© 2003 American Thoracic Society
Insulin Effect on Lung DiffusionNO PathwayTo the Editor:The article by Dr. Guazzi and colleagues (1) regarding impaired pulmonary diffusion in patients with diabetes mellitus and heart failure reported very interesting observations about the synergistic effect of these conditions in pulmonary gas exchange. It was shown that acute infusion of insulin facilitated immediately diffusion in diabetes, through an influence on alveolar-capillary conductance. The authors suggested three possible mechanisms for this result: reduction of hydrostatic forces, increased alveolar epithelial fluid clearance and activation of NO or vasodilating prostaglandins. Type 2 diabetes is characterized by hyperglycemia and insulin resistance. Hyperglycemia causes many diabetic complications leading to increased oxidative stress in tissues through stress-sensitive intracellular signaling pathways that also seem to play a key role in causing insulin resistance, enhanced oxygen free radical-mediated NO inactivation, and increased generation of vasoconstrictive prostanoids (2, 3). In diabetic patients, pulmonary dysfunction is thought to involve the presence of thickened alveolar capillary basal lamina due to microangiopathy and nonenzymatic glycosylation of tissue proteins (4). The observation of reduced baseline DLCO and DLCO/VA in diabetic patients compared with control subjects presented by the authors (1) is in accordance with our study (5). The fact that in vivo a single small dose of intravenous insulin improved alveolar-capillary conductance in diabetic patients raises questions concerning the pathophysiological consequences of insulin action on the alveolar-capillary unit leading to this result as: 1) the effect was immediately observed and 2) hemodynamic parameters were not involved, since insulin infusion did not affect pulmonary capillary blood volume. On the other hand, this insulin effect was produced in an environment in which lung tissue alterations affecting gas exchange due to diabetic metabolic parameters had already been established. We believe that the most tenable explanation for the acute effect of insulin in the alveolar-capillary unit involves, as the authors propose, the activation of the NO pathway. Hyperglycemia resulted in a significant downregulation of NO production, whereas insulin caused a dose-dependent upregulation of NO production in cultured human coronary endothelial cells (3). Our research group previously reported that insulin attenuated rabbit tracheal smooth muscle contraction by acting on epithelium and releasing NO and that this result was abolished by the presence of a nitric oxide synthase inhibitor (L-NAME) (6). The finding that insulin causes an acute effect in the improvement of pulmonary diffusion in diabetic patients intensifies the need to clarify the pathophysiological basis of insulin biological effects on lung tissue, since clinical application could be of great importance in diabetic patients.
University of Thessaly Larissa, Greece REFERENCES
From the Authors: We would like to thank Dr. Boulbou and associates for their appreciation and the emphasis placed on the pathophysiological and clinical relevance of our recent finding that insulin improves the alveolar-capillary membrane gas diffusive properties in patients with both type 2 diabetes and chronic heart failure (1). We hypothesize that chronic heart failure and diabetes can synergistically impair the alveolar-capillary membrane gas conductance through a number of mechanisms (1). We think it is important that insulin had little or no effect on alveolar gas diffusion in patients with chronic heart failure alone, but was beneficial in patients with diabeties without chronic heart failure (2), suggesting that diabetes provides the main substrate for the insulin activity. The mechanisms involved in this newly discovered pharmacological property of insulin cannot be determined with our data. We agree that nitric oxide (NO) release could mediate the effects on the alveolar membrane properties, but we do not believe that the evidence is sufficient to rule out many other possibilities. Experimental models that can help to elucidate the relative contribution of NO pathway in this setting need to be developed. The evidence provided by Papayianni and coworkers (3) that insulin attenuates tracheal smooth muscle contraction by releasing NO in a rabbit model, may or may not be relevant to our findings because of differences in the pathophysiological background that cause and sustain alveolar dysfunction in the presence of chronic heart failure and diabetes. Fluid clearance from the alveolar epithelial surface to capillary basement is dependent on specific Na+ channels as well as on a Na+-glucose co-transport system. In the presence of diabetes, insulin might activate this defective pathway, promote fluid reabsorption, and thereby improve gas exchange by shortening of the diffusion path (4). An active participation of others EDRFs, such as vasodilator prostaglandins, cannot be definitively ruled out. As to the clinical impact of our report, we take this opportunity to mention that recent findings from our laboratory (5) show that in patients with chronic heart failure and diabetes, improvement in lung diffusion translates into improved ventilatory efficiency (VE/VCO2) during exercise and a greater oxygen uptake at peak exercise. Considering the high prognostic power of both ventilatory efficiency and peak oxygen consumption, these results, at a minimum, support the need for an in-depth evaluation of the mechanisms whereby insulin affects lung microcirculation in diabetes, and the clinical correlates.
Università degli Studi di Milano Milan, Italy REFERENCES
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