Review
The diabetic lung: Relevance of alveolar microangiopathy for the use of inhaled insulin

https://doi.org/10.1016/j.amjmed.2004.09.019Get rights and content

Abstract

The alveolar-capillary network receives the entire cardiac output and constitutes the largest microvascular organ in the body, making it highly susceptible to systemic microangiopathy. Owing to its large reserves, symptoms and disability develop later in the lung than in smaller microvasculature such as the kidney or retina despite a comparable severity of anatomic involvement. Hence, pulmonary impairment in diabetes mellitus is under-recognized. Nonetheless, respiratory autonomic neuropathy and structural derangement of the thorax and lung parenchyma develop in many asymptomatic diabetic patients; the pathophysiology parallels that in other target organs. Even subclinical loss of alveolar microvascular reserves can be quantified noninvasively from lung diffusing capacity and its components (membrane diffusing capacity and alveolar-capillary blood volume) measured at a given cardiac output at rest or during exercise. The alveolar diffusion-perfusion relation tracks the recruitment of microvascular reserves in a manner independent of physical fitness. This article addresses the importance and pathophysiologic basis of diabetic pulmonary involvement, the assessment of diabetic alveolar microangiopathy, and the relevance of this understanding for the emerging use of inhaled insulin.

Section snippets

Pulmonary pathophysiology in diabetes

Insulin broadly modulates cell growth and metabolism via receptors in the lung. Insulin enhances proliferation of alveolar and bronchial epithelial cells and vascular smooth muscle,14, 15 inhibits apoptosis,16 and promotes vasodilatation.17, 18 Maternal diabetes delays fetal and postnatal lung development.19, 20 Preterm infants of diabetic mothers show accelerated muscularization of small pulmonary arteries that predisposes to neonatal pulmonary hypertension.21 At autopsy, diabetic lungs show

Pulmonary function in diabetes

The major categories of assessment are ventilatory control, mechanical function (volume, flow rates and elastic recoil), and microvascular function (gas exchange).

Relevance to inhaled insulin

Because the lung provides large surfaces and longer residence times for drug absorption, inhaled insulin rapidly reaches peak plasma level and metabolic effect without the invasiveness of subcutaneous injection.84 Comparable glycemia is achieved with supplemental inhaled insulin as with subcutaneous insulin alone,85 and adding inhaled insulin to conventional regimen may improve glycemic control.86, 87 Side effects are minor88 and patient satisfaction is high.89 Such advantage is balanced

Conclusion

Diabetic pulmonary complications are more prevalent than generally recognized. Conventional assessment of microangiopathy (retinopathy, nephropathy, neuropathy) is often complicated by organ failure as secondary complications, and effects of therapy may confound data interpretation. Established indexes of alveolar diffusion-perfusion relations that have been used to evaluate alveolar-capillary integrity independent of physical fitness could be applied to diabetes to provide noninvasive

References (93)

  • H. Guenard et al.

    Determination of lung capillary blood volume and membrane diffusing capacity in man by the measurements of NO and CO transfer

    Respir Physiol.

    (1987)
  • R.M. Tamhane et al.

    Pulmonary membrane diffusing capacity and capillary blood volume measured during exercise from nitric oxide uptake

    Chest

    (2001)
  • Y. Asanuma et al.

    Characteristics of pulmonary function in patients with diabetes mellitus

    Diabetes Res Clin Pract.

    (1985)
  • B.G. Cooper et al.

    Lung function in patients with diabetes mellitus

    Respir Med.

    (1990)
  • C.A. Benbassat et al.

    Pulmonary function in patients with diabetes mellitus

    Am J Med Sci.

    (2001)
  • J.S. Skyler et al.

    Efficacy of inhaled human insulin in type 1 diabetes mellitusa randomised proof-of-concept study

    Lancet

    (2001)
  • B.L. Laube

    Treating diabetes with aerosolized insulin

    Chest

    (2001)
  • J. Rosenstock et al.

    Effect of glycemic control on microvascular complications in patients with type I diabetes mellitus

    Am J Med.

    (1986)
  • P. Reichard et al.

    Intensified conventional insulin treatment retards the microvascular complications of insulin-dependent diabetes mellitus (IDDM)the Stockholm Diabetes Intervention Study (SDIS) after 5 years

    J Int Med.

    (1991)
  • H.P. Chase et al.

    Glucose control and the renal and retinal complications of insulin-dependent diabetes

    JAMA

    (1989)
  • R.L. Johnson

    Heart-lung interactions in the transport of oxygen

  • J.M. Turner et al.

    Elasticity of human lungs in relation to age

    J Appl Physiol.

    (1968)
  • K. Mellemgaard

    The alveolar-arterial oxygen differenceits size and components in normal man

    Acta Physiol Scand.

    (1967)
  • S.R. McClaran et al.

    Longitudinal effects of aging on lung function at rest and exercise in healthy active fit elderly adults

    J Appl Physiol.

    (1995)
  • J.M. Hagberg et al.

    A hemodynamic comparison of young and older endurance athletes during exercise

    J Appl Physiol.

    (1985)
  • T. Ogawa et al.

    Effects of aging, sex, and physical training on cardiovascular responses to exercise

    Circulation

    (1992)
  • D.L. Sherrill et al.

    Predictors of longitudinal change in diffusing capacity over 8 years

    Am J Respir Crit Care Med.

    (1999)
  • B. Saltin et al.

    Response to exercise after bed rest and after training

    Circulation

    (1968)
  • C.C. Hsia

    Coordinated adaptation of oxygen transport in cardiopulmonary disease

    Circulation

    (2001)
  • C.C. Leslie et al.

    Stimulation of DNA synthesis in cultured rat alveolar type II cells

    Exp Lung Res.

    (1985)
  • S.J. Wadsworth et al.

    Biosynthesized matrix provides a key role for survival signaling in bronchial epithelial cells

    Am J Physiol Lung Cell Mol Physiol.

    (2004)
  • K.T. Iida et al.

    Insulin inhibits apoptosis of macrophage cell line, THP-1 cells, via phosphatidylinositol-3-kinase-dependent pathway

    Arterioscler Thromb Vasc Biol.

    (2002)
  • M. Aye et al.

    Pulmonary vasodilation in the rat by insulin in vitro could indicate potential hazard for inhaled insulin

    Diabetologia

    (2003)
  • E.J. Stevens et al.

    Vasoreactivity and prostacyclin release in streptozotocin-diabetic ratseffects of insulin or aldose reductase inhibition

    Br J Pharmacol.

    (1993)
  • J. Thulesen et al.

    Epidermal growth factor and lung development in the offspring of the diabetic rat

    Pediatr Pulmonol.

    (2000)
  • C. Colpaert et al.

    Increased muscularization of small pulmonary arteries in preterm infants of diabetic mothersa morphometric study in noninflated, noninjected, routinely fixed lungs

    Pediatr Pathol Lab Med.

    (1995)
  • J. Farina et al.

    Nodular fibrosis of the lung in diabetes mellitus

    Virchows Arch.

    (1995)
  • I.M. Kodolova et al.

    Changes in the lungs in diabetes mellitus

    Arkh Patol.

    (1982)
  • R. Vracko et al.

    Basal lamina of alveolar epithelium and capillariesquantitative changes with aging and in diabetes mellitus

    Am Rev Respir Dis.

    (1979)
  • B. Weynand et al.

    Diabetes mellitus induces a thickening of the pulmonary basal lamina

    Respiration

    (1999)
  • K. Kida et al.

    Changes in lung morphologic features and elasticity caused by streptozotocin-induced diabetes mellitus in growing rats

    Am Rev Respir Dis.

    (1983)
  • D. Popov et al.

    Alterations of lung structure in experimental diabetes, and diabetes associated with hyperlipidaemia in hamsters

    Eur Respir J.

    (1997)
  • C.G. Plopper et al.

    Alterations in granular (type II) pneumocyte ultrastructure by streptozotocin-induced diabetes in the rat

    Lab Invest.

    (1978)
  • A.F. Ofulue et al.

    Experimental diabetes and the lung. II. In vivo connective tissue metabolism

    Am Rev Respir Dis.

    (1988)
  • A.F. Ofulue et al.

    Experimental diabetes and the lung. I. Changes in growth, morphometry, and biochemistry

    Am Rev Respir Dis.

    (1988)
  • L.S. Inselman et al.

    Obesity-induced hyperplastic lung growth

    Am Rev Respir Dis.

    (1987)
  • Cited by (80)

    • Well-controlled vs poorly-controlled diabetes in patients with COVID-19: Are there any differences in outcomes and imaging findings?

      2020, Diabetes Research and Clinical Practice
      Citation Excerpt :

      Several hypotheses exist for the role of hyperglycemia in the progression of viral respiratory infections. Elevated blood glucose levels may negatively impact pulmonary function, as well as suppressing the immune system and increasing the production of inflammatory cytokines [25–28]. In addition, angiotensin-converting enzyme 2 (ACE2), one of the main receptors for SARS-CoV-2, is expressed within the pancreas, suggesting that this novel coronavirus can directly damage pancreatic islets [29].

    • Lung function in patients with diabetes mellitus

      2016, Revue de Pneumologie Clinique
    • Effects of exercise intensity compared to albuterol in individuals with cystic fibrosis

      2015, Respiratory Medicine
      Citation Excerpt :

      The diffusion of the lungs for nitric oxide is theoretically based solely on membrane conductance as nitric oxide is scavenged 280 times faster by hemoglobin than CO, meaning its uptake into the blood is nearly instantaneous. For this reason, DLNO is considered a relatively direct measure of alveolar-capillary membrane conductance (DMNO), as the diffusion resistance of the blood is trivial [34–38]. In addition, more recent work has demonstrated that DLNO is closely related to anatomical abnormalities determined using computed tomography in patients with CF [39].

    View all citing articles on Scopus
    View full text