Introduction
Grade | Severity | Spirometry findings |
---|---|---|
GOLD 1
|
Mild
|
FEV
1
/FVC<0.7 and FEV
1
≥80% predicted
|
GOLD 2
|
Moderate
|
FEV
1
/FVC<0.7 and 50%≤FEV
1
≥80% predicted
|
GOLD 3
|
Severe
|
FEV
1
/FVC<0.7 and 30%≤FEV
1
≥50% predicted
|
GOLD 4
|
Very Severe
|
FEV
1
/FVC<0.7 and FEV
1
>30% predicted
|
Pathophysiology of glucose metabolism disturbances in COPD
Weight as a risk factor for COPD
Adipokines and COPD
Name | Major origin | Physiological function | Data on COPD | Data on DM |
---|---|---|---|---|
CRP | Liver/Hepatocyte | Proinflammatory. | COPD is independently associated with increased levels of CRP. Moreover, CRP may predict the future onset of COPD. | Elevated CRP levels may predict the development of onset of type 2 DM. |
TNF-α | Macrophages, other leukocytes and adipocytes | Proinflammatory and proapoptotic. Possible insulin antagonism. | COPD is independently associated with increased levels of TNF-α | May be a risk factor for the development of new onset type 2 DM. |
IL-1 | Macrophages, other leukocytes, dendritic cells etc. | Proinflammatory. Lymphocyte activation | IL-1 is implicated in the pathogenesis of COPD related inflammation. | An increase in IL-1β may predict the development of new onset type 2 DM. |
IL-6 | Lvier/Hepatocyte, macrophages, other leukocytes, adipocytes etc. | Proinflammatory. Upregulation of the synthesis of CRP and other proinflammatory cytokines in the liver. | COPD is independently associated with increased levels of IL-6. | IL-6 was shown to increase the risk for the new onset type 2 DM. |
Fibrinogen | Liver/Hepatocyte | Proinflammatory. Active participation in coagulation. | COPD is independently associated with increased fibrinogen levels. | No data on fibrinogen and the risk of new onset type 2 DM. |
Leptin | Adipocyte | Appetite regulation. Possible proinflammatory actions. | Leptin levels are increased in patients with COPD. May contribute to COPD related weight loss and pulmonary function decline. | Leptin may increase the risk of type 2 DM. Leptin may participate in the development of DM related complications via its proinflammatory actions. |
Adiponectin | Adipocyte | Antiinflammatory. Increase in insulin synthesis and increase in insulin sensitivity. | Adiponectin levels are increased in patients with COPD and low BMI, which may explain decreased mortality from cardiovascular causes in advanced COPD. | Adiponectin may prevent the development of type 2 DM via its anti-inflammatory and proinsulin actions. |
Resistin | Leukocytes | Proinflammatory and insulin antagonizing actions. | Resistin levels may be increased in COPD and mediate IR. | Resistin may directly participate in the development of IR. |
COPD, systemic inflammation and oxidative stress
Hypoxia and glucose metabolism
Muscle metabolic pathways in COPD
COPD and hormonal dysregulation
Clinical data on COPD and the risk of DM/MetS
COPD, reduced lung function and the risk of new onset type 2 DM
Reduced lung function and the risk of type 2 DM
First author and year | Country | Study design | Population studied | Findings |
---|---|---|---|---|
Lazarus et al.[119]; 1998 | USA | Prospective cohort study with a mean follow up of 20.9 years | n:1,050 men (with no self-reported DM) included in the final analysis mean age: 41.4 years mean BMI: 25.6 kg/m² | Reduced FVC, FEV1 and MMEF were associated with greater fasting insulin and fasting insulin resistance after logistic regression analysis. |
Engström et al.[124]; 2002 | Sweden | Prospective cohort study with a mean follow up of 13 years | n: 382 non-diabetic men age at the beginning of the study:55 years mean BMI: 24.4-24.7 years (depends on the pulmonary VC subgroup) | 15 new cases of type 2 DM were diagnosed during the follow up. DM and log glucose were inversely associated with baseline VC. |
Engström et al.[125]; 2003 | Sweden | Population based cohort study with a mean follow up of 13.9 years for men and 9.4 years for women | n: 2,332 non-diabetic subjects (men-1,436, 61.57%) mean age for men: 44.0-44.9 years (depends on the pulmonary FVC subgroup) mean age for women: 49.4-50.4 years (depends on the pulmonary FVC subgroup) mean BMI for men: 24.2-24.9 kg/m²(depends on the pulmonary FVC subgroup) mean BMI for women: 23.2-23.9 kg/m²(depends on the pulmonary FVC subgroup) | The association between baseline FVC and IR at follow up remained statistically significant after adjustment for gender, age at screening, follow up time, smoking/tobacco consumption, BMI and waist to hip ratio, physical activity and baseline log glucose |
Kwon et al.[126]; 2012 | Korea | Prospective cohort study with a follow up of 5 years | n: 9,220 men non-diabetic at baseline mean age: 41.4 years mean baseline BMI: 24.4 kg/m² for patients without type 2 DM at follow up and 26.7 kg/m² for patients with type 2 DM at follow up | 207 patients developed type 2 DM with the incidence of 2.2%. |
FEV1 and FVC were negatively associated with type 2 DM. | ||||
In patients with BMI<25 kg/m2 the lowest quartile of FVC and FEV1 had OR of 2.15 (95% CI 1.02-4.57) and 2.19 (95% CI 1.09-4.42) for incident type 2 DM. | ||||
Heianza et al.[132]; 2012 | Japan | Observational study with a 4 year follow up | n: 5,346 (100% men) mean age: 48.6 years mean BMI: 23.3 kg/m² | Compared with the highest FEV1 quartile, lower quartiles were associated with 1.79-1.86 greater risk for the new onset type 2 DM (95% CI, 1.10-2.91). |
COPD and the risk of type 2 DM
First author and year | Country | Study design | Population studied | Findings |
---|---|---|---|---|
Feary et al.[3]; 2010 | UK | Cross-sectional study using computerized records from 311 primary care practices | n: 1,204,100 (Men-618,090 subjects-51.3%) age: 35–44 years-327,800 subjects (27.2%), 45–54 years-274,375 subjects (22.8%), 55–64 years-254,472 subjects (21.1%), 65–74 years-177,102 subjects (14.7%) and ≥75 years- 170,361 subjects (14.2%) | COPD had OR of 2.04 (95% CI 1.97-2.12) for the development of new onset type 2 DM. |
Song et al.[134]; 2010 | USA | Prospective cohort study with a median follow up of 12.2 years | n:38,570 non-diabetic women mean age-:57.8 years(for patients with physician diagnosed COPD) mean BMI: 26.1 kg/m²(for patients with physician diagnosed COPD) | COPD had a multivariate adjuster RR of 1.38 (95% CI 1.14–1.67) for a new onset type 2 DM. |
Data on BMI not provided | ||||
Bolton et al.[135]; 2007 | UK | Cross-sectional study | n: 56 patients (30 men) with non-hypoxemic COPD and 29 healthy subjects (15 men) mean age: 66.7 years for COPD patients and 62.9 years for healthy controls mean BMI: 25.7 kg/m² for COPD patients and 26.5 kg/m² for healthy subjects | Patients with COPD had greater levels of CRP, IL-6 and TNF-α sr I and sr II. |
IR assessed by HOMA was 1.68 in COPD patients vs. 1.13 in healthy subjects. | ||||
Log10 IL-6 and BMI were found to be predictive for IR in stepwise regression analysis | ||||
Bayliss et al.[136]; 2011 | USA | Prospective cohort study in patients with established type 2 DM | 2,332 develop chronic pulmonary disease exacerbation (women-1,244, 53.34%), 582 (women-318, 54.64%) developed cancer and 2,959 developed depression (women-1,670, 56.44%) mean age at index date: 62.04 years for depression, 63.2 years for chronic pulmonary disease exacerbation and 65.53 years for cancer mean BMI: 31.09 kg/m² for cancer, 32.01 kg/m² for depression and 32.45 kg/m² for chronic pulmonary disease exacerbation | The researchers did not find any effect of chronic pulmonary disease exacerbation, depression and cancer on the glycated hemoglobin. |
Treatment of COPD and the risk of hyperglycemia
The impact of DM/Mets on the lung
Effects of DM on the pulmonary vasculature and diffusing capacity
First author and year | Country | Study design | Population studied | Findings |
---|---|---|---|---|
Guazzi et al.[149]; 2002 | Italy | In hospital study assessing the effects of regular insulin on the alveolar-capillary conductance. | n: 19 patients (11 men) with type 2 DM and normal cardiac function. mean age: 59.9 years mean weight: 75.8 kg. | DLCO and alveolar capillary membrane conductance were increased by 12% and 14% respectively by insulin therapy. |
DLCO and its subcomponents were measured. | ||||
Guazzi et al.[150]; 2002 | Italy | Cross-sectional study. | n: 30 patients with HF (19 men), 15 patients with type 2 DM (8 men) and 15 controls (8 men). mean age: 61.1 years for controls, 62.3 years for patients with type 2 DM, 62.8 years for patients with type 2 DM and HF and 64.1 years for patients with HF alone. mean weight: 75.2 kg for patients with HF and type 2 DM, 76.1 kg for patients with type 2 DM, 76.7 kg for patients with HF and 77.8 kg for controls. | Patients with type 2 DM had a lower DLCO than controls. |
Regular insulin improved DLCO in patients with type 2 DM and type DM and HF, with no improvement in patients with HF alone. The improvement in patients with type 2 DM and HF was greater than in patients with type 2 DM alone. | ||||
Guvener et al.[157]; 2003 | Turkey | Cross-sectional study. | n: 25 patients with type 2 DM (9 men) and 12 healthy controls (4 men). mean age: 56.3 years for patients with type 2 DM and 50.1 years for controlsmean BMI: 29.9 kg/m² for patients with type 2 DM and 29.5 kg/m² for controls. | Patients with type 2 DM had lower ratio of DLCO to VA. In a stepwise regression model with inclusion of age, duration of type 2 DM and microalbuminuria, only microalbuminuria was found to be independent predictor of DLCO/VA. |
Chance et al.[158]; 2008 | USA | Cross-sectional study assessing alveolar capillary bed in patients with type 2 DM. | n: 69 never smokers with type 2 DM and no overt cardiopulmonary disease (46% women) vs. 45 controls (45% women). mean age: 45 years for controls, 49 years for patients with type 2 DM and BMI>30 kg/m² and 45 years for patients with type 2 DM and BMI<30 kg/m². mean BMI: 28.8 kg/m2 for controls, 27.4 kg/m² and 34.4 kg/m² for aforementioned type 2 DM groups respectively. | Both non-obese (BMI<30 kg/m²) and obese (BMI≥30 kg/m²) patients with type 2 DM had reduced levels of the measured pulmonary function variables during exercise. However, the observed changes in obese patients were not fully explained by the baseline lung volumes. Moreover, the presence of retinopathy, neuropathy, microalbuminuria and control of diabetes were associated with the reduced pulmonary microvascular reserve |
Niranjan et al.[166]; 1997 | USA | Prospective observational study of cardio-pulmonary function at 7 years of follow up. Aerobic exercise capacity was measured with cycle ergometry. Lung volume and diffusing capacity were measured with rebreathing technique and ventialatory power was measured by esophageal balloon technique. | n: 18 subjects with type 1 DM (11 men) and 14 controls (10 men). mean age: 31 years for controls and 39 for patients with type 1 DM. mean BMI: 22 kg/m² for controls and 24.91-25.49 kg/m² among patients with type 1 DM. | Patients with poor glycemic control had worse restriction of lung volume, pulmonary diffusing capacity and membrane diffusing capacity. Cardiac stroke index was reduced among subjects with poor glycemic control. |
In the long-term analysis the rate of FEV1 and FVC decline was similar to those without DM. | ||||
Saler et al.[170]; 2009 | Turkey | Cross-sectional study assessing alveolar capillary bed in patients with type 1 and type 2 DM. | n: 44 subjects with type 1 DM (29 women), 68 subjects with type 2 DM (49 women) and 80 controls (58 women). mean age: 32.52 years for patients with type 1 DM, 52.4 years for patients with type 2 DM and 40.08 years for controls. mean BMI: 24.4 kg/m² for patients with type 1 DM, 27.0 kg/m² for patients with type 2 DM and 25.6 kg/m² for controls. | DLCO and the ratio of DLCO to VA were significantly decreased in patients with both types of DM, but not in control group. |
Wanke et al.[184]; 1991 | Austria | Cross-sectional study. | n: 36 patients with type 1 DM (31 men) and 40 controls (33 men). mean age: 33 years for patients with DM and 27 years for controls. mean BMI: 24.3 kg/m² for patients with DM and 22.3 kg/m² for controls. | Patients with type 1 DM had significantly lower inspiratory VC, which was in part explained by reduced maximal sniff transesophageal and transdiaphragmatic pressures in patients with type 1 DM. |
Walter et al.[194]; 2003 | USA | Prospective observational study with a follow up>15 years using the data of the Framingham Heart Study. | n: 3,254 (1,547 men) with 280 subjects having type 2 DM mean age: 53.9 years for patients without type 2 DM and 59.6 years for patients with type 2 DM. mean BMI: 27.3 kg/m² for patients without type 2 DM and 30.67 kg/m² for patients with type 2 DM. | Patients with type 2 DM had a lower mean FEV1, FVC. The FVC/FEV1 ratio was slightly higher in patients with type 2 DM. |
Higher fasting glucose levels had association with decreased FEV1, FVC and FVC/FEV1 ratio (only in current smokers). | ||||
Lawlor et al.[195]; 2004 | UK | Cross-sectional study. | N: 3,911 women (9.8% had type 2 DM). | FEV1 and FVC were inversely related to the HOMA score. |
Age: post-menopausal women aged 60–79 years | After adjustment for age, anthropometric variables, smoking, physical activity, childhood and adult social class and respiratory medications the higher FEV1 and FVC were associated with decrease in HOMA score of 3% and 5% respectively. | |||
Mean BMI: not provided. | Patients with higher values of FEV1 and FVC had lower prevalence of DM. | |||
Davis et al.[196]; 2004 | Australia | Prospective study using the data from the Fremantle Diabetes Study with a mean follow up of 7 years. | n: 125 subjects with type 2 DM. mean age: 61.5 years mean BMI: 29.9 kg/m² | Higher follow up fasting glucose, greater levels of follow up HbA1c and mean updated HbA1c were associated with a decrease in measured pulmonary parameters. |
FEV1, FVC, VC and PEF were measured at baseline and during follow up. | Decreased FEV1 was found to be independent predictor of all-cause mortality. | |||
McKeever et al.[197]; 2005 | UK | Study analyzing the data of the NHANES III. | n: 4,257 (1,943 men) mean age: 37 years mean BMI: 27.0 kg/m² | Patients with higher 2 hour 75 g glucose tolerance test had lower levels of FEV1 and FVC. |
Patients with a history of DM had lower levels of FEV1 and patients with poor control of DM had lower FEV1 than patients with controlled DM. | ||||
Litonjua et al.[198]; 2005 | USA | A nested case–control study using the data of Normative Aging Study. | n: 352 men who developed type 2 DM and 352 controls (all men) mean age: 43.1 years for patients with type 2 DM and 43.2 years for controls. mean BMI: 26.81 kg/m² for patients with type 2 DM and 25.31 kg/m² for controls. | Patients with type 2 DM had lower FEV1 and FVC values (but not FEV1/FVC) many years prior to the diagnosis of type 2 DM. |
However, there was no difference in the rate of annual decline of FEV1 and FVC in patients with type 2 DM and controls. | ||||
Baker et al.[207]; 2006 | UK | Cross-sectional study in patients admitted with acute exacerbation of COPD. | n: 284 subjects (167 men) mean age: from 72.9 to 76.7 years (depends on the glucose quartile, with higher glucose associated with older age) mean BMI: not provided | The RR of death and long hospital stay was greater in patients with glucose from 7.0-8.9 mmol/l and >9.0 mmol/l (RR 1.46 and 1.97 espectively), which was independent from age, gender, COPD severity and prior diagnosis of DM. |
The patients were divided into 3 groups based on the glucose quartile (<6.0mmol/l, 6.0-6.9 mmol/l 7.0-8.9 mmol/l and >9 mmol/l) | ||||
Each mole increase in glucose was associated with 15% greater risk for adverse clinical outcome. | ||||
Higher glucose level was associated with the isolation of Staphylococcus Aureus from the sputum. | ||||
Chakrabarti et al.[208]; 2009 | UK | An observation study on the effects of hyperglycemia on the outcome of non-invasive ventilation (NIV) during COPD exacerbation. | n: 88 in hospital patients (39 men). mean age: 70 years mean BMI: data not provided | Random blood glucose≥7.0 mmol/l was independently associated with an adverse NIV outcome such as NIV failure and greater risk for pneumonia. |
Küpeli et al.[209]; 2010 | Turkey | An observational study assessing the correlation between the presence of MetS and COPD exacerbation rate. | n: 106:29 patients with MetS (24 men) and 77 patients without MetS (67 men). mean age: 64.9 years for patients with MetS and 67.3 years for patients without MetS.mean BMI: 30.3 kg/m² for patients with MetS And 27.2 kg/m² for patients without MetS. | The mean COPD exacerbation rate was 2.4 in MetS group compared to 0.68 in the control group. Mean length of each exacerbation was 7.5 days in patients with MetS compared to 5 days in patients without MetS. Serum C-reactive protein, fasting blood glucose, and triglycerides were positively correlated with COPD exacerbation rate. |
Effects of DM on the respiratory muscles and physical endurance
DM as a potential risk factor for accelerated decline in lung function
Impact of DM on the COPD outcomes
DM therapies other than insulin and pulmonary function
OSA, overlap syndrome and the risk of type 2 DM
OSE Severity | Apnea Hypopnea Index |
---|---|
Mild | 5-14 |
Moderate | 15-29 |
Severe | ≥30 |