Abstract
COPD and Type 2 diabetes are two highly prevalent global health conditions associated with high mortality and morbidity. The connection between these two common diseases is complex, and more research is required for further understanding of these conditions. COPD is being increasingly recognized as a risk factor for the development of type2 diabetes through different mechanisms including systemic inflammation, obesity, hypoxia and use of corticosteroids. Also, hyperglycemia in diabetes patients is linked to the adverse impact on lung physiology, and a possible increase in the risk of COPD. In this review article, we discuss the studies demonstrating the associations between COPD and Type 2 Diabetes, underlying pathophysiology and recommended therapeutic approach in the management of patients with coexisting COPD and diabetes.
Keywords: COPD, diabetes, hyperglycemia, hypoxia, inflammation, metformin, obesity, outcome, oxidative stress, respiratory, smoking, steroids.
Graphical Abstract
[1]
Vestbo J, Hurd SS, Agustí AG, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2013; 187(4): 347-65.
[2]
Fabbri LM, Rabe KF. From COPD to chronic systemic inflammatory syndrome? Lancet 2007; 370(9589): 797-9.
[3]
Feary JR, Rodrigues LC, Smith CJ, Hubbard RB, Gibson JE. Prevalence of major comorbidities in subjects with COPD and incidence of myocardial infarction and stroke: A comprehensive analysis using data from primary care. Thorax 2010; 65(11): 956-62.
[4]
Adeloye D, Chua S, Lee C, et al. Global and regional estimates of COPD prevalence: Systematic review and meta-analysis. J Glob Health 2015; 5(2) 020415
[5]
Mirrakhimov AE. Chronic obstructive pulmonary disease and glucose metabolism: A bitter sweet symphony. Cardiovasc Diabetol 2012; 11: 132.
[6]
Mannino DM, Thorn D, Swensen A, Holguin F. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD. Eur Respir J 2008; 32(4): 962-9.
[7]
Zamarrón C, García Paz V, Morete E, del Campo Matías F. Association of chronic obstructive pulmonary disease and obstructive sleep apnea consequences. Int J Chron Obstruct Pulmon Dis 2008; 3(4): 671-82.
[8]
McNicholas WT. Chronic obstructive pulmonary disease and obstructive sleep apnea: Overlaps in pathophysiology, systemic inflammation, and cardiovascular disease. Am J Respir Crit Care Med 2009; 180(8): 692-700.
[9]
Azuma M, Chin K, Yoshimura C, et al. Associations among chronic obstructive pulmonary disease and sleep-disordered breathing in an urban male working population in Japan. Respiration 2014; 88(3): 234-43.
[10]
Divo M, Cote C, de Torres JP, et al. Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 186(2): 155-61.
[11]
Maitra A, Abbas AK. Endocrine system. In: Kumar V, Fausto N,
Abbas AK, Eds. Robbins and Cotran Pathologic basis of disease.
Philadelphia: Saunders 2005; 7th ed: 1156-226.
[13]
Hillas G, Perlikos F, Tsiligianni I, Tzanakis N. Managing comorbidities in COPD. Int J Chron Obstruct Pulmon Dis 2015; 10: 95-109.
[14]
Caughey GE, Roughead EE, Vitry AI, McDermott RA, Shakib S, Gilbert AL. Comorbidity in the elderly with diabetes: Identification of areas of potential treatment conflicts. Diabetes Res Clin Pract 2010; 87(3): 385-93.
[15]
Kerr EA, Heisler M, Krein SL, et al. Beyond comorbidity counts: how do comorbidity type and severity influence diabetes patients’ treatment priorities and self-management? J Gen Intern Med 2007; 22(12): 1635-40.
[16]
Miller J, Edwards LD, Agustí A, et al. Comorbidity, systemic inflammation and outcomes in the ECLIPSE cohort. Respir Med 2013; 107(9): 1376-84.
[17]
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(4): 284-9.
[18]
Parappil A, Depczynski B, Collett P, Marks GB. Effect of comorbid diabetes on length of stay and risk of death in patients admitted with acute exacerbations of COPD. Respirology 2010; 15(6): 918-22.
[19]
Ho TW, Huang CT, Ruan SY, Tsai YJ, Lai F, Yu CJ. Diabetes mellitus in patients with chronic obstructive pulmonary disease-The impact on mortality. PLoS One 2017; 12(4) e0175794
[20]
Cazzola M, Bettoncelli G, Sessa E, Cricelli C, Biscione G. Prevalence of comorbidities in patients with chronic obstructive pulmonary disease. Respiration 2010; 80(2): 112-9.
[21]
Lee CT-C, Mao I-C, Lin C-H, Lin S-H, Hsieh M-C. Chronic obstructive pulmonary disease: A risk factor for type 2 diabetes: A nationwide population-based study. Eur J Clin Invest 2013; 43(11): 1113-9.
[22]
Eriksson KF, Lindgärde F. Poor physical fitness, and impaired early insulin response but late hyperinsulinaemia, as predictors of NIDDM in middle-aged Swedish men. Diabetologia 1996; 39(5): 573-9.
[23]
Lazarus R, Sparrow D, Weiss ST. Baseline ventilatory function predicts the development of higher levels of fasting insulin and fasting insulin resistance index: The Normative Aging Study. Eur Respir J 1998; 12(3): 641-5.
[24]
Engström G, Janzon L. Risk of developing diabetes is inversely related to lung function: A population-based cohort study. Diabet Med 2002; 19(2): 167-70.
[25]
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(10): 2478-84.
[26]
Kwon C-H, Rhee E-J, Song J-U, Kim J-T, Kwag HJ, Sung K-C. Reduced lung function is independently associated with increased risk of type 2 diabetes in Korean men. Cardiovasc Diabetol 2012; 11: 38.
[27]
Alberti KGMM, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009; 120(16): 1640-5.
[28]
Franssen FME, O’Donnell DE, Goossens GH, Blaak EE, Schols AMWJ. Obesity and the lung: 5. Obesity and COPD. Thorax 2008; 63(12): 1110-7.
[29]
Vozoris NT, O’Donnell DE. Prevalence, risk factors, activity limitation and health care utilization of an obese, population-based sample with chronic obstructive pulmonary disease. Can Respir J 2012; 19(3): e18-24.
[30]
Eisner MD, Blanc PD, Sidney S, et al. Body composition and functional limitation in COPD. Respir Res 2007; 8: 7.
[31]
Leone N, Courbon D, Thomas F, et al. Lung function impairment and metabolic syndrome: The critical role of abdominal obesity. Am J Respir Crit Care Med 2009; 179(6): 509-16.
[33]
Paek Y-J, Jung K-S, Hwang Y-I, Lee K-S, Lee DR, Lee J-U. Association between low pulmonary function and metabolic risk factors in Korean adults: The Korean National Health and Nutrition Survey. Metab Clin Exp 2010; 59(9): 1300-6.
[34]
Gläser S, Krüger S, Merkel M, Bramlage P, Herth FJF. Chronic obstructive pulmonary disease and diabetes mellitus: a systematic review of the literature. Respiration 2015; 89(3): 253-64.
[35]
Al Mutairi SS, Mojiminiyi OA, Shihab-Eldeen A, Al Rammah T, Abdella N. Putative roles of circulating resistin in patients with asthma, COPD and cigarette smokers. Dis Markers 2011; 31(1): 1-7.
[36]
Broekhuizen R, Vernooy JHJ, Schols AMWJ, Dentener MA, Wouters EFM. Leptin as local inflammatory marker in COPD. Respir Med 2005; 99(1): 70-4.
[37]
Bruno A, Chanez P, Chiappara G, Siena L, Giammanco S, Gjomarkaj M, et al. Does leptin play a cytokine-like role within the airways of COPD patients? Eur Respir J 2005; 26(3): 398-405.
[38]
Yang Y, Sun T, Liu X. The role of serum leptin and tumor necrosis factor-alpha in malnutrition of male chronic obstructive pulmonary disease patients Chin Med J 2006 20; 119(8): 628-33
[39]
Kythreotis P, Kokkini A, Avgeropoulou S, et al. Plasma leptin and insulin-like growth factor I levels during acute exacerbations of chronic obstructive pulmonary disease. BMC Pulm Med 2009; 9: 11.
[40]
Barzilay JI, Abraham L, Heckbert SR, et al. The relation of markers of inflammation to the development of glucose disorders in the elderly: The Cardiovascular Health Study. Diabetes 2001; 50(10): 2384-9.
[43]
Rains JL, Jain SK. Oxidative stress, insulin signaling, and diabetes. Free Radic Biol Med 2011; 50(5): 567-75.
[44]
Oltmanns KM, Gehring H, Rudolf S, et al. Hypoxia causes glucose intolerance in humans. Am J Respir Crit Care Med 2004; 169(11): 1231-7.
[45]
Hjalmarsen A, Aasebø U, Birkeland K, Sager G, Jorde R. Impaired glucose tolerance in patients with chronic hypoxic pulmonary disease. Diabetes Metab 1996; 22(1): 37-42.
[46]
Jakobsson P, Jorfeldt L. Oxygen supplementation increases glucose tolerance during euglycaemic hyperinsulinaemic glucose clamp procedure in patients with severe COPD and chronic hypoxaemia. Clin Physiol Funct Imaging 2006; 26(5): 271-4.
[47]
Ottenheijm CA, Heunks LM, Dekhuijzen RP. Diaphragm adaptation ns in patients with COPD. Respir Res 2008; 9: 12.
[48]
Fierro B, Bennici S, Raimondo DM. Phrenic nerve conduction in diabetic patients. A preliminary study. Acta Neurol (Napoli) 1982; 4(5): 357-61.
[49]
Lange P, Parner J, Schnohr P, Jensen G. Copenhagen City Heart Study: longitudinal analysis of ventilatory capacity in diabetic and nondiabetic adults. Eur Respir J 2002; 20(6): 1406-12.
[50]
Song Y, Klevak A, Manson JE, Buring JE, Liu S. Asthma, chronic obstructive pulmonary disease, and type 2 diabetes in the Women’s Health Study. Diabetes Res Clin Pract 2010; 90(3): 365-71.
[51]
Lim SY, Rhee E-J, Sung K-C. Metabolic syndrome, insulin resistance and systemic inflammation as risk factors for reduced lung function in Korean nonsmoking males. J Korean Med Sci 2010 oct; 25(10): 1480-6.
[52]
Egbuonu F, Antonio FA, Edavalath M. Effect of inhaled corticosteroids on glycemic status. Open Respir Med J 2014; 8: 101-5.
[53]
Suissa S, Kezouh A, Ernst P. Inhaled corticosteroids and the risks of diabetes onset and progression. Am J Med 2010; 123(11): 1001-6.
[54]
O’Byrne PM, Rennard S, Gerstein H, Radner F, Peterson S, Lindberg B, et al. Risk of new onset diabetes mellitus in patients with asthma or COPD taking inhaled corticosteroids. Respir Med 2012; 106(11): 1487-93.
[55]
Papatheodorou A, Makrythanasis P, Kaliakatsos M, Dimakou A, Orfanidou D, Roussos C, et al. Development of novel microarray methodology for the study of mutations in the SERPINA1 and ADRB2 genes--their association with Obstructive Pulmonary Disease and Disseminated Bronchiectasis in Greek patients. Clin Biochem 2010; 43(1-2): 43-50.
[56]
Prior SJ, Goldberg AP, Ryan AS. ADRB2 haplotype is associated with glucose tolerance and insulin sensitivity in obese postmenopausal women. Obesity (Silver Spring) 2011; 19(2): 396-401.
[57]
Cazzola M, Rogliani P, Calzetta L, Lauro D, Page C, Matera MG. Targeting mechanisms linking COPD to Type 2 diabetes mellitus. Trends Pharmacol Sci 2017; 38(10): 940-51.
[58]
Shah SH, Sonawane P, Nahar P, Vaidya S, Salvi S. Pulmonary function tests in type 2 diabetes mellitus and their association with glycemic control and duration of the disease. Lung India 2013; 30(2): 108-12.
[59]
Litonjua AA, Lazarus R, Sparrow D, Demolles D, Weiss ST. Lung function in type 2 diabetes: The Normative Aging Study. Respir Med 2005; 99(12): 1583-90.
[60]
Aparna null. Pulmonary function tests in type 2 diabetics and non-diabetic people -a comparative study. J Clin Diagn Res 2013; 7(8): 1606-8.
[61]
Lim SY, Rhee E-J, Sung K-C. Metabolic syndrome, insulin resistance and systemic inflammation as risk factors for reduced lung function in Korean nonsmoking males. J Korean Med Sci 2010; 25(10): 1480-6.
[62]
Ehrlich SF, Quesenberry CP, Van Den Eeden SK, Shan J, Ferrara A. Patients diagnosed with diabetes are at increased risk for asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and pneumonia but not lung cancer. Diabetes Care 2010; 33(1): 55-60.
[63]
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(2): 195-203.
[64]
Makarevich AE, Valevich VE, Pochtavtsev AU. Evaluation of pulmonary hypertension in COPD patients with diabetes. Adv Med Sci 2007; 52: 265-72.
[65]
Dennis RJ, Maldonado D, Rojas MX, et al. Inadequate glucose control in type 2 diabetes is associated with impaired lung function and systemic inflammation: A cross-sectional study BMC Pulm Med 2010 26; 10: 38
[66]
van den Oever IAM, Raterman HG, Nurmohamed MT, Simsek S. Endothelial dysfunction, inflammation, and apoptosis in diabetes mellitus. Mediators Inflamm 2010; 2010792393
[67]
Pitocco D, Fuso L, Conte EG, et al. The diabetic lung--a new target organ? Rev Diabet Stud 2012; 9(1): 23-35.
[68]
Guazzi M, Brambilla R, De Vita S, Guazzi MD. Diabetes worsens pulmonary diffusion in heart failure, and insulin counteracts this effect. Am J Respir Crit Care Med 2002; 166(7): 978-82.
[69]
Cazzola M, Calzetta L, Rogliani P, Lauro D, Novelli L, Page CP, et al. High glucose enhances responsiveness of human airways smooth muscle via the Rho/ROCK pathway. Am J Respir Cell Mol Biol 2012; 47(4): 509-16.
[70]
Gudmundsson G, Ulrik CS, Gislason T, et al. Long-term survival in patients hospitalized for chronic obstructive pulmonary disease: A prospective observational study in the Nordic countries. Int J Chron Obstruct Pulmon Dis 2012; 7: 571-6.
[71]
Mahishale V, Eti A, Patil B, Lolly M, and Khan S. Impact of poor glycemic control on severity and clinical course of chronic obstructive pulmonary disease in patients with co-existing type 2 diabetes mellitus - one-year prospective study. SM J Pulm Med 2015; 1(2): 1009.
[72]
Terzano C, Colamesta V, Unim B, et al. Chronic obstructive pulmonary disease (COPD) exacerbation: Impact of comorbidities on length and costs during hospitalization. Eur Rev Med Pharmacol Sci 2017; 21(16): 3680-9.
[73]
Chakrabarti B, Angus RM, Agarwal S, Lane S, Calverley PMA. Hyperglycaemia as a predictor of outcome during non-invasive ventilation in decompensated COPD. Thorax 2009; 64(10): 857-62.
[74]
Küpeli E, Ulubay G, Ulasli SS, Sahin T, Erayman Z, Gürsoy A. Metabolic syndrome is associated with increased risk of acute exacerbation of COPD: A preliminary study. Endocrine 2010; 38(1): 76-82.
[75]
Louis M, Punjabi NM. Effects of acute intermittent hypoxia on glucose metabolism in awake healthy volunteers. J Appl Physiol 2009; 106(5): 1538-44.
[76]
Adrogué HJ, Chap Z, Okuda Y, et al. Acidosis-induced glucose intolerance is not prevented by adrenergic blockade. Am J Physiol 1988; 255(6 Pt 1): E812-23.
[77]
Fujiwara T, Cherrington AD, Neal DN, McGuinness OP. Role of cortisol in the metabolic response to stress hormone infusion in the conscious dog. Metab Clin Exp 1996; 45(5): 571-8.
[78]
McGuinness OP, Shau V, Benson EM, et al. Role of epinephrine and norepinephrine in the metabolic response to stress hormone infusion in the conscious dog. Am J Physiol 1997; 273(4 Pt 1): E674-81.
[79]
Kasirye Y, Simpson M, Mamillapalli CK, Epperla N, Liang H, Yale SH. Association between blood glucose level and outcomes in patients hospitalized for acute exacerbation of chronic obstructive pulmonary disease. WMJ 2013; 112(6): 244-9. quiz 250
[80]
McGhan R, Radcliff T, Fish R, Sutherland ER, Welsh C, Make B. Predictors of rehospitalization and death after a severe exacerbation of COPD. Chest 2007; 132(6): 1748-55.
[81]
Kinney G, Baker E. Type 2 diabetes mellitus and chronic obstructive pulmonary disease: Need for a double-pronged approach. Diabetes Management 2014; 4(4): 307-10.
[82]
Caughey GE, Preiss AK, Vitry AI, Gilbert AL, Roughead EE. Comorbid diabetes and COPD: impact of corticosteroid use on diabetes complications. Diabetes Care 2013; 36(10): 3009-14.
[83]
Walters JAE, Tan DJ, White CJ, Gibson PG, Wood-Baker R, Walters EH. Systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2014; (9): CD001288
[84]
Leuppi JD, Schuetz P, Bingisser R, et al. Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: The REDUCE randomized clinical trial. JAMA 2013; 309(21): 2223-31.
[85]
Cheng T, Gong Y, Guo Y, et al. Systemic corticosteroid for COPD exacerbations, whether the higher dose is better? A meta-analysis of randomized controlled trials. Clin Respir J 2013; 7(4): 305-18.
[86]
Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med 1995; 333(9): 550-4.
[87]
Park CS, Bang B-R, Kwon H-S, et al. Metformin reduces airway inflammation and remodeling via activation of AMP-activated protein kinase. Biochem Pharmacol 2012; 84(12): 1660-70.
[88]
Song P, Zou M-H. Regulation of NAD(P)H oxidases by AMPK in cardiovascular systems. Free Radic Biol Med 2012; 52(9): 1607-19.
[89]
Sexton P, Metcalf P, Kolbe J. Respiratory effects of insulin sensitisation with metformin: A prospective observational study. COPD 2014; 11(2): 133-42.
[90]
Kim HJ, Lee JY, Jung HS, et al. The impact of insulin sensitisers on lung function in patients with chronic obstructive pulmonary disease and diabetes. Int J Tuberc Lung Dis 2010; 14(3): 362-7.
[91]
Sulkin TV, Bosman D, Krentz AJ. Contraindications to metformin therapy in patients with NIDDM. Diabetes Care 1997; 20(6): 925-8.
[92]
Yen F-S, Chen W, Wei JC-C, Hsu C-C, Hwu C-M. Effects of metformin use on total mortality in patients with type 2 diabetes and chronic obstructive pulmonary disease: A matched-subject design. PLoS ONE 2018; 13(10) e0204859
[93]
Hitchings AW, Archer JRH, Srivastava SA, Baker EH. Safety of metformin in patients with chronic obstructive pulmonary disease and type 2 diabetes mellitus. COPD 2015; 12(2): 126-31.
[94]
Bishwakarma R, Zhang W, Lin Y-L, Kuo Y-F, Cardenas VJ, Sharma G. Metformin use and health care utilization in patients with coexisting chronic obstructive pulmonary disease and diabetes mellitus. Int J Chron Obstruct Pulmon Dis 2018; 13: 793-800.
[95]
Hitchings AW, Lai D, Jones PW, Baker EH. Metformin in COPD Trial Team. Metformin in severe exacerbations of chronic obstructive pulmonary disease: A randomised controlled trial. Thorax 2016; 71(7): 587-93.
[96]
Lai S-W, Liao K-F, Chen P-C, Tsai P-Y, Hsieh DPH, Chen C-C. Antidiabetes drugs correlate with decreased risk of lung cancer: A population-based observation in Taiwan. Clin Lung Cancer 2012; 13(2): 143-8.
[97]
Quinn CE, Hamilton PK, Lockhart CJ, McVeigh GE. Thiazolidinediones: effects on insulin resistance and the cardiovascular system. Br J Pharmacol 2008; 153(4): 636-45.
[98]
Birrell MA, Patel HJ, McCluskie K, et al. PPAR-gamma agonists as therapy for diseases involving airway neutrophilia. Eur Respir J 2004; 24(1): 18-23.
[99]
Rinne ST, Liu C-F, Feemster LC, et al. Thiazolidinediones are associated with a reduced risk of COPD exacerbations. Int J Chron Obstruct Pulmon Dis 2015; 10: 1591-7.
[100]
Bullock BP, Heller RS, Habener JF. Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor. Endocrinology 1996; 137(7): 2968-78.
[101]
Wei Y, Mojsov S. Tissue specific expression of different human receptor types for pituitary adenylate cyclase activating polypeptide and vasoactive intestinal polypeptide: Implications for their role in human physiology. J Neuroendocrinol 1996; 8(11): 811-7.
[102]
Viby N-E, Isidor MS, Buggeskov KB, Poulsen SS, Hansen JB, Kissow H. Glucagon-like peptide-1 (GLP-1) reduces mortality and improves lung function in a model of experimental obstructive lung disease in female mice. Endocrinology 2013; 154(12): 4503-11.
[103]
Rogliani P, Calzetta L, Capuani B, et al. Glucagon-Like Peptide 1 Receptor: A Novel Pharmacological Target for Treating Human Bronchial Hyperresponsiveness. Am J Respir Cell Mol Biol 2016; 55(6): 804-14.
Related Journals
Article Metrics
21
5
1
1