nary dysfunction develops in type 2 diabetes mellitus (T2DM) in direct correlation with glycemia and is exacerbated by obesity; however, the associated structural derangement has not been quantified. We studied lungs from obese diabetic (fa/fa) male Zucker diabetic fatty (ZDF) rats at 4, 12, and 36 wk of age, before and after onset of T2DM, compared with lean nondiabetic (ϩ/ϩ) rats. Surfactant proteins A and C (SP-A and SP-C) immunoexpression in lung tissue was quantified at ages 14 and 18 wk, after the onset of T2DM. In fa/fa animals, lung volume was normal despite obesity. Numerous lipid droplets were visible within alveolar interstitium, lipofibroblasts, and macrophages, particularly in subpleural regions. Total triglyceride content was 136% higher. By 12 wk, septum volume was 21% higher, and alveolar duct volume was 36% lower. Capillary basement membrane was 29% thicker. Volume of lamellar bodies was 45% higher. By age 36 wk, volumes of interstitial collagen fibers, cells, and matrix were respectively 32, 25, and 80% higher, and capillary blood volume was 18% lower. ZDF rats exhibited a strain-specific increase in resistance of the air-blood diffusion barrier with age, which was exaggerated in fa/fa lungs compared with ϩ/ϩ lungs. In fa/fa lungs, SP-A and SP-C expression were elevated at age 14 -18 wk; the normal age-related increase in SP-A expression was accelerated, whereas SP-C expression declined with age. Thus lungs from obese T2DM animals develop many qualitatively similar changes as in type 1 diabetes mellitus but with extensive lipid deposition, altered alveolar type 2 cell ultrastructure, and surfactant protein expression patterns that suggest additive effects of hyperglycemia and lipotoxicity. diabetes mellitus; lung morphometry; lipid deposition; collagen; surfactant-associated proteins THE LUNG IS A RECOGNIZED TARGET of diabetic microangiopathy, manifested by modest restrictions of ventilatory capacity, lung volume, and diffusing capacity (12,24,41). Because alveolar microvascular reserves are extensive, pulmonary dysfunction is usually not the presenting complaint in diabetes mellitus, although modest pulmonary dysfunction may become overtly debilitating under physiological stress (e.g., high-altitude exposure or exercise) or following the loss of alveolar microvascular reserves brought on by aging or disease (23,24). In patients with type 1 diabetes mellitus (T1DM), we have found a significant restrictive defect associated with decreased lung diffusing capacity for carbon monoxide (DL CO ) at a given pulmonary blood flow, mainly due to a reduction of membrane conductance compared with age-matched nondiabetic healthy subjects (41, 52). Structural abnormalities observed at autopsy in diabetic human lungs include thickened epithelial and capillary basement membranes (72, 77), alveolar septal destruction, and enlarged air spaces (32). In streptozotocin-induced T1DM, volumes of basal laminae, extracellular matrix, and interstitial connective tissue are increased in diabetic lungs compared with contr...