Reviews in Endocrine and Metabolic Disorders

, Volume 20, Issue 3, pp 303–319 | Cite as

Diabetic lung disease: fact or fiction?

  • Saeed KolahianEmail author
  • Veronika Leiss
  • Bernd Nürnberg


Diabetes mellitus is a chronic, progressive, incompletely understood metabolic disorder whose prevalence has been increasing steadily worldwide. Even though little attention has been paid to lung disorders in the context of diabetes, its prevalence has recently been challenged by newer studies of disease development. In this review, we summarize and discuss the role of diabetes mellitus involved in the progression of pulmonary diseases, with the main focus on pulmonary fibrosis, which represents a chronic and progressive disease with high mortality and limited therapeutic options.


Diabetes mellitus Pulmonary disease Lung Fibrosis 



acute lung injury


acute respiratory distress syndrome


advanced glycation end product


airway smooth muscle cells


airway surface liquid


carbon monoxide


chronic obstructive pulmonary disease


connective tissue growth factor


cystic fibrosis-related diabetes


diabetes mellitus


epithelial-mesenchymal transition


extracellular matrix


forced expiratory volume in one second


idiopathic pulmonary fibrosis




mitogen-activated protein kinase


NADPH oxidase


nuclear factor kappa-light-chain-enhancer of activated B-cells




reactive nitrogen species


reactive oxygen species


Rho-associated protein kinase


signal transducer and activator of transcription 3




T helper type 1 cell


T helper type 2 cell


transforming growth factor β


type 1 diabetes mellitus


type 2 diabetes mellitus



The authors thank Peter M. Weber (University of Tübingen, Tübingen, Germany) for the excellent illustration. S.K. is supported by fortüne grant funding from the University Hospital Tübingen (grant No: 2458-0-0). B.N. and V.L. are supported by Deutsche Forschungsgemeinschaft (grant NU: 53/9-2).

Author contributions

Conceptualization: SK, BN.

Writing – original draft: SK, VL.

Writing – review & editing: SK, VL, BN.

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest regarding the publication of this article.


  1. 1.
    Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. 2010;87:4–14.PubMedPubMedCentralGoogle Scholar
  2. 2.
    NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants. Lancet. 2016;387:1513–30.Google Scholar
  3. 3.
    International Federation Diabetes. Diabetes Atlas. 6th ed. International Diabetes federation. 2013;28:49.Google Scholar
  4. 4.
    American Diabetes Association. Diabetes Care. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2018. 2018;41:13–27.Google Scholar
  5. 5.
    Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular outcomes in type 1 diabetes: the DCCT/EDIC study 30-year follow-up. Diabetes Care. 2016;39:686–93.Google Scholar
  6. 6.
    Concannon P, Rich SS, Nepom GT. Genetics of type 1A diabetes. N Engl J Med. 2009;360:1646–54.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Greenhill C. Unravelling metformin's mechanism of action. Nat Rev Endocrinol. 2018;14:564.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017;60:1577–85.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Pitocco D, Fuso L, Conte EG, Zaccardi F, Condoluci C, Scavone G, et al. The diabetic lung-a new target organ? Rev Diabet Stud. 2012;9:23–35.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Lange P, Groth S, Kastrup J, Mortensen J, Appleyard M, Nyboe J, et al. Diabetes mellitus, plasma glucose and lung function in a cross-sectional population study. Eur Respir J. 1989;2:14–9.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Singh S, Prakash YS, Linneberg A, Agrawal A. Insulin and the lung: connecting asthma and metabolic syndrome. J Allergy (Cairo). 2013;2013:627384.Google Scholar
  12. 12.
    Bottini P, Scionti L, Santeusanio F, Casucci G, Tantucci C. Impairment of the respiratory system in diabetic autonomic neuropathy. Diabetes Nutr Metab. 2000;13:165–72.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Forgiarini LA Jr, Kretzmann NA, Porawski M, Dias AS, Marroni NA. Experimental diabetes mellitus: oxida oxidative stress and changes in lung structure. J Bras Pneumol. 2009;35:788–91.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Hsia CC, Raskin P. The diabetic lung: relevance of alveolar microangiopathy for the use of inhaled insulin. Am J Med. 2005;118:205–11.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Kuziemski K, Specjalski K, Jassem E. Diabetic pulmonary microangiopathy - fact or fiction? Endokrynol Pol. 2011;62:171–6.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Soulis T, Thallas V, Youssef S, Gilbert RE, McWilliam BG, Murray-McIntosh RP, et al. Advanced glycation end products and their receptors co-localise in rat organs susceptible to diabetic microvascular injury. Diabetologia. 1997;40:619–28.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Soulis T, Cooper ME, Sastra S, Thallas V, Panagiotopoulos S, Bjerrum OJ, et al. Relative contributions of advanced glycation and nitric oxide synthase inhibition to aminoguanidine-mediated renoprotection in diabetic rats. Diabetologia. 1997;40:1141–51.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Hamlin CR, Kohn RR, Luschin JH. Apparent accelerated aging of human collagen in diabetes mellitus. Diabetes. 1975;24:902–4.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Cavan DA, Parkes A, O’Donnell MJ, Freeman W, Cayton RM. Lung function and diabetes. Respir Med. 1991;85:257–8.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Ofulue AF, Thurlbeck WM. Experimental diabetes and the lung. II. In vivo connective tissue metabolism. Am Rev Respir Dis. 1988;138:284–9.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Kida K, Fujino Y. Lung structure and elastic recoil properties in hereditary diabetes mellitus in KK-mice, C57 black mice, and F1 hybrids. J Lab Clin Med. 1993;122:524–32.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Foster DJ, Ravikumar P, Bellotto DJ, Unger RH, Hsia CC. Fatty diabetic lung: altered alveolar structure and surfactant protein expression. Am J Physiol Lung Cell Mol Physiol. 2010;298:392–403.Google Scholar
  23. 23.
    Treviño-Alanís M, Ventura-Juárez J, Hernández-Piñero J, Nevárez-Garza A, Quintanar-Stephano A, González-Piña A. Delayed lung maturation of foetus of diabetic mother rats develop with a diminish, but without changes in the proportion of type I and II pneumocytes, and decreased expression of protein D-associated surfactant factor, Anat. Histol. Embryol. 2009;38:169–76.Google Scholar
  24. 24.
    Heimer D, Brami J, Lieberman D, Bark H. Respiratory muscle performance in patients with type 1 diabetes. Diabet Med. 1990;7:434–7.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Fuso L, Pitocco D, Longobardi A, Zaccardi F, Contu C, Pozzuto C, et al. Reduced respiratory muscle strength and endurance in type 2 diabetes mellitus. Diabetes Metab Res Rev. 2012;28:370–5.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Schuyler MR, Niewoehner DE, Inkley SR, Kohn R. Abnormal lung elasticity in juvenile diabetes mellitus. Am Rev Respir Dis. 1976;113:37–41.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Davis WA, Knuiman M, Kendall P, Grange V, Davis TM. Glycemic exposure is associated with reduced pulmonary function in type 2 diabetes: the Fremantle diabetes study. Diabetes Care. 2004;27:752–7.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Lange P, Groth S, Mortensen J, Appleyard M, Nyboe J, Schnohr P, et al. Diabetes mellitus and ventilatory capacity: a five year follow-up study. Eur Respir J. 1990;3:288–92.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Antonelli Incalzi R, Fuso L, Pitocco D, Basso S, Trove A, Longobardi A, et al. Decline of neuroadrenergic bronchial innervation and respiratory function in type 1 diabetes mellitus: a longitudinal study. Diabetes Metab Res Rev. 2007;23:311–6.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Weiss SR, Cheng SL, Kourides IA, Gelfand RA, Landschulz WH. Inhaled insulin provides improved glycemic control in patients with type 2 diabetes mellitus inadequately controlled with oral agents: a randomized controlled trial. Arch Intern Med. 2003;163:2277–82.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Skyler JS, Weinstock RS, Raskin P, Yale JF, Barrett E, Gerich JE, et al. Use of inhaled insulin in a basal/bolus insulin regimen in type 1 diabetic subjects: a 6-month, randomized, comparative trial. Diabetes Care. 2005;28:1630–5.PubMedPubMedCentralGoogle Scholar
  32. 32.
    McKeever TM, Weston PJ, Hubbard R, Fogarty A. Lung function and glucose metabolism: an analysis of data from the third National Health and nutrition examination survey. Am J Epidemiol. 2005;161:546–56.PubMedPubMedCentralGoogle Scholar
  33. 33.
    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.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Yeh HC, Punjabi NM, Wang NY, Pankow JS, Duncan BB, Cox CE, et al. Crosssectional and prospective study of lung function in adults with type 2 diabetes: the atherosclerosis risk in communities (ARIC) study. Diabetes Care. 2008;31:741–6.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Guvener N, Tutuncu BN, Akcay S, Eyuboglu F, Gokcel A. Alveolar gas exchange in patients with type 2 diabetes mellitus. Endocr J. 2003;50:663–7.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Klein OL, Kalhan R, Williams MV, Tipping M, Lee J, Peng J, et al. Lung spirometry parameters and diffusion capacity are decreased in patients with type 2 diabetes. Diabet Med. 2012;29:212–9.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Ozsahin K, Tugrul A, Mert S, Yüksel M, Tugrul G. Evaluation of pulmonary alveolo-capillary permeability in type 2 diabetes mellitus: using technetium 99mTc-DTPA aerosol scintigraphy and carbon monoxide diffusion capacity. J Diabetes Complicat. 2006;20:205–9.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Wheatley CM, Baldi JC, Cassuto NA, Foxx-Lupo WT, Snyder EM. Glycemic control influences lung membrane diffusion and oxygen saturation in exercise-trained subjects with type 1 diabetes: alveolar-capillary membrane conductance in type 1 diabetes. Eur J Appl Physiol. 2011;111:567–78.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Pitocco D, Santangeli P, Fuso L, Zaccardi F, Longobardi A, Infusino F, et al. Association between reduced pulmonary diffusing capacity and cardiac autonomic dysfunction in type 1 diabetes. Diabet Med. 2008;25:1366–9.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Nishimura M, Miyamoto K, Suzuki A, Yamamoto H, Tsuji M, Kishi F, et al. Ventilatory and heart responses to hypoxia and hypercapnia in patients with diabetes mellitus. Thorax. 1989;44:251–7.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Weisbrod CJ, Eastwood PR, O’Driscoll GO, Green DJ. Abnormal ventilatory responses to hypoxia in type 2 diabetes. Diabet Med. 2005;22:563–8.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Antonelli Incalzi R, Fuso L, Giordano A, Pitocco D, Maiolo C, Calcagni ML, et al. Neuroadrenergic denervation of the lung in type I diabetes mellitus complicated by autonomic neuropathy. Chest. 2002;121:443–51.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Santos e Fonseca CM, Manco JC, Gallo Junior L, Barreira AA, Foss MC. Cholinergic bronchomotor tone and airway caliber in insulin-dependent diabetes mellitus. Chest. 1992;101:1038–43.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Koziel H, Koziel MJ. Pulmonary complications of diabetes mellitus. Pneumonia Infect Dis Clin North Am. 1995;9:65–96.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Vojtková J, Ciljaková M, Michnová Z, Turčan T. Chronic complications of diabetes mellitus related to the respiratory system. Pediatr Endocrinol Diabetes Metab. 2012;18:112–5.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Scano G, Seghieri G, Mancini M, Filippelli M, Duranti R, Fabbri A, et al. Dyspnoea, peripheral airway involvement and respiratory muscle effort in patients with type I diabetes mellitus under good metabolic control. Clin Sci (Lond). 1999;96:499–506.Google Scholar
  47. 47.
    Wanke T, Formanek D, Auinger M, Popp W, Zwick H, Irsigler K. Inspiratory muscle performance and pulmonary function changes in insulin-dependent diabetes mellitus. Am Rev Respir Dis. 1991;143:97–100.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Villa MP, Cacciari E, Bernardi F, Cicognani A, Salardi S, Zapulla F. Bronchial reactivity in diabetic patients. Relationship to duration of diabetes and degree of glycemic control. Am J Dis Child. 1988;142:726–9.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Wanke TH, Formanek D, Auginer M, Zwick H, Irsigler K. Pulmonary gas exchange and oxygen uptake during exercise in patients with type 1 diabetes mellitus. Diabet Med. 1992;9:252–7.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Brassard P, Ferland A, Bogaty P, Desmeules M, Jobin J, Poirier P. Influence of glycemic control on pulmonary function and heart rate in response to exercise in subjects with type 2 diabetes mellitus. Metabolism. 2006;55:1532–7.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Ardigo D, Valtuena S, Zavaroni I, Baroni MC, Delsignore R. Pulmonary complications of diabetes mellitus: the role of glycemic control. Curr Drug Targets Inflamm Allergy. 2004;3:455–8.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Wolff SP, Dean RT. Glucose autoxidation and protein modification; potential role of autoxidative glycosylation in diabetes. Biochem J. 1987;245:243–50.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Goldman MD. Lung dysfunction in diabetes. Diabetes Care. 2003;26:1915–8.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Hsia CC, Raskin P. Lung function changes related to diabetes mellitus. Diabetes Technol Ther. 2007;9:73–82.Google Scholar
  55. 55.
    Hu FB, Manson JE, Liu S, Hunter D, Colditz GA, Michels KB, et al. Prospective study of adult onset diabetes mellitus (type 2) and risk of colorectal cancer in women. J Natl Cancer Inst. 1999;91:542–7.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Weiderpass E, Gridley G, Persson I, Nyren O, Ekbom A, Adami HO. Risk of endometrial and breast cancer in patients with diabetes mellitus. Int J Cancer. 1997;71:360–3.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Larsson SC, Wolk A. Diabetes mellitus and incidence of kidney cancer: a meta-analysis of cohort studies. Diabetologia. 2011;54:1013–8.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Chow WH, Gridley G, Nyren O, Linet MS, Ekbom A, Fraumeni JF Jr, et al. Risk of pancreatic cancer following diabetes mellitus: a nationwide cohort study in Sweden. J Natl Cancer Inst. 1995;87:930–1.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Argiles JM, Lopez-Soriano FJ. Insulin and cancer (review). Int J Oncol. 2001;18:683–7.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Kim WY, Jin Q, Oh SH, Kim ES, Yang YJ, Lee DH, et al. Elevated epithelial insulin-like growth factor expression is a risk factor for lung cancer development. Cancer Res. 2009;69:7439–48.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, et al. Diabetes and cancer: a consensus report. Diabetes Care. 2010;33:1674–85.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Ruano-Ravina A, Figueiras A, Barros-Dios JM. Lung cancer and related risk factors: an update of the literature. Public Health. 2003;117:149–56.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Strickler HD, Wylie-Rosett J, Rohan T, Hoover DR, Smoller S, Burk RD, et al. The relation of type 2 diabetes and cancer. Diabetes Technol Ther. 2001;3:263–74.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Wakai K, Ito Y, Suzuki K, Tamakoshi A, Seki N, Ando M, et al. Serum insulin-like growth factors, insulin-like growth factor-binding protein-3, and risk of lung cancer death: a case-control study nested in the Japan collaborative cohort (JACC) study. Jpn J Cancer Res. 2002;93:1279–86.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Ehrlich SF, Quesenberry CP Jr, 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;33:55–60.Google Scholar
  66. 66.
    Hall GC, Roberts CM, Boulis M, Mo J, MacRae KD. Diabetes and the risk of lung cancer. Diabetes Care. 2005;28:590–4.PubMedPubMedCentralGoogle Scholar
  67. 67.
    Lee JY, Jeon I, Lee JM, Yoon JM, Park SM. Diabetes mellitus as an independent risk factor for lung cancer: a meta-analysis of observational studies. Eur J Cancer. 2013;49:2411–23.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Dankner R, Boker LK, Boffetta P, Balicer RD, Murad H, Berlin A, et al. A historical cohort study on glycemic-control and cancer-risk among patients with diabetes. Cancer Epidemiol. 2018;57:104–9.PubMedPubMedCentralGoogle Scholar
  69. 69.
    De Giorgio R, Barbara G, Cecconi A, Corinaldesi R, Mancini AM. Diabetes is associated with longer survival rates in patients with malignant tumors. Arch Intern Med. 2000;160:2217.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Hatlen P, Grønberg BH, Langhammer A, Carlsen SM, Amundsen T. Prolonged survival in patients with lung cancer with diabetes mellitus. J Thorac Oncol. 2011;6:1810–7.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Rao Kondapally Seshasai S, Kaptoge S, Thompson A, Di Angelantonio E, Gao P, Sarwar N, et al. Emerging risk factors collaboration. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med. 2011;364:829–41.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Vasic L. Locally advanced non-small cell lung cancer—pretreatment prognostic factors: disease stage, tumor histopathological characteristics, the patient-related factors. Arch Oncol. 2007;15:19–23.Google Scholar
  73. 73.
    Karlin NJ, Amin SB, Buras MR, Kosiorek HE, Verona PM, Cook CB. Patient outcomes from lung cancer and diabetes mellitus: a matched case-control study. Future Sci OA. 2017;4:FSO248.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Satoh H, Ishikawa H, Kurishima K, Ohtsuka M, Sekizawa K. Diabetes is not associated with longer survival in patients with lung cancer. Arch Intern Med. 2001;161:485.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Xu T, Li D, He Y, Zhang F, Qiao M, Chen Y. Prognostic value of metformin for non-small cell lung cancer patients with diabetes. World J Surg Oncol. 2018;16:60.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Tsai MJ, Yang CJ, Kung YT, Sheu CC, Shen YT, Chang PY, et al. Metformin decreases lung cancer risk in diabetic patients in a dose-dependent manner. Lung Cancer. 2014;86:137–43.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Lin JJ, Gallagher EJ, Sigel K, Mhango G, Galsky MD, Smith CB, et al. Survival of patients with stage IV lung cancer with diabetes treated with metformin. Am J Respir Crit Care Med. 2015;191:448–54.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Ferrara A, Lewis JD, Quesenberry CP Jr, Peng T, Strom BL, Van Den Eeden SK, et al. Cohort study of pioglitazone and cancer incidence in patients with diabetes. Diabetes Care. 2011;34:923–9.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Smiechowski BB, Azoulay L, Yin H, Pollak MN, Suissa S. The use of metformin and the incidence of lung cancer in patients with type 2 diabetes. Diabetes Care. 2013;36:124–9.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Nie SP, Chen H, Zhuang MQ, Lu M. Anti-diabetic medications do not influence risk of lung cancer in patients with diabetes mellitus: a systematic review and meta-analysis. Asian Pac J Cancer Prev. 2014;15:6863–9.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Valerius N, Eff C, Hansen NE, Karle H, Nerup J, Søeberg B, et al. Neutrophil and lymphocyte function in patients with diabetes mellitus. Acta Med Scand. 1982;211:463–72.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Bhargava P, Lee CH. Role and function of macrophages in the metabolic syndrome. Biochem J. 2012;442:253–62.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Muller LM, Gorter KJ, Hak E, Goudzwaard WL, Schellevis FG, Hoepelman AI, et al. Increased risk of common infections in patients with type 1 and type 2 diabetes mellitus. Clin Infect Dis. 2005;41:281–8.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Peleg AY, Weerarathna T, McCarthy JS, Davis TM. Common infections in diabetes: pathogenesis, management and relationship to glycaemic control. Diabetes Metab Res Rev. 2007;23:3–13.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Fernández-Real JM, Valdés S, Manco M, Chico B, Botas P, Campo A, et al. Surfactant protein d, a marker of lung innate immunity, is positively associated with insulin sensitivity. Diabetes Care. 2010;33:847–53.PubMedPubMedCentralGoogle Scholar
  86. 86.
    Baker EH, Baines DL. Airway glucose homeostasis: a new target in the prevention and treatment of pulmonary infection. Chest. 2018;153:507–14.PubMedPubMedCentralGoogle Scholar
  87. 87.
    Nirmal J, Caputo GM, Weitekamp MR, Karchmer AW. Infections in patients with diabetes mellitus. N Engl J Med. 1999;341:1906–12.Google Scholar
  88. 88.
    Higa M. Clinical epidemiology of fungal infection in diabetes. Nihon Rinsho. 2008;66:2239–44.PubMedPubMedCentralGoogle Scholar
  89. 89.
    Diepersloot RJ, Bouter KP, Beyer WE, Hoekstra JB, Masurel N. Humoral immune response and delayed type hypersensitivity to influenza vaccine in patients with diabetes mellitus. Diabetologia. 1987;30:397–401.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Kornum JB, Thomsen RW, Riis A, Lervang HH, Schønheyder HC, Sørensen HT. Diabetes, glycemic control, and risk of hospitalization with pneumonia: a population- based case-control study. Diabetes Care. 2008;31:1541–5.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Falguera M, Pifarre R, Martin A, Sheikh A, Moreno A. Etiology and outcome of community-acquired pneumonia in patients with diabetes mellitus. Chest. 2005;128:3233–9.Google Scholar
  92. 92.
    Bader MS, Abouchehade KA, Yi Y, Haroon B, Bishop LD, Hawboldt J. Antibiotic administration longer than eight hours after triage and mortality of community-acquired pneumonia in patients with diabetes mellitus. Eur J Clin Microbiol Infect Dis. 2011;30:881–6.Google Scholar
  93. 93.
    van de Garde EM, Hak E, Souverein PC, Hoes AW, van den Bosch JM, Leufkens HG. Statin treatment and reduced risk of pneumonia in patients with diabetes. Thorax. 2006;61:957–61.PubMedPubMedCentralGoogle Scholar
  94. 94.
    van de Garde EM, Souverein PC, Hak E, Deneer VH, van den Bosch JM, Leufkens HG. Angiotensin-converting enzyme inhibitor use and protection against pneumonia in patients with diabetes. J Hypertens. 2007;25:235–9.Google Scholar
  95. 95.
    Seminog OO, Goldacre MJ. Risk of pneumonia and pneumococcal disease in people hospitalized with diabetes mellitus: English record-linkage studies. Diabet Med. 2013;30:1412–9.Google Scholar
  96. 96.
    Harries AD, Lin Y, Satyanarayana S, Lönnroth K, Li L, Wilson N, et al. The looming epidemic of diabetes-associated tuberculosis: learning lessons from the HIV-associated tuberculosis. Inter J Tuberc Lung Dis. 2011;15:1436–45.Google Scholar
  97. 97.
    Jeon CY, Murray MB. Diabetes mellitus increases the risk of active tuberculosis: a systematic review of 13 observational studies. PLoS Med. 2008;5:e152.PubMedPubMedCentralGoogle Scholar
  98. 98.
    Restrepo BI, Schlesinger LS. Host-pathogen interactions in tuberculosis patients with type 2 diabetes mellitus. Tuberculosis. 2013;93:10–4.Google Scholar
  99. 99.
    Singla R, Khan N, Al Sharif N, Ai-Sayegh MO, Shaikh MA, Osman MM. Influence of diabetes on manifestations and treatment outcome of pulmonary TB patients. Int J Tuberc Lung Dis. 2006;10:74–9.Google Scholar
  100. 100.
    Restrepo BI, Fisher-Hoch SP, Crespo JG, Whitney E, Perez A, Smith B, et al. Nuevo Santander tuberculosis trackers. Cross-sectional assessment reveals high diabetes prevalence among newly-diagnosed tuberculosis cases. Bull World Health Organ. 2011;89:352–9.PubMedPubMedCentralGoogle Scholar
  101. 101.
    Dooley KE, Chaisson RE. Tuberculosis and diabetes mellitus: convergence of two epidemics. Lancet Infect Dis. 2009;9:737–46.PubMedPubMedCentralGoogle Scholar
  102. 102.
    Baker MA, Harries AD, Jeon CY, Hart JE, Kapur A, Lönnroth K, et al. The impact of diabetes on tuberculosis treatment outcomes: a systematic review. BMC Med. 2011;9:81.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Delgado-Sánchez G, García-García L, Castellanos-Joya M, Cruz-Hervert P, Ferreyra-Reyes L, Ferreira-Guerrero E, et al. Association of Pulmonary Tuberculosis and Diabetes in Mexico: analysis of the National Tuberculosis Registry 2000-2012. PLoS One. 2015;10:e0129312.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Guirado E, Schlesinger LS, Kaplan G. Macrophages in tuberculosis: friend or foe. Semin Immunopathol. 2013;35:563–83.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Repasy T, Lee J, Marino S, Martinez N, Kirschner DE, Hendricks G, et al. Intracellular bacillary burden reflects a burst size for Mycobacterium tuberculosis In vivo. PLoS Pathog. 2013;9:e1003190.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Gomez DI, Twahirwa M, Schlesinger LS, Restrepo BI. Reduced Mycobacterium tuberculosis association with monocytes from diabetes patients that have poor glucose control. Tuberculosis. 2013;93:192–7.PubMedPubMedCentralGoogle Scholar
  107. 107.
    Restrepo BI, Twahirwa M, Rahbar MH, Schlesinger LS. Phagocytosis via complement or fc-gamma receptors is compromised in monocytes from type 2 diabetes patients with chronic hyperglycemia. PLoS One. 2014;26(9):e92977.Google Scholar
  108. 108.
    Musilli C, Paccosi S, Pala L, Gerlini G, Ledda F, Mugelli A, et al. Characterization of circulating and monocyte-derived dendritic cells in obese and diabetic patients. Mol Immunol. 2011;49:234–8.PubMedPubMedCentralGoogle Scholar
  109. 109.
    Zhang Q, Xiao HP, Cui HY, Sugawara I. Significant increase in natural-killer T cells in patients with tuberculosis complicated by type 2 diabetes mellitus. J Int Med Res. 2011;39:105–11.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Al-Attiyah RJ, Mustafa AS. Mycobacterial antigen-induced T helper type 1 (Th1) and Th2 reactivity of peripheral blood mononuclear cells from diabetic and non-diabetic tuberculosis patients and Mycobacterium bovis bacilli Calmette-Gue´ rin (BCG)–vaccinated healthy subjects. Clin Exp Immunol. 2009;158:64–73.PubMedPubMedCentralGoogle Scholar
  111. 111.
    Stalenhoef JE, Alisjahbana B, Nelwan EJ, van der Ven-Jongekrijg J, Ottenhoff TH, van der Meer JW, et al. The role of interferon-g in the increased tuberculosis risk in type 2 diabetes mellitus. Eur J Clin Microbiol Infect Dis. 2008;27:97–103.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Restrepo BI, Fisher-Hoch SP, Pino PA, Salinas A, Rahbar MH, Mora F, et al. Tuberculosis in poorly controlled type 2 diabetes: altered cytokine expression in peripheral white blood cells. Clin Infect Dis. 2008;47:634–41.PubMedPubMedCentralGoogle Scholar
  113. 113.
    Kumar NP, Sridhar R, Banurekha VV, Jawahar MS, Nutman TB, Babu S. Expansion of pathogen-specific Th1 and Th17 cells in pulmonary tuberculosis with coincident type 2 diabetes mellitus. J Infect Dis. 2013;208:739–48.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Kumar NP, Sridhar R, Banurekha VV, Jawahar MS, Fay MP, Nutman TB, et al. Type 2 diabetes mellitus coincident with pulmonary tuberculosis is associated with heightened systemic type 1, type 17 and other proinflammatory cytokines. Ann Am Thorac Soc. 2013;10:441–9.PubMedPubMedCentralGoogle Scholar
  115. 115.
    Kumar NP, Sridhar R, Nair D, Banurekha VV, Nutman TB, Babu S. Type 2 diabetes mellitus is associated with altered CD8(+) T and natural killer cell function in pulmonary tuberculosis. Immunology. 2015;144:677–86.PubMedPubMedCentralGoogle Scholar
  116. 116.
    Blackman SM, Hsu S, Vanscoy LL, Collaco JM, Ritter SE, Naughton K, et al. Genetic modifiers play a substantial role in diabetes complicating cystic fibrosis. J Clin Endocrinol Metab. 2009;94:1302–9.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Lewis C, Blackman SM, Nelson A, Oberdorfer E, Wells D, Dunitz J, et al. Diabetes-related mortality in adults with cystic fibrosis. Role of genotype and sex. Am J Respir Crit Care Med. 2015;191:194–200.PubMedPubMedCentralGoogle Scholar
  118. 118.
    van den Berg JM, Morton AM, Kok SW, Pijl H, Conway SP, Heijerman HG. Microvascular complications in patients with cystic fibrosis-related diabetes (CFRD). J Cyst Fibros. 2008;7:515–9.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Rosenecker J, Höfler R, Steinkamp G, Eichler I, Smaczny C, Ballmann M, et al. Diabetes mellitus in patients with cystic fibrosis: the impact of diabetes mellitus on pulmonary function and clinical outcome. Eur J Med Res. 2001;6:345–50.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Koch C, Rainisio M, Madessani U, Harms HK, Hodson ME, Mastella G, et al. Investigators of the European epidemiologic registry of cystic fibrosis. Presence of cystic fibrosis-related diabetes mellitus is tightly linked to poor lung function in patients with cystic fibrosis: data from the European epidemiologic registry of cystic fibrosis. Pediatr Pulmonol. 2001;32:343–50.PubMedPubMedCentralGoogle Scholar
  121. 121.
    Milla CE, Warwick WJ, Moran A. Trends in pulmonary function in patients with cystic fibrosis correlate with the degree of glucose intolerance at baseline. Am J Respir Crit Care Med. 2000;162:891–5.PubMedPubMedCentralGoogle Scholar
  122. 122.
    Lanng S, Thorsteinsson B, Nerup J, Koch C. Influence of the development of diabetes mellitus on clinical status in patients with cystic fibrosis. Eur J Pediatr. 1992;151:684–7.PubMedPubMedCentralGoogle Scholar
  123. 123.
    Rolon MA, Benali K, Munck A, Navarro J, Clement A, Tubiana-Rufi N, et al. Cystic fibrosis-related diabetes mellitus: clinical impact of prediabetes and effects of insulin therapy. Acta Paediatr. 2001;90:860–7.PubMedPubMedCentralGoogle Scholar
  124. 124.
    Hameed S, Morton JR, Field PI, Belessis Y, Yoong T, Katz T, et al. Once daily insulin detemir in cystic fibrosis with insulin deficiency. Arch Dis Child. 2012;97:464–7.PubMedPubMedCentralGoogle Scholar
  125. 125.
    Mozzillo E, Franzese A, Valerio G, Sepe A, De Simone I, Mazzarella G, et al. One-year glargine treatment can improve the course of lung disease in children and adolescents with cystic fibrosis and early glucose derangements. Pediatr Diabetes. 2009;10:162–7.PubMedPubMedCentralGoogle Scholar
  126. 126.
    Nousia-Arvanitakis S, Galli-Tsinopoulou A, Karamouzis M. Insulin improves clinical status of patients with cystic-fibrosis-related diabetes mellitus. Acta Paediatr. 2001;90:515–9.PubMedPubMedCentralGoogle Scholar
  127. 127.
    Dobson L, Hattersley AT, Tiley S, Elworthy S, Oades PJ, Sheldon CD. Clinical improvement in cystic fibrosis with early insulin treatment. Arch Dis Child. 2002;87:430–1.PubMedPubMedCentralGoogle Scholar
  128. 128.
    Limoli DH, Yang J, Khansaheb MK, Helfman B, Peng L, Stecenko AA, et al. Staphylococcus aureus and Pseudomonas aeruginosa co-infection is associated with cystic fibrosis-related diabetes and poor clinical outcomes. Eur J Clin Microbiol Infect Dis. 2016;35:947–53.PubMedPubMedCentralGoogle Scholar
  129. 129.
    Fahy JV. Type 2 inflammation in asthma—present in most, absent in many. Nat Rev Immunol. 2015;15:57–65.PubMedPubMedCentralGoogle Scholar
  130. 130.
    Douek IF, Leech NJ, Gillmor HA, Bingley PJ, Gale EA. Children with type 1 diabetes and their unaffected siblings have fewer symptoms of asthma. Lancet. 1999;353:1850.PubMedPubMedCentralGoogle Scholar
  131. 131.
    Dahlqvist G, Patterson C, Soltesz G. Decreased prevalence of atopic diseases in children with diabetes. The EURODIAB substudy 2 study group. J Pediatr. 2000;137:470–4.Google Scholar
  132. 132.
    Meerwaldt R, Odink RJ, Landaeta R, Aarts F, Brunekreef B, Gerritsen J, et al. A lower prevalence of atopy symptoms in children with type 1 diabetes mellitus. Clin Exp Allergy. 2002;32:254–5.Google Scholar
  133. 133.
    Cardwell CR, Shields MD, Carson DJ, Patterson CC. A metaanalysis of the association between childhood type 1 diabetes and atopic disease. Diabetes Care. 2003;26:2568–74.Google Scholar
  134. 134.
    Metsälä J, Lundqvist A, Virta LJ, Kaila M, Gissler M, Virtanen SM, et al. The association between asthma and type 1 diabetes: a paediatric case-cohort study in Finland, years 1981-2009. Int J Epidemiol. 2018;47:409–16.Google Scholar
  135. 135.
    Stene LC, Nafstad P. Relation between occurrence of type 1 diabetes and asthma. Lancet. 2001;357:607–8.Google Scholar
  136. 136.
    Kero J, Gissler M, Hemminki E, Isolauri E. Could Th1 and Th2 diseases coexist? Evaluation of asthma incidence in children with coeliac disease, type 1 diabetes, or rheumatoid arthritis: a register study. J Allergy Clin Immunol. 2001;108:781–3.PubMedPubMedCentralGoogle Scholar
  137. 137.
    Hsiao YT, Cheng WC, Liao WC, Lin CL, Shen TC, Chen WC, et al. Type 1 diabetes and increased risk of subsequent asthma: a Nationwide population-based cohort study. Medicine (Baltimore). 2015;94:e1466.Google Scholar
  138. 138.
    Kondrashova A, Seiskari T, Ilonen J, Knip M, Hyöty H. The 'Hygiene hypothesis' and the sharp gradient in the incidence of autoimmune and allergic diseases between Russian Karelia and Finland. APMIS. 2013;121:478–93.Google Scholar
  139. 139.
    Black MH, Anderson A, Bell RA, Dabelea D, Pihoker C, Saydah S, et al. Prevalence of asthma and its association with glycemic control among youth with diabetes. Pediatrics. 2011;128:839–47.Google Scholar
  140. 140.
    Rachmiel M, Bloch O, Bistritzer T, Weintrob N, Ofan R, Koren-Morag N, et al. TH1/TH2 cytokine balance in patients with both type 1 diabetes mellitus and asthma. Cytokine. 2006;34:170–6.Google Scholar
  141. 141.
    Rachmiel M, Bloch O, Shaul AA, Ben-Yehudah G, Bistritzer Z, Weintrob N, et al. Young patients with both type 1 diabetes mellitus and asthma have a unique IL-12 and IL-18 secretory pattern. Pediatr Diabetes. 2011;12:596–603.Google Scholar
  142. 142.
    Kolahian S, Asadi F, Nassiri SM. Airway inflammatory events in diabetic-antigen sensitized Guinea pigs. Eur J Pharmacol. 2011;659:252–8.PubMedPubMedCentralGoogle Scholar
  143. 143.
    Cavalher-Machado SC, de Lima WT, Damazo AS, de Frias Carvalho V, Martins MA, de Silva PM, Sannomiya P. Down-regulation of mast cell activation and airway reactivity in diabetic rats: role of insulin. Eur Respir J 2004;24:552–558.PubMedPubMedCentralGoogle Scholar
  144. 144.
    Szilvássy J, Sziklai I, Horvath P, Szilasi M, Németh J, Kovács P, et al. Feeble bronchomotor responses in diabetic rats in association with decreased sensory neuropeptide release. Am J Physiol Lung Cell Mol Physiol. 2002;282:1023–30.Google Scholar
  145. 145.
    Belmonte K, Jacoby D, Fryer A. Increased function of inhibitory neuronal M2 muscarinic receptors in diabetic rat lungs. Br J Pharmacol. 1997;121:1287–94.PubMedPubMedCentralGoogle Scholar
  146. 146.
    Belmonte K, Fryer A, Costello R. Role of insulin in antigen-induced airway eosinophilia and neuronal M2 muscarinic receptor dysfunction. J Appl Physiol. 1998;85:1708–18.Google Scholar
  147. 147.
    Lee EJ, In KH, Ha ES, Lee KJ, Hur GY, Kang EH, et al. Asthma-like symptoms are increased in the metabolic syndrome. J Asthma. 2009;46:339–42.Google Scholar
  148. 148.
    Thuesen BH, Husemoen LL, Hersoug LG, Pisinger C, Linneberg A. Insulin resistance as a predictor of incident asthma-like symptoms in adults. Clin Exp Allergy. 2009;39:700–7.Google Scholar
  149. 149.
    Ma J, Xiao L, Knowles SB. Obesity, insulin resistance and the prevalence of atopy and asthma in US adults. Allergy. 2010;65:1455–63.Google Scholar
  150. 150.
    Husemoen LL, Glümer C, Lau C, Pisinger C, Mørch LS, Linneberg A. Association of obesity and insulin resistance with asthma and aeroallergen sensitization. Allergy. 2008;63:575–82.Google Scholar
  151. 151.
    Movahed M, Hashemzadeh M, Jamal M. Increased prevalence of asthma in patients with type 2 diabetes mellitus. Chest. 2006;130:160S.Google Scholar
  152. 152.
    Beuther DA, Sutherland ER. Overweight, obesity, and incident asthma: a metaanalysis of prospective epidemiologic studies. Am J Respir Crit Care Med. 2007;175:661–6.PubMedPubMedCentralGoogle Scholar
  153. 153.
    Pradeepan S, Garrison G, Dixon AE. Obesity in asthma: approaches to treatment. Curr Allergy Asthma Rep. 2013;13:434–42.PubMedPubMedCentralGoogle Scholar
  154. 154.
    Azad MB, Becker AB, Kozyrskyj AL. Association of maternal diabetes and child asthma. Pediatr Pulmonol. 2013;48(6):545–52.Google Scholar
  155. 155.
    Scholtens S, Wijga AH, Brunekreef B, Kerkhof M, Postma DS, Oldenwening M, et al. Maternal overweight before pregnancy and asthma in offspring followed for 8 years. Int J Obes. 2010;34:606–13.Google Scholar
  156. 156.
    Viardot A, Grey ST, Mackay F, Chisholm D. Potential antiinflammatory role of insulin via the preferential polarization of effector T cells toward a T helper 2 phenotype. Endocrinology. 2007;148:346–53.Google Scholar
  157. 157.
    Lessmann E, Grochowy G, Weingarten L, Giesemann T, Aktories K, Leitges M, et al. Insulin and insulin-like growth factor-1 promote mast cell survival via activation of the phosphatidylinositol-3-kinase pathway. Exp Hematol. 2006;34:1532–41.Google Scholar
  158. 158.
    Noveral JP, Bhala A, Hintz RL, Grunstein MM, Cohen P. Insulin-like growth factor axis in airway smooth muscle cells. Am J Phys. 1994;267:761–5.Google Scholar
  159. 159.
    Gosens R, Nelemans SA, Hiemstra M, Grootte Bromhaar MM, Meurs H, Zaagsma J. Insulin induces a hypercontractile airway smooth muscle phenotype. Eur J Pharmacol. 2003;481:125–31.Google Scholar
  160. 160.
    Gosens R, Schaafsma D, Meurs H, Zaagsma J, Nelemans SA. Role of rho-kinase in maintaining airway smooth muscle contractile phenotype. Eur J Pharmacol. 2004;483:71–8.Google Scholar
  161. 161.
    Mirrakhimov AE. Chronic obstructive pulmonary disease and glucose metabolism: a bitter sweet symphony. Cardiovasc Diabetol. 2012;11:132.PubMedPubMedCentralGoogle Scholar
  162. 162.
    Kinney GL, Black-Shinn JL, Wan ES, Make B, Regan E, Lutz S, et al. COPDGene investigators. Pulmonary function reduction in diabetes with and without chronic obstructive pulmonary disease. Diabetes Care. 2014;37:389–95.PubMedPubMedCentralGoogle Scholar
  163. 163.
    Mannino DM, Thorn D, Swensen A, Holguin F. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD. Eur Respir J. 2008;32:962–9.Google Scholar
  164. 164.
    Miller J, Edwards LD, Agustí A, Bakke P, Calverley PM, Celli B, et al. Evaluation of COPD longitudinally to identify predictive surrogate endpoints (ECLIPSE) investigators. Comorbidity, systemic inflammation and outcomes in the ECLIPSE cohort. Respir Med. 2013;107:1376–84.Google Scholar
  165. 165.
    Baker EH, Janaway CH, Philips BJ, Brennan AL, Baines DL, Wood DM, et al. Hyperglycaemia is associated with poor outcomes in patients admitted to hospital with acute exacerbations of chronic obstructive pulmonary disease. Thorax. 2006;61:284–9.PubMedPubMedCentralGoogle Scholar
  166. 166.
    Chakrabarti B, Angus RM, Agarwal S, Lane S, Calverley PM. Hyperglycaemia as a predictor of outcome during non-invasive ventilation in decompensated COPD. Thorax. 2009;64:857–62.Google Scholar
  167. 167.
    Mamillapalli C, Tentu R, Jain NK, Bhandari R. COPD and type 2 diabetes. Curr Respir Med Rev. 2019;15:1–8.Google Scholar
  168. 168.
    Cazzola M, Bettoncelli G, Sessa E, Cricelli C, Biscione G. Prevalence of comorbidities in patients with chronic obstructive pulmonary disease. Respiration. 2010;80:112–9.Google Scholar
  169. 169.
    Lee T, Mao IC, Lin CH, Lin SH, Hsieh MC. Chronic obstructive pulmonary disease: a risk factor for type 2 diabetes: a nationwide population-based study. Eur J Clin Investig. 2013;43:1113–9.Google Scholar
  170. 170.
    Lindberg A, Larsson LG, Rönmark E, Lundbäck B. Co-morbidity in mild-to-moderate COPD: comparison to normal and restrictive lung function. COPD. 2011;8:421–8.Google Scholar
  171. 171.
    Joo H, Park J, Lee SD, Oh YM. Comorbidities of chronic obstructive pulmonary disease in Koreans: a population-based study. J Korean Med Sci. 2012;27:901–6.PubMedPubMedCentralGoogle Scholar
  172. 172.
    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;106:1487–93.Google Scholar
  173. 173.
    Habib G, Dar-Esaif Y, Bishara H, Artul S, Badarny S, Chernin M, et al. The impact of corticosteroid treatment on hemoglobin A1C levels among patients with type-2 diabetes with chronic obstructive pulmonary disease exacerbation. Respir Med. 2014;108:1641–6.Google Scholar
  174. 174.
    Bishwakarma R, Zhang W, Lin YL, Kuo YF, 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.PubMedPubMedCentralGoogle Scholar
  175. 175.
    Yen FS, Chen W, Wei JC, Hsu CC, Hwu CM. 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:e0204859.PubMedPubMedCentralGoogle Scholar
  176. 176.
    Yu S, Christiani DC, Thompson BT, Bajwa EK, Gong MN. Role of diabetes in the development of acute respiratory distress syndrome. Crit Care Med. 2013;41:2720e2732.Google Scholar
  177. 177.
    Singla A, Turner P, Pendurthi MK, Agrawal V, Modrykamien A. Effect of type II diabetes mellitus on the outcomes in patients with acute respiratory distress syndrome. J Crit Care. 2014;29:66e69.Google Scholar
  178. 178.
    Boyle AJ, Madotto F, Laffey JG, Bellani G, Pham T, Pesenti A, et al. ESICM trials group. Identifying associations between diabetes and acute respiratory distress syndrome in patients with acute hypoxemic respiratory failure: an analysis of the LUNG SAFE database. Crit Care. 2018;22:268.PubMedPubMedCentralGoogle Scholar
  179. 179.
    Esper A, Moss M. Diabetes and acute respiratory distress syndrome: can we finally believe the epidemiology? Crit Care Med. 2013;41:2822–3.Google Scholar
  180. 180.
    Kor DJ, Warner DO, Alsara A, Fernández-Pérez ER, Malinchoc M, Kashyap R, et al. Derivation and diagnostic accuracy of the surgical lung injury prediction model. Anesthesiology. 2011;115:117–28.PubMedPubMedCentralGoogle Scholar
  181. 181.
    Koh GC, Vlaar AP, Hofstra JJ, de Jong HK, van Nierop S, Peacock SJ, et al. In the critically ill patient, diabetes predicts mortality independent of statin therapy but is not associated with acute lung injury: a cohort study. Crit Care Med. 2012;40:1835–43.PubMedPubMedCentralGoogle Scholar
  182. 182.
    Moss M, Guidot DM, Steinberg KP, Duhon GF, Treece P, Wolken R, et al. Diabetic patients have a decreased incidence of acute respiratory distress syndrome. Crit Care Med. 2000;28:2187–92.PubMedPubMedCentralGoogle Scholar
  183. 183.
    Gong MN, Thompson BT, Williams P, Pothier L, Boyce PD, Christiani DC. Clinical predictors of and mortality in acute respiratory distress syndrome: potential role of red cell transfusion. Crit Care Med. 2005;33:1191–8.PubMedPubMedCentralGoogle Scholar
  184. 184.
    Iscimen R, Cartin-Ceba R, Yilmaz M, Khan H, Hubmayr RD, Afessa B, et al. Risk factors for the development of acute lung injury in patients with septic shock: An observational cohort study. Crit Care Med. 2008;36:1518–22.PubMedPubMedCentralGoogle Scholar
  185. 185.
    Trillo-Alvarez C, Cartin-Ceba R, Kor DJ, Kojicic M, Kashyap R, Thakur S, et al. Acute lung injury prediction score: derivation and validation in a population-based sample. Eur Respir J. 2011;37:604–9.PubMedPubMedCentralGoogle Scholar
  186. 186.
    Dabbagh O, Park PK, Adesanya A, Chang SY, Hou P, Anderson H 3rd, et al. Early identification of patients at risk of acute lung injury: evaluation of lung injury prediction score in a multicenter cohort study. Am J Respir Crit Care Med. 2011;183:462–70.Google Scholar
  187. 187.
    Esper AM, Moss M, Martin GS. The effect of diabetes mellitus on organ dysfunction with sepsis: An epidemiological study. Crit Care. 2009;13:R18.PubMedPubMedCentralGoogle Scholar
  188. 188.
    Alba-Loureiro TC, Munhoz CD, Martins JO, Cerchiaro GA, Scavone C, Curi R, et al. Neutrophil function and metabolism in individuals with diabetes mellitus. Braz J Med Biol Res. 2007;40:1037–44.Google Scholar
  189. 189.
    Filgueiras LR Jr, Martins JO, Serezani CH, Capelozzi VL, Montes MB, Jancar S. Sepsis-induced acute lung injury (ALI) is milder in diabetic rats and correlates with impaired NFkB activation. PLoS One. 2012;7:e44987.Google Scholar
  190. 190.
    Ahamed K, Epaud R, Holzenberger M, Bonora M, Flejou JF, Puard J, et al. Deficiency in type 1 insulin-like growth factor receptor in mice protects against oxygen-induced lung injury. Respir Res. 2005;6:31.PubMedPubMedCentralGoogle Scholar
  191. 191.
    Bellmeyer A, Martino JM, Chandel NS, Scott Budinger GR, Dean DA, Mutlu GM. Leptin resistance protects mice from hyperoxiainduced acute lung injury. Am J Respir Crit Care Med. 2007;175:587–94.Google Scholar
  192. 192.
    De Oliveira MJ, Meyer-Pflug AR, Alba-Loureiro TC, Melbostad H, Costa da Cruz JW, Coimbra R, et al. Modulation of lipopolysaccharide-induced acute lung inflammation: role of insulin. Shock. 2006;25:260–6.Google Scholar
  193. 193.
    Wright JK, Nwariaku FN, Clark J, Falck JC, Rogers T, Turnage RH. Effect of diabetes mellitus on endotoxin-induced lung injury. Arch Surg. 1999;134:1354–9.Google Scholar
  194. 194.
    Alba-Loureiro TC, Martins EF, Landgraf RG, Jancar S, Curi R, Sannomiya P. Role of insulin on PGE2 generation during LPS-induced lung inflammation in rats. Life Sci. 2006;78:578–85.Google Scholar
  195. 195.
    Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345:1359–67.Google Scholar
  196. 196.
    Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;354:449–61.Google Scholar
  197. 197.
    Chen HI, Yeh DY, Liou HL, Kao SJ. Insulin attenuates endotoxin-induced acute lung injury in conscious rats. Crit Care Med. 2006;34:758–64.PubMedPubMedCentralGoogle Scholar
  198. 198.
    Filgueiras LR, Capelozzi VL, Martins JO, Jancar S. Sepsis-induced lung inflammation is modulated by insulin. BMC Pulm Med. 2014;14:177.PubMedPubMedCentralGoogle Scholar
  199. 199.
    Liu D, Zeng BX, Zhang SH, Wang YL, Zeng L, Geng ZL, et al. Rosiglitazone, a peroxisome proliferator-activated receptorgamma agonist, reduces acute lung injury in endotoxemic rats. Crit Care Med. 2005;33:2309–16.PubMedPubMedCentralGoogle Scholar
  200. 200.
    Zmijewski JW, Lorne E, Zhao X, Tsuruta Y, Sha Y, Liu G, et al. Mitochondrial respiratory complex I regulates neutrophil activation and severity of lung injury. Am J Respir Crit Care Med. 2008;178:168–79.PubMedPubMedCentralGoogle Scholar
  201. 201.
    Kawasaki T, Chen W, Htwe YM, Tatsumi K, Dudek SM. DPP4 inhibition by sitagliptin attenuates LPS-induced lung injury in mice. Am J Physiol Lung Cell Mol Physiol. 2018;315:834–45.Google Scholar
  202. 202.
    Wösten-van Asperen RM, Lutter R, Haitsma JJ, Merkus MP, van Woensel JB, van der Loos CM, et al. ACE mediates ventilator-induced lung injury in rats via angiotensin II but not bradykinin. Eur Respir J. 2008;31:363–71.PubMedPubMedCentralGoogle Scholar
  203. 203.
    Yao HW, Mao LG, Zhu JP. Protective effects of pravastatin in murine lipopolysaccharideinduced acute lung injury. Clin Exp Pharmacol Physiol. 2006;33:793–7.PubMedPubMedCentralGoogle Scholar
  204. 204.
    Jacobson JR, Barnard JW, Grigoryev DN, Ma SF, Tuder RM, Garcia JG. Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury. Am J Physiol Lung Cell Mol Physiol. 2005;288:1026–32.Google Scholar
  205. 205.
    Galiè N, Torbicki A, Barst R, Dartevelle P, Haworth S, Higenbottam T, et al. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The task force on diagnosis and treatment of pulmonary arterial hypertension of the European Society of Cardiology. Eur Heart J. 2004;25:2243–78.PubMedPubMedCentralGoogle Scholar
  206. 206.
    Cooper ME, Bonnet F, Oldfield M, Jandeleit-Dahm K. Mechanisms of diabetic vasculopathy: an overview. Am J Hypertens. 2001;14:475–86.PubMedPubMedCentralGoogle Scholar
  207. 207.
    Movahed MR, Hashemzadeh M, Jamal MM. The prevalence of pulmonary embolism and pulmonary hypertension in patients with type II diabetes mellitus. Chest. 2005;128:3568–71.PubMedPubMedCentralGoogle Scholar
  208. 208.
    Poms AD, Turner M, Farber HW, Meltzer LA, McGoon MD. Comorbid conditions and outcomes in patients with pulmonary arterial hypertension: a REVEAL registry analysis. Chest. 2013;144:169–76.PubMedPubMedCentralGoogle Scholar
  209. 209.
    Benson L, Brittain EL, Pugh ME, Austin ED, Fox K, Wheeler L, et al. Impact of diabetes on survival and right ventricular compensation in pulmonary arterial hypertension. Pulm Circ. 2014;4:311–8.PubMedPubMedCentralGoogle Scholar
  210. 210.
    Abernethy AD, Stackhouse K, Hart S, Devendra G, Bashore TM, Dweik R, et al. Impact of diabetes in patients with pulmonary hypertension. Pulm Circ. 2015;5:117–23.PubMedPubMedCentralGoogle Scholar
  211. 211.
    Lopez-Lopez JG, Moral-Sanz J, Frazziano G, Gomez-Villalobos MJ, Flores-Hernandez J, Monjaraz E, et al. Diabetes induces pulmonary artery endothelial dysfunction by NADPH oxidase induction. Am J Physiol Lung Cell Mol Physiol. 2008;295:727–32.Google Scholar
  212. 212.
    Russ RD, Tobin BW. Differential pulmonary vascular effects of streptozotocin diabetes in male and female rats. Proc Soc Exp Biol Med. 1998;217:74–80.PubMedPubMedCentralGoogle Scholar
  213. 213.
    Pugh ME, Robbins IM, Rice TW, West J, Newman JH, Hemnes AR. Unrecognized glucose intolerance is common in pulmonary arterial hypertension. J Heart Lung Transplant. 2011;30:904–11.PubMedPubMedCentralGoogle Scholar
  214. 214.
    Zamanian RT, Hansmann G, Snook S, Lilienfeld D, Rappaport KM, Reaven GM, et al. Insulin resistance in pulmonary arterial hypertension. Eur Respir J. 2009;33:318–24.PubMedPubMedCentralGoogle Scholar
  215. 215.
    Belly MJ, Tiede H, Morty RE, Schulz R, Voswinckel R, Tanislav C, et al. HbA1c in pulmonary arterial hypertension: a marker of prognostic relevance? J Heart Lung Transplant. 2012;31:1109–14.PubMedPubMedCentralGoogle Scholar
  216. 216.
    Van Marter LJ, Leviton A, Allred EN, Pagano M, Sullivan KF, Cohen A, et al. Persistent pulmonary hypertension of the newborn and smoking and aspirin and nonsteroidal antiinflammatory drug consumption during pregnancy. Pediatrics. 1996;97:658–63.PubMedPubMedCentralGoogle Scholar
  217. 217.
    Grinnan D, Farr G, Fox A, Sweeney L. The role of hyperglycemia and insulin resistance in the development and progression of pulmonary arterial hypertension. J Diabetes Res. 2016;2016:2481659.PubMedPubMedCentralGoogle Scholar
  218. 218.
    Widya RL, van der Meer RW, Smit JW, Rijzewijk LJ, Diamant M, Bax JJ, et al. Right ventricular involvement in diabetic cardiomyopathy. Diabetes Care. 2013;36:457–62.PubMedPubMedCentralGoogle Scholar
  219. 219.
    Di Paolo S, Gesualdo L, Ranieri E, Grandaliano G, Schena FP. High glucose concentration induces the overexpression of transforming growth factor-beta through the activation of a platelet-derived growth factor loop in human mesangial cells. Am J Pathol. 1996;149:2095–106.PubMedPubMedCentralGoogle Scholar
  220. 220.
    Hua H, Goldberg HJ, Fantus IG, Whiteside CI. High glucose-enhanced mesangial cell extracellular signal-regulated protein kinase activation and alpha1(IV) collagen expression in response to endothelin-1: role of specific protein kinase C isozymes. Diabetes. 2001;50:2376–83.PubMedPubMedCentralGoogle Scholar
  221. 221.
    Dewachter L, Dewachter C, Belhaj A, Lalande S, Rondelet B, Remmelink M, et al. Insulin-like growth factor-1 contributes to the pulmonary artery smooth muscle cell proliferation in pulmonary arterial hypertension. Eur Respir J. 2014;44:P316.Google Scholar
  222. 222.
    Ameshima S, Golpon H, Cool CD, Chan D, Vandivier RW, Gardai SJ, et al. Peroxisome proliferator-activated receptor gamma (PPARgamma) expression is decreased in pulmonary hypertension and affects endothelial cell growth. Circ Res. 2003;92:1162–9.PubMedPubMedCentralGoogle Scholar
  223. 223.
    Callaghan MJ, Ceradini DJ, Gurtner GC. Hyperglycemia-induced reactive oxygen species and impaired endothelial progenitor cell function. Antioxid Redox Signal. 2005;7:1476–82.PubMedPubMedCentralGoogle Scholar
  224. 224.
    Kizub IV, Klymenko KI, Soloviev AI. Protein kinase C in enhanced vascular tone in diabetes mellitus. Int J Cardiol. 2014;174:230–42.PubMedPubMedCentralGoogle Scholar
  225. 225.
    Gribbin J, Hubbard R, Smith C. Role of diabetes mellitus and gastro-oesophageal reflux in the etiology of idiopathic pulmonary fibrosis. Respir Med. 2009;103:927–31.PubMedPubMedCentralGoogle Scholar
  226. 226.
    Alakhras M, Decker PA, Nadrous HF, Collazo-Clavell M, Ryu JH. Body mass index and mortality in patients with idiopathic pulmonary fibrosis. Chest. 2007;131:1448–53.PubMedPubMedCentralGoogle Scholar
  227. 227.
    Matsubara T, Hara F. The pulmonary function and histopathological studies of the lung in diabetes mellitus. Nippon Ika Daigaku Zasshi. 1991;58:528–36.PubMedPubMedCentralGoogle Scholar
  228. 228.
    Farina J, Furio V, Fernandez-Acenero MJ, Muzas MA. Nodular fibrosis of the lung in diabetes mellitus. Virchows Arch. 1995;427:61–3.PubMedPubMedCentralGoogle Scholar
  229. 229.
    Vracko R, Thorning D, Huang TW. Basal lamina of alveolar epithelium and capillaries: quantitative changes with aging and in diabetes mellitus. Am Rev Respir Dis. 1979;120:973–83.PubMedPubMedCentralGoogle Scholar
  230. 230.
    Weynand B, Jonckheere A, Frans A, Rahier J. Diabetes mellitus induces a thickening of the pulmonary basal lamina. Respiration. 1999;66:14–9.PubMedPubMedCentralGoogle Scholar
  231. 231.
    Enomoto T, Usuki J, Azuma A, Nakagawa T, Kudoh S. Diabetes mellitus may increase risk for idiopathic pulmonary fibrosis. Chest. 2003;123:2007–11.PubMedPubMedCentralGoogle Scholar
  232. 232.
    García-Sancho Figueroa MC, Carrillo G, Pérez-Padilla R, Fernández-Plata MR, Buendía-Roldán I, Vargas MH, et al. Risk factors for idiopathic pulmonary fibrosis in a Mexican population. A case-control study. Respir Med. 2010;104:305–9.PubMedPubMedCentralGoogle Scholar
  233. 233.
    Hu Y, Ma Z, Guo Z, Zhao F, Wang Y, Cai L, et al. Type 1 diabetes mellitus is an independent risk factor for pulmonary fibrosis. Cell Biochem Biophys. 2014;70:1385–91.PubMedPubMedCentralGoogle Scholar
  234. 234.
    Kim YJ, Park JW, Kyung SY, An CH, Lee SP, Chung MP, et al. Association of diabetes mellitus and metabolic syndrome with idiopathic pulmonary fibrosis. Tuberc Respir Dis. 2009;67:113–20.Google Scholar
  235. 235.
    Kim YJ, Park JW, Kyung SY, Lee SP, Chung MP, Kim YH, et al. Clinical characteristics of idiopathic pulmonary fibrosis patients with diabetes mellitus: the national survey in Korea from 2003 to 2007. J Korean Med Sci. 2012;27:756–60.PubMedPubMedCentralGoogle Scholar
  236. 236.
    Hyldgaard C, Hilberg O, Bendstrup E. How does comorbidity influence survival in idiopathic pulmonary fibrosis? Respir Med. 2014;108:647–53.PubMedPubMedCentralGoogle Scholar
  237. 237.
    Matsuse T, Ohga E, Teramoto S, Fukayama M, Nagai R, Horiuchi S, et al. Immunohistochemical localisation of advanced glycation end products in pulmonary fibrosis. J Clin Pathol. 1998;51:515–9.PubMedPubMedCentralGoogle Scholar
  238. 238.
    Ofulue AF, Kida K, Thurlbeck WM. Experimental diabetes and the lung. I. Changes in growth, morphometry, and biochemistry. Am Rev Respir Dis. 1988;137:162–6.PubMedPubMedCentralGoogle Scholar
  239. 239.
    Usuki J, Enomoto T, Azuma A, Matsuda K, Aoyama A, Kudoh S. Influence of hyperglycemia to the severity of pulmonary fibrosis. Chest. 2001;120:71S.PubMedPubMedCentralGoogle Scholar
  240. 240.
    Kida K, Utsuyama M, Takizawa T, Thurlbeck WM. Changes in lung morphologic features and elasticity caused by streptozotocin-induced diabetes mellitus in growing rats. Am Rev Respir Dis. 1983;128:125–31.PubMedPubMedCentralGoogle Scholar
  241. 241.
    Forgiarini LA Jr, Kretzmann NA, Porawski M, Dias AS, Marroni NA. Experimental diabetes mellitus: oxidative stress and changes in lung structure. J Bras Pneumol. 2009;35:788–91.PubMedPubMedCentralGoogle Scholar
  242. 242.
    Gumieniczek A, Hopkala H, Wojtowicz Z, Wysocka M. Changes in antioxidant status of lung tissue in experimental diabetes in rabbits. Clin Biochem. 2002;35:147–9.PubMedPubMedCentralGoogle Scholar
  243. 243.
    Kinalski M, Sledziewski A, Telejko B, Zarzycki W, Kinalska I. Lipid peroxidation and scavenging enzyme activity in streptozotocin- induced diabetes. Acta Diabetol. 2000;37:179–83.PubMedPubMedCentralGoogle Scholar
  244. 244.
    Oztay F, Kandil A, Gurel E, Ustunova S, Kapucu A, Balci H, et al. The relationship between nitric oxide and leptin in the lung of rat with streptozotocin-induced diabetes. Cell Biochem Funct. 2008;26:162–71.PubMedPubMedCentralGoogle Scholar
  245. 245.
    Zheng F, Lu W, Wu F, Li H, Hu X, Zhang F. Recombinant decorin ameliorates the pulmonary structure alterations by down-regulating transforming growth factor-beta1/SMADS signaling in the diabetic rats. Endocr Res. 2010;35:35–49.PubMedPubMedCentralGoogle Scholar
  246. 246.
    Kolahian S, Sadri H, Shahbazfar AA, Amani M, Mazadeh A, Mirani M. The effects of leucine, zinc, and chromium supplements on inflammatory events of the respiratory system in type 2 diabetic rats. PLoS One. 2015;10:e0133374.PubMedPubMedCentralGoogle Scholar
  247. 247.
    Carlson EC, Audette JL, Veitenheimer NJ, Risan JA, Laturnus DI, Epstein PN. Ultrastructural morphometry of capillary basement membrane thickness in normal and transgenic diabetic mice. Anat Rec A Discov Mol Cell Evol Biol. 2003;271:332–41.PubMedPubMedCentralGoogle Scholar
  248. 248.
    Oishi K, Ohkura N, Kasamatsu M, Fukushima N, Shirai H, Matsuda J, et al. Tissue-specific augmentation of circadian PAI-1 expression in mice with streptozotocin-induced diabetes. Thromb Res. 2004;114:129–35.PubMedPubMedCentralGoogle Scholar
  249. 249.
    Yang JL, Tan Y, Ma ZS, Miao LN, Zhao FL, Cai L. Lung fibrosis in experimental type 1 diabetic mouse model: role of oxidative stress and inflammation. Diabetes. 2010;59:A245.Google Scholar
  250. 250.
    Wang CM, Hsu CT, Niu HS, Chang CH, Cheng JT, Shieh JM. Lung damage induced by hyperglycemia in diabetic rats: the role of signal transducer and activator of transcription 3 (STAT3). J Diabetes Complicat. 2016;30:1426–33.PubMedPubMedCentralGoogle Scholar
  251. 251.
    Yang J, Tan Y, Zhao F, Ma Z, Wang Y, Zheng S, et al. Angiotensin II plays a critical role in diabetic pulmonary fibrosis most likely via activation of NADPH oxidase-mediated nitrosative damage. Am J Physiol Endocrinol Metab. 2011;301:132–44.Google Scholar
  252. 252.
    Papinska AM, Soto M, Meeks CJ, Rodgers KE. Long-term administration of angiotensin (1-7) prevents heart and lung dysfunction in a mouse model of type 2 diabetes (db/db) by reducing oxidative stress, inflammation and pathological remodeling. Pharmacol Res. 2016;107:372–80.PubMedPubMedCentralGoogle Scholar
  253. 253.
    Kroll MH, Afshar-Kharghan V. Platelets in pulmonary vascular physiology and pathology. Pulm Circ. 2012;2:291–308.PubMedPubMedCentralGoogle Scholar
  254. 254.
    Jagadapillai R, Rane MJ, Lin X, Roberts AM, Hoyle GW, Cai L, Gozal E. Diabetic Microvascular Disease and Pulmonary Fibrosis: The Contribution of Platelets and Systemic Inflammation. Int J Mol Sci. 2016;17.PubMedPubMedCentralGoogle Scholar
  255. 255.
    Singh S, Bodas M, Bhatraju NK, Pattnaik B, Gheware A, Parameswaran PK, et al. Hyperinsulinemia adversely affects lung structure and function. Am J Physiol Lung Cell Mol Physiol. 2016;310:837–45.Google Scholar
  256. 256.
    Mexas AM, Hess RS, Hawkins EC, Martin LD. Pulmonary lesions in cats with diabetes mellitus. J Vet Intern Med. 2006;20:47–51.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Saeed Kolahian
    • 1
    • 2
    • 3
    Email author
  • Veronika Leiss
    • 1
  • Bernd Nürnberg
    • 1
    • 2
  1. 1.Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, and Interfaculty Center of Pharmacogenomics and Drug Research (ICePhA)Eberhard Karls University Hospitals and ClinicsTübingenGermany
  2. 2.Department of Toxicology, Institute of Experimental and Clinical Pharmacology and ToxicologyEberhard Karls University Hospitals and ClinicsTübingenGermany
  3. 3.Department of PharmacogenomicsUniversity of TübingenTübingenGermany

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