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

The American Journal of Medicine (2005) 118, 205–211

REVIEW

The diabetic lung: Relevance of alveolar microangiopathy for the use of inhaled insulin Connie C. W. Hsia, MD, Philip Raskin, MD Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas. KEYWORDS: Diabetes mellitus; Oxygen transport; Lung diffusing capacity; Cardiac output; Pulmonary capillary blood volume; Gas exchange

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. © 2005 Elsevier Inc. All rights reserved.

Diabetic microangiopathy results from generalized derangement of protein glycosylation due to hyperglycemia.1–3 Because retinopathy, neuropathy, nephropathy, and cardiovascular impairment overtly contribute to morbidity and mortality, the prevalent but frequently occult pulmonary dysfunction is under-recognized. There are compelling reasons for understanding pulmonary dysfunction in diabetes. First, the alveolar-capillary network is the largest microvascular organ (surface area ⬃140 m2) and receives the entire cardiac output. Because pulmonary capacity for oxygen uptake is nearly twice that of other oxygen transport steps (cardiovascular delivery, peripheral tissue extraction, and cellular oxidative metabolism), pulmonary oxygen upRequests for reprints should be addressed to Connie C. W. Hsia, MD, Department of Internal Medicine, Pulmonary and Critical Care Medicine, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9034.

0002-9343/$ -see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2004.09.019

take does not limit oxygen transport at sea level.4 Owing to the larger pulmonary reserves, symptoms and disability develop earlier in other organs than in the lung at a comparable severity of anatomic organ destruction. Nevertheless, subclinical pulmonary dysfunction becomes overt under circumstances where reserves are diminished by aging, high altitude exposure, smoking, or primary lung disease. The lung is exposed continuously to fluctuating environmental temperature, pressure, humidity, pollutants, and allergens. Perhaps due to this exposure, spirometry, elastic recoil, and gas exchange5–7 decline more rapidly with aging than do stroke volume or arteriovenous oxygen extraction in fit persons.8,9 Age-related decline in lung diffusing capacity begins after about 20 years of age and accelerates after 40 years of age regardless of sex or smoking history.10,11 Thus, early moderate pulmonary dysfunction can become debilitating later. At high altitude, lung diffusing capacity is the predominant factor limiting oxygen transport, and even

206 mild pulmonary impairment is debilitating. In addition, subclinical pulmonary dysfunction exacerbates morbidity associated with existing cardiac or renal failure. Second, the lung is the only oxygen transport organ in which the effective size of the microvascular bed (capillary surface area and volume) is accessible to noninvasive quantification under basal (resting) and loaded (exercise) conditions, that is, from the linear relation between lung diffusing capacity and cardiac output. This relation defines alveolar microvascular reserves that can be recruited to augment oxygen uptake, and has been validated against ultrastructural determinants of diffusion. As a comparative example, in the kidney, glomerular filtration rate (flux) but not microvascular filtration capacity (e.g., glomerular capillary surface area) can be estimated noninvasively. Loss of one kidney is compensated for by hemodynamic adjustment and hypertrophy of the remaining kidney, which returns glomerular filtration rate to normal without causing symptoms of renal insufficiency, but the net change in glomerular capacity (i.e., filtration reserve) cannot be assessed noninvasively. Third, the capacity for oxygen transport by the heart and skeletal muscle varies with physical conditioning; such intrinsic variation can confound interpretation of intervention trials where clinical improvement may be due to changing physical activity rather than the primary intervention being studied. This source of error does not complicate alveolar oxygen transport because lung diffusing capacity measured at a given cardiac output is not altered by physical training.12,13 Finally, the lung is a highly effective route for drug delivery. Current interests in inhaled insulin delivery necessitate a better understanding of diabetic pulmonary dysfunction to evaluate reciprocal interactions between inhaled insulin and lung function.

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 microangiopathy involving alveolar septal capillaries and pulmonary as well as pleural arterioles, including thickened epithelial and capillary basement membranes, vascular hyalinosis, intraseptal nodular fibrosis, granulomas, and focal proteinosis with emphysema-like septal obliteration.22–26 Thickened basement membrane is associated with increased extracellular matrix and connective tissue.27,28 The lungs of untreated diabetic rats show increased synthesis and diminished degradation of collagen and elastin; phospholipids and phosphatidylcholine

The American Journal of Medicine, Vol 118, No 3, March 2005 contents are decreased in proportion to a reduced alveolar surface area. Type II pneumocyte morphology is altered markedly with dilated cisterna of granular endoplasmic reticulum and Golgi saccules.29 The volume proportion of alveolar septa is higher with smaller air spaces. These changes normalize after insulin administration.27,30,31 In diabetic hamsters, about 35% of the alveolar capillaries are narrowed and the alveoli are compressed by hyperplastic interstitium; abnormalities are exacerbated by hyperlipidemia.28 An elevated insulin level in diet-induced obesity is also associated with hyperplastic interstitium as well as diminished alveolar surface-to-volume ratio that increases the blood-gas diffusion barrier.32,33 Pulmonary structural abnormalities generally parallel that in retina, kidney, peripheral nerve, and skeletal muscle,1,34 –38 supporting a common pathogenesis. Diabetic mice show enhanced pulmonary endothelial permeability.38 In addition, epithelial clearance of inhaled tracers is delayed in 50% of nonsmoking diabetic patients,39 especially those with end-organ complications,40 which suggests impaired elimination of inhaled particles and pathogens.

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).

Ventilatory control One third of diabetic patients in a study by Williams et al41 showed blunted ventilatory response to hypoxia, hypercapnia, or exercise; a subset showed excessively high tidal volumes during exercise resembling postvagotomy changes. Other manifestations of autonomic neuropathy include a higher incidence of aspiration,42 disordered breathing during sleep,43 diminished perception of inspiratory loading,44,45 and diminished or absent cough reflex.46 Bronchodilator response to anticholinergic drugs47 and bronchoconstrictive response to cold air inhalation48 are diminished, although bronchial smooth muscle reactivity to inhaled histamine is normal or increased,49 indicating a depressed respiratory vagal tone but intact end-organ response to direct stimulation. Respiratory autonomic neuropathy could delay the onset of dyspnea in diabetic patients with substantial pulmonary impairment.

Mechanical function In conducting airways (1st to 16th generations), oxygen transport occurs by convection. In respiratory airways (17th to 23rd generations), oxygen transport occurs predominantly by diffusion. Convective function is commonly assessed from the forced vital capacity (FVC, the maximum volume expired), the forced expired volume after 1 second (FEV1, an indicator of large airway flow), and the average

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flow rate in the midportion of FVC (FEF25-75, an indicator of small airway flow). Total lung capacity and end-expiratory lung volume are measured by inert gas dilution or plethysmography. Abnormal lung function is detected in up to 73% of young asymptomatic type 1 diabetic patients;50 FVC, FEV1, and FEF25-75 are reduced by 8% to 20%, consistent with a modest restrictive defect without airway obstruction.51–53 In nonsmoking young asymptomatic patients with longstanding type 1 diabetes, total lung capacity and end-expiratory lung volume measured at rest or exercise are about 30% below normal and inversely related to glycosylated hemoglobin level.52 Volume reduction is associated with a loss of lung elastic recoil54 and limited joint mobility,55 reflecting parenchymal derangement as well as chest wall stiffness. A loss of elastic recoil increases mechanical respiratory loading,45 work of breathing, and oxygen requirement of respiratory muscles during exercise.52 Such mechanical derangement resembles accelerated aging and has been linked to collagen glycosylation of lung parenchyma but may also result from loss of alveolar microvascular bed.56,57 In large cohorts of type 2 diabetic patients, lung volume is also reduced modestly in an inverse relation to insulin resistance.58,59

Alveolar gas exchange The alveolar region consists of about 85% air and 15% septa; the latter is comprised equally of tissue and capillary blood. This dense alveolar-capillary network maximizes surface areas for gas exchange while the extremely thin (⬍1 ␮m) blood-gas barrier minimizes diffusion distance. The uptake of an inhaled gas bolus along a pressure gradient across alveolar membrane, plasma, and erythrocytes followed by chemical binding to hemoglobin (lung diffusing capacity, in mL of gas.min⫺1.mm Hg⫺1) is commonly measured to monitor clinical evolution of pulmonary microvascular disease,60,61 increased alveolar-capillary permeability,62,63 and interstitial fibrosis.64,65 Lung diffusing capacity has two components: 1

207 methane) in air or oxygen is inhaled; disappearance of CO is measured at the mouth with respect to the tracer after breath holding, during slow exhalation, or during a rebreathing maneuver. Since CO and oxygen compete for the same heme binding sites, membrane diffusing capacity and pulmonary capillary blood volume can be determined by measuring CO uptake at two alveolar oxygen tensions. Trace amounts of inhaled nitric oxide (NO) can also be added.66 – 68 As NO is scavenged by hemoglobin 280 times faster than oxygen, NO uptake by blood is nearly instantaneous and the uptake of inhaled NO approximates a direct estimate of membrane diffusing capacity. Given a direct relation between diffusing capacities for NO and CO,68,69 simultaneous NO and CO uptake has been used to estimate membrane diffusing capacity and pulmonary capillary blood volume in a single maneuver.

Microvascular reserves Lung diffusing capacity increases linearly with cardiac output from rest to exercise62,70 (Figure); this increase reflects greater utilization of alveolar microvascular reserves and is used to evaluate microvascular integrity. At rest, some but not all alveolar units are ventilated. As ventilation increases during exercise, alveolar units unfold and distend, causing enlargement of gas exchange surfaces and about a 20% increase in lung diffusing capacity. Similarly, not all alveolar capillaries at rest are perfused by erythrocytes; the remainder are perfused by plasma or not at all. As cardiac output increases, more capillaries open and distend, causing enlargement of gas exchange surfaces71 and a 40% to 100% increase in lung diffusing capacity. At peak exercise when microvascular reserves are almost utilized fully, diffusing capacity quantitatively reflects alveolar ultrastructure (i.e., surface area and barrier thickness).72 A low diffusing capacity at a given cardiac output suggests diminished microvascular reserves, whereas an abnormally depressed slope of increase suggests impaired recruitment; the latter predicts the likelihood of developing arterial hypoxemia upon exertion.

Diffusing capacity of lung ⫽

1 Diffusing capacity of membrane ⫹

1 Diffusing capacity of blood

Membrane diffusing capacity is related directly to alveolarcapillary surface area and inversely to barrier thickness. Diffusing capacity of blood is related directly to alveolarcapillary blood volume and hemoglobin concentration. Because diffusing capacity for oxygen is impractical to measure, diffusing capacity for carbon monoxide is used clinically to infer diffusing capacity for oxygen. A known volume containing small concentrations of carbon monoxide (CO) and an inert insoluble tracer gas (e.g., helium or

Loss of reserves in diabetes Nonsmoking, young, type 1 diabetic patients who are at rest50,73 show a modest (⬃8%) reduction in average lung diffusing capacity per unit alveolar volume. Taking into account a reduced lung volume, Ramirez et al53 found an absolute reduction in resting lung diffusing capacity of 35% in poorly controlled and 13% in well-controlled type 1 diabetic patients; similar reductions are seen in type 2 diabetes.74,75 In patients with end-organ complications, a low lung diffusing capacity correlates with diabetes duration76,77 and microalbuminuria.74 In contrast, other studies reported a normal lung diffusing capacity in diabetes;78 – 80 inconsistent results may be partly due to differences in patient sampling, age, smoking history, or measurement technique.

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Figure Associations of lung diffusing capacity and membrane diffusing capacity with cardiac index from rest to exercise in nondiabetic healthy subjects (solid lines showing 95% confidence intervals) and in type 1 diabetic patients who maintained either hyperglycemia or near-normoglycemia over 6 years. At a given cardiac index, lung and membrane diffusing capacities are below normal in the majority of hyperglycemic patients but not different from normal in near-normoglycemic patients. From Niranjan et al.52

More importantly, resting measurements alone cannot adequately assess microvascular reserves, and a variable cardiac output, a key determinant of lung diffusing capacity, was not accounted for in most studies. Niranjan et al52 directly assessed alveolar microvascular reserves by measuring lung diffusing capacity and cardiac output simultaneously in asymptomatic patients with longstanding type 1 diabetes after 6 years of either standard or intensive insulin therapy that resulted in two stable levels of glycosylated hemoglobin. In chronically hyperglycemic patients, maximal oxygen uptake and maximal cardiac output are 30% to 40% below normal. At a given cardiac output at rest or exercise, lung diffusing capacity is up to 30% to 40% below normal due to a reduced membrane diffusing capacity (Figure), while pulmonary capillary blood volume is preserved. In contrast, measurements in normoglycemic patients are not different from normal. In both diabetic groups, the slopes of the increase in lung and membrane diffusing capacities as well as pulmonary capillary blood volume with respect to cardiac output are normal. This pattern suggests

The American Journal of Medicine, Vol 118, No 3, March 2005 that in diabetes the reduction in alveolar microvascular reserves is related to glycemic control, that alveolar microvascular dysfunction results primarily from a loss of surface area or membrane thickening but not from capillary obliteration, and that alveolar capillary recruitment remains normal. The lower diffusing capacities in hyperglycemic patients correlate qualitatively with a higher prevalence of retinopathy, nephropathy, and neuropathy. The proportional reductions in maximal oxygen uptake, maximal diffusing capacity, and maximal cardiac output suggest a similar severity of alveolar and myocardial microangiopathy. Macrovascular complications (e.g., atherosclerosis) restrict maximal cardiac output but do not alter lung diffusing capacity measured at a given cardiac output. However, end-organ insufficiency (chronic cardiac and renal failure) and anemia of chronic disease could further impair lung and membrane diffusing capacities as well as pulmonary capillary blood volume independent of diabetes.81– 83 Longitudinal follow-up of alveolar microvascular function in diabetic patients is not yet available. Extrapolating from the rates of normal age-related decline in lung diffusing capacity10 and assuming the diabetic groups studied by Niranjan et al52 had similar lung diffusing capacity upon initiation of standard or intensive insulin treatment, lung diffusing capacity in chronically hyperglycemic patients likely declined at an accelerated rate, whereas diffusing capacity in near-normoglycemic patients did not decline or actually improved following intensive insulin treatment. Hence, it remains possible that even established microvascular impairment could be partially reversed.

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 against a lower drug bioavailability necessitating a higher inhaled dose90 and as yet uncertain long-term interaction between insulin and alveolar tissue. Unlike most inhaled drugs, insulin is a peptide with immunogenic, proinflammatory, and anabolic properties. One unresolved issue is the importance of increased circulating insulin-binding antibodies with inhaled delivery; these antibodies may be a reservoir for prolonged insulin release.88 A second issue is whether repeated supraphysiologic alveolar deposition of insulin induces unintended local effects. For example, insulin promotes pulmonary vasodilation in vitro at local concentrations much below that expected from inhalation.17 In clinical trials, spirometry has remained stable after up to 6 months of inhaled insulin

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administration with resting lung diffusing capacity showing no change or only a slight tendency to fall.85,87,91 Extended longitudinal observation spanning a wide age range and relating diffusing capacity to cardiac output will be important to address the long-term effects of inhaled insulin on alveolar microvascular reserves. A third issue is reciprocal effects between inhaled insulin and coexisting lung disease. Inhaled insulin is absorbed more rapidly in smokers92 and more slowly in asthmatic patients,93 likely because of altered mucosal blood flow, inflammation, or permeability. Respiratory infection, asthmatic exacerbation, altered smoking habit, or even varying cardiac output may necessitate dose adjustment. The efficacy and safety in chronic obstructive, inflammatory, or vascular lung diseases are unknown. Given the high prevalence and general under-recognition of pulmonary impairment in diabetes, a cautious approach to the long-term use of inhaled insulin is advisable until more data are available.

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 quantitative indicators of microangiopathic progression in a large capillary bed. Future investigation should prospectively examine the sensitivity of these indexes in following diabetic progression and reversibility, their interactions with aging, lung disease, extrapulmonary complications, or the use of inhaled insulin.

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