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BRIEF REPORT |
Divisions of Endocrinology, Diabetes, and Clinical Nutrition (N.M., M.K., B.M., U.K., J.J.P.) and Central Laboratory (C.P.G.N.), Division of Pulmonary Medicine (S.S., M.T.), University Hospital, CH-4031 Basel, Switzerland; and Department of Medicine (J.J.P.), Columbia University College of Physicians and Surgeons, New York, New York 10032
Address all correspondence and requests for reprints to: Jardena J. Puder, M.D., Division of Endocrinology, Diabetes, and Clinical Nutrition, Department of Medicine, University Hospital, Petersgraben 4, 4031 Basel, Switzerland. E-mail: puderj{at}uhbs.ch.
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Abstract |
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Objective: The objective of the study was to assess changes in body composition and the serum concentrations of adiponectin, a marker of negative energy balance and insulin sensitivity, in adult patients with CF.
Design: This was a cross-sectional study.
Setting: The study was conducted at an outpatient clinic of the University Hospital of Basel, Switzerland.
Participants: Twenty-four stable adult CF patients and 24 healthy controls, matched for body mass index, age, sex, and hormonal therapy in women participated in the study.
Main Outcome Measures: Changes in body composition (assessed by dual x-ray absorptiometry) and serum adiponectin levels were measured.
Results: Body mass index, percent fat mass (in percentage of body weight), and percent lean body mass were similar in patients and controls, whereas central fat accumulation was increased [trunk to extremity fat ratio 1.2 (0.99–1.51) vs. 0.99 (0.81–1.25), P = 0.01] in patients with CF, compared with controls. Decreased lean mass and increased highly sensitive C-reactive protein levels were independently associated with worse lung function in CF patients. Despite similar insulin resistance (homeostasis model assessment) and similar SHBG serum concentrations, the serum concentrations of adiponectin were higher in CF patients, compared with controls, independent of other confounders (P = 0.01).
Conclusions: Central fat accumulation is increased in patients with CF. It is postulated that the energy deficit-induced increase in serum adiponectin could explain the preservation of insulin sensitivity in these patients despite the increase in central fat and in highly sensitive C-reactive protein serum concentrations and could prevent a further deterioration of protein catabolism.
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Introduction |
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In other chronic inflammatory diseases, a change in regional fat distribution is observed with a shift to a more central fat distribution (4). The latter is associated with an increase in low-grade chronic inflammation, insulin resistance, and cardiovascular risk (5, 6). Body mass index (BMI) and gender influence lean mass and regional fat distribution. However, previous studies investigating differences in body composition between patients with CF and healthy controls were not BMI matched, and/or the findings were not adjusted for gender and age.
CF patients are also characterized by a chronic energy deficit. Adiponectin, a hormone secreted by adipocytes, regulates not only lipid and glucose metabolism with a subsequent increase in insulin sensitivity but also energy homeostasis (7). In experimental conditions of negative energy balance, increases in adiponectin tissue mRNA expression and serum concentrations have been described (8, 9).
We wanted to compare body composition and serum adiponectin levels of patients with CF with those of healthy controls matched for BMI, age, and sex. In patients with CF, we also examined whether absolute lean body mass or serum concentrations of inflammatory mediators were associated with disease severity independent of BMI or other clinical parameters.
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Subjects and Methods |
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We examined 24 of 26 adult patients with CF followed up at the University Hospital of Basel (Table 1
). When examined, patients had to be stable without an exacerbation in the preceding 6 wk before the investigation. Twelve of the CF patients had diabetes, as diagnosed by the American Diabetes Association criteria. One patient was treated by diet only. Three patients were treated only with long-acting insulins (insulin NPH and glargine), six patients were on long- and short-acting insulins (regular insulin and lispro), and two patients were on insulin lispro alone (Table 1). Diagnosis of CF had been confirmed by a pathological sweat chloride test and genetic testing in all patients. Four patients had undergone lung transplantation 1–8 yr before the study. Immunosuppression consisted of cyclosporine, mycophenolic mofetil, and 5 mg prednisone per day. During the study, two patients used the equivalent of more than 5 mg oral prednisone per day for allergic bronchopulmonary aspergillosis.
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Study design
All subjects were screened by a medical history and physical examination, and physical activity was assessed using a validated questionnaire (10).
In CF patients, the number of iv antibiotic treatment courses per year in the preceding 3 yr and cumulative glucocorticoid intake were assessed by questionnaire and verified by the medical records.
Body composition and regional fat distribution were measured by a dual x-ray absorptiometry using an Expert densitometer (Lunar, Madison, WI) (11, 12).
Routine pulmonary function tests were performed outside a clinical exacerbation within 3 months of the visit. The severity of lung disease was classified according to the values of the forced expiratory 1 sec volume as percent of predicted (FeV1). We thereby used the Global Initiative for Chronic Obstructive Lung Disease criteria that range from 1 (mild obstructive lung disease, FeV1 > 80%) to 4 (very severe obstructive lung disease, FeV1 < 30% of predicted) (13).
On the study day, morning blood samples were drawn in CF patients and healthy controls after an overnight fast. Women without hormonal therapy were studied in their early follicular phase and women taking hormonal therapy in the first part of their menstrual cycle.
The study was approved by the local ethical committee in Basel, Switzerland, and all subjects signed and received a copy of a written informed consent form.
Assays
Blood was immediately centrifuged, and serum was divided into 1-ml aliquots and stored at –70 C until batch analyzed for estradiol, testosterone, SHBG, TNF
, highly sensitive C-reactive protein (hs-CRP), glucose, insulin, IGF-I, and adiponectin as well as a blood count and routine chemistry. The characteristics of the specific assays and the calculation of the homeostasis model assessment (HOMA-IR) scores have been previously described (12).
IGF-I was measured by a chemiluminescence enzyme immunoassay (Diagnostic Products Corp., Los Angeles, CA) and adiponectin by an ELISA (R&D Systems, Minneapolis, MN). At the lower reference range, the intraassay coefficient of variation was 2.5%, and the interassay coefficient of variation 6.8%. Samples for each subject were run in the same assay.
Statistical analysis
Data are shown as means ± SD for normally distributed variables and as median and interquartile ranges for not normally distributed variables, respectively. Variables with a skewed distribution were log transformed for all analyses. Characteristics of patients with CF and their paired healthy controls were compared by t tests. We tested the independent association of lean body mass or hs-CRP concentrations with lung function in multiple ordinal regression analysis. P < 0.05 was considered statistically significant. Statistical analyses were done by Statistica for Windows (version 6; StatSoft Inc., Tulsa OK) or Intercooled STATA (version 8; StataCorp LP, College Station, TX).
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Results |
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Characteristics of patients with CF and healthy controls are shown in Tables 1–3
. Despite similar BMI, patients with CF were lighter and shorter, compared with controls. Percent body fat and percent lean mass were similar in patients and controls, but patients had a more central fat distribution, either expressed as the trunk to extremity fat ratio or as waist to hip ratio when compared with controls (Table 3). CF patients had higher serum concentrations of hs-CRP, compared with controls (Table 2 and Fig. 1).
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Compared with controls, patients with CF had higher adiponectin serum concentrations (Table 2 and Fig. 1). Eliminating the two outliers with high adiponectin levels did not alter this difference (P = 0.04). It was also independent of other factors known to influence adiponectin levels (effect of CF status on adiponectin levels: beta coefficient 4.84, 95% confidence interval 1.08–8.60, P = 0.01 after adjusting for sex, BMI, trunk to extremity fat ratio, HOMA-IR, serum concentrations of SHBG, TNF-, hs-CRP, IGF-I, and estradiol). Independent of CF status and sex, adiponectin levels were inversely correlated to the serum concentrations of albumin (r = –0.56, P < 0.0001) and hs-CRP (r = –0.28, P = 0.06).
Association of lung function with lean body mass or hs-CRP serum concentrations in patients with CF
Decreased lean body mass was associated with decreased lung function (as assessed by the Global Initiative for Chronic Obstructive Lung Disease criteria), independent of sex and BMI (odds ratio OR 0.85, 95% confidence interval 0.71–1.01, P = 0.06).
Increased hs-CRP serum concentrations during clinical stability was associated with decreased lung function, independent of sex and BMI (odds ratio 28, 95% confidence interval 3.2–242, P = 0.003). Both decreased lean body mass and increased hs-CRP concentrations correlated significantly with poor lung function, independent of sex and the number of iv antibiotic treatment courses/year, sex and total physical activity, or sex and the total cumulative steroid dose (all P 
0.03 and all P 0.003, respectively; data not shown).
Adjustments for heterogeneity of the CF population
Diabetes, lung transplantation, and use of glucocorticoids or immunosuppressive drugs can affect some of the main parameters that were measured. However, eliminating either the four patients who had undergone lung transplantation or the two patients taking more than 5 mg prednisone per day did not change the observed differences in trunk to extremity fat ratio, adiponectin or hs-CRP serum concentrations between CF patients and controls. In addition, trunk to extremity fat ratio, adiponectin, or hs-CRP serum concentrations were not different between the CF patients with and those without exocrine (all P 
0.25) or endocrine (all P 0.15) pancreatic insufficiency.
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Discussion |
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Previous studies have suggested that, compared with healthy controls, patients with CF have a reduced lean body mass (1, 2), which is an important predictor for disease morbidity and possibly mortality in this patient population (2, 3, 14, 15, 16). Unfortunately, the control groups in these studies were not matched for BMI or weight. In our study, the percent lean body mass, i.e. lean body mass in percentage for weight, was similar in CF patients, compared with healthy controls.
Both increased serum concentrations of hs-CRP, measured during clinical and laboratory stability, and decreased absolute lean body mass correlated with decreased FeV1 in our CF patients, independently of other factors known to be associated with disease severity. This close association could point to an independent role of inflammatory markers or absolute lean body mass in the prognosis of these patients.
Low-grade chronic inflammation in obese subjects is closely linked to increased total fat, central fat accumulation, and insulin resistance (6). We showed that underweight and normal-weight patients with CF have increased central fat accumulation, compared with controls. This could be due to chronic inflammation but also to other factors related to CF like corticosteroid therapy, physical inactivity, or possibly to a decrease in anabolic hormones, namely hypogonadism or relative GH deficiency.
Because central fat correlates to insulin resistance, one would expect CF patients to be more insulin resistant. However, it is debated whether insulin resistance is generally increased in these patients (17). In our study, insulin resistance, as measured by HOMA-IR or SHBG, did not differ between patients and controls.
Adiponectin is thought to be a candidate for adipose tissue signaling and a marker of insulin sensitivity (7). Thus, serum levels of adiponectin are usually decreased in insulin-resistant and inflammatory states. Because adiponectin increases in response to a short-term food restriction or high-intensity exercise training (8, 9), increased adiponectin concentrations could also be a marker of energy deficiency. For example, serum levels of adiponectin are elevated in patients with anorexia nervosa (18, 19). In CF, chronic energy deficiency is often prevalent (20), explaining presumably the present adiponectin findings in CF. We also found that adiponectin serum concentrations were inversely correlated to the serum concentrations of albumin, a marker of protein malnutrition.
Because we included almost all adult CF patients treated in a clearly defined region, the data should be representative. However, the study is limited by its small sample size and its cross-sectional design as well as the fact that CF patients have an inherent wide range of disease severity, making it per se a heterogeneous population. We therefore adjusted the data for multiple possible confounders.
In summary, we found that in stable adult CF patients, central fat accumulation is increased, compared with healthy controls. We also observed that serum levels of adiponectin were increased in CF patients, possibly related to their state of chronic energy deficit. This could explain in turn the preservation of insulin sensitivity in these patients despite the increase in central fat distribution and hs-CRP serum concentrations. This energy deficiency-adiponectin-insulin sensitivity cycle could serve to prevent further deterioration of protein catabolism and deleterious loss of lean body mass in these subjects prone to malnutrition.
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Acknowledgments |
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Footnotes |
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This abstract was presented at the 87th Annual Meeting of The Endocrine Society, San Diego, CA, June 2005 (Abstract P2-387).
None of the authors has any potential conflicts of interest.
First Published Online February 7, 2006
Abbreviations: BMI, Body mass index; CF, cystic fibrosis; FeV1, forced expiratory 1 sec volume as percent of predicted; HOMA-IR, homeostasis model assessment; hs-CRP, highly sensitive C-reactive protein.
Received September 26, 2005.
Accepted January 30, 2006.
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References |
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