Surfactant Protein D, a Marker of Lung Innate Immunity, Is Positively Associated With Insulin Sensitivity

OBJECTIVE

Impaired lung function and innate immunity have both attracted growing interest as a potentially novel risk factor for glucose intolerance, insulin resistance, and type 2 diabetes. We aimed to evaluate whether surfactant protein D (SP-D), a lung-derived innate immune protein, was behind these associations.

RESEARCH DESIGN AND METHODS

Serum SP-D was evaluated in four different cohorts. The cross-sectional associations between SP-D and metabolic and inflammatory parameters were evaluated in two cohorts, the cross-sectional relationship with lung function in one cohort, and the longitudinal effects of weight loss on fasting and circadian rhythm of serum SP-D and cortisol concentrations in one prospective cohort.

RESULTS

In the cross-sectional studies, serum SP-D concentration was significantly decreased in subjects with obesity and type 2 diabetes (P = 0.005) and was negatively associated with fasting and postload serum glucose. SP-D was also associated with A1C, serum lipids, insulin sensitivity, inflammatory parameters, and plasma insulinase activity. Smoking subjects with normal glucose tolerance, but not smoking patients with type 2 diabetes, showed significantly higher serum SP-D concentration than nonsmokers. Serum SP-D concentration correlated positively with end-tidal carbon dioxide tension (r = 0.54, P = 0.034). In the longitudinal study, fasting serum SP-D concentration decreased significantly after weight loss (P = 0.02). Moreover, the main components of cortisol and SP-D rhythms became synchronous after weight loss.

CONCLUSIONS

These findings suggest that lung innate immunity, as inferred from circulating SP-D concentrations, is at the cross-roads of inflammation, obesity, and insulin resistance.Impaired lung function has attracted growing interest in association with metabolic disorders (1–6). Decreased lung function has been proposed as a potential novel risk factor for glucose intolerance, insulin resistance, and type 2 diabetes (1–6). In prospective studies of middle-aged men and women without known lung disease, lower vital capacity predicted the subsequent development of type 2 diabetes. Lower forced vital capacity and forced expiratory volume in 1 s at baseline predicted hyperinsulinemia and estimated insulin resistance over 20 years of follow-up, independent of age, adiposity, and smoking (1).Possible mechanisms for the hypothesized link include direct effects of hypoxemia on glucose and insulin regulation (7), adverse early-life exposures and their effects on organ development (8), and lung-related inflammatory mediators and their effects on insulin signaling (9). In fact, nuclear factor interleukin-6, early growth response-1, and hypoxia-inducible factor-1 mediate inflammatory responses to chronic hypoxia in macrophages, pulmonary vascular endothelium, and smooth muscle (6,9). Cigarette smoking, an independent predictor of type 2 diabetes (10), provokes an inflammatory response (11) and is inversely associated with vital capacity. However, the link between lower vital capacity and diabetes risk was completely independent of cigarette exposure and was stronger in never-smokers (6).Reduced vital capacity is a common residual effect of lower respiratory tract infections, including those in childhood and infancy (8), that might provoke an inflammatory response. A reduced ability to sense and eradicate pathogens could thus cause frequent respiratory tract infections, reduced vital capacity, and chronic inflammation resulting in insulin resistance and type 2 diabetes (12). The total incidence rate of infections needing hospitalization in diabetic patients was 41/1,000 persons-years compared with 16/1,000 person-years of follow-up in the general population. Roughly half of the infections were severe lung infections, suggesting impaired lung immunity in patients with type 2 diabetes (13).Pulmonary surfactant is a complex mixture of lipids (90%) and proteins (5–10%) that constitutes the mobile liquid phase covering the large surface area of the alveolar epithelium. It maintains minimal surface tension within the lungs to avoid lung collapse during respiration. The innate immune system, by upregulating SP-D synthesis, can immediately respond to intrusion of foreign agents by helping to prevent further invasion (14). This recognition is important in the day-to-day physiology. Each day, we breathe >7,000 liters of air, laden with inorganic and organic particles and an array of microbes. Secreted primarily by alveolar epithelial type II pneumocytes, plasma SP-D appears to increase early in the clinical course of lung injury, and its concentration is thought to reflect pulmonary epithelial injury (15).Subtle deficiencies in proteins of the sensing arm of the innate immune system have been found to be associated with alterations of glucose metabolism. These deficiencies run in parallel with inflammation and impaired insulin action (16).We hypothesized that SP-D could be behind the association of lung function with impaired insulin action. For that reason, we aimed to evaluate SP-D according to metabolic and inflammatory parameters. As SP-D was associated with obesity status and impaired glucose metabolism, we evaluated the influence of weight loss on both fasting and circadian serum SP-D concentration. As glucocorticoids seem to regulate SP-D production in in vitro studies (17), we investigated the influence of circadian cortisol rhythm on serum SP-D concentration. Finally, we also studied the association of SP-D with lung function tests.