Diabetes mellitus is a group of disorders characterized by hyperglycemia and the resulting macrovascular and microvascular complications. The prevalence of diabetes is on the rise in the United States; in 2007, 23.6 million persons had diabetes, 17.9 million received the diagnosis, and another 5.7 million persons had diabetes that remained undiagnosed.1
The US health care costs of diabetes are staggering and continue to grow. Based on prevalence and demographic data from 2007, the total estimated cost of diabetes is $174 billion: $116 billion in excess medical expenditures and $58 billion as a result of a reduction in national productivity. In addition, 50% of the medical expenditure cost is attributable to hospital inpatient care related to diabetes.2
Diabetes is a leading cause of morbidity and death as a result of its systemic manifestations, and its effects on the renal, cardiovascular, and nervous systems have been well described.3 Several population-based epidemiological studies have documented reduced ventilatory function among patients with diabetes; in fact, the prevalence of coexisting chronic obstructive pulmonary disease (COPD) and diabetes is 1.6% to 16%.4,5
In this article, we review the current knowledge regarding the relationship between diabetes mellitus and chronic lung disease.
DIABETES AND LUNG FUNCTION
Diabetes mellitus has been associated with abnormalities in markers of systemic inflammation and with an increased risk of other diseases, such as cardiovascular disease. Several studies suggest that diabetes is associated with impaired pulmonary function.6-8
Walter and associates8 explored the relationship of diabetes and of fasting blood glucose concentration to the level of pulmonary function, using data from the Offspring Cohort of the Framingham Heart Study. They found that a diagnosis of diabetes was associated with a lower mean adjusted forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC). This relationship was more pronounced in current smokers than in those who had never smoked. Regardless of smoking status, the mean residual FEV1 decreased with increasing fasting blood glucose level. The patients in the highest quartile of fasting blood glucose had an average residual FEV1 that was 85 mL lower than those in the lowest quartile.
The prevalence of diabetes and acute hyperglycemia has been shown to be increased in patients with COPD.9 In a prospective cohort study, Rana and associates10 found that women with COPD had a 1.8-fold increased risk of type 2 diabetes mellitus. However, this association was not found in women who had asthma. Overall, 14% to 15% of patients with COPD admitted to the hospital have diabetes.11
The temporal relationship between diabetes and reduced lung function and the clinical significance of the association between the two are not clearly understood. Possible links between respiratory impairment and diabetes may be attributable to increased body mass index, subsequent loss of respiratory compliance, neuropathies, loss of strength of the respiratory muscles, and other confounding variables.12 Multiple studies suggest that the lung is an end-organ target for damage induced by sustained hyperglycemia. Histological evidence obtained from the lungs of diabetic patients reveals changes in the microvasculature, such as thickening of the pulmonary capillary basal laminae.13 However, the association between these histological changes and the occurrence of clinical disease remains unclear. Other studies indicate that reduced ventilatory function, as measured by FVC, FEV1, and carbon monoxide–diffusing capacity, may be a risk factor for impaired glucose tolerance and overt diabetes mellitus.6,12,14
The pathogenesis of COPD is thought to involve the up-regulation of inflammatory cells and markers with subsequent connective-tissue degradation, an inflammatory event that is usually spurred by smoking.15 In fact, the annual decline in FEV1 is steeper in smokers than in nonsmokers. Systemic inflammatory markers, such as interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α), have been shown to play a role in the development of COPD and are associated with increased insulin resistance, and several studies have elucidated the association between higher levels of inflammatory markers and type 2 diabetes mellitus.16-22
Thus, lung function and insulin resistance may be independently influenced by systemic inflammation.23 Advanced glycosylation end-products can alter matrix proteins and influence endothelial cell expression of cytokines and other inflammatory markers.24 If diabetes is proinflammatory, then impairment of glycemic control may cause ventilatory dysfunction, either independently or synergistically with smoking exposure.8
Litonjua and colleagues25 conducted a nested case-control analysis using the cohort from the Normative Aging Study to explore the relationship between type 2 diabetes mellitus and lung function. The Normative Aging Study was instituted in 1961 by the Veterans Administration to investigate the process of aging; healthy persons were chosen from the Boston area, and those with chronic medical ailments were excluded.26 Participants in the study had diminished lung function several years (median, 13.6 years) before the diagnosis of diabetes. The authors concluded that glycosylation of proteins in the lung prompted by hyperglycemia may lead to damage to the lung tissue, which eventually progresses to clinically evident disease.25,27
The Fremantle Diabetes Study also explored the relationship between pulmonary function and type 2 diabetes mellitus.7 The study was conducted in Australia with persons of Anglo-Celt/European descent and no history of chronic lung disease. The results were in concordance with those of previous studies: predicted values of FVC, FEV1, vital capacity, and peak expiratory flow were, on average, at least 9.5% lower in diabetic than in nondiabetic persons.15,26 Regression analysis indicated that the duration of diabetes was an independent predictor of reduced pulmonary function. There was no association between glycemic control and spirometric measures. This suggests a more complicated pathophysiology of diabetes-related lung disease than previously proposed.
In contrast, pulmonary function was not associated with known or newly diagnosed type 2 diabetes mellitus in a group of older persons in the Rancho Bernardo Study.28 However, the duration of diabetes (10 or more years) was associated with reduction in age- and height-adjusted FEV1 in men. Since this gender-specific correlation was revealed in post hoc analysis, it warrants further analysis. There are several possible explanations for why lung function was not associated with diabetes in the Rancho Bernardo Study: the population was older (72.3 years) and men and women who had both diabetes and pulmonary disease may have been lost because of death or morbidity, leading to a selection bias.
Metabolic syndrome and COPD
Metabolic syndrome is a complex constellation of risk factors for cardiovascular disease as well as for diabetes. In 1988, Reaven29 first described metabolic syndrome, also known as syndrome X, as a factor in diabetes mellitus, hypertension, and atherosclerotic heart disease with dyslipidemia.
The risk factors that characterize the metabolic syndrome include abdominal obesity; atherogenic dyslipidemia; hypertension; insulin resistance; and defects in inflammation, coagulation, and fibrinolysis. The diagnostic criteria based on the consensus statement by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) are as follows: waist circumference greater than 102 cm in men and 88 cm in women, fasting triglyceride levels of 150 mg/dL or higher, high-density lipoprotein cholesterol levels of less than 40 mg/dL in men and less than 50 mg/dL in women, blood pressure of 130/85 mm Hg or higher, and fasting blood glucose levels of 110 mg/dL or higher.30
A number of reports have established that patients with COPD are at greater risk for cardiovascular disease–related death, but the nature of this association remains largely undefined.31-33 In 2005, Marquis and colleagues34 hypothesized that an increased prevalence of metabolic syndrome in patients with COPD may explain this association. They evaluated the prevalence of metabolic syndrome in COPD patients who participated in a cardiopulmonary rehabilitation program in Canada. The prevalence of metabolic syndrome was higher in participants with COPD (n = 38, 47%) than in a control group without COPD and cardiovascular disease in the general population (n = 34, 21%) matched for age and sex.34 The NCEP ATP III criteria were used for evaluating patients for metabolic syndrome. The criteria included indentifying 3 or more of the following features: abdominal obesity (waist circumference of more than 102 cm in men and more than 88 cm in women), triglyceride levels of 1.69 mmol/L or higher, high-density lipoprotein cholesterol levels of less than 1.0 mmol/L in men and less than1.3 mmol/L in women, blood pressure of 130/85 mm Hg or higher, and fasting glucose levels of 6.1 mmol/L or higher.
This relationship was not established for women with COPD. The prevalence of metabolic syndrome was higher in women with COPD than in the control group, but was lower than in age-matched women without COPD in the general population. The investigators proposed that the chronic debilitation and sedentary lifestyle resulting from COPD could explain the relationship between COPD and metabolic syndrome. However, further study is warranted to fully delineate this association. Generalization from the above-mentioned study is limited because the study included only Caucasians, and the prevalence of metabolic syndrome varies among ethnic groups. Thus, these findings cannot be confidently generalized to the multiethnic population of the United States.
Lawlor and associates35 proposed a more dynamic approach to the relationship between lung function and type 2 diabetes mellitus. They performed a cross-sectional study of almost 4000 elderly women from the British Women’s Heart and Health Study. FVC and FEV1 were measured, and blood samples were taken to measure levels of fasting glucose, insulin, and proinsulin. Insulin resistance was calculated using the homeostasis model assessment (the product of fasting glucose and insulin divided by a constant). This measure was used only in nondiabetic persons, because it has been proved to be less accurate in elderly diabetic patients. Leg length was used as a biomarker for early life environmental exposures affecting growth.
The major findings of this study were that the measures of lung function were inversely correlated with the presence of insulin resistance and type 2 diabetes mellitus. This association was still apparent after adjustment for confounding factors such as smoking exposure. Early life exposures that affect lung growth and insulin resistance are proposed to be catalysts for this eventual association later in life. There is evidence that independent risk factors for type 2 diabetes mellitus and atherosclerosis provide a common soil for the development of either one or both of these conditions. The insulin resistance syndrome is linked to both genetic and environmental causality. Evidence exists that links fetal and early postnatal nutritional stress resulting in low birth weight and low weight gain during the first year to later risk of insulin resistance, diabetes, or atherosclerotic disease.36
1. Centers For Disease Control and Prevention. National diabetes fact sheet, 2007. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf. Accessed January 11, 2010.
2. American Diabetes Association. Economic costs of diabetes in the US in 2007 [published correction appears in Diabetes Care. 2008;31:1271]. Diabetes Care. 2008;31:596-615.
3. American Diabetes Association. Clinical practice recommendations 2009. Diabetes Care. 2009;32(suppl 1):S1-S98.
4. Engström G, Janzon L. Risk of developing diabetes is inversely related to lung function: a population-based cohort study. Diabet Med. 2002;19:167-170.
5. Chatila WM, Thomashow BM, Minai OA, et al. Comorbidities in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2008;5:549-555.
6. Lange P, Groth S, Kastrup J, et al. Diabetes mellitus, plasma glucose and lung function in a cross sectional population. Eur Respir J. 1989;2:14-19.
7. Davis TM, Knuiman M, Kendall P, et al. Reduced pulmonary function and its associations in type 2 diabetes: the Fremantle Diabetes Study. Diabetes Res Clin Pract. 2000;50:153-159.
8. Walter RE, Beiser A, Givelber RJ, et al. Association between glycemic state and lung function: the Framingham Heart Study. Am J Respir Crit Care Med. 2003;167:911-916.
9. Baker EH, Janaway CH, Philips BJ, et al. Hyperglycaemia is associated with poor outcomes in patients admitted to hospital with acute exacerbations of chronic obstructive pulmonary disease. Thorax. 2006;61:284-289.
10. Rana JS, Mittleman MA, Sheikh J, et al. Chronic obstructive pulmonary disease, asthma, and risk of type 2 diabetes in women. Diabetes Care. 2004;27:2478-2484.
11. Antonelli Incalzi R, Fuso L, De Rosa M, et al. Co-morbidity contributes to predict mortality of patients with chronic obstructive pulmonary disease. Eur Respir J. 1997;10:2794-2800.
12. Ford ES, Mannino DM; National Health and Nutrition Examination Survey Epidemiologic Follow-up Study. Prospective association between lung function and the incidence of diabetes: findings from the National Health and Nutrition Examination Survey Epidemiologic Follow-up Study. Diabetes Care. 2004;27:2966-2970.
13. Ardigo D, Valtuena S, Zavaroni I, et al. Pulmonary complications in diabetes mellitus: the role of glycemic control. Curr Drug Targets Inflamm Allergy. 2004;3:455-458.
14. Strojek K, Ziora D, Sroczynski JW, Oklek K. Pulmonary complications of type 1 (insulin-dependent) diabetic patients. Diabetologia. 1992;35:1173-1176.
15. Barnes PJ. Mechanisms in COPD: differences from asthma. Chest. 2000;117:108-148.
16. Bhowmik A, Seemungal TA, Sapsford RJ, Wedzicha JA. Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations. Thorax. 2000;55:114-120.
17. Soler N, Ewig S, Torres A, et al. Airway inflammation and bronchial microbial patterns in patients with stable chronic obstructive pulmonary disease. Eur Respir J. 1999;14:1015-1022.
18. Bloomgarden ZT. American Diabetes Association Annual Meeting, 1999: more on cardiovascular disease. Diabetes Care. 2000;23:845-852.
19. Moller DE. Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes. Trends Endocrinol Metab. 2000;11:212-217.
20. Duncan BB, Schmidt MI, Offenbacher S, et al. Factor VIII and other hemostasis variables are related to the incidence of diabetes in adults: the Atherosclerosis Risk in Communities (ARIC) study. Diabetes Care. 1999;22:767-772.
21. Rodríguez-Morán R, Guerrero-Romero F. Increased levels of C-reactive protein in noncontrolled type II diabetic subjects. J Diabetes Complications. 1999;13:211-215.
22. Schmidt MI, Duncan BB, Sharrett AR, et al. Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study. Lancet. 1999;353:1649-1652.
23. Will JC, Galuska DA, Ford ES, et al. Cigarette smoking and diabetes mellitus: evidence of a positive association from a large prospective cohort study. Int J Epidemiol. 2001;30:540-546.
24. Arnalich F, Hernanz A, López-Maderuelo D, et al. Enhanced acute-phase response and oxidative stress in older adults with type II diabetes. Horm Metab Res. 2000;32:407-412.
25. Litonjua AA, Lazarus R, Sparrow D, et al. Lung function in type 2 diabetes: the Normative Aging Study. Respir Med. 2005;99:1583-1590.
26. Bell B, Rose C, Damon A. The Normative Aging Study: an interdisciplinary and longitudinal study of health and aging. Aging Hum Dev. 1972;3:4-17.
27. Cavan DA, Parkes A, O’Donnell MJ, et al. Lung function and diabetes. Respir Med. 1991;85:257-258.
28. Barrett-Connor E, Frette C. NIDDM, impaired glucose tolerance, and pulmonary function in older adults. The Rancho Bernardo Study. Diabetes Care. 1996;19:1441-1444.
29. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37:1595-1607.
30. National Cholesterol Education Program Expert Panel. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.
31. Engström G, Lind P, Hedblad B, et al. Lung function and cardiovascular risk: relationship with inflammation-sensitive plasma proteins. Circulation. 2002;106:2555-2560.
32. Friedman GD, Klatsky AL, Siegelaub AB. Lung function and risk of myocardial infarction and sudden cardiac death. N Engl J Med. 1976;294:1071-1075.
33. Hole DJ, Watt GCM, Davey-Smith G, et al. Impaired lung function and mortality risk in men and women: findings from the Renfrew and Paisley prospective population study. BMJ. 1996;313:711-715.
34. Marquis K, Maltais F, Duguay V, et al. The metabolic syndrome in patients with chronic obstructive pulmonary disease. J Cardiopulm Rehabil. 2005;25:226-232; discussion 233-224.
35. Lawlor DA, Ebrahim S, Smith GD. Associations of measures of lung function with insulin resistance and Type 2 diabetes: findings from the British Women’s Heart and Health Study. Diabetologia. 2004;47:195-203.
36. Garvey WT, Hermayer, KL. Clinical implications of the insulin resistance syndrome. Clin Cornerstone. 1998;1:13-28.
37. Sutherland ER, Martin RJ. Airway inflammation in chronic obstructive pulmonary disease: comparisons with asthma. J Allergy Clin Immunol. 2003;112:819-827; quiz 828.
38. Wood-Baker RR, Gibson PG, Hannay M, et al. Systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2005(1):CD001288.
39. Davies L, Angus RM, Calverley PM. Oral corticosteroids in patients admitted to hospital with exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial. Lancet. 1999;354:456-460.
40. Erbland ML, Deupree RH, Niewoehner DE. Systemic Corticosteroids in Chronic Obstructive Pulmonary Disease Exacerbations (SCCOPE): rationale and design of an equivalence trial. Veterans Administration Cooperative Trials SCCOPE Study Group. Control Clin Trials. 1998;19:404-417.
41. Walters JA, Walters EH, Wood-Baker R. Oral corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2005(3):CD005374.
42. Patil SP, Krishnan JA, Lechtzin N, Diette GB. In-hospital mortality following acute exacerbations of chronic obstructive pulmonary disease. Arch Intern Med. 2003;163:1180-1186.
43. Mannino DM, Thorn D, Swensen A, Holguin F. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD. Eur Respir J. 2008;32:962-969.
44. Gudmundsson G, Gislason T, Lindberg E, et al. Mortality in COPD patients discharged from hospital: the role of treatment and co-morbidity. Respir Res. 2006;7:109-116.
45. Chung KF. Cytokines in chronic obstructive pulmonary disease. Eur Respir J Suppl. 2001;34:50s-59s.
46. Umpierrez GE, Isaacs SD, Bazargan N, et al. Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab. 2002;87:978-982.
47. van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001;345:1359-1367.
48. Krinsley JS. Effect of an intensive glucose management protocol on the mortality of critically ill adult patients [published correction appears in Mayo Clin Proc. 2005;80:1101]. Mayo Clin Proc. 2004;79:992-1000.
49. Finney SJ, Zekveld C, Elia A, Evans TW. Glucose control and mortality in critically ill patients. JAMA. 2003;290:2041-2047.
49. Krinsley J, Grissler B. Intensive glycemic management in critically ill patients. Jt Comm J Qual Patient Saf. 2005;3:308-312.
50. Hirsch IB. Effect of insulin therapy on nonglycemic variables during acute illness. Endocr Pract. 2004;10(suppl 2):63-70.