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. 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 compo- nents (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 impor- tance 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. KEYWORDS: Diabetes mellitus; Oxygen transport; Lung diffusing capacity; Cardiac output; Pulmonary capillary blood volume; Gas exchange Diabetic microangiopathy results from generalized de- rangement of protein glycosylation due to hyperglyce- mia. 1–3 Because retinopathy, neuropathy, nephropathy, and cardiovascular impairment overtly contribute to morbidity and mortality, the prevalent but frequently occult pulmo- nary dysfunction is under-recognized. There are compelling reasons for understanding pulmonary dysfunction in diabe- tes. First, the alveolar-capillary network is the largest micro- vascular organ (surface area 140 m 2 ) and receives the entire cardiac output. Because pulmonary capacity for ox- ygen uptake is nearly twice that of other oxygen transport steps (cardiovascular delivery, peripheral tissue extraction, and cellular oxidative metabolism), pulmonary oxygen up- 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 com- parable severity of anatomic organ destruction. Neverthe- less, subclinical pulmonary dysfunction becomes overt un- der circumstances where reserves are diminished by aging, high altitude exposure, smoking, or primary lung disease. The lung is exposed continuously to fluctuating environ- mental temperature, pressure, humidity, pollutants, and al- lergens. Perhaps due to this exposure, spirometry, elastic recoil, and gas exchange 5–7 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 debili- tating later. At high altitude, lung diffusing capacity is the predominant factor limiting oxygen transport, and even Requests 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 The American Journal of Medicine (2005) 118, 205–211