DIABETIC LUNG
Sultan Ayoub Meo
MBBS, M.Phil, Ph.D
Department of Physiology, College of Medicine, King Khalid University Hospital, King Saud
University Riyadh, Kingdom of Saudi Arabia
Statement of proprietary interest: No conflict of interest with any institution / organization.
Word count: Abstract = 196; key words = 8; Literature review = 1759; References = 47.
Running title: Diabetes mellitus and pulmonary complications.
Key words: Diabetes mellitus, Lungs, Respiratory Diseases, Pulmonary Function Test.
Address for correspondence:
*Dr. Sultan Ayoub Meo, Associate Professor, Department of Physiology (29), College of
Medicine, King Khalid University Hospital, King Saud University, P.O. Box 2925. Riyadh
11461. K.S.A. Tel: 009661-4671604. Fax. 009661- 4672567. Email: sultanmeo@hotmail.com or
smeo@ edu.ksu.sa
ABSTRACT
Background: Diabetes mellitus is a leading cause of illness and death across the world and is
responsible for a growing proportion of global health care expenditures. In spite of effective
interventions centered towards the complication of diabetes mellitus including coronary artery
disease, diabetic nephropathy, retinopathy and neuropathy. However, diabetic lung have been
poorly characterized. Therefore, the aim of this review is to gather and highlight the different
studies concerning with diabetes mellitus and its potential effects with lung diseases.
Methods: We reviewed English-language MEDLINE publications from 1966 to July 2007 for
experimental, observational and clinical studies having relation to diabetes mellitus with lung
diseases. Approximately 72 publications were reviewed based on the relevance, strength and
quality of design and methods, 47 publications were selected for inclusion.
Results: Diabetes mellitus can cause impaired lung function, decreased respiratory muscles
endurance, develop diaphragmatic paralysis, dsyponea, pulmonary hypertension, pulmonary
infection and pulmonary tuberculosis.
Conclusion: Diabetes mellitus plays a significant role in patho-physiological process involved in
lung diseases and lung is the target organ in diabetes mellitus. Moreover, physicians should
know the size of problem of pulmonary complications and must consider the lung as serious as
other complications of diabetes mellitus.
Key words: Diabetes mellitus, Lungs, Respiratory Diseases, Pulmonary Function Test.
2
Diabetes Mellitus: Diabetes mellitus is a group of metabolic diseases characterized by
hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic
hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of
various organs, especially the eyes, kidneys, nerves, heart, and blood vessels. Long-term
complications of diabetes include retinopathy with potential loss of vision; nephropathy leading
to renal failure; peripheral neuropathy with risk of foot ulcers, amputations, and Charcot joints;
and autonomic neuropathy causing gastrointestinal, genitourinary, and cardiovascular symptoms
and sexual dysfunction. Patients with diabetes have an increased incidence of atherosclerotic
cardiovascular, peripheral arterial and cerebrovascular disease. Hypertension and abnormalities
of lipoprotein metabolism are often found in people with diabetes 1. Diabetes mellitus is a major
public health care problem with increasing incidence and long term complications. It is incurable
life-long disease, involves the multiple systems with wide ranging and devastating complications
which end up in severe disability and death 2. More recently, researchers seriously consider the
lung as a target organ in diabetes mellitus3.
Prevalence of Diabetes Mellitus: Since last three decades, the life style of urban population
worldwide has dramatically changed. With this modernized change peoples are eating more and
exercising less. This life style change has triggered a rapid increase in the prevalence of diabetes
mellitus. In 2003, 194 million people had diabetes mellitus, by 2025 it is estimated that
approximately 333 million will develop diabetes mellitus with a doubling of the prevalence in
the Middle East, North Africa, South Asia and Sub-Saharan Africa 4-6. In these spots of the earth,
India and China are greatly affected.
Diabetes Mellitus in China: Until just over a decade ago, diabetes mellitus was very rare in
China. However, in the run up to the end of the millennium, diabetes mellitus has increased
3
dramatically, the scale of the problems started to become apparent in the large numbers of people
in China. The most probable cause of diabetes mellitus in China is that the economic
development in the urban areas is at its greatest and traditional dietary practices are eroded
speedily. That is why the urban areas are the hotspots for diabetes mellitus in China. As China
has become modernized, the sedentary lifestyle favored by western people has infiltrated
Chinese culture, leading the people to eating more and exercising less7. China has a huge
population, estimated at 1.3 billion, with the number of adults with diabetes estimated at about
30 million. This total number of people with diabetes in China may be one of the largest diabetes
populations in the world 8. Indeed, two years ago, with a diabetes population of 23.8 million,
China was second in the world to India (35.5 million). Twenty years from now, this figure is
expected to rise above 46 million 5.
Diabetes Mellitus and annual medical cost: Diabetes mellitus not only affects the health of the
large number of population all over the world, but it also gravely affects the economy of the
world. Worldwide estimates suggest that the annual direct medical costs of diabetes is at least
US$ 129 billion and may be as high as US$ 241 billion, or 2.5% to 15.0% of global annual health
care budgets 5.
Diabetes and Death: All over the world almost one million people each year and about 2 people
per minute die due to the complications of diabetes mellitus and two-thirds of these are in
developing countries 1. In China the number of diabetes-related deaths is also on the rise. Data
from the Annual Statistical Reports of Death, Injuries and Causes of Death 2002 revealed a
three-fold increase in the mortality rate per 100000 people from 5.1 per 100000, 20 years ago, to
15.4, five years ago9.
4
Patho-physiology / Causes of pulmonary complications in diabetes mellitus: Diabetes
mellitus is associated with ongoing malfunction of numerous organs2 and its complications are
mainly a consequence of macro-vascular and micro-vascular damage
10
. The mechanism by
which impaired glycemic control may lead to a reduction in the lung function is uncertain,
though it has been suggested that the increased systemic inflammation associated with diabetes 11
may result in pulmonary inflammation
12
and hence air way damage 13. Moreover, secondary
reduction in antioxidant defense of the lung and increased susceptibility to environmental
oxidative insults resulting in subsequent loss of lung function
14
and ultimately lung damage. It
has also been demonstrated that the pulmonary complications in diabetes mellitus are due to
thickened walls of alveoli, alveolar capillaries and pulmonary arterioles and these changes cause
pulmonary dysfunction 15,16. Moreover, Ljubic et al, 17 also found that diabetes mellitus can cause
the pulmonary complications due to collagen and elastin changes as well as micro-angiopathy.
Furthermore, pulmonary function impairment and lung dysfunction in diabetic patients is
secondary due to the immune function impairment 18.
Diabetes mellitus and lung function: Lung function test is the most basic, widely used,
pulmonary function test (PFT). It typically assesses lung volumes and flows and is ideally suited
to describe the effects of obstruction or restriction on lung function
19
. It is now regarded as an
integral component of any respiratory medical surveillance programs. PFT has assumed a key
role in epidemiological studies investigating the incidence, natural history and causality of lung
disease20. The role of lung function test in diabetic patients is further increased when a new
strategy [Inhaled insulin] has been introduced for the treatment of diabetes mellitus 21.
In normal healthy non smoker subject after the age of 35, the expected decline in lung function
(FEV1) is 25–30 ml/year. However, the average rate of decline of lung function in diabetic
5
patients as measured by Forced Expiratory Volume in 1 sec (FEV1) is 71 ml/year 22. McKeever
et al.,
23
observed that increase in mean HbA1c is associated with decrease in lung function
parameters FVC & FEV1. They hypothesized that impaired glucose auto- regulation is
associated with impaired lung function.
Asanuma et al., 24 Lange et al., 25 Boulbou et al.,10 reported that FVC and FEV1 were reduced in
diabetic subjects compared to control subjects. Similarly, Cazzato et al.,
26
conducted a cross-
sectional study to assess the pulmonary function in children with insulin-dependent diabetes
mellitus (IDDM) and reported that the FVC, FEV1 were found to be significantly lower in
diabetics than controls. Similarly, Makkar et al., 27 performed Spirometry on patients with IDDM
and reported that the IDDM patients had a reduced FVC, FEV1 and MEF 25-75% compared to
their matched control. Moreover, Rosenecker et al. 28 demonstrated that in patients with diabetes,
FVC and FEV1 declined significantly over the five year study period whereas patients without
diabetes did not show a significant decline during the study period.
Davis et al.,
29
reported that the Forced Vital Capacity (FVC), Forced Expiratory Volume in 1 s
(FEV1), Vital Capacity (VC) and Peak Expiratory Flow (PEF) were reduced in diabetic patients.
Similarly, Meo et al., 21,30 reported that lung function parameters Forced Vital Capacity (FVC)
and Forced Expiratory Volume in one Second (FEV1), and Peak Expiratory Flow (PEF) in type
1 and type 2 diabetic patients were impaired compared to their matched controls. Stratification of
results by years of disease showed a duration of disease-response effect on lung function.
Diabetes Mellitus and alveolar gas exchange: Diabetic patients showed impaired alveolar gas
exchange capacity and reduced pulmonary elastic recoil compared with healthy controls.3,10,31,32.
It has also been found that the impairment of pulmonary diffusion capacity for carbon monoxide
was common in Type 2 diabetes mellitus in Asian Indian patients 33.
6
Diabetes Mellitus and respiratory muscles strength: Respiratory muscle endurance is of
interest in pulmonary, critical care and many other areas of medicine. Reduced muscle strength
has been reported in diabetic patients. Bilateral or unilateral diaphragmatic paralysis has been
observed in diabetic patients 34-36. In addition, Meo et al.,37 conducted a study and determined the
respiratory muscles endurance by a direct MVV test during inspiratory and expiratory phases of
respiration by using a MP-100 student Bio Pac system. They reported that the respiratory
muscles endurance was impaired and a greater perception of respiratory exertion was noticed in
diabetic patients relative to their matched controls. Moreover, breathlessness on exertion and
orthopnea in association with Type 2 diabetes mellitus has been also reported. Investigation
showed that bilateral diaphragmatic paralysis due to phrenic neuropathy. Phrenic neuropathy
may be an important, although rare, complication of diabetes and diaphragmatic function should
be considered in any patient with unexplained breathlessness and orthopnoea38.
Diabetic lung and Electron microscopic findings: Electron microscopic study shows that in
diabetic patients all parts of the lung are equally affected and the thickening of basal lamina is of
the same magnitude in lung and kidney 18.
Diabetes Mellitus and pulmonary infection: The frequency and enhanced severity of
pulmonary tract infections in uncontrolled diabetes are well known before and after the
discovery of Insulin. The availability of antibiotics has made a great difference, but infection is
probably a more serious threat to life in a diabetic than in the non-diabetic. Diabetes mellitus is
recognized as an independent risk factor for developing lower respiratory tract infections 39-40.
The mechanism for the increased susceptibility to infection is due to an alteration in chemotactic,
phagocytic and bactericidal activity of polymorphonuclear leukocytes41. The impaired
phagocytic function is also one of the major causes of pulmonary infection in diabetic patients.
7
Diabetes mellitus and pulmonary tuberculosis: Pulmonary tuberculosis and diabetes mellitus
are coexisting frequently 42. Diabetic patients have an increased tendency to acquire tuberculosis.
The frequency of tuberculosis was 4-5 times more than in non-diabetics. The disease was more
aggressive in poorly controlled diabetics and is significantly associated with the development of
pleural effusion
43
. Increased reactivation of tuberculosis lesions has also been recorded in
44
diabetics . It has been also reported that the development of tuberculosis occurred ten times
more frequently in juvenile diabetes and the occurrence of tuberculosis was increased with the
duration of diabetes 45 and causes a significantly greater mortality 46.
Diabetes Mellitus and pulmonary embolism and Pulmonary hypertension: Patients with
diabetes mellitus suffer from hypercoagulable state which may increase their risk for
thromboembolism. Diabetic patients have a significantly higher prevalence of pulmonary
hypertension 47.
Conclusion: Diabetes mellitus can cause impaired lung function, decreased respiratory muscles
endurance, develop diaphragmatic paralysis, dsyponea, pulmonary hypertension, pulmonary
embolosm, pulmonary infection and pulmonary tuberculosis. It is also observed that diabetes
mellitus play a significant role in patho-physiological process involved in lung diseases and lung
is the target organ in diabetes mellitus. Therefore, physicians should know the size of problem of
pulmonary complications and must consider the lung as serious as other complications of
diabetes mellitus.
8
REFERENCES:
1. American Diabetes Association: Diagnosis and Classification of Diabetes Mellitus. Diabetes
Care, 2007; 30: S42-S47.
2. James R Gavin, Alberti KGMM, Mayer B Davidson, Ralph A DeFronzo, Allan Drash, Steven
G. et al., Report on the expert committee on the diagnosis and classification of diabetes mellitus.
Diabetes Care, 2002; 25: S5-S20.
3: Sandler M. Is the lung a 'target organ' in diabetes mellitus. Arch Intern Med. 1990; 150(7):
1385-8.
4. World Health Organization. Global burden of diabetes for the year 2001 by world bank region,
for the use in disease control priorities in developing countries, 2nd edition, Geneva, The World
Health Report, 2002.
5. International Diabetes Federation. Diabetes Atlas, Second Edition. International Diabetes
Federation, Brussels, 2003.
6. Venkat Narayan KM, Zang P, Williams D, Engelgau M, Imperatore G Kanaya A and
Ramachandran A, Can Med Ass J, 2006; 175(7): 733-736.
7.
National
diabetes
programme
China.
Available
from
http://www.worlddiabetesfoundation.org/composite-118.htm cited dated July, 2007.
8. Pan C. Diabetes care in China: Meeting the Challenge. Diabetes Voice, 2005; 50: 2, 9-12
9. The Western Pacific Declaration on Diabetes: Kuala Lumpur, June 2000. International
Diabetes Foundation (Western Pacific Regional Office), The World Health Organization,
Regional Office for the Western Pacific Community, Secretariat of the Pacific Community.
Manila 2000.
9
10. Boulbou MS, Gourgoulianis KI, Klisiaris VK, Tsikrikas TS, Stathakis NE, Molyvdas PA.
Med Princ Pract 2003; 12 (2): 87-91.
11. Arnalich F, Hernanz A, Lopez-Maderuelo D. Enhanced acute-phase response and oxidative
stress in older adults with type II diabetes. Horm Metab Res, 2000; 32:407–12.
12. Walter R, Beiser A, Givelber R. The association between glycemic state and lung function:
The Framingham Heart Study. Am J Respir Crit Care Med, 2003; 167:911–16.
13. Cirillo D, Agrawal Y, Cassano P. Lipids and pulmonary function in the Third National
Health and Nutrition Examination Survey. Am J Epidemiol, 2002;155:842–8.
14. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature
2001; 414:813–20.
15. Sandler M, Bunn AE, Stewart RI. Pulmonary function in young insulin-dependent, Chest.
1986; 90 (5): 670-5.
16. Matsubara T, Hara F. [The pulmonary function and histopathological studies of the lung in
diabetes mellitus] Nippon Ika Daigaku Zasshi. 1991; 58(5): 528-36.
17. Ljubić S, Metelko Z, Car N, Roglić G, Drazić Z. Reduction of diffusion capacity for carbon
monoxide in diabetic patients. Chest, 1998; 114(4): 1033-5.
18. Weynand B, Jonckheere A, Frans A, Rahier J. Diabetes mellitus induces a thickening of the
pulmonary basal lamina. : Respiration, 1999; 66(1): 14-9.
19. Ruppel GL. Pulmonary function testing. Trends and techniques. Resp. Care Clinics. North
America. 1997; 3: 155-181.
20. McKay, Ray. T. and Horvath, Edward, P. Pulmonary function testing in industry. In:
Occupational Medicine. Edited by Carl, Zenz., O, Bruca. Dickerson. Edward, P. Horvath.
Mosby London, Third edition, 1984, pp. 229.
10
21. Meo SA, Al-Drees AM, Arif M, Al-Rubean K. Lung function in type 2 Saudi diabetic
patients. Saudi Med J. 2006; 27 (3): 338-43.
22. Davis WA, Knuiman M, Kendall P, Grange V, Davis TM; Fremantle Diabetes Study.
Glycemic exposure is associated with reduced pulmonary function in type 2 diabetes: the
Fremantle Diabetes Study. Diabetes Care. 2004 Mar; 27(3):752-7.
23. 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.
American Journal of Epidemiology, 2005; 161 (6):546-556.
24. Asanuma Y, Fujiya S, Ide H, Agishi Y. Characteristics of pulmonary function in patients
with diabetes mellitus. Diabetes Res Clin Pract, 1985; 1(2): 95-101.
25. 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 (1)
14-9.
26. Cazzato S, Bernardi F, Salardi S, Tassinari D, Corsini I, Ragni L et al.. Lung function in
children with diabetes mellitus. Pediatr Pulmonol, 2004: 37 (1): 17-23.
27. Makkar P, Gandhi M, Agrawal RP, Sabir M, Kothari RP. Ventilatory pulmonary function
tests in type 1 diabetes mellitus. J Assoc Physicians India 2000; 48 (10): 962-6.
28. Rosenecker J, Hofler 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; 27, 6 (8): 345-50.
29. Davis T, Knuiman M, Kendall P, Vu H, Davis WA: Reduced pulmonary function and its
associations in type 2 diabetes: the Fremantle Diabetes Study. Diabetes Res Clin Pract, 2000; 50
153–159.
11
30. Meo SA, Abdul Majeed Al Drees, Muhammad Arif, Sayed Fayaz Ahmed Shah& Khalid AlRubean. Lung Function in type 1 Diabetic Patients. Saudi Medical Journal, 2005; 26(11): 17281733.
31. Ramirez LC, Dal Nogare A, Hsia C, Arauz C, Butt I, Strowig SM, Schnurr-Breen L, Raskin
PRelationship between diabetes control and pulmonary function in insulin-dependent diabetes
mellitus. Am J Med. 1991 Oct;91(4):371-6.
32. Guvener N, Tutuncu NB, Akcay S, Eyuboglu F, Gokcel A. Alveolar gas exchange in patients
with type 2 diabetes mellitus. Endocr J. 2003 Dec;50(6):663-7.
33. Sinha S, Guleria R, Misra A, Pandey RM, Yadav R, Tiwari S. Pulmonary functions in
patients with type 2 diabetes mellitus & correlation with anthropometry & microvascular
complications. : Indian J Med Res. 2004 Feb;119(2):66-71.
34. Andersen H, Poulsen PL, Mogensen CE, Jakobsen J. Isokinetic muscle strength in long-term
IDDM patients in relation to diabetic complications. Diabetes. 1996 Apr;45(4):440-5.
35. Van Schie CH, Vermigli C, Carrington AL, Boulton A. Muscle weakness and foot
deformities in diabetes: relationship to neuropathy and foot ulceration in caucasian diabetic men.
Diabetes Care. 2004 Jul;27(7):1668-73.
36. Kadosh S, Qupti G, Flatau E. [Unilateral diaphragmatic paralysis in a diabetes patient]
Harefuah. 2005 Dec;144(12):834-5, 911.
37. Meo SA, Abdul Majeed AlDrees, Muhammad Arif & Khalid Al-Rubean. Assessment of
respiratory muscles endurance in diabetic patients. Saudi Medical Journal 2006; 27 (2)223-226.
38. White JE, Bullock RE, Hudgson P, Home PD, Gibson GJ. Phrenic neuropathy in association
with diabetes. Diabet Med. 1992 Dec;9(10):954-6.
12
39. Bhansali A, Suresh V, Chaudhry D, Vaiphei K, Dash RJ, Kotwal N. Postgrad Med J.
Diabetes and rapidly advancing pneumonia. 2001 Nov;77(913):734-5, 740-1
40. Ardigo D, Valtuena S, Zavaroni I, Baroni MC, Delsignore R. Pulmonary complications in
diabetes mellitus: the role of glycemic control. Curr Drug Targets Inflamm Allergy. 2004
Dec;3(4):455-8.
41. Marvisi M, Marani G, Brianti M, Della Porta R. [Pulmonary complications in diabetes
mellitus] Recenti Prog Med. 1996 Dec;87(12):623-7.
42. Jabbar A, Hussain SF, and Khan AA. Clinical characteristics of pulmonary tuberculosis in
adult Pakistani patients with co-existing diabetes mellitus, Health Journal, 2006; 12(5):552- 527.
43. Falguera M, Pifarre R, Martin A, Sheikh A, Moreno A. Etiology and outcome of communityacquired pneumonia in patients with diabetes mellitus. Chest, 2005 Nov;128(5):3233-9.
44. Edsall J, Collins J, Gray J. The reactivation of tuberculosis in New York city in 1967. Am
Rev Respir Dis, 1970, 102, 725
45. Guptan A and Shah A. Tuberculosis and Diabetes: An Appraisal. Ind J Tub, 47 (3): 2-8.
46. Kondo A, Sakatani M, Tsuchiya T, et. al: Multidisciplinary analysis of chronic excretors of
M.tuberculosis bacilli, Kekkaku 1996, 71, 25
47. Movahed MR, Hashemzadeh M, Jamal MM. The prevalence of pulmonary embolism and
pulmonary hypertension in patients with type II diabetes mellitus. Chest. 2005;128(5):3568-71.
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