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Published online February 19, 2008
Diabetes Care 31:958-963, 2008
DOI: 10.2337/dc07-2173
© 2008 by the American Diabetes Association
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Pathophysiology/Complications
Original Research

Circulating Surfactant Protein A (SP-A), a Marker of Lung Injury, Is Associated With Insulin Resistance

José Manuel Fernández-Real, MD, PHD1, Berta Chico1, Masanori Shiratori, MD, PHD2, Yusuke Nara, MD2, Hiroki Takahashi, PHD2 and Wifredo Ricart, MD1

1 Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomédica de Girona and CIBER Fisiopatología de la Obesidad y Nutrición, Girona, Spain
2 Third Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan

Corresponding author: J.M. Fernández-Real, MD, PhD, Unit of Diabetes, Endocrinology and Nutrition, Hospital de Girona "Dr Josep Trueta," Ctra. França s/n, 17007 Girona, Spain. E-mail: uden.jmfernandezreal{at}htrueta.scs.es


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 References
 
OBJECTIVES—Impaired lung function and inflammation have both attracted interest as potentially novel risk factors for glucose intolerance, insulin resistance, and type 2 diabetes. We hypothesized that circulating levels of surfactant protein (SP)-A, which reflects interstitial lung injury, could be associated with altered glucose tolerance and insulin resistance.

RESEARCH DESIGN AND METHODS—Circulating SP-A concentration and metabolic variables (including insulin sensitivity by minimal model method, n = 89) were measured in 164 nonsmoking men.

RESULTS—Circulating SP-A concentration was significantly higher among patients with glucose intolerance and type 2 diabetes than in subjects with normal glucose tolerance, even after adjustment for BMI, age, and smoking status (ex/never). The most significant differences were found in overweight and obese subjects with altered glucose tolerance (n = 59) who showed significantly increased serum SP-A concentrations (by a mean of 24%) compared with obese subjects with normal glucose tolerance (n = 58) (log SP-A 1.54 ± 0.13 vs. 1.44 ± 0.13; P < 0.0001). Insulin sensitivity (P = 0.003) contributed independently to 22% of SP-A variance among all subjects. In subjects with altered glucose tolerance, insulin sensitivity (P = 0.01) and fasting triglycerides (P = 0.02) contributed to 37% of SP-A variance. Controlling for serum creatinine or C-reactive protein in these models did not significantly change the results.

CONCLUSIONS—Lung-derived SP-A protein was associated with altered glucose tolerance and insulin resistance in 164 nonsmoking men.

Abbreviations: SP, surfactant protein • WHR, waist-to-hip ratio


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 References
 
Impaired lung function has attracted interest as a potentially novel risk factor for glucose intolerance, insulin resistance, and type 2 diabetes (1–6). Lower forced vital capacity, lower forced expiratory volume in 1 s, and lower maximal midexpiratory flow rate at baseline predicted hyperinsulinemia and estimated insulin resistance over 20 years of follow-up, independent of age, adiposity, and smoking (1). Possible mechanisms for this 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).

Some components of the lung surfactant have been shown to be important host defense components against respiratory pathogens and allergens. 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 in order to avoid lung collapse during respiration. Four surfactant proteins (SPs), SP-A, SP-B, SP-C, and SP-D, are intimately associated with surfactant lipids in the lung (10). SP-A is the major surfactant-associated protein, constituting ~3–4% of the total mass of isolated surfactant and 50% of the total surfactant protein.

These surfactant proteins occur physiologically in small amounts in blood (11), and because they are secreted into the respiratory tract, their occurrence in serum can only be explained by leakage into the vascular compartment. Although the exact mechanisms by which these proteins enter the blood remain poorly understood, intravascular leakage increases in conditions characterized by pulmonary inflammation and/or pulmonary epithelial injury (11).

By upregulating SP-A synthesis, the innate immune system can immediately respond to intrusion of foreign agents by helping to prevent further invasion. This recognition is very important in day-to-day physiology. Each day we breathe more than 7,000 l of air laden with inorganic and organic particles and an array of microbes.

We have previously reported that the circulating concentration of several proteins of the sensing arm of the innate immune system is linked to insulin sensitivity and glucose tolerance (12,13). We thus aimed to evaluate whether circulating SP-A concentration is associated with insulin resistance or altered glucose tolerance. Given that serum SP-A concentration is elevated by smoking (14,15), we studied only nonsmoking subjects.


   RESEARCH DESIGN AND METHODS—
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
RESULTS--
 CONCLUSIONS--
 References
 
A total of 164 Caucasian subjects were recruited and studied in an ongoing study dealing with nonclassical cardiovascular risk factors in northern Spain. Subjects were randomly localized from a census and invited to participate. The participation rate was 71%. A 75-g oral glucose tolerance test according to American Diabetes Association criteria was performed in all subjects. All subjects with normal glucose tolerance (n = 92) had fasting plasma glucose <7.0 mmol/l and 2-h postload plasma glucose <7.8 mmol/l after a 75-g oral glucose tolerance test. Isolated impaired fasting glucose (≥4.5 and <7 mmol/l) was present in 11 subjects, glucose intolerance (postload glucose between 7.8 and 11.1 mmol/l) was diagnosed in 37 subjects, and previously unknown type 2 diabetes (postload glucose 11.1 mmol/l) was present in 24 subjects according to American Diabetes Association criteria. Inclusion criteria for subjects reported in this study were BMI <40 kg/m2, absence of systemic disease, absence of infection within the previous month, and no medication or evidence of metabolic disease other than obesity. The subjects did not present symptoms or signs of chronic respiratory disease.

Alcohol and caffeine were withheld within 12 h of performing the insulin sensitivity test. A smoker was defined as any person consuming at least one cigarette a day in the previous 6 months. Ex-smokers were defined as previous smokers who gave up cigarette smoking for at least 1 year. Resting blood pressure was measured as previously reported (12). Liver disease and thyroid dysfunction were specifically excluded by biochemical workup. Renal function (serum creatinine concentration) was normal in all subjects.

All subjects gave written informed consent after the purpose of the study was explained to them. The institutional review board of the Hospital of Girona "Dr Josep Trueta" approved the protocol.

Study of insulin sensitivity
In those subjects who agreed (n = 89; 53 with normal and 36 with altered glucose tolerance), insulin sensitivity and glucose effectiveness were measured using the frequently sampled intravenous glucose tolerance test with minimal model analysis. In brief, the experimental protocol started between 8:00 and 8:30 A.M. after an overnight fast. A butterfly needle was inserted into an antecubital vein, and patency was maintained with a slow saline drip. Basal blood samples were drawn at –30, –10 and –5 min, after which glucose (300 mg/kg body wt) was injected over 1 min starting at time 0, and insulin (0.03 units/kg, Actrapid; Novo Nordisk, Denmark) was administered at 20 min. Additional samples were obtained from a contralateral antecubital vein up to 180 min, as previously described (12).

Analytical methods
Serum glucose concentrations were measured in duplicate by the glucose oxidase method using a Beckman glucose analyzer II (Beckman Instruments, Brea, CA). Total serum cholesterol was measured through the reaction of cholesterol esterase/cholesterol oxidase/peroxidase. Total serum triglycerides were measured through the reaction of glycerol-phosphate-oxidase and peroxidase. A1C was measured by the high-performance liquid chromatography method (Jokoh HS-10 autoanalyzer; Bio-Rad, Muenchen, Germany). Intra- and interassay coefficients of variation (CVs) were <4% for all these tests. Serum insulin was measured in duplicate by monoclonal immunoradiometric assay (Medgenix Diagnostics, Fleunes, Belgium). The intra-assay CVs were 5.2% and 3.4% at concentrations of 10 mU/l and 130 mU/l, respectively. The interassay coefficients of variation were 6.9 and 4.5% at 14 and 89 mU/l, respectively.

Serum C-reactive protein (ultrasensitive assay; Beckman, Fullerton, CA) was determined by routine laboratory test, with intra- and interassay CVs <4%. The lower limit of detection is 0.02 mg/l. Serum creatinine was measured by routine laboratory methods.

Measurement of SP-A
SP-A assay was performed by ELSIA F300 assay system using enzyme immunoassay kits (SP-A test "Kokusai"F) provided by Sismex (Kobe, Japan). The assay was performed by sandwich enzyme immunoassay method using two monoclonal antibodies against human SP-A: PE10 and PC6. A measured 50 µl of serum from each patient was applied to the assay. The method of assay as described below is based on that of Shimizu et al. (16), adapted with minor modifications. The intra-assay CVs in this assay were 4.4 and 2.9% at concentrations of 51.3 and 91.1 ng/ml, respectively. The interassay CVs were 4.6 and 3.5% at 38.0 and 92.4 ng/ml, respectively (17).

Statistical methods
Descriptive results of continuous variables are expressed as means ± SD. Before statistical analysis, normal distribution and homogeneity of the variances were evaluated using Levene's test and then variables were given a base 10 log transformation if necessary. These parameters (Si, triglycerides, and SP-A) were analyzed on a log scale and tested for significance on that scale. The anti–log-transformed values of the means (geometric mean) are reported in the Tables. Relationships between variables were tested using Pearson's test and stepwise multiple linear regression analysis. We used the {chi}2 test for comparisons of proportions and unpaired t tests and ANOVA test (with post hoc Tukey's test) for comparisons of quantitative variables. General linear model was also used to calculate circulating SP-A values after adjusting for age and BMI. The statistical analyses were performed using the program SPSS (version 12.0).


   RESULTS—
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
CONCLUSIONS--
 References
 
Characteristics of the subjects according to glucose tolerance status are shown in Table 1. Subjects with glucose intolerance or type 2 diabetes were significantly older and heavier and showed lower insulin sensitivity than subjects with normal glucose tolerance. Circulating SP-A concentration was significantly higher among patients with glucose intolerance and type 2 diabetes than in subjects with normal glucose tolerance (Fig. 1), even after adjustment for BMI, age, and smoking status (ex/never).


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  		Table 1— Anthropometric and biochemical variables of study subjects

 

Figure 1
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  		Figure 1— CI for the mean of serum log SP-A according to glucose tolerance status in all subjects (A) and in overweight and obese subjects (B).

 
In all subjects as a whole, circulating SP-A correlated significantly and positively with BMI, WHR, fasting and postload serum glucose, glycated hemoglobin, fasting and postload serum insulin, and fasting triglycerides and negatively with insulin sensitivity (Table 2). SP-A was not associated with age. In subjects with altered glucose tolerance, these associations were strengthened (Fig. 2). The associations between SP-A and metabolic variables were similar in subjects who never smoked and ex-smokers.


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  		Table 2— Correlation between circulating SP-A and biochemical variables

 

Figure 2
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  		Figure 2— Linear association between serum SP-A concentration and insulin sensitivity. r = –0.41; P < 0.001. r = –0.55; P < 0.0001 in altered glucose tolerance.

 
The most significant differences were found in overweight and obese subjects with altered glucose tolerance (impaired fasting glucose, glucose intolerance, or type 2 diabetes) (n = 59) who showed significantly increased serum SP-A concentrations (by a mean of 24%) compared with obese subjects with normal glucose tolerance (n = 58) (log SP-A 1.54 ± 0.13 vs. 1.44 ± 0.13; P < 0.0001) (Fig. 1B).

We performed a multiple linear regression analysis to predict circulating SP-A. Insulin sensitivity (P = 0.003) contributed independently to 22% of SP-A variance among all subjects. In another model, serum creatinine and C-reactive protein did not change the independent influence of insulin sensitivity on circulating SP-A concentration (Table 3). In subjects with altered glucose tolerance, insulin sensitivity (P = 0.01) and fasting triglycerides (P = 0.02) contributed to 37% of SP-A variance after controlling for the effects of BMI, WHR, and serum glucose at 120 min during the oral glucose tolerance test (Table 3). Again, serum creatinine and C-reactive protein did not contribute to SP-A variance once insulin sensitivity was controlled for. Adding the influence of smoking status to the model did not significantly change the results.


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  		Table 3— Multiple linear regression analysis with serum SP-A as dependent variable

 

   CONCLUSIONS—
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
References
 
We here describe that increased circulating SP-A concentrations were associated with altered glucose tolerance and insulin resistance. Surfactant proteins are compartmentalized in the alveoli by only apical secretion. The healthy lung maintains an epithelial lining fluid-to-plasma gradient of ~1,500:1. However, when the alveolocapillary barrier is damaged, surfactant proteins are no longer effectively partitioned and increased amounts leak into the bloodstream. Circulating levels reflect changes in lung permeability (11). Elevated SP-A levels can be due to increased production, decreased clearance, increased leakiness, or a combination of any of these mechanisms.

Different parameters (fasting and postload serum glucose and insulin, glycated hemoglobin, fasting triglycerides, and insulin resistance) were in direct association with circulating SP-A concentration. In multivariant models, the association between serum SP-A and insulin sensitivity persisted after controlling for BMI, WHR, fasting triglycerides, serum creatinine, and serum C-reactive protein in different models (Table 3). The contribution of insulin sensitivity to circulating SP-A variance was remarkable in subjects with altered glucose tolerance (37–38% of their variance [Table 3]). The lack of association between SP-A and C-reactive protein in multivariate analyses (Table 3) suggests that generalized inflammation does not significantly contribute to increased SP-A concentration.

Insulin receptors are present in rabbit type II pneumocytes (18), and insulin led to increased surfactant synthesis in in vitro studies (19). Glucagon-like peptide 1, known to stimulate insulin secretion, also stimulates surfactant secretion in human type II pneumocytes (20). In a rat model of diabetic pregnancy, insulin treatment resulted in a substantial increase in SP-A mRNA levels over those from untreated diabetic pregnancies (21). Increased insulin levels found in insulin resistance could be speculated to contribute to increased SP-A concentrations.

We cannot ignore other factors associated with insulin resistance and impaired glucose tolerance that could also play a role. Sugahara et al. (22) studied SP-A mRNA in streptozotocin-induced diabetic rats and observed increased SP-A mRNA in alveolar type II cells and Clara cells from diabetic lungs compared with those from control lungs. The relative abundance of SP-A mRNA increased approximately twofold in bronchiolar epithelial cells of diabetic lungs above that in controls (23).

These in vivo findings contrast with in vitro observations. In fetal rat lung explants, no consistent alteration in SP-A mRNA content was observed at different glucose concentrations (24). Insulin at pharmacological doses inhibited surfactant protein A gene expression in vitro (25,26).

Obese subjects had significantly increased serum SP-A concentrations. Alterations in lung function and surfactant lipids and proteins have been described in dietary-induced obesity (high-fat–fed rats) (27). Disaturated phosphatidylcholine in lung tissue and SP-A and SP-B levels in large aggregates were higher in obese (high-fat–fed) than control rats. The authors speculated that intrapulmonary lipid deposition and possible surfactant deficiency relative to alveolar surface area may contribute to the reduction in lung compliance in obese rats (27). It could be argued that obesity was the most important factor in increasing levels of SP-A, as BMI and WHR associations stand in all groups. Obesity, with all its possible implications, namely chronic hypoxia, could be considered the draining force. However, when we tested the most simple multivariate analyses (only BMI, WHR, and insulin sensitivity), the latter retained its independent contribution to circulating SP-A.

The strengths of this study are the collection of data from a population-based random sample and the use of a strong measure of insulin sensitivity (minimal model). The study limitations include the lack of pulmonary function tests. Data concerning indirect exposure to smoke, such as cotinine b levels, would have been informative. It would have also been useful to test whether serum SP-A levels serve as a marker of sleep apnea in obese subjects. In summary, the circulating lung protein SP-A is associated with altered glucose tolerance and insulin resistance.


   Acknowledgments
 
This work was supported by research grants from the Ministerio de Educación y Ciencia (BFU2004-03654).


   Footnotes
 
Published ahead of print at http://care.diabetesjournals.org on 19 February 2008. DOI: 10.2337/dc07-2173.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received for publication November 20, 2007. Accepted for publication February 11, 2008.


   References
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 References
 

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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
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