European Journal of Internal Medicine 26 (2015) 273–278
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European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original Article
Decline of the lung function and quality of glycemic control in type 2 diabetes mellitus Leonello Fuso a,⁎, Dario Pitocco b, Carola Condoluci a, Emanuele Conte a, Chiara Contu a, Alessandro Rizzi b, Giulia Angeletti a, Benedetta F. Bibi a, Raffaele Antonelli-Incalzi c a b c
Pulmonary Medicine Unit, Catholic University, Rome, Italy Diabetology Unit, Catholic University, Rome, Italy Department of Geriatrics, Campus Biomedico University, Rome, Italy
a r t i c l e
i n f o
Article history: Received 14 August 2014 Received in revised form 9 February 2015 Accepted 24 February 2015 Available online 11 March 2015 Keywords: Glycemic control Pulmonary diffusing capacity Respiratory function Respiratory muscle
a b s t r a c t Objective: The aim of this study was to verify to which extent in type 2 diabetes mellitus respiratory function and respiratory muscle efficiency decline over time in relation to the quality of glycemic control (GC). Methods: Forty-five non-smoker diabetic patients without pulmonary diseases performed a complete respiratory function assessment at baseline and after a follow-up of 4.9 ± 0.6 years. The respiratory muscle efficiency was assessed by maximal inspiratory pressure (MIP) and maximum voluntary ventilation (MVV). Patients with an average yearly value of glycosylated hemoglobin ≥ 7.5% at least in two years during follow-up were considered to have a poor GC. Results: Residual volume and pulmonary diffusing capacity significantly declined over time in the whole sample of patients (p = 0.049 and 0.025, respectively), but without difference between patients with poor (n. 12) and good (n. 33) GC. MIP declined in patients with poor GC (from 83.75 ± 32.42 to 71.16 ± 30.43% pred), and increased in those with good GC (from 76.22 ± 26.00 to 82.42 ± 30.34% pred), but the difference between groups was not significant (p = 0.091). Finally, MVV significantly declined in patients with poor GC (from 70.60 ± 25.49 to 68.10 ± 18.82% pred) and increased in those with good GC (from 66.40 ± 20.39 to 84.00 ± 23.09% pred) with a significant difference between the two groups (p = 0.003). Conclusion: These results show that, in type 2 diabetic patients, respiratory muscle efficiency, but not lung volumes and diffusing capacity, might suffer from a poor GC over time. © 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction An association between diabetes mellitus and impaired lung function has been frequently observed and various respiratory functional disorders have been described in patients with either type 1 or type 2 diabetes mellitus [1]. Mechanisms potentially explaining the association between lung impairment and diabetes are microangiopathy of the alveolar capillaries and pulmonary arterioles, chronic inflammation, autonomic neuropathy involving the respiratory muscles, loss of elastic recoil secondary to collagen glycosylation of lung parenchyma, hypoxia-induced insulin resistance and low birth weight [2]. A significant time-related effect of lung injury caused by diabetes mellitus has also been detected in some longitudinal studies, showing Abbreviations: ANOVA, analysis of variance; BMI, body mass index; DLCO, pulmonary diffusing capacity for carbon monoxide; FVC, forced vital capacity; GC, glycemic control; HbA1c, glycosylated hemoglobin; KCO, coefficient of diffusion; MEP, maximal expiratory pressure; MIP, maximal inspiratory pressure; MVV, maximum voluntary ventilation; PASE, physical activity scale for the elderly; RV, residual volume; TLC, total lung capacity. ⁎ Corresponding author at: Unità di Pneumologia, Università Cattolica S. Cuore, Largo A. Gemelli 8, 00168 Roma, Italy. Tel.: +39 06 30154236; fax: +39 06 30154304. E-mail address: [email protected] (L. Fuso).
an accelerated decline in lung function in patients with diabetes [3,4]. However, in two other longitudinal studies, the Copenhagen City Heart Study [5] and the Normative Aging Study [6], lung function declined comparably in non-diabetic and diabetic subjects. In all these studies only some functional parameters have been monitored during the follow-up, particularly dynamic lung volumes, whereas the pulmonary diffusing capacity for carbon monoxide (DLCO) and the static lung volumes, such as residual volume (RV) and total lung capacity (TLC) have not. Similarly, the respiratory muscle efficiency has been rarely studied in patients with diabetes mellitus. The respiratory muscle strength has been found reduced both in type 1 [7, 8] and in type 2 diabetic patients [9] and this impairment might to some extent explain the restrictive functional pattern typically observed in patients with diabetes mellitus [10]. Further complicating the issue is the existence of conflicting data about the relationship between poor glycemic control and reduction in dynamic lung volumes [11–13]. A recent metaanalysis found that the glycemic state did not appear to influence the association between reduced lung function and diabetes mellitus [10]. This longitudinal study was designed to verify in patients with type 2 diabetes mellitus to which respective extent lung volumes, pulmonary
http://dx.doi.org/10.1016/j.ejim.2015.02.022 0953-6205/© 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
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L. Fuso et al. / European Journal of Internal Medicine 26 (2015) 273–278
diffusing capacity and respiratory muscle efficiency decline over time and whether the decline of the lung function is related or not to the quality of the glycemic control. Since respiratory and skeletal muscle weakness are strictly related [14], general physical activity has also been assessed in all the patients and related to glycemic control and muscle efficiency. 2. Materials and methods 2.1. Patients and study design We studied 45 patients (28 males and 17 females) with type 2 diabetes mellitus, diagnosed according to standardized criteria [15]. We had the opportunity of following up patients previously enrolled in another study on the respiratory effects of diabetes [9] and 45 of them agreed to be recalled in order to control their respiratory function. Criteria of exclusion from the study were current history of smoking and history or functional-radiological evidence of lung disease. The study was in accordance with the recommendations of the Helsinki Declaration. All subjects gave informed consent to participate in the study. Considering that neither interventions nor invasive procedures had to be performed on patients, the local Ethical Committee judged that the study protocol conformed to the Institution policy and did not need a formal discussion. At baseline the patients underwent a complete respiratory function assessment which was repeated at the end of the follow-up. Patients had to be in stable metabolic condition, as reflected by normal glycemic 6-point profile and absence of glycosuria, in the week prior to each assessment. The physical activity scale for the elderly (PASE) was assessed at the end of the follow-up as a measure of the physical activity [16]. During the follow-up, the patients were monitored every 3 months by a clinical visit and measurements of glycosylated hemoglobin (HbA1c) were performed to evaluate the quality of the metabolic control. Patients with an average yearly value of HbA1c ≥7.5% at least in two years during the follow-up were considered to have a poor glycemic control. We remind that the HbA1c value of 7.5% is associated with the lowest hazard for all-cause mortality [17] and, then, can be considered a reasonable cut off for categorizing the quality of glycemic control. All patients were treated with oral antidiabetic agents and 9 of them also with insulin for all the follow-up period. Lifestyle interventions, such as diet and physical activity, were strengthened in all patients during the follow-up and the dosage of the antidiabetic drugs was eventually adjusted. 2.2. Respiratory function assessment The respiratory function assessment was performed by using a computerized system (Sensor Medics Vmax 229; SensorMedics Corporation, Yorba Linda, CA, USA). Lung volumes and flows had to meet the American Thoracic Society criteria of acceptability and reproducibility of curves [18], whereas DLCO was measured by the single-breath method [19]. The coefficient of diffusion (KCO), derived from DLCO divided by lung volume, was considered as a measure of diffusion per unit of alveolar volume. All values were expressed as percentage of a normal reference population. The respiratory muscle strength and functioning was evaluated by the same computerized system measuring maximal inspiratory and expiratory pressures (MIP, MEP) and maximum voluntary ventilation (MVV). While comfortably sitting and wearing a nose clip, the patient had to seal the lips firmly around a rubber mouthpiece with flanges. An occlusion valve, distal to the pneumotachograph, could be occluded at the beginning of the manoeuvre. A small hole contained in the valve allowed an air leak and this prevented the patient from generating pressure by using the cheek muscles. To measure MIP, the patient was instructed to exhale slowly and completely up to RV and then to pull in as hard as possible against the occluded valve. The inspiratory pressure had to be maintained for at least 1.5 sec, and the largest negative
pressure sustained for at least 1 sec was recorded. The maximum MIP value of at least three different manoeuvres that varied by less than 10% was reported. For MEP measurement, the patient had to inhale completely up to TLC and then to push (or blow) as hard as possible against the occluded valve. The expiratory pressure had to be maintained for at least 1.5 sec, and the largest positive pressure sustained for at least 1 sec was recorded. The maximum MEP value of at least three different manoeuvres that varied by less than 10% was reported. In order to measure MVV, the patient was instructed to make at least three resting tidal breaths and then to breathe as deeply and rapidly as possible over a 12-sec period with a tidal volume greater than the own resting tidal volume. The breathing frequency had to be about 90 breaths/min. 2.3. Statistical analysis Unpaired t-test or chi-square test, as appropriate, were used to evaluate differences between groups. Paired t-test was used to assess differences in respiratory function indexes measured at baseline and at the end of follow-up. Differences between groups in changes of recorded variables from baseline to follow-up were assessed by the analysis of variance (ANOVA) for repeated measures having the group membership as the grouping factor. A p-value b0.05 was assumed as significant. 3. Results The follow-up lasted (mean ± SD) 4.9 ± 0.6 years. The main characteristics of the patients are reported in Table 1. The patients were, on average, overweight at the beginning of the study and their body mass index (BMI) remained substantially unchanged at the end of followup. Also hemoglobin did not change during the follow-up. On the contrary, the number of patients with diabetic complications increased, particularly those with cardiovascular comorbidity. However, no patients had signs and symptoms of an overt heart failure such to decrease the cardiac output at the end of follow-up. Changes over time in the respiratory function are reported in Table 2. Both dynamic (forced vital capacity: FVC) and static (RV and TLC) lung volumes were normal at baseline. Only RV significantly declined during the follow-up. Similarly, DLCO was normal at baseline and significantly decreased at the end of follow-up. Also KCO, a measure of diffusion per unit of alveolar volume, significantly decreased during the follow-up, thus showing that the decline of DLCO did not simply reflect a change in lung volume. Both respiratory muscle strength and functioning were slightly reduced at baseline, being less than 80% of predicted values. MIP and MEP did not significantly change during the follow-up whereas MVV surprisingly improved at the end of follow-up. The HbA1c level was on average reduced during the follow-up, from 7.18% in the first year, to 6.65% in the last year. According to the criteria mentioned above, the quality of the glycemic control during the followTable 1 Patient characteristics at the beginning of the study (baseline) and at the end of the followup. At baseline N. Gender, M/F Age, years BMI, kg/m2 Hemoglobin, g/dL Duration of disease, years Neuropathy, n. Nephropathy, n. Rethinopathy, n. Cardiovascular disease, n. PASE score
45 28/17 63.81 ± 6.36 29.46 ± 4.99 13.49 ± 1.28 15.88 ± 7.94 3 3 4 7
Values are expressed as mean ± SD. BMI: body mass index; PASE: physical activity score for the elderly.
After follow-up
68.79 ± 8.35 29.20 ± 5.08 13.57 ± 1.46 21.19 ± 11.58 8 6 6 19 116.26 ± 55.41
L. Fuso et al. / European Journal of Internal Medicine 26 (2015) 273–278 Table 2 Changes over time of the respiratory function.
FVC, % pred FEV1, % pred FEV1/FVC, % TLC, % pred RV, % pred DLCO, % pred KCO, % pred MIP, % pred MEP, % pred MVV, % pred
At baseline
After follow-up
p-value a
101.82 ± 16.96 97.43 ± 18.29 76.04 ± 6.11 91.81 ± 12.76 87.42 ± 23.72 84.76 ± 19.06 96.64 ± 26.25 78.32 ± 27.75 71.41 ± 23.97 67.60 ± 21.66
104.66 ± 15.82 101.62 ± 26.26 74.88 ± 6.88 91.44 ± 13.46 79.72 ± 15.84 78.07 ± 20.93 86.71 ± 19.05 79.28 ± 30.43 66.61 ± 18.62 79.46 ± 22.88
0.181 0.208 0.076 0.837 0.049 0.025 0.007 0.849 0.150 0.0007
Values are expressed as mean ± SD. FVC: forced vital capacity; FEV1: forced expiratory volume in 1 sec; TLC: total lung capacity; RV: residual volume; DLCO: pulmonary diffusing capacity for carbon monoxide; KCO: coefficient of diffusion; MIP: maximal inspiratory pressure; MEP: maximal expiratory pressure; MVV: maximum voluntary ventilation. a By paired t-test.
up was good in 33 patients and poor in the remaining 12. Nine of these 12 patients had a poor glycemic control in the first two years of followup: in 4 of them HbA1c levels did not change for all the follow-up period, while in the remaining 5 patients HbA1c decreased to a value b7.5%. As reported in Table 3, patients with poor glycemic control during the follow-up were at baseline somewhat older, had a significantly higher duration of disease and prevalence of diabetic complications. They had also a significantly lower value of DLCO. The changes over time of the respiratory function data in patients with good and poor glycemic control are reported in Table 4. RV and DLCO declined in both groups, irrespective of the quality of glycemic control. As shown in Fig. 1, the DLCO changes in each group were nearly significant (p = 0.069) but without difference between groups (p = 0.744). MIP and MEP did not significantly change in both groups, but MIP slightly increased in patients with a good glycemic control and decreased in those with a poor control and the difference between groups was nearly significant (p = 0.091). Similarly, as shown in Fig. 2, MVV improved in patients with a good glycemic control and decreased in those with a poor glycemic control. The MVV changes over time were significant in each group (p = 0.021) and also significant was the difference between groups (p = 0.003). Finally, the PASE score was significantly higher in patients with a good than in patients with a poor glycemic control (126.58 ± 51.78 vs 88.75 ± 57.55, respectively; t = 2.09, p = 0.042), as expression of a greater physical activity in the former group of patients. 4. Discussion This study shows that diabetes, in the absence of overt pulmonary disease, is a risk factor for the decline of DLCO and, to a lesser extent, Table 3 Comparison at baseline between patients with good (n. 33) and poor (n. 12) glycemic control (GC).
Age, years BMI, kg/m2 Duration of disease, years At least one complication, n. (%) FVC, % pred TLC, % pred RV, % pred DLCO, % pred
Good GC
Poor GC
p-value a
62.87 ± 6.63 28.85 ± 4.71 11.97 ± 6.66 5 (15%)
66.33 ± 4.99 31.11 ± 5.54 20.00 ± 8.32 7 (58%)
0.109 0.183 0.002 0.012
103.12 ± 17.47 93.00 ± 14.13 88.55 ± 26.92 88.55 ± 18.87
98.33 ± 15.69 88.75 ± 7.95 84.50 ± 12.61 74.09 ± 14.41
0.410 0.333 0.621 0.028
Values are expressed as mean ± SD. BMI: body mass index; FVC: forced vital capacity; TLC: total lung capacity; RV: residual volume; DLCO: pulmonary diffusing capacity for carbon monoxide. a By unpaired t-test or chi-square test, as appropriate.
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RV over time. However, the lack of decline of TLC casts some doubt about whether the accelerated decline of RV might explain the high prevalence of a restrictive dysfunction observed in diabetic patients [10]. On the other hand, we could not observe any significant decrease of dynamic lung volumes, which to some extent differs from the majority of studies on this topic. Indeed, in the Freemantle study, the decline of FVC was faster than expected and directly related to glycemic exposure, as expressed by HbA1c values [3]. The Atherosclerosis Risk in Communities Study confirmed that diabetes is associated with lower baseline values and accelerated decline of FVC over 3 years [4]. In another study, both FVC and DLCO significantly diminished during a 5-year follow-up in a small group of type 1 diabetic patients [20]. On the other hand, in two longitudinal studies the association between HbA1c levels and spirometric measurements was weak or absent [12, 13], and a recent metaanalysis denied any association between glycemic control and lung function [10]. In conclusion, there is no consensus of opinion on how quality of glycemic control relates to decline of dynamic lung function. However, the fact that in the study by Davis et al [3], the glycemic exposure, in the form of the updated mean or follow-up HbA1c, was a strong and consistent negative predictor of follow-up lung function supports the link between glycemic control and evolution of dynamic lung volumes. Accordingly, the good glycemic control achieved in the vast majority of our patients likely accounted for the lack of association between glycemic control and evolution of FVC. Our data confirm that DLCO significantly declined over time and therefore could be considered a sensitive index of lung damage in diabetes mellitus [20]. This could explain also the lower value of DLCO recorded at baseline in our patients with a poor glycemic control during the follow-up. Indeed, they had a significantly longer duration of disease at baseline in comparison with the patients with a good glycemic control and this feature could have negatively affected this sensitive functional index. Like in other organs, diabetic microangiopathy likely underlies DLCO changes; indeed, the reduction of DLCO in diabetic patients correlates with the severity of other vascular complications, such as retinopathy and renal microangiopathy, as expressed by an elevated 24-hour protein excretion rate (microalbuminuria) [21]. In diabetic lung, the increased thickness of the alveolar-capillary barrier and the expansion of the interstitium result in a reduction of alveolar space and a narrowing of the pulmonary capillary network [22]. These findings likely underlie the defective recruitment of pulmonary capillaries in response to increased requests, as during physical exercise or after postural changes [23,24]. Therefore, the reduction of DLCO in diabetic patients reflects both decreased pulmonary capillary blood volume and alveolarcapillary membrane conductance, both expressions of diabetic pulmonary microangiopathy. However, the fact that DLCO decline was unrelated to the quality of glycemic control, which is known to affect the progression of microangiopathy [25,26], challenges this interpretation. Thus, it might be useful to monitor DLCO in diabetic patients: identifying fast decliners might allow recognize, as for the well-known diabetic complications such as neuropathy or nephropathy, the inherent profile of risk. Our data showed a distinctive relationship between glycemic control and respiratory muscle efficiency. Indeed, MIP and especially MVV increased in patients with a good glycemic control and decreased in those with a poor glycemic control. The higher prevalence of well controlled patients (n. 33 vs 12) accounts for the seemingly paradoxical increased average MVV in the whole sample, as reported in Table 2. Although MIP is commonly considered an index of respiratory muscle strength, MVV is a parameter that reflects not only the respiratory muscle functioning but also lung volume changes, compliance of the thorax-lung complex and airway resistance [27]. However, it can be used as a simple tool for assessment of respiratory muscle weakness [28]. The respiratory muscle efficiency has been rarely investigated in diabetes, mainly in type 1 diabetic patients and only in cross-sectional
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Table 4 Changes over time of the respiratory function in patients with good (n. 33) and poor (n. 12) glycemic control (GC).
RV, % pred Good GC RV, % pred Poor GC DLCO, % pred Good GC DLCO, % pred Poor GC MIP, % pred Good GC MIP, % pred Poor GC MEP, % pred Good GC MEP, % pred Poor GC MVV, % pred Good GC MVV, % pred Poor GC
At baseline
After follow-up
p-value a
88.54 ± 26.92 84.50 ± 12.61 88.55 ± 19.09 74.09 ± 15.03 76.22 ± 26.00 83.75 ± 32.42 71.31 ± 22.59 71.67 ± 28.42 66.40 ± 20.39 70.60 ± 25.49
79.48 ± 17.38 80.33 ± 11.55 81.29 ± 19.62 69.00 ± 22.79 82.42 ± 30.34 71.16 ± 30.43 67.25 ± 19.54 64.92 ± 16.58 84.00 ± 23.09 68.10 ± 18.82
Within groups difference: p = 0.129 Between groups difference: p = 0.569 Within groups difference: p = 0.069 Between groups difference: p = 0.744 Within groups difference: p = 0.559 Between groups difference: p = 0.091 Within groups difference: p = 0.153 Between groups difference: p = 0.719 Within groups difference: p = 0.021 Between groups difference: p = 0.003
Values are expressed as mean ± SD. RV: residual volume; DLCO: pulmonary diffusing capacity for carbon monoxide; MIP: maximal inspiratory pressure; MEP: maximal expiratory pressure; MVV: maximum voluntary ventilation. a By ANOVA for repeated measures.
studies. In these studies, respiratory muscle strength has been found to be generally depressed [7,8]. In a previous study conducted in 75 type 2 diabetic patients, we showed that their respiratory muscle strength was reduced in comparison with control subjects and significantly related to lung volumes [9]. In the same study, more than one third of patients had reduced MVV, and this deficit was more prevalent in the presence of diabetic microvascular complications [9]. Present data confirm that an optimal glycemic control, which is known to prevent microangiopathy [25,26], preserves muscle efficiency. A greater physical activity, as assessed by the PASE score, likely contributed to a better glycemic control. Indeed, exercise contrasts insulin resistance in muscle tissue as efficiently in diabetic patients as in healthy subjects [29]. Furthermore, exercise might per se improve muscle strength and functioning [30]. Thus, exercise is expected to improve muscle efficiency, and better glycemic control might be an intermediate rather than a primary protective mechanism. Present data do not allow solve this doubt. They only point at better glycemic control and greater physical activity as notable correlates of preserved muscle efficiency. Present findings might have implications for the diagnosis and characterization of chronic obstructive pulmonary disease (COPD), which frequently coexists with diabetes [31]. Indeed, COPD is associated with
important changes in the structure and function of respiratory muscles [32] as well as with impaired DLCO, mainly in the emphysematous phenotype [33]. Furthermore, a consistent proportion of COPD patients has a mixed, i. e. partly restrictive, lung dysfunction [34]. Thus, diabetes might exacerbate these traits and contribute to phenotyping COPD patients. Accordingly, attempts at characterizing subsets of COPD patients on pathophysiological and clinical bases imply that the contributory role of diabetes be taken into account. Limitations of this study deserve consideration. First, we dealt with a convenient and small sample of patients so that our data need to be considered preliminary in nature. Second, the fact that our patients had their glycemia carefully controlled likely makes our data not fully representative of what happens in an average diabetic population. Finally, we could not explore the possibility that the type of hypoglycemic therapy per se affected the outcome. However, all the patients were homogeneously treated with oral antidiabetic agents and 9 of them also with insulin. These were 5 in group with a poor glycemic control and 4 in group with a good control and thus, we can speculate that insulin therapy likely did not affect results. In conclusion, these findings suggest that a strict glycemic control slows the decline of respiratory muscle efficiency, but not of pulmonary
Fig. 1. Changes over time in pulmonary diffusing capacity (DLCO) in patients with good (continuous line) and poor (dashed line) glycemic control. Within groups difference: p = 0.069 and between groups difference: p = 0.744, by ANOVA for repeated measures. The mean values for the whole group, at baseline and after follow-up, are reported. Values are expressed as mean with standard error.
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Fig. 2. Changes over time in maximum voluntary ventilation (MVV) in patients with good (continuous line) and poor (dashed line) glycemic control. Within groups difference: p = 0.021 and between groups difference: p = 0.003, by ANOVA for repeated measures. The mean values for the whole group, at baseline and after follow-up, are reported. Values are expressed as mean with standard error.
volumes and gas exchanges. While pulmonary microangiopathy and, thus, impaired alveolar-capillary gas transfer seems to mediate several respiratory untoward effects of diabetes [2], the fact that better glycemic control did not afford protection against DLCO decline calls for alternative explanations and stimulates inherent research. Learning points • This study shows that diabetes mellitus is a risk factor for the decline over time of static lung volumes such as the residual volume. This could contribute to explain the high prevalence of a restrictive functional pattern observed in diabetic patients. • Pulmonary diffusing capacity significantly declined over time and therefore could be considered a sensitive index of lung damage in diabetes mellitus. • The decline of the lung function was not related to the quality of glycemic control during the follow-up. • A distinctive relationship was found between glycemic control and respiratory muscle efficiency which increased in patients with a good glycemic control and decreased in those with a poor glycemic control.
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Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original Article
Decline of the lung function and quality of glycemic control in type 2 diabetes mellitus Leonello Fuso a,⁎, Dario Pitocco b, Carola Condoluci a, Emanuele Conte a, Chiara Contu a, Alessandro Rizzi b, Giulia Angeletti a, Benedetta F. Bibi a, Raffaele Antonelli-Incalzi c a b c
Pulmonary Medicine Unit, Catholic University, Rome, Italy Diabetology Unit, Catholic University, Rome, Italy Department of Geriatrics, Campus Biomedico University, Rome, Italy
a r t i c l e
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Article history: Received 14 August 2014 Received in revised form 9 February 2015 Accepted 24 February 2015 Available online 11 March 2015 Keywords: Glycemic control Pulmonary diffusing capacity Respiratory function Respiratory muscle
a b s t r a c t Objective: The aim of this study was to verify to which extent in type 2 diabetes mellitus respiratory function and respiratory muscle efficiency decline over time in relation to the quality of glycemic control (GC). Methods: Forty-five non-smoker diabetic patients without pulmonary diseases performed a complete respiratory function assessment at baseline and after a follow-up of 4.9 ± 0.6 years. The respiratory muscle efficiency was assessed by maximal inspiratory pressure (MIP) and maximum voluntary ventilation (MVV). Patients with an average yearly value of glycosylated hemoglobin ≥ 7.5% at least in two years during follow-up were considered to have a poor GC. Results: Residual volume and pulmonary diffusing capacity significantly declined over time in the whole sample of patients (p = 0.049 and 0.025, respectively), but without difference between patients with poor (n. 12) and good (n. 33) GC. MIP declined in patients with poor GC (from 83.75 ± 32.42 to 71.16 ± 30.43% pred), and increased in those with good GC (from 76.22 ± 26.00 to 82.42 ± 30.34% pred), but the difference between groups was not significant (p = 0.091). Finally, MVV significantly declined in patients with poor GC (from 70.60 ± 25.49 to 68.10 ± 18.82% pred) and increased in those with good GC (from 66.40 ± 20.39 to 84.00 ± 23.09% pred) with a significant difference between the two groups (p = 0.003). Conclusion: These results show that, in type 2 diabetic patients, respiratory muscle efficiency, but not lung volumes and diffusing capacity, might suffer from a poor GC over time. © 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction An association between diabetes mellitus and impaired lung function has been frequently observed and various respiratory functional disorders have been described in patients with either type 1 or type 2 diabetes mellitus [1]. Mechanisms potentially explaining the association between lung impairment and diabetes are microangiopathy of the alveolar capillaries and pulmonary arterioles, chronic inflammation, autonomic neuropathy involving the respiratory muscles, loss of elastic recoil secondary to collagen glycosylation of lung parenchyma, hypoxia-induced insulin resistance and low birth weight [2]. A significant time-related effect of lung injury caused by diabetes mellitus has also been detected in some longitudinal studies, showing Abbreviations: ANOVA, analysis of variance; BMI, body mass index; DLCO, pulmonary diffusing capacity for carbon monoxide; FVC, forced vital capacity; GC, glycemic control; HbA1c, glycosylated hemoglobin; KCO, coefficient of diffusion; MEP, maximal expiratory pressure; MIP, maximal inspiratory pressure; MVV, maximum voluntary ventilation; PASE, physical activity scale for the elderly; RV, residual volume; TLC, total lung capacity. ⁎ Corresponding author at: Unità di Pneumologia, Università Cattolica S. Cuore, Largo A. Gemelli 8, 00168 Roma, Italy. Tel.: +39 06 30154236; fax: +39 06 30154304. E-mail address: [email protected] (L. Fuso).
an accelerated decline in lung function in patients with diabetes [3,4]. However, in two other longitudinal studies, the Copenhagen City Heart Study [5] and the Normative Aging Study [6], lung function declined comparably in non-diabetic and diabetic subjects. In all these studies only some functional parameters have been monitored during the follow-up, particularly dynamic lung volumes, whereas the pulmonary diffusing capacity for carbon monoxide (DLCO) and the static lung volumes, such as residual volume (RV) and total lung capacity (TLC) have not. Similarly, the respiratory muscle efficiency has been rarely studied in patients with diabetes mellitus. The respiratory muscle strength has been found reduced both in type 1 [7, 8] and in type 2 diabetic patients [9] and this impairment might to some extent explain the restrictive functional pattern typically observed in patients with diabetes mellitus [10]. Further complicating the issue is the existence of conflicting data about the relationship between poor glycemic control and reduction in dynamic lung volumes [11–13]. A recent metaanalysis found that the glycemic state did not appear to influence the association between reduced lung function and diabetes mellitus [10]. This longitudinal study was designed to verify in patients with type 2 diabetes mellitus to which respective extent lung volumes, pulmonary
http://dx.doi.org/10.1016/j.ejim.2015.02.022 0953-6205/© 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
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diffusing capacity and respiratory muscle efficiency decline over time and whether the decline of the lung function is related or not to the quality of the glycemic control. Since respiratory and skeletal muscle weakness are strictly related [14], general physical activity has also been assessed in all the patients and related to glycemic control and muscle efficiency. 2. Materials and methods 2.1. Patients and study design We studied 45 patients (28 males and 17 females) with type 2 diabetes mellitus, diagnosed according to standardized criteria [15]. We had the opportunity of following up patients previously enrolled in another study on the respiratory effects of diabetes [9] and 45 of them agreed to be recalled in order to control their respiratory function. Criteria of exclusion from the study were current history of smoking and history or functional-radiological evidence of lung disease. The study was in accordance with the recommendations of the Helsinki Declaration. All subjects gave informed consent to participate in the study. Considering that neither interventions nor invasive procedures had to be performed on patients, the local Ethical Committee judged that the study protocol conformed to the Institution policy and did not need a formal discussion. At baseline the patients underwent a complete respiratory function assessment which was repeated at the end of the follow-up. Patients had to be in stable metabolic condition, as reflected by normal glycemic 6-point profile and absence of glycosuria, in the week prior to each assessment. The physical activity scale for the elderly (PASE) was assessed at the end of the follow-up as a measure of the physical activity [16]. During the follow-up, the patients were monitored every 3 months by a clinical visit and measurements of glycosylated hemoglobin (HbA1c) were performed to evaluate the quality of the metabolic control. Patients with an average yearly value of HbA1c ≥7.5% at least in two years during the follow-up were considered to have a poor glycemic control. We remind that the HbA1c value of 7.5% is associated with the lowest hazard for all-cause mortality [17] and, then, can be considered a reasonable cut off for categorizing the quality of glycemic control. All patients were treated with oral antidiabetic agents and 9 of them also with insulin for all the follow-up period. Lifestyle interventions, such as diet and physical activity, were strengthened in all patients during the follow-up and the dosage of the antidiabetic drugs was eventually adjusted. 2.2. Respiratory function assessment The respiratory function assessment was performed by using a computerized system (Sensor Medics Vmax 229; SensorMedics Corporation, Yorba Linda, CA, USA). Lung volumes and flows had to meet the American Thoracic Society criteria of acceptability and reproducibility of curves [18], whereas DLCO was measured by the single-breath method [19]. The coefficient of diffusion (KCO), derived from DLCO divided by lung volume, was considered as a measure of diffusion per unit of alveolar volume. All values were expressed as percentage of a normal reference population. The respiratory muscle strength and functioning was evaluated by the same computerized system measuring maximal inspiratory and expiratory pressures (MIP, MEP) and maximum voluntary ventilation (MVV). While comfortably sitting and wearing a nose clip, the patient had to seal the lips firmly around a rubber mouthpiece with flanges. An occlusion valve, distal to the pneumotachograph, could be occluded at the beginning of the manoeuvre. A small hole contained in the valve allowed an air leak and this prevented the patient from generating pressure by using the cheek muscles. To measure MIP, the patient was instructed to exhale slowly and completely up to RV and then to pull in as hard as possible against the occluded valve. The inspiratory pressure had to be maintained for at least 1.5 sec, and the largest negative
pressure sustained for at least 1 sec was recorded. The maximum MIP value of at least three different manoeuvres that varied by less than 10% was reported. For MEP measurement, the patient had to inhale completely up to TLC and then to push (or blow) as hard as possible against the occluded valve. The expiratory pressure had to be maintained for at least 1.5 sec, and the largest positive pressure sustained for at least 1 sec was recorded. The maximum MEP value of at least three different manoeuvres that varied by less than 10% was reported. In order to measure MVV, the patient was instructed to make at least three resting tidal breaths and then to breathe as deeply and rapidly as possible over a 12-sec period with a tidal volume greater than the own resting tidal volume. The breathing frequency had to be about 90 breaths/min. 2.3. Statistical analysis Unpaired t-test or chi-square test, as appropriate, were used to evaluate differences between groups. Paired t-test was used to assess differences in respiratory function indexes measured at baseline and at the end of follow-up. Differences between groups in changes of recorded variables from baseline to follow-up were assessed by the analysis of variance (ANOVA) for repeated measures having the group membership as the grouping factor. A p-value b0.05 was assumed as significant. 3. Results The follow-up lasted (mean ± SD) 4.9 ± 0.6 years. The main characteristics of the patients are reported in Table 1. The patients were, on average, overweight at the beginning of the study and their body mass index (BMI) remained substantially unchanged at the end of followup. Also hemoglobin did not change during the follow-up. On the contrary, the number of patients with diabetic complications increased, particularly those with cardiovascular comorbidity. However, no patients had signs and symptoms of an overt heart failure such to decrease the cardiac output at the end of follow-up. Changes over time in the respiratory function are reported in Table 2. Both dynamic (forced vital capacity: FVC) and static (RV and TLC) lung volumes were normal at baseline. Only RV significantly declined during the follow-up. Similarly, DLCO was normal at baseline and significantly decreased at the end of follow-up. Also KCO, a measure of diffusion per unit of alveolar volume, significantly decreased during the follow-up, thus showing that the decline of DLCO did not simply reflect a change in lung volume. Both respiratory muscle strength and functioning were slightly reduced at baseline, being less than 80% of predicted values. MIP and MEP did not significantly change during the follow-up whereas MVV surprisingly improved at the end of follow-up. The HbA1c level was on average reduced during the follow-up, from 7.18% in the first year, to 6.65% in the last year. According to the criteria mentioned above, the quality of the glycemic control during the followTable 1 Patient characteristics at the beginning of the study (baseline) and at the end of the followup. At baseline N. Gender, M/F Age, years BMI, kg/m2 Hemoglobin, g/dL Duration of disease, years Neuropathy, n. Nephropathy, n. Rethinopathy, n. Cardiovascular disease, n. PASE score
45 28/17 63.81 ± 6.36 29.46 ± 4.99 13.49 ± 1.28 15.88 ± 7.94 3 3 4 7
Values are expressed as mean ± SD. BMI: body mass index; PASE: physical activity score for the elderly.
After follow-up
68.79 ± 8.35 29.20 ± 5.08 13.57 ± 1.46 21.19 ± 11.58 8 6 6 19 116.26 ± 55.41
L. Fuso et al. / European Journal of Internal Medicine 26 (2015) 273–278 Table 2 Changes over time of the respiratory function.
FVC, % pred FEV1, % pred FEV1/FVC, % TLC, % pred RV, % pred DLCO, % pred KCO, % pred MIP, % pred MEP, % pred MVV, % pred
At baseline
After follow-up
p-value a
101.82 ± 16.96 97.43 ± 18.29 76.04 ± 6.11 91.81 ± 12.76 87.42 ± 23.72 84.76 ± 19.06 96.64 ± 26.25 78.32 ± 27.75 71.41 ± 23.97 67.60 ± 21.66
104.66 ± 15.82 101.62 ± 26.26 74.88 ± 6.88 91.44 ± 13.46 79.72 ± 15.84 78.07 ± 20.93 86.71 ± 19.05 79.28 ± 30.43 66.61 ± 18.62 79.46 ± 22.88
0.181 0.208 0.076 0.837 0.049 0.025 0.007 0.849 0.150 0.0007
Values are expressed as mean ± SD. FVC: forced vital capacity; FEV1: forced expiratory volume in 1 sec; TLC: total lung capacity; RV: residual volume; DLCO: pulmonary diffusing capacity for carbon monoxide; KCO: coefficient of diffusion; MIP: maximal inspiratory pressure; MEP: maximal expiratory pressure; MVV: maximum voluntary ventilation. a By paired t-test.
up was good in 33 patients and poor in the remaining 12. Nine of these 12 patients had a poor glycemic control in the first two years of followup: in 4 of them HbA1c levels did not change for all the follow-up period, while in the remaining 5 patients HbA1c decreased to a value b7.5%. As reported in Table 3, patients with poor glycemic control during the follow-up were at baseline somewhat older, had a significantly higher duration of disease and prevalence of diabetic complications. They had also a significantly lower value of DLCO. The changes over time of the respiratory function data in patients with good and poor glycemic control are reported in Table 4. RV and DLCO declined in both groups, irrespective of the quality of glycemic control. As shown in Fig. 1, the DLCO changes in each group were nearly significant (p = 0.069) but without difference between groups (p = 0.744). MIP and MEP did not significantly change in both groups, but MIP slightly increased in patients with a good glycemic control and decreased in those with a poor control and the difference between groups was nearly significant (p = 0.091). Similarly, as shown in Fig. 2, MVV improved in patients with a good glycemic control and decreased in those with a poor glycemic control. The MVV changes over time were significant in each group (p = 0.021) and also significant was the difference between groups (p = 0.003). Finally, the PASE score was significantly higher in patients with a good than in patients with a poor glycemic control (126.58 ± 51.78 vs 88.75 ± 57.55, respectively; t = 2.09, p = 0.042), as expression of a greater physical activity in the former group of patients. 4. Discussion This study shows that diabetes, in the absence of overt pulmonary disease, is a risk factor for the decline of DLCO and, to a lesser extent, Table 3 Comparison at baseline between patients with good (n. 33) and poor (n. 12) glycemic control (GC).
Age, years BMI, kg/m2 Duration of disease, years At least one complication, n. (%) FVC, % pred TLC, % pred RV, % pred DLCO, % pred
Good GC
Poor GC
p-value a
62.87 ± 6.63 28.85 ± 4.71 11.97 ± 6.66 5 (15%)
66.33 ± 4.99 31.11 ± 5.54 20.00 ± 8.32 7 (58%)
0.109 0.183 0.002 0.012
103.12 ± 17.47 93.00 ± 14.13 88.55 ± 26.92 88.55 ± 18.87
98.33 ± 15.69 88.75 ± 7.95 84.50 ± 12.61 74.09 ± 14.41
0.410 0.333 0.621 0.028
Values are expressed as mean ± SD. BMI: body mass index; FVC: forced vital capacity; TLC: total lung capacity; RV: residual volume; DLCO: pulmonary diffusing capacity for carbon monoxide. a By unpaired t-test or chi-square test, as appropriate.
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RV over time. However, the lack of decline of TLC casts some doubt about whether the accelerated decline of RV might explain the high prevalence of a restrictive dysfunction observed in diabetic patients [10]. On the other hand, we could not observe any significant decrease of dynamic lung volumes, which to some extent differs from the majority of studies on this topic. Indeed, in the Freemantle study, the decline of FVC was faster than expected and directly related to glycemic exposure, as expressed by HbA1c values [3]. The Atherosclerosis Risk in Communities Study confirmed that diabetes is associated with lower baseline values and accelerated decline of FVC over 3 years [4]. In another study, both FVC and DLCO significantly diminished during a 5-year follow-up in a small group of type 1 diabetic patients [20]. On the other hand, in two longitudinal studies the association between HbA1c levels and spirometric measurements was weak or absent [12, 13], and a recent metaanalysis denied any association between glycemic control and lung function [10]. In conclusion, there is no consensus of opinion on how quality of glycemic control relates to decline of dynamic lung function. However, the fact that in the study by Davis et al [3], the glycemic exposure, in the form of the updated mean or follow-up HbA1c, was a strong and consistent negative predictor of follow-up lung function supports the link between glycemic control and evolution of dynamic lung volumes. Accordingly, the good glycemic control achieved in the vast majority of our patients likely accounted for the lack of association between glycemic control and evolution of FVC. Our data confirm that DLCO significantly declined over time and therefore could be considered a sensitive index of lung damage in diabetes mellitus [20]. This could explain also the lower value of DLCO recorded at baseline in our patients with a poor glycemic control during the follow-up. Indeed, they had a significantly longer duration of disease at baseline in comparison with the patients with a good glycemic control and this feature could have negatively affected this sensitive functional index. Like in other organs, diabetic microangiopathy likely underlies DLCO changes; indeed, the reduction of DLCO in diabetic patients correlates with the severity of other vascular complications, such as retinopathy and renal microangiopathy, as expressed by an elevated 24-hour protein excretion rate (microalbuminuria) [21]. In diabetic lung, the increased thickness of the alveolar-capillary barrier and the expansion of the interstitium result in a reduction of alveolar space and a narrowing of the pulmonary capillary network [22]. These findings likely underlie the defective recruitment of pulmonary capillaries in response to increased requests, as during physical exercise or after postural changes [23,24]. Therefore, the reduction of DLCO in diabetic patients reflects both decreased pulmonary capillary blood volume and alveolarcapillary membrane conductance, both expressions of diabetic pulmonary microangiopathy. However, the fact that DLCO decline was unrelated to the quality of glycemic control, which is known to affect the progression of microangiopathy [25,26], challenges this interpretation. Thus, it might be useful to monitor DLCO in diabetic patients: identifying fast decliners might allow recognize, as for the well-known diabetic complications such as neuropathy or nephropathy, the inherent profile of risk. Our data showed a distinctive relationship between glycemic control and respiratory muscle efficiency. Indeed, MIP and especially MVV increased in patients with a good glycemic control and decreased in those with a poor glycemic control. The higher prevalence of well controlled patients (n. 33 vs 12) accounts for the seemingly paradoxical increased average MVV in the whole sample, as reported in Table 2. Although MIP is commonly considered an index of respiratory muscle strength, MVV is a parameter that reflects not only the respiratory muscle functioning but also lung volume changes, compliance of the thorax-lung complex and airway resistance [27]. However, it can be used as a simple tool for assessment of respiratory muscle weakness [28]. The respiratory muscle efficiency has been rarely investigated in diabetes, mainly in type 1 diabetic patients and only in cross-sectional
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Table 4 Changes over time of the respiratory function in patients with good (n. 33) and poor (n. 12) glycemic control (GC).
RV, % pred Good GC RV, % pred Poor GC DLCO, % pred Good GC DLCO, % pred Poor GC MIP, % pred Good GC MIP, % pred Poor GC MEP, % pred Good GC MEP, % pred Poor GC MVV, % pred Good GC MVV, % pred Poor GC
At baseline
After follow-up
p-value a
88.54 ± 26.92 84.50 ± 12.61 88.55 ± 19.09 74.09 ± 15.03 76.22 ± 26.00 83.75 ± 32.42 71.31 ± 22.59 71.67 ± 28.42 66.40 ± 20.39 70.60 ± 25.49
79.48 ± 17.38 80.33 ± 11.55 81.29 ± 19.62 69.00 ± 22.79 82.42 ± 30.34 71.16 ± 30.43 67.25 ± 19.54 64.92 ± 16.58 84.00 ± 23.09 68.10 ± 18.82
Within groups difference: p = 0.129 Between groups difference: p = 0.569 Within groups difference: p = 0.069 Between groups difference: p = 0.744 Within groups difference: p = 0.559 Between groups difference: p = 0.091 Within groups difference: p = 0.153 Between groups difference: p = 0.719 Within groups difference: p = 0.021 Between groups difference: p = 0.003
Values are expressed as mean ± SD. RV: residual volume; DLCO: pulmonary diffusing capacity for carbon monoxide; MIP: maximal inspiratory pressure; MEP: maximal expiratory pressure; MVV: maximum voluntary ventilation. a By ANOVA for repeated measures.
studies. In these studies, respiratory muscle strength has been found to be generally depressed [7,8]. In a previous study conducted in 75 type 2 diabetic patients, we showed that their respiratory muscle strength was reduced in comparison with control subjects and significantly related to lung volumes [9]. In the same study, more than one third of patients had reduced MVV, and this deficit was more prevalent in the presence of diabetic microvascular complications [9]. Present data confirm that an optimal glycemic control, which is known to prevent microangiopathy [25,26], preserves muscle efficiency. A greater physical activity, as assessed by the PASE score, likely contributed to a better glycemic control. Indeed, exercise contrasts insulin resistance in muscle tissue as efficiently in diabetic patients as in healthy subjects [29]. Furthermore, exercise might per se improve muscle strength and functioning [30]. Thus, exercise is expected to improve muscle efficiency, and better glycemic control might be an intermediate rather than a primary protective mechanism. Present data do not allow solve this doubt. They only point at better glycemic control and greater physical activity as notable correlates of preserved muscle efficiency. Present findings might have implications for the diagnosis and characterization of chronic obstructive pulmonary disease (COPD), which frequently coexists with diabetes [31]. Indeed, COPD is associated with
important changes in the structure and function of respiratory muscles [32] as well as with impaired DLCO, mainly in the emphysematous phenotype [33]. Furthermore, a consistent proportion of COPD patients has a mixed, i. e. partly restrictive, lung dysfunction [34]. Thus, diabetes might exacerbate these traits and contribute to phenotyping COPD patients. Accordingly, attempts at characterizing subsets of COPD patients on pathophysiological and clinical bases imply that the contributory role of diabetes be taken into account. Limitations of this study deserve consideration. First, we dealt with a convenient and small sample of patients so that our data need to be considered preliminary in nature. Second, the fact that our patients had their glycemia carefully controlled likely makes our data not fully representative of what happens in an average diabetic population. Finally, we could not explore the possibility that the type of hypoglycemic therapy per se affected the outcome. However, all the patients were homogeneously treated with oral antidiabetic agents and 9 of them also with insulin. These were 5 in group with a poor glycemic control and 4 in group with a good control and thus, we can speculate that insulin therapy likely did not affect results. In conclusion, these findings suggest that a strict glycemic control slows the decline of respiratory muscle efficiency, but not of pulmonary
Fig. 1. Changes over time in pulmonary diffusing capacity (DLCO) in patients with good (continuous line) and poor (dashed line) glycemic control. Within groups difference: p = 0.069 and between groups difference: p = 0.744, by ANOVA for repeated measures. The mean values for the whole group, at baseline and after follow-up, are reported. Values are expressed as mean with standard error.
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Fig. 2. Changes over time in maximum voluntary ventilation (MVV) in patients with good (continuous line) and poor (dashed line) glycemic control. Within groups difference: p = 0.021 and between groups difference: p = 0.003, by ANOVA for repeated measures. The mean values for the whole group, at baseline and after follow-up, are reported. Values are expressed as mean with standard error.
volumes and gas exchanges. While pulmonary microangiopathy and, thus, impaired alveolar-capillary gas transfer seems to mediate several respiratory untoward effects of diabetes [2], the fact that better glycemic control did not afford protection against DLCO decline calls for alternative explanations and stimulates inherent research. Learning points • This study shows that diabetes mellitus is a risk factor for the decline over time of static lung volumes such as the residual volume. This could contribute to explain the high prevalence of a restrictive functional pattern observed in diabetic patients. • Pulmonary diffusing capacity significantly declined over time and therefore could be considered a sensitive index of lung damage in diabetes mellitus. • The decline of the lung function was not related to the quality of glycemic control during the follow-up. • A distinctive relationship was found between glycemic control and respiratory muscle efficiency which increased in patients with a good glycemic control and decreased in those with a poor glycemic control.
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