Most common symptoms of SAHS include loud snoring, excessive daytime sleepiness, personality changes and deterioration of quality of life. Overlap syndrome is characterized by older, more hypoxemic and hypercapnic patients with higher mean pulmonary pressure and similar or less BMI as compared with single SAHS. Thus, the overlap syndrome is a singular entity that may allow a deeper knowledge of the interactions between COPD, SAHS and glycemic-metabolic related disruptions.

**4. Chronic obstructive pulmonary disease and diabetes** *mellitus* **related** 

COPD and DM share relevant features in their genesis and course. Hypoxia, insulin resistance, oxidative stress and inflammation are the basis of a common pathogenesis. Concomitant factors such as tobacco, obesity and sleep disorders merge in endothelial dysfunction and atherosclerosis leading to a high cardiovascular risk of both conditions

Inflammation is a well recognized phenomenon in COPD and DM pathogenesis. In COPD, inflammation and oxidative stress require an energy expenditure that exacerbate the preexisting hypoxia. In a parallel way, inflammatory cytokines exacerbate insulin resistance through diverse mechanisms. Impaired function of the type 1 insulin receptor substrate (IRS-1) is a key, direct mechanism. Thus, there is a chronic, subclinical inflammation at the background of COPD and DM. The question about its significance in patients with simultaneous COPD and DM is then arised. Being not fully clarified, we propose the following sequence of events: common COPD and DM related pathogenesis would start by hypoxia and insulin resistance followed by systemic inflammation, oxidative stress and a

final coexistence of endothelial dysfunction and subsequent cardiovascular events.

Hypoxemia and also hypercapnia, though in a less extent, are a stimulus for the hyperactivation of the sympathetic nervous system. In this setting, the activity of the sympathetic system is sustained in a non-resting anomalous way (Ashley et al., 2010; Heindl et al., 2001; Raupauch et al., 2008). Sustained hypoxia in COPD is an important central sympathetic system drive. A higher and long-lasting muscle sympathetic nerve activity (MSNA) is seen in COPD patients. Its direct consequence is a permanent vasoconstriction of the muscle vessels. Ashley et al. did not only show a sympathetic burst of multiple neurones, but they also graded the intensity of the response. The method used was the measurement of the firing probability and mean firing rates of single muscle vasoconstrictor

weight change) (Reichmuth et al., 2005).

**pathogenesis** 

(Figure 1).

**4.1 Hypoxia** 

Conversely, development of DM once COPD has been diagnosed was also shown by Mannino et al. (Ford & Mannino, 2004; Mannino et al., 2008). Again, more than 60% of patients with COPD and DM were overweight or obese. Stronger evidence of the COPD-DM association comes from the Nurses Health Study (NHS) that involved 97,245 30-55 year old female nurses, 1,342 of whom reported COPD (Rana et al., 2004). The risk of DM among COPD patients was statistically significant (RR 1.8, 95%CI 1.1-2.8) despite the scarce number of incident diabetes cases (n = 19) and after exhaustive adjustment for covariates. It has to be said that a detection bias can not be ruled out in NHS and other cited studies. Besides, among other limitations, data from NHS could only be generalized to median-age Caucasian women. Nevertheless, this study provides the best evidence available due to the homogeneous anthropometry and lifestyle habits of the nurses enrolled including smoking, dietary and exercise, and because of the long-term prospective follow-up.

Beyond diabetes itself, glycemic exposure seems to be relevant. Severity of hyperglycemia was a negative predictor of a reduced lung volume in the FDS. With reference to COPD, a complementary analyses by Ehrlich et al. (Ehrlich et al., 2010) showed the disease was more prevalent among poorly controlled diabetic patients, with an hazard ratio of 1.03 (95%CI 1.01-1.04) per each unit increase in baseline glycated hemoglobin (A1C). To the date, diabetes has not been proven to be a determinant factor for COPD exacerbations, but poor glycemic control is a risk factor of pneumonia related hospitalization in type 1 and type 2 diabetes *mellitus* (Kornum., 2008). Consistent with this findings, in vitro studies under hyperglycemic conditions have shown an abnormal neutrophil function such impaired chemotaxis, phagocytes and bacterial killing (Pozzilli, 1994, as cited in Ehrlich et al., 2010).

We can assume there is a high proportion of undiagnosed glucose intolerance, obstructive and restrictive lung disorders. Thus, one possibility is that untreated diabetes contributes to pulmonary dysfunction and that non diagnosed decreased lung function favors diabetes development in predisposed patients (Davis et al., 2004). Once diabetes is evident, a vital capacity loss was found in the ARIC study. An 8% different FVC in diabetic compared to nondiabetic subjects was found in the Copenhagen City Heart Study (Heindl et al., 2001). The baseline difference was similar in ARIC, but further declining linked to diabetes was not found after 15 years of follow-up. In contrast, more rapid declines of FVC and FEV1 were observed in patients with higher baseline A1C in FDS. Tobacco may contribute to explain these differences. A secondary analysis of diabetic individuals in the Framingham Cohort Study found that the decrease in pulmonary function, with a restrictive pattern, was greater in smokers than in never smokers, inferring that diabetes may increase susceptibility to the adverse pulmonary effects of smoking. A similar interaction was proposed in the NHS (Rana et al., 2004; Walter et al., 2003).

To add complexity, sleep apnea hypopnea syndrome is often added in many of diabetic patients. SAHS is mainly secondary to obesity and is also associated with an increased insulin resistance. There have been several studies linking SAHS and DM. This relationship could be based on a common point such as obesity. In this sense, members of the Wisconsin Sleep Cohort were followed for four years. It was demonstrated that patients with an AHI ≥ 15 had an increased risk of developing diabetes type 2 (odds ratio 2.3 [1.28 to 4 11], adjusted for age, gender and body habitus) (Watz et al., 2009). In the same line, longitudinal followup of the cohort of Affairs Connecticut Healthcare System Veteran concluded an independent association between SAHS and incidence of new cases of diabetes type 2

Conversely, development of DM once COPD has been diagnosed was also shown by Mannino et al. (Ford & Mannino, 2004; Mannino et al., 2008). Again, more than 60% of patients with COPD and DM were overweight or obese. Stronger evidence of the COPD-DM association comes from the Nurses Health Study (NHS) that involved 97,245 30-55 year old female nurses, 1,342 of whom reported COPD (Rana et al., 2004). The risk of DM among COPD patients was statistically significant (RR 1.8, 95%CI 1.1-2.8) despite the scarce number of incident diabetes cases (n = 19) and after exhaustive adjustment for covariates. It has to be said that a detection bias can not be ruled out in NHS and other cited studies. Besides, among other limitations, data from NHS could only be generalized to median-age Caucasian women. Nevertheless, this study provides the best evidence available due to the homogeneous anthropometry and lifestyle habits of the nurses enrolled including smoking,

Beyond diabetes itself, glycemic exposure seems to be relevant. Severity of hyperglycemia was a negative predictor of a reduced lung volume in the FDS. With reference to COPD, a complementary analyses by Ehrlich et al. (Ehrlich et al., 2010) showed the disease was more prevalent among poorly controlled diabetic patients, with an hazard ratio of 1.03 (95%CI 1.01-1.04) per each unit increase in baseline glycated hemoglobin (A1C). To the date, diabetes has not been proven to be a determinant factor for COPD exacerbations, but poor glycemic control is a risk factor of pneumonia related hospitalization in type 1 and type 2 diabetes *mellitus* (Kornum., 2008). Consistent with this findings, in vitro studies under hyperglycemic conditions have shown an abnormal neutrophil function such impaired chemotaxis, phagocytes and bacterial killing (Pozzilli, 1994, as cited in Ehrlich et al., 2010). We can assume there is a high proportion of undiagnosed glucose intolerance, obstructive and restrictive lung disorders. Thus, one possibility is that untreated diabetes contributes to pulmonary dysfunction and that non diagnosed decreased lung function favors diabetes development in predisposed patients (Davis et al., 2004). Once diabetes is evident, a vital capacity loss was found in the ARIC study. An 8% different FVC in diabetic compared to nondiabetic subjects was found in the Copenhagen City Heart Study (Heindl et al., 2001). The baseline difference was similar in ARIC, but further declining linked to diabetes was not found after 15 years of follow-up. In contrast, more rapid declines of FVC and FEV1 were observed in patients with higher baseline A1C in FDS. Tobacco may contribute to explain these differences. A secondary analysis of diabetic individuals in the Framingham Cohort Study found that the decrease in pulmonary function, with a restrictive pattern, was greater in smokers than in never smokers, inferring that diabetes may increase susceptibility to the adverse pulmonary effects of smoking. A similar interaction was proposed in the NHS

To add complexity, sleep apnea hypopnea syndrome is often added in many of diabetic patients. SAHS is mainly secondary to obesity and is also associated with an increased insulin resistance. There have been several studies linking SAHS and DM. This relationship could be based on a common point such as obesity. In this sense, members of the Wisconsin Sleep Cohort were followed for four years. It was demonstrated that patients with an AHI ≥ 15 had an increased risk of developing diabetes type 2 (odds ratio 2.3 [1.28 to 4 11], adjusted for age, gender and body habitus) (Watz et al., 2009). In the same line, longitudinal followup of the cohort of Affairs Connecticut Healthcare System Veteran concluded an independent association between SAHS and incidence of new cases of diabetes type 2

dietary and exercise, and because of the long-term prospective follow-up.

(Rana et al., 2004; Walter et al., 2003).

(hazard ratio: 1.43 [1.10 to 1.86], adjusted for age, gender, race, fasting glucose, BMI and weight change) (Reichmuth et al., 2005).

A further step would be the association of COPD and SAHS in the same individual or "overlap syndrome". The prevalence of overlap varies depending on SAHS clinical or subclinical definition. The latter identifies individuals with at least 5 hypopneas or apneas per hour during a polysomnography or polygraphy whom diurnal sleepiness does not necessarily occur. The prevalence of SAHS is estimated to be 1-4% in general population. The percentage of overlap is 3-11% among subjects with SAHS and 16-20% among COPD patients (Owens & Malhotra, 2010; Zamarrón et al., 2008). COPD clinics is characterized by cough, sputum production and dyspnea. Most common symptoms of SAHS include loud snoring, excessive daytime sleepiness, personality changes and deterioration of quality of life. Overlap syndrome is characterized by older, more hypoxemic and hypercapnic patients with higher mean pulmonary pressure and similar or less BMI as compared with single SAHS. Thus, the overlap syndrome is a singular entity that may allow a deeper knowledge of the interactions between COPD, SAHS and glycemic-metabolic related disruptions.
