Diabetes y Pulmon

Pulmonary function and sleep breathing: two new targets for type 2
diabetes care.
Albert Lecube (Ph.D.), Rafael Simó (Ph.D.), Maria Pallayova (Ph.D.), Naresh M Punjabi
ADVANCE ARTICLE: Endocrine Reviews
(Ph.D.), Carolina López-Cano (M.D.), Cecilia Turino (M.D.), Cristina Hernández (Ph.D.),
Ferran Barbé (Ph.D.)
Endocrine Reviews
Endocrine Society
Submitted: June 26, 2017

Accepted: August 29, 2017
First Online: September 04, 2017
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Endocrine Reviews; Copyright 2017 DOI: 10.1210/er.2017-00173
Type 2 diabetes, pulmonary function and sleep.
Pulmonary function and sleep breathing: two new targets for type 2
diabetes care.
Albert Lecube* (Ph.D.) 1, 2, Rafael Simó* (Ph.D.) 2, 3, Maria Pallayova (Ph.D.) 4, 5, Naresh M
Punjabi (Ph.D.) 6, 7, Carolina López-Cano (M.D.) 1, Cecilia Turino (M.D.) 8, Cristina
Hernández (Ph.D.) 2, 3, Ferran Barbé (Ph.D.) 8, 9
1
Endocrinology and Nutrition Department. Hospital Universitari Arnau de Vilanova, IRB Lleida, Universitat
de Lleida, Lleida, Catalonia, Spain.
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2
Centro de Investigación en Red en Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto
de Salud Carlos III (ISCIII), Madrid, Spain.
3
Endocrinology and Nutrition Department, Hospital Universitari Vall d’Hebron, Diabetes and Metabolism
Research Unit, VHIR, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain.
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4
Department of Medicine, Weill Cornell Medicine in Qatar and New York, USA.
5
Department of Human Physiology and Sleep Laboratory, Pavol Jozef Safarik University Faculty of Medicine,
Kosice, Slovak Republic.
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6
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University,
Baltimore, Maryland, United States of America
7
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Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore,
Maryland, United States of America
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8
Respiratory Department. Hospital Universitari Arnau de Vilanova-Santa María, IRB Lleida, Universitat de
Lleida, Lleida, Catalonia, Spain
9
Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud
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Carlos III (ISCIII), Madrid, Spain.

Received 26 June 2017. Accepted 29 August 2017.
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Abbreviations:
AGE: advanced glycation end products
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ARIC: atherosclerosis risk in communities

AT-II: alveolar type II cells
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BL: basal lamina

BMI: body mass index
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CF: cystic fibrosis

CFRD: cystic fibrosis-related diabetes
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CRP: C-reactive protein

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CT90: cumulative percentage of time spent with oxygen saturations below 90%
DAN: diabetic autonomic neuropathy
DLCO: diffusing capacity for carbon monoxide
DTPA: diethyltriaminepentaaceticacid
ERV: expiratory reserve volume
ESS: Epworth Sleepiness Scale
FEF25-75: maximum midexpiratory flow
FEV1: forced expiratory volume in 1 second
FPG: fasting plasma glucose
1
FVC: forced vital capacity

GLP-1: glucagon like peptide 1
HbA1c: glycated hemoglobin
IGT: impaired glucose tolerance
IR: insulin resistance
MVV: maximum voluntary ventilation
NGT: normal glucose tolerance
PEF: peak expiratory flow
PImax: maximum static inspiratory pressure
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RAGE: receptors for advanced glycation end products
REM: rapid eye movement
RV: residual volume
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SP-D: surfactant protein D
STZ: streptozotocin
TLC: total lung capacity
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TNF: tumor necrosis factor
VC: vital capacity
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Search strategy and selection criteria: References for this review were identified through
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searches of PubMed for articles published from January 1979 to May 2017, by use of the
terms type 2 diabetes, pulmonary function, pulmonary dysfunction, spirometry, sleep apnea
syndrome, sleep breathing disorders, fasting plasma glucose, and glycated hemoglobin.
Selection for inclusion was based on our expertise and our perception of the relevance and
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impact on the field of lung diseases and type 2 diabetes.

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Population based studies showing the negative impact of type 2 diabetes (T2D) on lung
function are overviewed. Among the well-recognized pathophysiological mechanisms, the
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metabolic pathways related to insulin resistance, low-grade chronic inflammation, leptin

resistance, microvascular damage, and autonomic neuropathy are emphasized.
Histopathological changes are exposed, and findings reported from experimental models are
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clearly differentiated from those described in humans. The accelerated decline in pulmonary
function that appears in patients with cystic fibrosis with related abnormalities of glucose
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tolerance and diabetes is considered as an example to further investigate the relationship

between T2D and the lung. Furthermore, a possible causal link between antihyperglycemic
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therapies and pulmonary function is examined.

T2D similarly affect breathing during sleep, becoming an independent risk factor for higher
rates of sleep apnea, leading to nocturnal hypoxemia and daytime sleepiness. Therefore, the
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impact of T2D on sleep breathing and its influence on sleep architecture is analyzed. Finally,
the effect of improving some pathophysiological mechanisms, primarily insulin resistance
and inflammation, as well as the optimization of blood glucose control on sleep breathing is
evaluated.
In summary, the lung should be considered by those providing care for people with diabetes,
and raise the central issue of whether the normalization of glucose levels can improve
pulmonary function and ameliorate sleep-disordered breathing. Therefore, patients with T2D
should be considered a vulnerable group for pulmonary dysfunction. However, further
research aimed at elucidating how to screen for the lung impairment in diabetic population in
a cost-effective manner is needed.
2
Current evidence supporting the link between type 2 diabetes, pulmonary dysfunction, and sleep
disorders is reviewed. We conclude the lung is a new target for the deleterious effects of diabetes.
ESSENTIAL POINTS
1. Type 2 diabetes exerts a deleterious effect on pulmonary function.
2. The reduced lung function is negatively associated with fasting plasma glucose, glycated
hemoglobin, diabetes duration, and its severity.
3. Insulin and leptin resistance, low-grade chronic inflammation, microvascular damage, and
autonomic neuropathy play an essential role in the lung damage associated with type 2
diabetes.
4. The histopathological findings include the thickening of the alveolar epithelia and pulmonary
capillary basal lamina, the reduction of the alveolar space, higher degrees of fibrosis and
microangiopathy, and modifications in mucus secretion.
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5. Type 2 diabetes affect breathing during sleep, is an independent risk factor for higher rates of
sleep apnea, and leads to nocturnal hypoxemia and daytime sleepiness.
6. The role of some therapeutic options such as insulin sensitizers and incretin-based therapies
on lung function deserve further research.
7. Patients with type 2 diabetes are recommended to be considered a vulnerable group for
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pulmonary dysfunction.
I. INTRODUCTION
Type 2 diabetes mellitus (T2D) is a complex disease that affects 12% of the middle-aged
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population (1). Its global prevalence is expanding dramatically, driven by an obesogenic
environment that promotes easier access to high energy-dense food along with sedentary
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behavior, acting on susceptible genotypes. In addition, the increase in the ageing population
is a significant contributing factor.
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T2D is associated with devastating health consequences, affecting both large and small
vessels, and leading to retinopathy and visual loss, nephropathy and impaired kidney
function, and peripheral neuropathy and amputations, as well as life threatening
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macrovascular disease (2). As a consequence, it has become one of the main threats to public
health worldwide. The problem increases when we take into account that up to one half of all
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sufferers are unaware they have the disease, as people can develop T2D without symptoms
(3). However, subjects with undiagnosed T2D share the same risk factors for micro- and
macrovascular disease, and diabetic complications increase over time (4).
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Although the lung has not classically been included in the list of organs that could be
affected by diabetes, its great vascularisation and abundant collagen and elastin fibres make
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the lung parenchyma a potential target for chronic hyperglycemia (5). In fact, there are good
reasons to believe that the same histological and physiologic disturbances that account for
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complications in other organ systems may also affect pulmonary function (6, 7). In this
regard, it should be noted that the increased glycemic exposure is associated with reduced
pulmonary function in T2D, and the 10% decrease in forced expiratory volume in one second
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(FEV1) is an independent predictor of all-cause mortality in this population (8). Basic

research and epidemiological and clinical data also support the notion that T2D has a
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deleterious effect on sleep breathing, becoming an independent risk factor for severe
nocturnal hypoxemia (9).
Although this review mainly focuses on the clinical and epidemiological evidence for an
association between T2D and pulmonary function, the impact of T2D on sleep breathing and
sleep architecture is also updated. In addition, an overview of the underlying
pathophysiological mechanisms involved in this association is given.
II. CLINICAL AND EPIDEMIOLOGICAL EVIDENCE

A. Baseline spirometric values are lower in patients with T2D
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Cross-sectional studies conducted during the last two decades have shown that adults with
T2D have lower forced vital capacity (FVC) and FEV1 values than adults without T2D (6,
10, 11) (Table 1, Figure 1). A majority of the available reports have examined relatively
large cohorts and have taken into account several cofounding factors such as age, gender, the
body mass index (BMI), smoking history and diabetes duration. In one of the earliest
published works, the Cardiovascular Health Study, in which the spirometric reference values
for a healthy population aged 65 to 85 years were determined, it was observed that T2D was
significantly associated with a reduction in FEV1 (10). Three years later, in 1996, Barrett-
Connor et al. noted that in the Rancho Bernardo Study, involving 525 men and 714 women,
aged from 51 to 95 years, the FEV1 and FVC values were independently lower in men with
T2D than in men without diabetes, particularly in those patients with diabetes duration of at
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least 10 years (12). Interestingly, no associations were detected between lung function and
the prevalence of T2D or fasting plasma glucose (FPG) levels in women, probably because of
the small number of women included in the study. Since then, several large epidemiological
studies including the Fremantle Diabetes Study, the Framingham Heart Study, the British
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Women’s Heart and Health Study, the Normative Aging Study, the Copenhagen City Heart
Study, the Atherosclerosis Risk in Communities (ARIC) Study, and the Strong Heart Study
have consistently found an association between T2D and several respiratory parameters such
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as FEV1, FVC and the FEV1/FVC ratio (13-21). In addition, a meta-analysis of 40 studies on
lung function in 3,182 patients with diabetes and 27,080 healthy controls, and a systematic
review of 34 studies both supported the epidemiological evidence that T2D is associated with
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mild, but significant, ventilation abnormalities, more resembling a restrictive pattern (6, 11).
Although most of the empirical data is from North America and Europe, there is
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corroborating evidence that T2D is also associated with impaired lung function in Asians (22-
26). For example, in a cross-sectional study comprising 35,456 Korean over 18 years of age,
individuals with T2D and those with impaired fasting glucose showed an increased odds ratio
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(OR=1.38 [1.23-1.55]) for presenting a restrictive ventilatory pattern, which remained

significant after controlling for smoking, BMI, waist circumference, gender, and age (27).
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Another study conducted in a Japanese population demonstrated that vital capacity (VC) was
independent and negatively associated with the presence of T2D in both genders (22). A
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recent study involving data from 14,455 subjects from the Hispanic and Latin American
community has also revealed that those with T2D had lower mean FEV1 and FVC values,
and also a higher punctuation in a dyspnea index, than those without diabetes, with higher
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impairment when the analysis was performed separately for those with a known lung disease
(28). Finally, when in the same clinical setting the role of different races regarding the
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negative impact of T2D on lung function was compared, Caucasians seemed to show more
global impairment than African-Americans and Hispanics (19).
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Apart from spirometry, there are also data on the association between impaired diffusing
capacity for carbon monoxide (DLCO) corrected for alveolar volume and T2D (11, 19, 29).
Despite a small study sample, Chance et al. reported that DLCO at rest was similar between
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control subjects, non-obese subjects with T2D, and obese patients with T2D (29). With
exercise, however, patients with T2D had a 10-25% reduction in DLCO compared to those
without diabetes. While the decrease in DLCO with exercise remained even after several
covariates had been taken into consideration, the significant differences persisted only in
obese subjects with diabetes. These data suggest that alterations in the lung parenchyma of
obese individuals with diabetes may impair alveolar-capillary recruitment during exercise due
to connective tissue deposition (29). Reduced lung diffusing capacity in the lungs of subjects
with T2D could also result from the observed aberrations in lung parenchyma. The decrease
in the microvascular surface area and the increase in perfusion heterogeneity appear to be
correlated with disease duration and the presence of diabetes-related extra-pulmonary
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complications (25, 30). For example, the reduction in DLCO in patients with T2D has been
found to be more common in those with signs of diabetic microangiopathy, as indicated by a
significant positive correlation with the 24-hour protein excretion rate (31).
Other spirometric measures that have been described as being reduced in patients with
T2D include peak expiratory flow (PEF), maximum voluntary ventilation (MVV), total lung
capacity (TLC), and maximum expired pressure (13, 22-26).
B. The association between metabolic data and spirometric values
The reduced lung function in patients with T2D is associated with an increase of fasting
plasma glucose, glycated hemoglobin (HbA1c), diabetes duration and its severity (11, 13, 14,
17, 24, 26). In the ARIC study, a graded inverse association was observed between FVC and
FEV1 and fasting glucose, and diabetes severity (stratified by duration of diabetes and the
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types of anti-diabetes medications used) (17). Data from the Fremantle Diabetes Study
showed that T2D duration, more than glycemic control, was associated with reduced
pulmonary function, mainly FEV1 and PEF (13). On the other hand, data from the Hispanic
Community Health Study/Study of Latinos has shown that the presence of macroalbuminuria
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in patients with T2D is related to a 10% lower FVC, and a 6% lower FEV1 than those with
normoalbuminuria (28).
The inverse relation between metabolic data and spirometric values has also been
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described in non-diabetic subjects. In the Rancho Bernardo Study, higher FPG values were
correlated with lower FEV1 and FVC in men without diabetes, suggesting that the negative
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effect of glycemia on pulmonary function might precede the diagnosis of diabetes (12). Also
among the 11,479 participants not known to have T2D assessed in the cross-sectional
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Copenhagen City Heart Study, there was a significant association between elevated plasma
glucose and a reduction in lung function (21). In the Normative Aging Study, in which only
male subjects were included, those who developed T2D had lower FEV1 and FVC than non-
diabetic subjects (16). In addition, differences in lung function between groups were observed
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both prior to the diagnosis of diabetes and at the moment when the diagnostic criteria for
diabetes were met, even after adjustment for age, height, weight, and smoking status (16). In
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a Japanese population, a lower VC was independently associated with FPG in men, but the
relationship was not conclusive in women (22).
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C. Is the decline in spirometric values accelerated in subjects with T2D?

While an independent association exists between impaired lung function and T2D, inferences
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regarding causal effects cannot be made due to the cross-sectional nature of some of the
available studies. Although longitudinal studies are available, data on causal effects are
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equivocal with a comparable number of positive and negative studies on the differences in the
longitudinal change in FEV1 and FVC between those with and without T2D.
The ARIC Study and the Fremantle Diabetes Study revealed a greater decline in FVC in
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subjects with T2D than in the control population, after 3 and 7-years follow-up, respectively
(8, 13, 17). In the prospective ARIC study conducted on a T2D population (n=1,100) with
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three years of follow-up, a significant decrease in FVC in diabetic patients was observed
compared to the control group of 10,162 healthy middle-aged subjects (64 vs. 58 ml/year;
p=0.01) (13). In addition, T2D severity, as indicated by the use of anti-diabetes medications,
showed faster and graded relationship with absolute FVC and FVC decline (17). In the
Fremantle Diabetes Study a forced spirometry was performed in a group of 125 Australian
non-smoking patients with T2D at the beginning of the study (8). After seven years of
observation, a significant annual FEV1 decline of 71 ml was revealed in comparison to a
decline of 25-30 ml in the healthy, non-smoking controls. More importantly, the study
revealed a significant positive correlation between FVC decline and a higher baseline HbA1c:
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for every 1% increase in the HbA1c level, a FVC decline of 4% predicted value was observed
(8).
By contrast, when lung function was longitudinally analyzed in the 200 Danish patients
with T2D included in the Copenhagen City Heart Study over a 5-year period, the decline of
FVC and FEV1 was similar to that observed in their non-diabetic counterparts (32). Similar
results were reported by the same group when 266 diabetic patients were followed over a 15
year period. These findings suggest that the reduced pulmonary function described in patients
with T2D seems not to be progressive in the long term (20). However, it should be noted that
the 266 recruited patients with diabetes were the sum of 48 insulin-dependent and 218 non-
insulin dependent diabetes mellitus subjects, and that the definition of diabetes was self-
reported or based on a single measurement of non-fasting blood glucose ≥200 mg/dl (20).
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Differing results were also observed when lung function was evaluated in healthy subjects
according to whether they developed T2D during the follow-up period. In the longitudinal
analysis of 9,051 subjects participating in the Copenhagen City Heart Study, after adjusting
for confounders, the 126 participants newly diagnosed with T2D lost 29 ml of FVC and 25
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ml of FEV1 annually over a 5-year observation period, almost twice as much as control
subjects (32). By contrast, in the Normative Aging Study there were no differences in the rates
of FEV1 or FVC change over time between men who developed diabetes and non-diabetic
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subjects (16).
Collectively, the cross-sectional and longitudinal data indicate that, although patients with
T2D may have lower FEV1, FVC, and DLCO values than non-diabetic subjects, the causal
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relationship between T2D and lung function is not well defined. Nonetheless, although the
loss in lung function in patients with T2D is of moderate magnitude and even subclinical, it
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may be of clinical significance, particularly given the high prevalence of comorbid associated
conditions such as cardiac and renal failure in T2D.
D. What comes first, lung dysfunction or T2D?
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The vast majority of studies that have evaluated this question have considered how often the
spirometric parameters are capable of identifying healthy subjects who will develop T2D. In
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the Fremantle Diabetes Study, the decline in lung function began approximately 3 years
before the diagnosis of T2D (13). Previously, in the Copenhagen City Heart Study, an
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association between the newly diagnosed diabetes and impaired pulmonary function was also
observed (32). Likewise, in a Swedish cohort, Engstrom et al reported that low FVC and
FEV1 predicted incident diabetes independent of adiposity (33, 34). Also, data from the
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National Health and Nutrition Examination reported that FVC and FEV1, together with the
presence of a restrictive ventilatory pattern, were significantly and inversely associated with
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the incidence of diabetes in the United States (35). More recently, in the Strong Heart Study
of Native Americans, an impaired lung function was detected before the development of
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metabolic syndrome or T2D (18). In this regard, the risk of incident T2D increased by 2% for
every 1% decrease in predicted FVC% during the 4-year follow-up (18).
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Overall, these findings suggest that the etiopathogenic mechanisms that precede the
development of T2D, such as insulin resistance and low-grade chronic inflammation, also
play an essential role in the lung damage and respiratory abnormalities associated with T2D.
III. PATHOPHYSIOLOGICAL MECHANISMS UNDERLYING PULMONARY

DYSFUNCTION IN T2D
The association between pulmonary dysfunction and T2D has been increasingly documented.
However, the underlying causes of its initiation and aggravation have not been fully
elucidated. Few pathophysiological mechanisms have been well documented to participate in
the development of the “diabetic lung”, but the potential impact of other suggested
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underlying mechanisms on the lung function still requires further evidence before being
formally recognized (Figure 1). Although described separately, each explains a part of the
whole picture, and many of them act simultaneously in patients with T2D (Figure 2).
A. Well-recognized pathogenic mechanisms
Insulin resistance
Insulin resistance (IR) is one of the main pathophysiological mechanisms leading to T2D, and
its role in initiating lung abnormalities merits attention (36). The relationship between
ventilatory function and indirect measures of IR was first assessed with cross-sectional data
from 922 non-diabetic male participants in the Normative Aging Study (37). Males in the
highest tertile of fasting insulin levels showed a significant decrease in their mean unadjusted
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FVC of 220 mL in comparison with males in the lowest tertile. After adjusting for potential
confounders including age, height, the BMI, the waist to hip circumference ratio, physical
activity, alcohol intake and smoking in separate multiple linear regression models, fasting
insulin and the fasting insulin resistance index were negatively associated not only with FVC
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but also with FEV1. In this study, the extent to which variation in fasting insulin levels was
associated with variability in FVC was comparable in magnitude to the effect of lifetime
cigarette smoking (37).
Similar results were extended to women when the baseline data from 3,185 non-diabetic
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women between 60 and 79 years of age participating in the British Women’s Heart and
Health Study showed a linear inverse association of IR with lung function measurements
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such as FEV1 and FVC (16). With full adjustment for all potential confounding factors, for
every standard deviation increase in log FEV1 and log FVC, the homeostatic model
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assessment of IR (HOMA-IR) score decreased by 3% and 5%, respectively (16). The authors
suggested that the association was, at least in part, explained by early life factors which
affected lung growth and programmed IR. In a study of 75 non-diabetic morbidly obese
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women, IR was also recognized as an independent determinant of pulmonary dysfunction

(38). In this regard, patients with HOMA-IR ≥3.8 showed altered lower airway resistance,
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with lower values of FEV1 and maximum midexpiratory flow (FEF25–75) in comparison
with women with lower IR. In addition, IR contributed independently to FEV1, FEF25–75,
and FVC variance among all subjects (38). In another study, 171 non-smoker subjects (83.5%
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females) without lung disease were divided according to HOMA-IR ≥2.5. A logistic
regression analysis revealed an increase in the likelihood of having IR of 0.86 times with
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every 1-point decrease in the percent FEV1/FVC ratio for predicted values (39).
More recently, among a total of 168 Hispanic and African-American adolescents, aged 13
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to 18 years, those with HOMA-IR in the top quartile had a lower percent FEV1/FVC ratio in
addition to a lower residual volume (RV), RV/TLC ratio, expiratory reserve volume (ERV),
and FRC (40). After adjusting for general and truncal adiposity, HOMA-IR remained a
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significant predictor of ERV and the FEV1/FVC ratio in multivariate analysis.

Mechanisms linking pulmonary function impairment in insulin-resistant populations
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remain to be elucidated. One of the advocated mechanisms is a reduction in mitochondrial

fitness in the skeletal muscle, provoking an impairment of muscle strength (41, 42). In this
regard, in the Normative Aging Study of 655 men, the handgrip dynamometry, a measurement
of skeletal muscle strength, was negatively associated with fasting insulin levels after
adjustment for potential confounders (43).
The systemic inflammation mediated by IR may also be a contributing factor. In this way,
when the relationship between pulmonary function and systemic inflammation was assessed
among Hispanic and African American obese adolescents with asthma, Rastogi et al showed
that Th-cell response was associated with IR (44). In addition, when data from 9,581
nonsmoking Korean male subjects without a history of malignancy, asthma, chronic lung
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disease, pulmonary tuberculosis, liver disease, or severe cardiovascular disease were divided
into quartiles based on FVC or FEV1 (% predicted), HOMA-IR significantly increased as the
FVC or FEV1 (% predicted) decreased, whereas the individuals in the lowest FVC or
FEV1 quartile had the highest high sensitive C-reactive protein (CRP) level (45). Stepwise
multiple logistic regression analyses showed that higher high sensitive CRP and HOMA-IR,
together with abdominal obesity, were independent predictors of the lowest FVC and
FEV1 (% predicted) quartiles.
The relationship between IR and inflammation also offers a biological explanation for its
link with incident asthma-like symptoms among adults (39, 46-48). The consequences of
hyperinsulinemia include the ability to increase the proliferation of primary human airway
smooth muscle cells, and also its hyperresponsiveness and contractility upon insulin exposure
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(49, 50). Additionally, the administration of intranasal insulin in mice increased collagen
deposition in the lungs, and positively regulated the activation of β-catenin, a positive
regulator of epithelial-mesenchymal transition and fibrosis, through the mediation of
PI3K/Akt (49). In a prospective study with a total of 4,516 subjects from the general
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population in Denmark who participated in a health examination between 1999 and 2001,
baseline IR was associated with an increased risk of developing wheezing and asthma-like
symptoms after a 5-year follow-up period (46). This effect was independent of gender and
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stronger than that of obesity. Similarly, in a representative sample of adolescents from United
States with and without asthma in the 2007-2010 National Health and Nutrition Examination
Survey, IR was negatively associated with FEV1 and FVC (48). However, this finding was
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significant only in overweight or obese adolescents, and was more pronounced for
FEV1 among adolescents with asthma. For example, an increment in HOMA-IR from the
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25th percentile to the 75th percentile was associated with ~90 mL lower FEV1 and ~100 mL
lower FVC. Similarly, in a retrospective study performed with 1,058 Korean subjects who
visited for a routine health check-up, HOMA-IR showed a significant correlation with FEV1
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in men, and in binary logistic regression analysis HOMA-IR was independently associated
with airway hyperresponsiveness in both genders (51).
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A final explanation accounting for the deleterious effects of IR on lung function may be
related to insulin receptors that have been isolated in type II alveolar epithelial cells (52, 53).
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These receptors play an important role by mediating the cellular uptake of glucose, which is a
major substrate for the biosynthesis of surfactant phospholipids (54). Recently, in a
population-based random sample, Fernández-Real et al. described how increased circulating
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levels of surfactant protein A, the major surfactant-associated protein, were associated with
altered glucose tolerance and IR (55). Therefore, surfactant defects in insulin resistant
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subjects may also lead to an increase in airway resistance. Altogether, the metabolic
pathways related to insulin resistance could be crucial in initiating lung abnormalities in
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patients with T2D, and points to the lung as a new component of the metabolic syndrome.
Leptin resistance and leptin induced inflammation
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Leptin is a pro-inflammatory cytokine, derived from adipose tissue, that mediates the balance
between food intake and energy expenditure (56). However, leptin is also involved in fetal
lung development, protects type II alveolar epithelial cells from hypoxia-induced apoptosis,
and increases surfactant protein B in animal models (57, 58). In human lung, leptin is
produced in bronchial epithelial cells and alveolar macrophages (59), and fully functional
receptors for leptin have been identified in bronchial and alveolar epithelial cells and in
bronchial smooth muscle cells (60, 61). Therefore, leptin may play a role in the regulation of
airway diameter and the pathogenesis of respiratory diseases (57, 58). In addition, leptin also
leads to bronchodilation by signaling through its receptor in the brain cholinergic neurons,
which decreases parasympathetic tone in smooth muscle cells (62).
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The presumed negative effect of leptin on airways caliber is mediated through two
different ways: (i) its inflammatory role inducing focal epithelial injury, small airway
disappearance and centrilobular emphysema, and (ii) the development of leptin-resistance,
leading to increased parasympathetic tone, which in turn causes bronchoconstriction (63).
Leptin resistance has also been related to an imbalance between alpha-1 antitrypsin and the
neutrophil elastase (NE) activity, resulting in an overactivity of NE that may degrade lung
tissue proteins, thus leading to pulmonary disorders (64). Both conditions, inflammation and
leptin resistance, are common disturbances in patients with T2D (63).
In cross-sectional studies, serum leptin was related to impaired lung function. Data from a
representative sample of 2,808 non-obese subjects participating in the Third National Health,
Nutrition, and Examination Survey showed that, independently of other risk factors,
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circulating leptin levels were inversely related to FEV1 (65). Additionally, there was a
significant association between serum leptin and inflammatory markers such as CRP,
leucocytes, and fibrinogen (65). Similarly, in 4,679 African-American men and women in the
Jackson Heart Study, serum leptin was strongly inversely and independently associated with
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FEV1 and FVC (% predicted) values, especially in men and obese women (66). Moreover, in
a group of 138 healthy 8-year-old children, an association between higher leptin
concentrations and lower lung function, FEV1, and FVC was shown, independent of
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adiposity (67). Finally, in a nested case-control study of rescue workers during the terrorist
attacks on September 11, 2001 in New York City, elevated leptin was associated with more
than two-fold increased chances of abnormal FEV1 after adjustment for BMI (68).
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More related with leptin-resistance, a significant negative correlation between leptin and
FEV1 and MVV was observed in a small group of obese children and adolescents,
A
reinforcing the idea that leptin status is a key factor in developing a restrictive lung pattern
(69). It is worth mentioning that in a subset of 1,955 subjects aged 16-77 years from the
Global Asthma and Allergy Network of Excellence clinical follow-up survey, serum leptin
E
was positively associated with the severity of asthma, especially in females (70). On the other
hand, the magnitude of the reduction in leptin levels was a predictor of improvements in
C
FVC, FEV1, and PEF after 1 year of interdisciplinary intervention to achieve weight loss in
84 postpuberal obese adolescents (71).
N
Nevertheless, to the best of our knowledge there are no studies assessing serum leptin
concentrations and pulmonary function in subjects with T2D that could unequivocally
confirm this association.
A
Low-grade chronic inflammation state

Low-grade chronic inflammation is inherent in T2D pathophysiology (72). Therefore,
V
persistent inadequate glucose control over time may alter the regulation of inflammatory
pathways that are involved in the impairment of pulmonary function (72-74). In this regard,
D
the relevance of tumour necrosis factor (TNF)-α in the inflammatory processes of the lung
has been demonstrated in a mouse model of acute lung inflammation (75). In this model,
A
pharmacologic (etanercept) and genetic TNF-α inhibition (TNF-α R1KO) significantly

reduced inflammatory cell infiltration, proapoptotic pathway activation and tight junction
abnormalities in the lung (76). In humans, the administration of etanercept in patients with
refractory asthma significantly improved their respiratory function and, in particular, post-
bronchodilator FEV1 when compared with placebo (77). Moreover, in obese non-smoking
women without prior respiratory disease, the soluble TNF-α receptor 1 (TNF-R1) contributed
independently to FEV1 and FVC impairments (78). It should be noted that TNF-R1 is mainly
expressed on epithelial lung cells whereas TNF-R2 is primarily found on the surface of cells
of myeloid origin (79).
Cross-sectional studies also indicate that systemic inflammation may be linked to
early perturbations of pulmonary function. Among 1,131 subjects without known pulmonary
9
disease there was a strong inverse association between CRP levels and quartiles of FEV1 that
remained significantly high after adjustment for age, sex, components of metabolic
syndrome, and fitness level (80). More recently, the British Regional Heart Study of 4,434
subjects aged 40-59 years and with no history of cardiovascular disease or diabetes
demonstrated significant inverse associations of baseline FVC, FEV1, and the FEV1/FVC
ratio with blood glucose levels and markers of inflammation (CRP, IL-6, and leukocyte
count), even after adjustment for a wide range of variables including age, BMI, and smoking
status (82). Finally, among a total of 495 subjects with T2D from Colombia, those with
HbA1c>7% (n=352) had significantly lower residual values (observed minus predicted) for
FVC and FEV1 in comparison with patients with adequate metabolic control (82). These
differences were not explained by the usual determinants of lung function such as age, height,
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gender, cigarette smoking or other lifetime exposures. More interestingly, there was a trend
towards lower lung function, especially for FVC, and increased levels of inflammatory
mediators, specially CRP, as HbA1c levels increased (82). These results reinforce the
potential association between inflammatory markers and decreased lung function in patients
IC
with T2D.
It should be noted that although significantly reduced, the lung parameters in the above-
mentioned studies generally remined within the normal range.
T
Microvascular damage and lung microangiopathy
The lung alveolar-capillary network constitutes the largest microvascular bed in
R
humans, making it extremely susceptible to be a target for T2D associated microangiopathy
(83). However, it has been suggested that owing to its large reserves, symptoms and disability
A
occur in the lung later than in smaller microvasculature of the kidney or retina, despite a
similar severity of anatomic involvement (83). Hence, diabetic lung microangiopathy causes
pulmonary dysfunctions that may remain undiagnosed for a prolonged period of time.
The loss of lung microvascular reserve can be quantified noninvasively from DLCO,
E
and its ratio to the alveolar ventilation. In fact, lung volume and DLCO can decline almost by
50% without dyspnea at rest. It should be noted that, although subclinical, significant
C
decrements in pulmonary DLCO have been reported in patients with T2D (26, 84, 85). More
importantly, the reduction of DLCO significantly correlated with the degree of diabetic
N
retinopathy and the 24-hour protein excretion rate, suggesting that the processes related to
microangiopathy in T2D are also involved in lung damage (32, 86).
A
The clinical studies in this field have been performed with limited sample size. However,
consistent results have been reported showing a decreased DLCO when adjusted to alveolar
volume in diabetic patients, in particular in those with diabetic retinopathy or
V
microalbuminuria (26, 85, 87, 88). Recently, the Hispanic Community Health Study/Study of
Latinos comprising 14,455 subjects showed that pulmonary function impairment mirrored
D
kidney microangiopathy, as those with T2D and macroalbuminuria showed significantly

lower lung function (FVC and FEV1) and higher dyspnea score, than those without T2D and
A
with normoalbuminuria (29).

The permeability of lung epithelium was also assessed in 50 non-smoking T2D patients
with no history of cardio-respiratory disease, aged 40-70 years, who underwent a technetium
99m-diethyltriaminepentaaceticacid (99mTc-DTPA) aerosol scintigraphy: 58% of them
showed a delayed 99mTc-DTPA clearance, mainly those with late complications and diabetes
duration longer than 10 years (89).
Physiologically, one part of pulmonary microcirculation is inactive. However, closed
vessels are gradually recruited in case of higher demand for oxygen, e.g. during physical
exercise, that normally leads to an increase of DLCO (90). In a cross-sectional study
involving 69 nonsmoking patients with T2D without overt cardiopulmonary disease and 45
healthy nondiabetic nonsmoking subjects, Chance et al. quantified pulmonary microvascular
10
reserves (30). Patients with T2D showed a 10-25% lower pulmonary blood flow, pulmonary
capillary blood volume, and DLCO corrected by pulmonary blood flow at exercise than
control subjects, with diminished recruitment of alveolar capillaries. Lung microvascular
indexes were significantly related to HbA1c, and extrapulmonary microangiopathy, including
retinopathy, abnormalities in both motor and sensory nerves, and microalbuminuria (30).
More recently, similar results have been observed using a postural variation of DLCO as an
early marker of impaired alveolar-capillary recruitment (91).
Autonomic neuropathy
Although more involved in sleep breathing disorders and pulmonary dysfunction in type 1
diabetes, diabetic autonomic neuropathy (DAN) has also been associated with an increased
prevalence of lung function impairment in T2D (92, 93). DAN may affect up to 30% of the
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diabetic population, but there is little information regarding its involvement in the
abnormalities of pulmonary function. When the kinetics of norepinephrine were studied in
patients with DAN, the lung clearance of iodine-131-meta-iodobenzylguanidine was
significantly decreased compared to patients without sympathetic nervous dysfunction (94).
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In patients with DAN both abnormalities in the bronchomotor tone and specific airway
responsiveness to different stimuli have been described, indicating a defective control of
mechanisms regulating bronchial caliber (93). In this regard, in 5 patients with severe
T
symptomatic DAN, bronchial provocation testing with cold air failed to show a significant
reduction in specific airways conductance in comparison with 5 patients without DAN (95).
R
Similarly, a group of 20 subjects with DAN presented a significantly raised cough reflex
threshold in contrast to non-neuropathic T2D patients, supporting the vagal denervation of
A
the respiratory tract (96). Another group of 6 patients with DAN showed an increased
bronchial reactivity after the nebulization of histamine, reducing their FEV1 by at least 20%
compared with a 6 matched control group subjects with no evidence of DAN (97). Moreover,
11 patients with DAN presented a significantly lower capacity of bronchodilatation after
E
inhalation of the atropine-like drug ipratropium bromide than a control group of 11 patients
without DAN (98).
C
Peculiar changes in breathing pattern and greater ventilatory requirements have been
observed during incremental exercise in subjects with DAN, also suggesting an altered
N
control of breathing in stressful conditions (93). For example, 10 subjects with DAN
responded to heavy exercise by excessively increasing their respiratory rate and alveolar
A
ventilation in comparison with 10 patients without DAN (99). Likewise, autonomic

neuropathy involving respiratory muscles may also impair thoracic mobility (100).
Subsequently, 12 patients with DAN showed reduced respiratory muscle strength (measured
V
as maximum static inspiratory pressure, PImax) than 12 controls without DAN, with a
negative correlation between muscle strength and both resting heart rate and diabetes duration
D
(100). Finally, when assessed by the neuropathy disability score, diabetic polyneuropathy was
associated with substantially respiratory muscle impairment in 21 males with T2D without
A
pulmonary disease (101, 102). Altogether, reduced airway vagal tone seems to play a
nontrivial role in the relation between T2D and impaired lung function.
B. Other potential pathogenic mechanisms
Decreased muscle strength
Decreases in muscle mass and functional muscle capacity, two key factors in pulmonary
function, have been reported in T2D (103). In fact, the prevalence of inspiratory muscle
weakness in a sample of 148 patients with T2D from Brazil was 29% (104). Data from 655
subjects from the cross-sectional Normative Aging Study showed that handgrip strength was
negatively associated with fasting insulin after adjustment for potential confounders including
age, BMI, and usual physical activity level (46). More recently, a clear deterioration of lean
11
mass and muscle functions was observed among 100 adult patients with T2D of up to 60
years old (103). Impairment in muscular strength may be due to lower levels of physical
activity, but hyperglycemia and IR can also impair muscle contractile function and muscle
force generation (46, 103). In addition, patients with T2D also present lower levels of plasma
carnitine (an amino acid stored in skeletal muscles) than healthy controls, while carnitine
levels in patients with T2D positively correlated with FVC, FEV1, FEV1/FVC, and
inspiratory muscle strength (105). Therefore, it seems reasonable to postulate that this
reduced functional capacity of skeletal muscle, particularly the diaphragm but also the
accessory skeletal muscles of respiration, can have negative consequences for lung function
(106).
Muscle strength and the muscle endurance were explored through the PImax and the
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maximum voluntary ventilation in 75 non-smoking patients with T2D without lung disease
and compared with that of 40 healthy subjects (107). Muscle strength was significantly
reduced and related to lung volumes and the HbA1c level, whereas impaired endurance of
respiratory muscles prevailed in patients with microvascular complications (107). More
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recently, in the Berlin Aging Study II, involving 1,369 subjects with a mean age of 69 ± 4
years, muscle mass and abdominal obesity proved to be the most important factors
influencing lung function in T2D, and the measurement of grip strength was recommended
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for a better interpretation of pulmonary function tests in this population (108). Finally, 8
weeks of inspiratory muscle training (IMT) reversed the loss of inspiratory muscle strength in
a small group of 17 subjects with T2D (104). However, this improvement in inspiratory
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muscle strength was not accompanied by changes in FEV1, FVC, or MVV (104).
A
Non-enzymatic glycosylation of lung proteins
It has been suggested that non-enzymatic glycosylation of pulmonary connective
tissue proteins, especially collagen but also elastin and fibronectin, may favor the observed
restrictive pattern described in patients with T2D as a consequence of a less compliant
E
pulmonary parenchyma (109, 110). It should be noted that glycosylated collagen has a low
physiological turnover rate, more stiffness, and more resistance to digestion by collagenase
C
and pepsin than nondiabetic collagen (111). Therefore, the deleterious effect on collagen
structure in pulmonary parenchyma and cartilages of the chest wall will limit chest mobility
N
(62, 82). In a study involving 23 patients with insulin dependent diabetes mellitus, those with
limited joint mobility showed a significant decrease in total lung capacity, FVC and FEV1
A
compared to those without joint limitation, suggesting that altered respiratory mechanics were
another manifestation of a generalized disturbance in collagen metabolism (112). It is also
important to note that type II alveolar epithelial cells specifically express the mRNA of the
V
receptors for AGE (RAGE) (113). The AGE-RAGE ligation activates pathophysiological
cascades leading to pulmonary endothelial cell dysfunction, pro-inflammatory effects and cell
D
apoptosis (114, 115). In this regard, it should be noted that RAGE plays a role in asthma
irrespective of the identity of the allergens involved in animal models (116).
A
Defects in the bronchiolar surfactant layer and the deficit in GLP-1 concentrations
Defects in the bronchiolar surfactant layer that is involved in maintaining airway stability and
diameter, may likewise be considered a contributing factor to the impairment of airway
calibre regulation in patients with T2D. When the alveolocapillary barrier is damaged,
surfactant proteins escape from the alveolar space into the vascular compartment. Therefore,
serum concentration of surfactant protein D (SP-D) has been evaluated in a large variety of
pulmonary diseases, and proposed as a potential systemic biomarker for lung diseases (117,
118). In addition, it is worth mentioning that elevated serum levels of SP-D have also been
found in non-pulmonary diseases that adversely affect the lungs as part of their systemic
repercussion (119, 120). A population-based random sample study described how increased
12
circulating levels of surfactant protein A, the major surfactant-associated protein, were

associated with altered glucose tolerance and insulin resistance (58). Therefore, we suggest
that serum surfactant proteins should be contemplated as a serum biomarker of lung
impairment, as a first step towards identifying those T2D patients for whom a respiratory
function study would be recommendable.
Glucagon like peptide 1 (GLP-1) receptor has been found abundantly in the lung, where it
seems to be implicated in the regulation of the lipid fraction of surfactants (121). In addition,
experimental studies have shown that GLP-1 plays a role in the stimulation of surfactant
production by pneumocytes (122, 123). In fact, in a rat model of lung hypoplasia, surfactant
production was improved by the administration of the GLP-1 receptor agonist liraglutide
(124). And, in a rat model with streptozotocin (STZ)-induced diabetes, reduced lung levels of
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surfactant A and B were restored after this treatment was administered (125). Therefore, the
underlying deficit in GLP-1 concentrations that exists in T2D could also enhance the airway
resistance observed in these patients. Furthermore, treatment with GLP-1 analogues could
result in an improvement in ventilatory patterns. A clinical trial specifically designed to
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address this question is ongoing (ClinicalTrials.gov: NCT02889510).
V.- THE HISTOPATHOLOGICAL EVIDENCE
T
The histopathological changes induced by the pathophysiological mechanisms previously
described include the thickening of the alveolar epithelia and pulmonary capillary basal
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lamina (BL), the reduction of the alveolar space, a higher degree of fibrosis, the presence of
centrolobular emphysema and pulmonary microangiopathy, and modifications in mucus
secretion (126, 127). These abnormalities are homogeneous throughout the whole lung
A
parenchyma. Findings reported from experimental models will be clearly differentiated from
those reported in humans (Figure 3).
E
A. Experimental evidence: animal experiments

Thickness of basement membranes and expansion of interstitium
C
Experimental studies on mice and hamsters rendered diabetics by STZ injection, have shown
that hyperglycemia affects the structure and functional properties of the alveolar capillary
N
endothelial cells (128). Compared to age-matched animals, diabetic animals exhibited a

thickened BL provided with focal nodules, similar in density and distribution to those found
in the glomerular BL in diabetes, with approximately 30% of lung capillaries showing a
A
narrowed or collapsed lumen (128, 129). Moreover, reduced capillary blood volume,
impaired alveolar microvascular perfusion, and reduced alveolar-capillary recruitment have
V
been observed in model rats with T2D (130). A reduced breakdown of the connective tissue
proteins contributing to the increased thickness of both the alveolar and endothelial BL has
D
been found in STZ rats with diabetes in comparison with non-diabetic rats (131). The
interstitial space between the alveolar and the endothelial BL is also expanded in animal
models exposed to chronic hyperglycemia. This is due to an increase of matrix proteins,
A
mainly type I and III collagen and elastin fibers while a simultaneous reduction of sulfate
proteoglycan concentrations occurs (132). The non-enzymatic glycation of collagen increases
matrix stiffness, challenges its digestion by proteases, and slows down its turn-over (133,
134). In addition, AGE may also up-regulate the tissue expression of pro-fibroting cytokines
(235, 136). In this regard, the abnormal connective tissue metabolism as well as collagen
crosslinking in thoracic and lung tissue might limit chest mobility and lung function (120).
This expansion of the interstitium results in fibrosis and induration of the lung which in turn
leads to a reduction in lung volume and its compliance in these animals. In addition,
emphysema has been observed in lungs from rabbits with alloxan-induced diabetes (137).
Changes in alveolar epithelial cells and alveolus morphology
13
No alterations related to chronic hyperglycemia have been reported in the structure of the
alveolar epithelial type I cell. These are large and squamous cells responsible for gas
exchange and ion transport, and constitute 95% of the alveolar epithelial layer. However, an
altered morphology of the smaller cuboidal alveolar type II cells (AT-II), which are involved
in surfactant production, has been observed in the Zucker diabetic fatty rat, an animal model
which reproduces T2D (130). The most prevalent abnormalities described in AT-II are
dilated endoplasmic reticulum, an age-related increase in the volume of lamellar bodies, and
impaired surfactant production (130). The altered surfactant production, in combination with
the increased extracellular matrix, may induce a partial alveolus collapse and, consequently, a
reduction of the alveolar space. In fact, microscopic observation of lungs from D-STZ rats
showed smaller alveoli, but increased in number, in comparison with non-diabetic lung
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samples (131).
In addition, structural alterations have also been described in lung endothelial cells,
including an expanded endoplasmic reticulum, an increased number of multivesicular bodies
and lysosomes, and the presence of fused plasmalemmal vesicles (132).
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Changes in muscle and airway mucus secretion
The alterations detected in the respiratory muscles consist of structural changes with muscle
atrophy, augmented lipid deposition, decreased mitochondria as well as muscle fiber
T
transformation (138). These changes are related to a reduced cellular glucose uptake and fatty
acid oxidation as a consequence of insulin resistance.
R
Two studies have shown that amylin, a pancreatic hormone co-secreted with insulin,
could stimulate mucus secretion at the submucosal side of isolated rat trachea (139-141). As
A
amylin receptors have been detected in lung membrane, these data suggest a physiological
role for this molecule in lung changes found in T2D, where hyperinsulinemia is the rule.
However, so far, no studies have been conducted in diabetic models with T2D.
E
B. Human evidence: post-mortem examinations

Thickness of basement membranes and expansion of interstitium
C
Long-standing T2D is characterized by widespread alterations to the BL. An early report

based on autopsy observations from 28 patients with T2D confirmed the presence of
N
microangiopathy in the lung, involving alveolar septa and pleura, and appearing not only as a
thickening of the basal membrane, but also as hyalinosis, plasmorrhagia, and insudation
(142). Interestingly, similar to the retina, vascular leakage also occurs in the lung of T2D
A
patients. In this regard, perfusion chest computed tomographies have shown increased
vascular permeability in T2D (143). Similarly, the epithelial and capillary BL of alveoli were
V
significantly thicker in patients with diabetes than they were in age-matched control subjects
(144), with a significant correlation with the thickness of the BL of renal tubules and muscle
D
capillaries, suggesting a similar pathologic mechanism (127, 144). Furthermore, in a

histopathological study of the lungs of 35 autopsied patients with T2D and 26 non-diabetic
controls, the thickness of alveolar capillary walls, pulmonary arteriolar walls and alveolar
A
walls had significantly increased in the former group (145). From electron micrograph
images obtained from autopsy material, the BL separating the capillary from the alveolar
space in 6 patients with T2D was approximately 30% thicker compared with 6 controls
without diabetes (176 ± 27 vs. 121 ± 11 nm, p < 0.01) (127). Therefore, the thickening of the
capillary BL and the accumulation of connective tissue in the interstitial space could induce a
narrowing of the capillary wall and a partial collapse of capillary lumen (127, 144).
Overall, the thickening of the walls of pulmonary alveoli caused by increased amounts of
interstitial matrix proteins and the thickening of the basal membrane of alveoli leads to a
decrease in pulmonary parenchyma elasticity (127, 142, 145).
14
Changes in alveolar epithelial cells and alveolus morphology

When histopathological changes in the lung obtained from the autopsies of 61 patients with
T2D were compared to findings in the lung of 50 non-diabetic subjects, the former showed a
significant increase in the amount of collagen in the alveolar walls, in the main airways and
in the walls of the great vessels, and also pulmonary hemorrhages (146). In addition, a
specific type of fibrosis, a nodular deposition of collagen in the interstitium of the alveolar
walls, was described in the lung of subjects with T2D (146).
V.- THE PARADIGM OF CYSTIC FIBROSIS-RELATED DIABETES

Cystic fibrosis (CF) is a systemic disease involving pulmonary function and abnormalities of
glucose tolerance and diabetes, which allows to investigate the deleterious impact of chronic
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hyperglycemia on lung function.
A. Cystic fibrosis and cystic fibrosis-related diabetes
CF is the most common autosomal recessive condition in the Caucasian population, affecting
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approximately one out of every 3,000 live births (147). CF is caused by defects in an
epithelial chloride channel, the CF transmembrane regulator, which is expressed across
tissues, including airways, intestine, and pancreas (148, 149). The incidence of diabetes in
patients with CF is nearly 100 times greater than in the general population, and is considered
T
a clinical entity distinct from that of T1D and T2D (150). Cystic fibrosis-related diabetes
(CFRD) may reach a prevalence of up to 50% in adults with CF, with a higher incidence in
R
females. It is associated with impaired lung function and an increased chance of treatment
failure in pulmonary exacerbations (151).
A
The hallmark of CFRD is an early insulin deficiency due to reduced beta cell mass (149).
However, the destruction of beta cells is incomplete, and other mechanisms such as insulin
resistance, genetic predisposition, the impairment of the enteroinsular axis, inflammation, and
E
increased oxidative stress have also been described as playing a contributory role (152-156).
Insulin resistance is usually mild and related to infection status and steroid therapy (149).
Using longitudinal data from 2006 to 2009 in 520 individuals with diabetes from the U.K.
C
Cystic Fibrosis Registry, an HbA1c value of ≥ 6.5% was associated with a threefold
increased risk of death, independently of other potential confounders (157).
N
B. The influence of glucose intolerance and diabetes on pulmonary function in CF

In a cross-sectional analysis of 7,566 patients with CF enrolled in the European
A
Epidemiologic Registry of Cystic Fibrosis, the predicted FEV1% was lower in people with
diabetes than in those without diabetes across all ages (158). Thus, the mean value of
V
predicted FEV1% in the group of 30 years or older was 53% in the non-diabetic patients, as
compared to 44% in the diabetic group. In addition, the predicted FVC value was also lower
D
in people with CFRD than in those without diabetes in all age groups. Similarly, according to
data from the U.K. Cystic Fibrosis Database, CFRD in female subjects without chronic
Pseudomona aeruginosa infection was associated with a 20% lower predicted FEV1
A
compared with CF subjects with normal glucose tolerance (159).

According to recent data, in individuals with CF, the decline in FEV1 is driven primarily
by the episodic pulmonary exacerbations, and only 39% of them fully recover their 6-month
baseline lung function after intravenous antibiotic treatment (160). In addition, the decline in
lung function is accelerated after the development of CFRD. In this regard, in a prospective
multicenter study following 56 patients with CF for 5 years, both FEV1 and FVC declined
significantly in the CFRD, whereas patients without diabetes did not show any significant
change (161).
It is worth mentioning that pulmonary function begins to decline as early as 1 to 4 years
prior to the diagnosis of CFRD, implying that impaired glucose tolerance may also be
15
detrimental. Lavie at al. showed that CF patients with impaired glucose tolerance (IGT)
presented a lower mean predicted FEV1 than patients with normal glucose tolerance (57±19
vs. 74±21%, p<0.01) (162).
In a prospective study enrolling 152 patients with CF, the rate of lung function decline
over a four-year observation period was directly related to the baseline oral glucose tolerance
test (OGTT) classification: patients with IGT had a greater loss of lung function than those
with NGT, and those with CFRD without fasting hyperglycemia had the greatest loss (163).
The functional pulmonary parameters (FEV1 and FVC) and the BMI at baseline were
comparable, and the results were independent of gender, age, BMI, respiratory microbiology,
and use of corticosteroids. In addition, patients in the lowest quartile for insulin production at
baseline experienced the highest rates of pulmonary function decline over time, suggesting a
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linear inverse relationship between insulin production and lung deterioration (163). Similarly,
in a retrospective study involving 38 patients with CFRD and 38 CF patients without
diabetes, matched by age, gender, and chronic Pseudomonas aeruginosa lung infection,
statistically significant differences in FEV1 and FVC between groups emerged 1.25 and 3
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years prior to the diagnosis of diabetes, respectively (164). More recently, a retrospective
study comprising 32 patients with CF showed marked decreases in FVC, FEV1, and forced
expiratory flow at 75% of expired FVC in CFRD with the onset of 1 year prior to the
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diagnosis of diabetes (165).
Similar results appeared when other measures of glucose intolerance apart from
OGTT were used in patients with CF without CFRD. In this regard, patients with normal
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OGTT but with a maximum continuous glucose monitoring value ≥11 mmol/l exhibited a
significant impairment in lung function (FEV1: 68.2±25.6 vs 87.3±17%, p=0.01; FVC:
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86.1±19.4% vs 99.3±13.4%, p=0.021) independent of age, age at diagnosis, gender,
genotype, exocrine pancreatic insufficiency, the BMI, and Pseudomona aeruginosa
colonization (166).
E
C. Why does cystic fibrosis-related diabetes accelerate lung dysfunction?

The mechanisms leading to impaired pulmonary function in CFRD are unclear, but the
C
combined effects of hyperglycemia and insulin deficiency would seem to be the main
contributing factor. Lung function in subjects with CF is critically dependent on maintaining
N
normal weight and lean body mass. Therefore, insulin deficiency might impact pulmonary
function by creating a catabolic state with excessive protein and fat breakdown (149, 167).
On the other hand, hyperglycemia could cause a decline in pulmonary function directly by
A
reducing the defense capacity against infection (168). In this way, patients with T2D show a
significative decrease in the percentage of activated macrophages when compared with non-
V
diabetic subjects, that is partially normalized after metabolic improvement (169, 170). In
addition, when blood glucose levels are modestly elevated (>144 mg/dl, 8.0 mmol/l), the
D
presence of glucose in airway fluid contributes to the progression of respiratory disease (171).
Furthermore, hyperglycemia has been noted to be associated with increased oxidative stress
A
in CF, contributing to lung disease by creating a proinflammatory environment in the airways

(172, 173). The Th17 pathway, and the production of interleukin 17 could provide a better
understanding of the relation between beta-cell dysfunction and lung impairment in CF. In
fact, Th17 has been involved in beta cell destruction occurring in T1D and T2D, and
interestingly, in lung inflammation as well (174, 175).
Two mechanisms previously related to the negative impact of T2D on lung function could
also affect the progression toward CFRD with CF, namely AGEs and the decreased levels of
GLP-1. Plasma AGE and neutrophil derived human S100A12 levels are significantly elevated
in CFRD and correlate negatively with FEV1 (176). After a standardized breakfast, patients
with CF and CFRD were found to have significantly decreased GLP-1 compared to healthy
controls (154). Finally, based on chest computed tomography, CFRD has also been
16
associated with structural lung disease that occurs prior to changes in lung function such as
FEV1 (177).
D. Insulin treatment and lung function
To date, there is no significant convincing proof that long-acting insulins, short-acting
insulins, insulin analogues, or oral antidiabetic agents have a distinctive advantage over one
another in controlling hyperglycemia or other clinical outcomes associated with CFRD (178).
However, the Cystic Fibrosis Foundation (USA) clinical practice guidelines support the
administration of insulin as the mainstay therapy, and this remain the most widely-used
treatment method (179).
Some uncontrolled trials suggest that a once-daily injection of intermediate or long-acting
insulin improves weight and lung function. Following 3 years of insulin administration in 28
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CF patients older than 10 years with abnormal OGTT in spite of normal fasting glycemia,
FEV1 stabilized in insulin-treated insulinopenic subjects (73.8±4.3% vs 73.5±4.4%), but
decreased in NGT patients who remained without insulin treatment (71.1±3.8% vs.
61.0±4.0%, p=0.001) (180). However, two trials with data for the comparison of insulin vs.
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placebo in CFRD did not report any significant differences between the groups regarding the
primary outcomes of blood glucose level, lung function and nutritional status (178, 181).
Whether insulin may be of greater benefit to respiratory function when given prior to the
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diagnosis of CFRD, after which structural lung disease may be irreversible, is a subject for
future investigation (182).
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VI. THE DELETERIOUS EFFECT OF T2D ON SLEEP BREATHING DISORDERS
AND SLEEP ARCHITECTURE
A
In recent years, increasing evidence has also appeared suggesting an association between
sleep apnea syndrome (SAS) and T2D (183). The available data suggest that long-term
E
exposure to intermittent hypoxemia and sleep fragmentation increases sympathetic nerve

activity which favors the disorders of glucose metabolism (184). Alternatively, some studies
propose the idea that T2D might contribute to the development of sleep breathing disorders
C
(Figure 4).
N
A. Nighttime awakenings, sleep quality and daytime sleepiness in T2D

Disruptions of sleep occur more frequently in T2D patients than in the non-diabetic
population. Depending on age, diabetes control and duration, diabetes treatment, and
A
associated complications and comorbidities, nocturnal awakenings in T2D might be due to

nocturia, thirst, symptomatic nocturnal hypoglycemia, pain due to peripheral neuropathy, the
V
associated restless legs syndrome, or the need for the self-monitoring of blood glucose during
the night (185-189). These frequent nighttime awakenings contribute to sleep quality
D
reduction, and according to the Pittsburgh Sleep Quality Index (PSQI), almost 2 out of every
3 patients with T2D are classified as “poor sleepers” (PSQI global score >5) (190). In
addition, sleep quality reduction has been found to be associated with basal hyperglycemia
A
but not with HbA1c, thus strengthening the potential relationship between nocturnal
hyperglycemia and sleep quality (190).
T2D is also related to excessive daytime sleepiness independently of other classic risk
factors such as SAS (190, 191). In 1,055 consecutive, obese subjects waiting for bariatric
surgery, the Epworth Sleepiness Scale (ESS) global score was higher in men, older patients,
and those with T2D, whereas no relationship between daytime somnolence and
polysomnography measurements, including the apnea-hypopnea index (AHI), were reported
(189). Similarly, in a case-control study involving 826 individuals, the excessive daytime
sleepiness (ESS score >10) was almost double among patients with T2D in comparison with
control subjects (23.9% vs. 16.9%), and those with HbA1c ≥6.4% and FPG ≥ 13.1 mmol/l
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showed a higher risk of excessive daytime sleepiness than subjects with HbA1c <6.4%
(OR=3.9, 95% CI 1.8-7.9, p= 0.0003) (190).
B. Pathophysiological mechanisms underlying sleep breathing disorders in T2D
Breathing control is critical for respiratory responses to changes in the internal and external
environment, including but not limited to sleep, physical activity, stress, acute and chronic
diseases, and other conditions (192, 193). In adults with T2D, previous research has
demonstrated abnormal and blunted ventilatory responses to isocapnic hypoxia with an
altered breathing pattern, whereas the ventilatory response to hypercapnia is well preserved
(Table 2) (194, 195). In fact, although the respiratory minute volume, was similar between
groups, the increase in the amount of air that was breathed during one minute in response to
hypoxia was almost 4 times less in patients with T2D in comparison to control subjects (194).
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Therefore, patients with T2D seem to be unable to respond in a homeostatic manner to
hypoxic challenge. The main pathophysiological mechanisms involved in the sleep breathing
disorders that occur in T2D patients are summarized in Table 2.
Although the underlying pathophysiology remains poorly understood, the findings
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suggest that the chemoreflex, an integrated response involving chemoreceptor detection, the
activity of respiratory centers in the medulla, afferent and efferent neural conduction, and
respiratory muscle function, are altered in T2D, which may impact the regulation of blood
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gases and oxygen delivery with significant clinical implications (196-198). Other, non-
chemoreflex influences, may also contribute to reduced ventilatory responses to hypoxia in
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T2D. Specifically, DAN can lead to alterations in both afferent and efferent motor pathway
functions (106, 199). Consequently, impaired respiratory muscle function with decreased
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respiratory muscle strength, impaired chest wall function, and/or airflow limitation may result
in a blunted ventilatory response to hypoxemia in T2D. Among the humoral ventilatory
control mechanisms, leptin plays an important role in the respiratory system, ranging from its
actions in the lung to its involvement in many common disorders of the respiratory system
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(200, 201). As previously mentioned, the metabolic pathways related to leptin resistance in
diabetes could therefore contribute to deficiencies in central respiratory control mechanisms
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and the defective responses of peripheral and central chemoreceptors (202, 203). Finally, the
breathing pattern generator and the ventilatory rhythm generator responsible for the central
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control of ventilation could be affected in some persons with T2D who develop vascular
lesions and/or brain atrophy (204-206).
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C. The bidirectional relation between T2D and sleep breathing disorders

As mentioned previously, T2D, breathing, and sleep are closely interrelated. During the last
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two decades, increasing evidence has appeared suggesting an association between SAS and
T2D, two common disorders that occur with increased frequency in the obese population
(183). The available data suggest that long-term exposure to intermittent hypoxemia and
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sleep fragmentation increases sympathetic nerve activity, contributing to glucose metabolism

disorders (207). In this regard, a high prevalence of fasting hyperglycemia, insulin resistance,
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and T2D has been found among SAS patients in comparison with healthy subjects (208).
Alternatively, both obesity-hypoventilation syndrome and SAS are common
comorbidities of T2D that have been linked to lung dysfunction and various adverse
metabolic outcomes (208-211). Thus, some studies propose that IR and chronic
hyperglycemia might contribute to the development of sleep apnea syndrome (SAS).
Vgontzas et al. found that women with polycystic ovary syndrome, a condition associated
with IR, were much more likely to have SAS and daytime sleepiness than controls,
suggesting that IR is a mediator of SAS in humans (212). Additionally, the analysis of cross-
sectional data from the Sleep Heart Health Study, found that subjects with clinically
diagnosed T2D had more episodes of periodic breathing, an abnormality of the central control
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of ventilation, and more severe sleep hypoxemia; after correcting for the main factors
involved in the development of SAS, the difference in sleep hypoxemia was eliminated (213).
Recently, the Sweet Sleep Study has described how the presence of T2D produces a more
severe pattern of sleep breathing characterized by higher rates of sleep apneas for the same
apnea-hypopnea index (214). This deleterious effect of T2D on sleep breathing leads to
excessive daytime sleepiness, a feature that affects almost one quarter of the general
population with T2D (190).
In addition, the established changes in chemoreflex sensitivity, along with sympathetic
activation and HPA axis hyperactivity present in T2D significantly increase the risk of the
exacerbation of other clinical abnormalities in response to hypoxia/hypoxemia (e.g., in states
of obesity, sleep-disordered breathing, coronary artery disease, etc).
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D. Effects of T2D on sleep architecture and microaurousals
Sleep is an active state with its own characteristic stages that recurs throughout the night. The
succession of cycles and the length of each stage and cycle compose the sleep architecture of
each person (215). Besides the non-stage specific disruptions of sleep, stage-specific
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disturbances can also occur in diabetes. However, the results do not always exhibit the same
concordance. For example, Palloyva et al. reported a significantly increased percentage time
in rapid eye movement (REM) sleep in subjects with T2D compared to non-T2D controls
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(216). More recently, the small reduction in the amount of time that patients with T2D spent
in stage 2 of Non-REM, disappeared when patients and control subjects were matched by the
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AHI (214). In a similar way, baseline differences for Non-REM sleep stages reported
between participants with and without T2D in the Sleep Heart Health Study disappeared in
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the multivariate regression analyses when the means for age, sex, BMI, race, and neck
circumference were adjusted (213).
On the other hand, patients with T2D showed higher sleep fragmentation through higher
rates of microaurousals during sleep than control subjects, and these differences were mainly
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observed during the Non-REM sleep (214). Microarousals, characterized by central nervous
system reactivity producing electroencephalographic activation and sympathetic overactivity,
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were independently associated with fasting plasma glucose (214). Interestingly, data from the
Coronary Artery Risk Development in Young Adults Sleep Study showed that a 10% rise in
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sleep fragmentation was associated with increments in fasting insulin and fasting glucose by
30% and 9%, respectively (217). Therefore, it seems that a relationship between sleep
fragmentation and T2D exists. In addition, as sleep fragmentation is involved with increased
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levels of lipids and blood pressure, this enlarged rate in the microaurousal index may also be
implicated in the progression of cardiovascular disease in T2D (218, 219).
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E. T2D and nocturnal hypoxemia

T2D is an independent risk factor for severe nocturnal hypoxemia in obese patients. In fact,
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the duration of sleeping time with oxygen saturation below 90% (CT90) was 3 to 4-fold
higher in T2D patients in comparison with non-diabetic subjects matched according to their
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BMI and waist circumference (9). In addition, intermittent hypoxemia is favored during the
REM sleep in patients with T2D (216). This is an important finding because sleep related
hypoxemia in SAS patients is known to be a major stimulus leading to oxidative stress and
endothelial dysfunction, and may contribute to the increased risk of cardiovascular events
observed in the diabetic population (220).
In addition, findings from previous studies suggest that when T2D occurs in parallel with
SAS, it is associated with a specific breathing pattern during sleep that cannot be explained
by age, sex, BMI, or SAS severity (214, 216, 221). In this way, the composition of AHI in
patients with T2D is characterized by an increase in apnea events, with no differences or even
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a reduction in hypopnea episodes (221). This result suggests that at the same level of AHI,
patients with T2D have more severe sleep breathing disorders than non-diabetic subjects.
Finally, laboratory based investigations have implicated DAN in this relationship, so that
T2D patients with DAN are more likely to have not only central, but also obstructive sleep
apnea, than those without it (222). Therefore, an impairment of the upper airway reflexes,
possibly due to alterations to the autonomic nervous fibers involved in their regulation, could
lead to an inability of individuals with diabetes to respond appropriately to nocturnal airflow
reduction episodes, leading to more severe intermittent hypoxemic episodes.
VII. THERAPEUTIC IMPLICATIONS

The previous data raise the central issue of whether the normalization of blood glucose levels
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can significantly improve pulmonary function and ameliorate sleep breathing disorders in
T2D. However, only experimental data and pilot interventional studies aimed at exploring the
impact on respiratory parameters of some therapeutic options such as the effect of improving
glycemic control on sleep breathing are currently available. Therefore, further research on
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this issue is warranted.
A. Data from experimental models
The beneficial effects of both metformin, a drug currently used to raise insulin sensitivity,
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and insulin on pulmonary development, sleep breathing and lung function have been
observed in some experimental models (223-225).
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Ramadan et al. showed direct evidence for the contribution of insulin resistance to the
development of apneic episodes, and how oral treatment with metformin, not only prevented
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but also reversed apnea episodes in Sprage-Dawley rats (224). More recently, Chen et al.
have demonstrated that the subcutaneous administration of metformin (25 and 100 mg/kg) in
neonatal Wistar rats with experimental bronchopulmonary dysplasia was accompanied by a
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significant reduction in lung inflammation, alveolar septum thickness, and fibrosis, as well as
improvements in vascularization and survival (223).
Regarding the effect of insulin, Hein et al. demonstrated, in streptozotocin-induced
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diabetic rats, that the decreased ventilatory responses to hypercapnic and hypoxic challenges
that appeared by the third and fourth week was prevented with insulin treatment (225).
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However, it is difficult to ascertain whether this effect was attributed to the single reduction
in blood glucose, or to the insulin signaling itself, or a combination of both effects.
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B. Data from human studies: insulin sensitizers and insulin

Two studies have evaluated the effect of drugs used to raise insulin sensitivity in subjects
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with chronic obstructive pulmonary disease (COPD) and T2D. In a retrospective one,
involving 61 Korean patients, treatment with insulin sensitizers was independently associated
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with improvements in FVC compared to insulin therapy (226). More recently, in an open-
label prospective study that evaluated 17 patients with COPD and T2D or impaired glucose
tolerance, treatment with metformin for 6 months improved the St George's Respiratory
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Questionnaire score by a median of 5 points, and the transition dyspnea index by 2 points
(227). In addition, inspiratory mouth pressure increased by 7.5 cm H2O. Similarly, in a cross-
sectional study investigating pulmonary function among 196 T2D patients from Colombia
without known lung diseases, the metformin group showed significantly lower differences
from the expected values of FVC compared to those treated with secretagogues after
adjustment for metabolic control and the duration of the disease (228).
On the other hand, patients on insulin therapy present lower spirometric values. In this
regard, data from 284 subjects with T2D participating in the cross-sectional Copenhagen City
Heart Study demonstrated that the impairment of pulmonary function was more pronounced
in patients treated with insulin compared to those only treated with oral agents or diet; the
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average FEV1 and FVC were 122 and 150 ml lower in insulin-treated patients than in those
treated with oral agents (21). However, these negative data on lung function associated with
insulin therapy may be related more with the severity and duration of diabetes than with the
insulin itself. Another confounding factor not considered in these studies is the weight gain
associated with insulin therapy, a significant clinical effect which could result in a negative
impact on lung function.
The influence of insulin on alveolar-capillary membrane conductance was also explored
in 19 asymptomatic nonsmoking patients with T2D receiving diet and hypoglycemic drugs
(229). After the infusion of 10 IU of regular insulin for 2 days a significant improvement in
DLCO and alveolar capillary membrane conductance in comparison with saline infusion was
found, independently of the metabolic effects. As no variations in VC, FEV1, pulmonary
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wedge pressure nor pulmonary arteriolar resistance were observed, it seemed that the effect
of insulin improving gas exchange was mediated through the facilitation of alveolar-capillary
interface conductance (229).
C. Data from humans: glucose optimization and improvement of inflammation
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More recently, a case-control study comprising 30 patients with T2D and 10 non-diabetic
controls provided evidence that the increased number of nocturnal oxygen desaturations
described in diabetes exhibited a significant reversibility after a 5-day period of blood
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glucose optimization (230). This positive effect on the repetitive nocturnal hypoxemia and
reoxygenation cycle might be attributable not only to the normalization of the diabetic milieu,
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but also to the effect of exogenous insulin. However, there was not a significant increase in
total insulin dosage, pointing to glycemic optimization rather than the effect of insulin per se
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as the main factor accounting for the improvement of nocturnal oximetry.
The improvement of inflammation has also been reported as having beneficial effects on
pulmonary function and sleep breathing (77, 231). However, most of the patients recruited for
these studies had no T2D. The outcome of the neutralization of TNF-α by etanercept (a
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fusion protein that binds to TNF-α molecules and blocks their interaction with the cell
surface) was explored in 8 obese male patients with sleep apnea syndrome. In this placebo-
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controlled double-blind study, the anti-inflammatory action of the drug was associated with a
significant decrease in sleepiness, and also with a marked reduction in the sum of apneas and
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hypopnea events per hour compared with placebo (231). Treatment with etanercept in
patients with refractory asthma has also improved the respiratory function, and in particular
post-bronchodilator FEV1, in comparison with subjects who received placebo, raising the
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possibility that anti-TNF-α agents could be useful in the prevention and/or management of
the impairment of lung function associated with T2D (77).
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D. Potential benefits of other therapeutic options: inhaled insulin and incretin-based therapies
For several years, alternative routes of insulin administration have been investigated, in order
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to overcome the limitations related to its subcutaneous administration (232). Thus, the
approval of delivering insulin by inhalation has resulted in new insights into the relationship
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between T2D and the lung, especially when insulin receptors have been revealed in type II
pneumocytes, favoring surfactant synthesis (52). Using a dry-powder inhalation device,
insulin is combined with an excipient that dissolves instantaneously in lung fluid and releases
recombinant insulin for absorption, acting as a prandial insulin. Small reductions in FEV1
have been shown with inhaled insulin, although this outcome is not progressive over time and
is reversed when the treatment is discontinued (233). The potential effect of inhaled insulin
on T2D subjects with some degree of lung involvement will need to be addressed in the next
future.
The underlying deficit of GLP-1 in T2D could also be involved in the impairment of
airway calibre. The GLP-1 receptor is abundant in the lungs, and it plays a role in the
21
stimulation of pulmonary surfactant production by type II alveolar cells in experimental

studies (124, 125). Therefore, the potential pulmonary benefit of incretin-based therapies is
particularly relevant, and efforts might be done to answer the question whether GLP-1
analogues could improve pulmonary function. Moreover, the pulmonary effects of alternative
routes to subcutaneous administration, such as GLP-1 adsorbed onto Technosphere
microparticles for oral inhalation, that produce plasma levels of GLP-1 like those of parenteral
administration need to be evaluated (234). Finally, deserve further attention whether the
pharmacological inhibition of the dipeptidyl peptidase-4 (DPP-4), preventing the inactivation of
the endogenous GLP-1 and prolonging their enhanced secretion after meal ingestion exerts
any effect on pulmonary function.
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VIII.- CLINICAL GAPS, CONTROVERSIES, AND FUTURE DIRECTIONS
The general assumption that the lung is a new target of diabetic complications should
strengthen the relationship not only between endocrinologists and pulmonologist, but also
with primary care physicians. However, there are still some research controversies and
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clinical gaps that need further investigation.
A. Which patients with T2D are at risk for pulmonary disease?
This review offers a better understanding of the conditions underlying pulmonary
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involvement in T2D, a relatively common but generally under-recognized complication.
Although this involvement appears to be mediated primarily by pathological mechanisms
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associated with a restrictive pulmonary pattern, also obstructive mechanisms are implicated.
The aim is a comprehensive diagnosis that will lead to the treatment that can be adapted for
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both lung disease and T2D. Like other chronic complications associated with diabetes
microangiopathy, lung dysfunction appears to be more frequent in patients with longer
duration of the disease and poorer metabolic control. Similarly, the relationship between T2D
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and obesity is of such interdependence that the term ‘diabesity’ has been coined. Therefore,
weight excess must be considered as a risk factor contributing to restrictive lung disease in
subjects with T2D (73, 235). In this regard, cross-sectional studies have reported a reduction
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in FVC and FEV1 in obesity (236-239). The mechanical effects of truncal obesity and the
metabolic effects of adipose tissue partly explain the impairment of pulmonary function in
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obese subjects (73).

B. Is it recommendable to screen patients with T2D for pulmonary dysfunction and sleep
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disturbances? If so, how should it be done?

The first question concerns the most cost-effective manner of screening pulmonary
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dysfunction and sleep breathing abnormalities in T2D patients. This is an important issue in
terms of community healthcare and its economic burden. Appropriate studies aimed at
determining the cost-effectiveness of including in routine visits such simple diagnostic tests
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as forced spirometry maneuvers and questionnaires to evaluate daytime sleepiness and sleep
quality are needed.
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C. Will lung dysfunction modify therapy for T2D?

Another subject that merits exploration is the impact of improving metabolic control on
pulmonary function and sleep breathing, as well as the differential actions and effects of the
various treatments. In this regard, as previously mentioned, the potential beneficial effects of
incretin-based therapies, mainly GLP-1 receptor agonists, on pulmonary function seem
particularly relevant because of their capacity to increase lung surfactant production and to
enhance airway stability and diameter. In addition, the treatment of patients with T2D and
pulmonary involvement includes improvements in lifestyle habits (smoking cessation,
healthy diet, and a good level of physical activity), nutritional measurements, and muscle
training.
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D. How do lung dysfunction and sleep breathing disorders affect the patient with T2D?
Both T2D and the degree of poor glycemic control are related to respiratory function
impairment, and also seem to adversely affect breathing during sleep, becoming an
independent risk factor for higher rates of sleep apnea, while leading to more severe
nocturnal hypoxemia and daytime sleepiness. The complex pathomechanisms underlying
breathing disorders in T2D remain to be further investigated, but it seems that the metabolic
pathways related to insulin resistance and low-grade chronic inflammation are crucial in
initiating lung abnormalities.
In summary, the current evidence strongly supports the link between T2D and respiratory
dysfunction, and indicates that pulmonary function should be taken into consideration by
health-care providers. Specific pilot screening programs would be very useful for obtaining
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preliminary results, which could provide further general guidance on this issue. The current
evidence points to the lung as a new end target for T2D complications, and supports the
recommendation that patients with T2D be considered a vulnerable group for pulmonary
dysfunction.
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ACKNOWLEDGMENTS:
José María Martí, from MDG Comunicación, for his support in the elaboration of figures.
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*Co-corresponding authors: Albert Lecube M.D., Ph.D, Endocrinology and
Nutrition Department, Hospital Universitari Arnau de Vilanova, Institut de Recerca
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Biomèdica de Lleida, Avda. Rovira Roure 80. 25198-Lleida, Spain, Phone: +34 973
70 51 83; Fax: +34 973 70 51 89, e-mail: alecube@gmail.com. Rafael Simó M.D.,
Ph.D, Endocrinology and Nutrition Department, Hospital Universitari Vall d’Hebron,
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Diabetes and Metabolism Research Unit, Vall d’Hebron Institut de Recerca, Pg. Vall
d’Hebron 119-129. 08024-Barcelona, Spain, Phone: +34 93; Fax: +34 93, e-mail:
rafael.simo@vhebron.net
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Name and address of person to whom reprint requests should be addressed:

Albert Lecube
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Supporting sources: This work was supported by grants from de Instituto de Salud Carlos
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III ISCIII (Fondo de Investigación Sanitaria, PI06/0476, PI12/00803, PI15/00260), European

Union (European Regional Development Fund, Fondo Europeo de Desarrollo Regional,
FEDER, “Una manera de hacer Europa”), and Fundación Sociedad Española Endocrinología
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y Nutrición (FSEEN). CIBER de Diabetes y Enfermedades Metabólicas Asociadas

(CIBERDEM) and CIBER de Enfermedades Respiratorias (CIBERES) are an initiative of the
V
Instituto Carlos III.

Disclosure Statement: FB, MP, CLC, CT, CH, and RS have nothing to declare. AL received
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grant from Novo Nordisk that is unrelated to the submitted work. NMP received grants from
Resmed and Philips-Respironics that are unrelated to the submitted work.
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Figure 1. World distribution of cross-sectional studies evaluating the relationship between

type 2 diabetes and impaired lung function.
Figure 2. Well-recognized pathogenic mechanisms underlying pulmonary dysfunction in

type 2 diabetes. ASM: airway smooth muscle; NE: neutrophil elastase.
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Figure 3. Human lung histopathological evidence induced by type 2 diabetes.
Figure 4. The deleterious effect of type 2 diabetes on sleep breathing disorders and sleep
architecture.
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Table 1. Cross-sectional studies evaluating the relationship between type 2 diabetes and
impaired lung function.
T2D vs. non-T2D
T
Author Year Sample N FEV1 FVC DLCO
Barrett-Connor et al. 12 1996 Rancho Bernardo Study 1,239 ↓a ↓a -
Davis et al. 13 2000 Fremantle Diabetes Study 495 ↓ ↓ -
Lange et al. 20
Walter et al. 14
Lawlor et al. 15
2002
2003
2004
Copenhagen City Heart Study
Framingham Heart Study
R
British Women’s Heart and Health
12,062
3,254
3,911
↓
↓
↓
↓
↓
↓
-
-
-
A
Study
Litonjua et al. 16 2005 Normative Aging Study 704 ↓b ↓b -
Chance et al. 29 2008 Type 2 diabetic patients and nonsmokers 114 ↔ ↓ ↓c
Yeh HC et al. 17 2008 Atherosclerosis Risk in Communities 11,262 ↓ ↓ -
E
Study
Oda et al. 22 2009 Japanese men and women 2,608 - ↓ -
Oda et al. 23 2009 Japanese men and women 1,353 - ↓ -
C
Yeh F et al. 18 2011 Strong Heart Study 2,396 ↓ ↓ -

Klein et al. 19 2012 Clinical setting study 4,164 ↓ ↓ ↓
Huang et al. 26 2014 Clinical setting study 584 ↓ ↓ -
N
Klein et al. 28 2016 Hispanic Community Health 14,455 ↓ ↓ -

Study/Study of Latinos
a
Association only noted in those with a diabetes duration of more than 10 years; b FEV1 and FVC lower in the
regular smokers but not in non-smokers; c Decrease in DLCO only noted with exercise and not at rest.
A
Table 2. Pathophysiological mechanisms contributing to the deleterious effect of type 2

V
diabetes on sleep breathing.

Changes in chemoreflex sensitivity
D
Abnormal threshold in chemoreceptor activation

Afferent and efferent neural condition
Respiratory muscle function
A
Changes in non-chemoreflex influences

Decreased respiratory muscle strength
Diabetic autonomic neuropathy
Situations that produce airflow limitation
Humoral ventilatory control mechanisms
Insulin resistance
Leptin resistance
Changes in breathing pattern and ventilatory rhythm generator
Cerebrovascular disease
Brain atrophy
Sympathetic hyperactivity
Hypothalamus pituitary axis hyperactivity
37
Endocrinology
A
D
V
A
N
C
E
A
R
T
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Endocrinology
A
D
V
A
N
C
E
A
R
T
IC
LE
Endocrinology
A
D
V
A
N
C
E
A
R
T
IC
LE
Endocrinology
A
D
V
A
N
C
E
A
R
T
IC
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Pulmonary function and sleep breathing: two new targets for type 2

Submitted: June 26, 2017

Type 2 diabetes, pulmonary function and sleep.

Research Unit, VHIR, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain.

Carlos III (ISCIII), Madrid, Spain.

ARIC: atherosclerosis risk in communities

BL: basal lamina

CF: cystic fibrosis

CRP: C-reactive protein

FVC: forced vital capacity

RV: residual volume

impact on the field of lung diseases and type 2 diabetes.

metabolic pathways related to insulin resistance, low-grade chronic inflammation, leptin

tolerance and diabetes is considered as an example to further investigate the relationship

therapies and pulmonary function is examined.

(FEV1) is an independent predictor of all-cause mortality in this population (8). Basic

II. CLINICAL AND EPIDEMIOLOGICAL EVIDENCE

(OR=1.38 [1.23-1.55]) for presenting a restrictive ventilatory pattern, which remained

C. Is the decline in spirometric values accelerated in subjects with T2D?

III. PATHOPHYSIOLOGICAL MECHANISMS UNDERLYING PULMONARY

women, IR was also recognized as an independent determinant of pulmonary dysfunction

significant predictor of ERV and the FEV1/FVC ratio in multivariate analysis.

remain to be elucidated. One of the advocated mechanisms is a reduction in mitochondrial

Low-grade chronic inflammation state

pharmacologic (etanercept) and genetic TNF-α inhibition (TNF-α R1KO) significantly

kidney microangiopathy, as those with T2D and macroalbuminuria showed significantly

with normoalbuminuria (29).

significantly decreased compared to patients without sympathetic nervous dysfunction (94).

ventilation in comparison with 10 patients without DAN (99). Likewise, autonomic

respiratory muscles prevailed in patients with microvascular complications (107). More

circulating levels of surfactant protein A, the major surfactant-associated protein, were

result in an improvement in ventilatory patterns. A clinical trial specifically designed to

V.- THE HISTOPATHOLOGICAL EVIDENCE

A. Experimental evidence: animal experiments

endothelial cells (128). Compared to age-matched animals, diabetic animals exhibited a

and lysosomes, and the presence of fused plasmalemmal vesicles (132).

B. Human evidence: post-mortem examinations

Long-standing T2D is characterized by widespread alterations to the BL. An early report

capillaries, suggesting a similar pathologic mechanism (127, 144). Furthermore, in a

Changes in alveolar epithelial cells and alveolus morphology

V.- THE PARADIGM OF CYSTIC FIBROSIS-RELATED DIABETES

B. The influence of glucose intolerance and diabetes on pulmonary function in CF

compared with CF subjects with normal glucose tolerance (159).

C. Why does cystic fibrosis-related diabetes accelerate lung dysfunction?

in CF, contributing to lung disease by creating a proinflammatory environment in the airways

exposure to intermittent hypoxemia and sleep fragmentation increases sympathetic nerve

A. Nighttime awakenings, sleep quality and daytime sleepiness in T2D

associated complications and comorbidities, nocturnal awakenings in T2D might be due to

Although the underlying pathophysiology remains poorly understood, the findings

C. The bidirectional relation between T2D and sleep breathing disorders

sleep fragmentation increases sympathetic nerve activity, contributing to glucose metabolism

E. T2D and nocturnal hypoxemia

VII. THERAPEUTIC IMPLICATIONS

B. Data from human studies: insulin sensitizers and insulin

C. Data from humans: glucose optimization and improvement of inflammation

stimulation of pulmonary surfactant production by type II alveolar cells in experimental

obese subjects (73).

disturbances? If so, how should it be done?

C. Will lung dysfunction modify therapy for T2D?

Name and address of person to whom reprint requests should be addressed:

III ISCIII (Fondo de Investigación Sanitaria, PI06/0476, PI12/00803, PI15/00260), European

y Nutrición (FSEEN). CIBER de Diabetes y Enfermedades Metabólicas Asociadas

Instituto Carlos III.