Recruitment of alveolar microvascular reserves, assessed from the relationship between pulmonary diffusing capacity (DLCO) and perfusion ((Q)over dot(c)), is critical to the maintenance of arterial blood oxygenation. Leptin-resistant ZDF fatty diabetic (fa/fa) rats exhibit restricted cardiopulmonary physiology under anesthesia. To assess alveolar microvascular function in conscious, non-sedated, non-instrumented, and minimally restrained animals, we adapted a rebreathing technique to study fa/fa and control non-diabetic (+/+) rats (4-5 and 7-11 mo old) at rest and during mild spontaneous activity. Measurements included O-2 uptake, lung volume, (Q)over dot(c), DLCO, membrane diffusing capacity (DMCO), capillary blood volume (V-c) and septal tissue-blood volume. In older fa/fa than +/+ animals, DLCO and DMCO at a given (Q)over dot(c) were lower; V-c was reduced in proportion to (Q)over dot(c). Results demonstrate the consequences of alveolar microangiopathy in the metabolic syndrome: lung volume restriction, reduced (Q)over dot(c), and elevated membrane resistance to diffusion. At a given (Q)over dot(c), DLCO is lower in rats and guinea pigs than dogs or humans, consistent with limited alveolar microvascular reserves in small animals. Published by Elsevier B.V.