Poor growth and low body weight occur frequently in children with cystic fibrosis (CF). In the United States, 13% of children and 22% of adults with CF are less than 85% of ideal body weight (1). Malnutrition adversely affects survival and is prevalent among patients with CF who have deteriorating pulmonary function (2,3). Short-term weight gain and enhanced nitrogen deposition occur if nutritionally compromised children with CF receive enteral nutritional supplementation (4–7). Several studies indicate that nutritional supplementation decreases the rate of deterioration of pulmonary function (5,7–9). However, the positive effect of nutritional repletion on pulmonary function has not been consistently observed, and intensive nutritional supplementation has not resulted in sustained improvement (10). These discordant observations may reflect, in part, intrasubject variability, limited sensitivity of pulmonary function tests, or the variable rate of progression of lung disease in children with CF (11). Nevertheless, nutritional supplementation is indicated in undernourished children with CF who do not respond to optimization of pancreatic enzyme replacement therapy and aggressive pulmonary therapy (11).
Patients with CF frequently manifest hormonal abnormalities that may contribute to malnutrition, including decreased insulin release, decreased insulin sensitivity, and low circulating concentrations of insulinlike growth factor 1 (IGF-1). IGF-1 levels correlate with height standard deviation score, body mass index, and Shwachman score, a clinical measure of disease activity (12). On the basis of observations demonstrating the anabolic properties of growth hormone (GH) and IGF-1 and the demonstrated benefits of nutritional repletion in CF, it is clinically relevant to learn whether treatment with growth-promoting peptides improves nutritional status and growth in children with CF. The studies to date on the effect of growth-promoting peptides in children with CF have focused on the use of GH and have found that growth rate is increased with GH treatment (13–15). However, GH causes hyperglycemia, and, hence, its efficacy as an anabolic agent in children with CF may be limited. Moreover, children with CF may have relative insensitivity to GH (16,17). In contrast to GH, treatment with IGF-1 increases nitrogen retention without causing hyperglycemia (18–20).
Because IGF-1 has insulinlike effects in terms of carbohydrate metabolism and is growth promoting, we hypothesized that treatment with IGF-1 would increase linear growth rate and increase the glucose/insulin ratio, an indirect index of insulin sensitivity in children with CF. The principal aim of this study was to determine whether administration of rhIGF-1 improved growth in children with CF. To accomplish our goal, we performed a double-blind crossover study of seven prepubertal children with CF who had decreased body mass index.
MATERIALS AND METHODS
Prepubertal children with CF who had body mass index less than the 25th percentile were eligible for participation in the study (21). The diagnosis of CF was suspected by the presence of one or more typical clinical features or positive family history and established by elevated sweat chloride concentration or confirmed by genotype analysis (22). We excluded children with insulin-dependent diabetes mellitus, severe pulmonary disease defined by forced expiratory volume at 1 second (FEV 1 ) less than 30% of predicted, or more than two exacerbations of pulmonary disease requiring hospitalization in the year before entry. We also excluded those patients with severe hepatobiliary disease defined by clinical signs of portal hypertension, hyperbilirubinemia, synthetic dysfunction, or hepatic encephalopathy. Patients colonized with Pseudomonas cepacia were excluded from entry because of its significant negative impact on longevity and pulmonary function. The Institutional Review Board of the Children's Hospital Medical Center in Cincinnati, Ohio, approved the study. Informed consent was obtained from the study participants and their parents.
We performed a randomized double-blind crossover study. The study was divided into four phases of 6 months each. Phase 1 and phase 3 were for observation and to eliminate residual drug effects. Subjects received treatment with placebo or 80 μg/kg IGF given by subcutaneous injection twice daily in phase 2 and the alternate therapy in phase 4. We chose to treat subjects with 80 μg/kg IGF twice daily, because this dose promotes linear growth in patients with GH insensitivity syndrome and is tolerated by children with liver disease and children with GH insensitivity syndrome (23,24). Genentech (South San Francisco, CA) provided recombinant human IGF-1. Of note, we were not able to enroll additional subjects in this study, because there was unanticipated decrease in availability of IGF-1. During the second and fourth phases, patients and parents/guardians performed home blood glucose monitoring before breakfast, supper, and bedtime using glucose oxidase strips and an Accuchek III meter. Parents were instructed to call the investigators for readings less than 40 or greater than 200 mg/dL or for symptoms of hypoglycemia. Compliance was assessed by physical evidence of injection. In addition, patients and/or their parents maintained written records of injections and blood glucose levels during the second and fourth phases. Used and unused vials containing placebo and rhIGF-1 were returned and counted.
The primary outcome measure was linear growth rate. Secondary outcome measures were changes in body mass index, body composition determined by dual energy x-ray absorptiometry, FEV 1 , and the blood glucose/insulin ratio. At baseline and every 3 months until completion of the study, the principal investigator (JB) and the study coordinators (MPA, SK) reviewed the interim history, assessed compliance, identified adverse events, and performed a physical examination. Pubertal stage was documented at each visit. We measured height and weight at baseline and every 3 months and body composition, FEV 1 , and blood glucose and insulin levels every 6 months. Patients in phase 2 or 4 continued to receive IGF-1 or placebo during assessment of the outcome measures. A 3-day prospective dietary record was obtained at baseline and every 6 months. Resting energy expenditure was determined using a Sensormedics Deltatrac Cart (Yorba Linda, Ca) after an overnight fast and sleep to avoid intrasubject variability associated with physical activity and eating. The measurements were collected every 5 to 10 minutes until a steady state period was achieved.
Pharmacokinetics of IGF-1 Clearance
Serum IGF-1 levels were measured at baseline and 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours after subcutaneous administration of IGF-1, 80 μg/kg. After determination of the elimination rate constant, we corrected each concentration for sampling time in the dosage interval and reduced the analysis to a `single-dose' profile. By use of noncompartmental methods, the clearance and volume of distribution were estimated, assuming that bioavailability was 100% after subcutaneous dosing. The IGF-1 concentration time data were subjected to curve fitting, and pharmacokinetic parameters were determined.
Assessment of Outcome Measures
A stadiometer was used to measure height to the nearest 0.1 cm. Height was measured by one of two trained observers (SK, MA) and was determined from the mean of three separate measurements. Weight was measured to the nearest 0.1 kg. Body mass index was determined from the weight measured in kilograms ÷ (height measured in meters 2 ). Linear growth velocity was determined from interval height measurements over the 6-month treatment phases. Changes in percentage body fat and fat-free mass were determined using dual energy x-ray absorptiometry. We measured FEV 1 and expressed the result as a percentage of predicted value for age, gender, and height. To assess glucose tolerance, we collected blood to measure fasting blood insulin and glucose levels. We then administered a standard glucose load (1.75 g/kg) and collected 2-hour postprandial glucose and insulin levels. A research dietitian used the University of Minnesota Nutrition Data System to estimate energy and protein intakes. Complications and adverse events were recorded.
Measurement of Serum Levels of IGF-1 and IGF Binding Protein-3 (IGFBP3)
A double-antibody radioimmunoassay method was used to measure serum IGF-1 concentrations as previously described (25,26). The intraassay coefficient of variation (CV) was less than 7% and interassay CV was 10%. Serum IGF-BP3 level was measured by radioimmunoassay using a commercial kit (Diagnostic Systems Laboratories, Webster, TX).
Measurement of Blood Glucose and Serum Insulin Levels
Blood glucose determinations were performed using a Yellow Springs Instrument glucose analyzer. The intraassay CV was 1.2% and the interassay CV was 1.4%. A double-antibody radioimmunoassay using porcine insulin for labeling and standards and a guinea pig antiporcine insulin antibody was used to measure serum insulin concentrations (25). The intraassay CV was 5% and interassay CV was 7%.
Descriptive statistics were used to describe the study population and Student's paired t test to compare the differences between groups. Significance was defined as a P value less than 0.05.
The mean height z score at baseline was −1.5 ± 0.8 (Table 1). At entry, all patients had a body mass index less than the 25th percentile for age and gender, and three of seven patients had a body mass index less than the 5th percentile. At baseline, two patients had fasting blood glucose concentrations that were greater than 100. The mean calorie and protein intakes were 113% and 178% of the recommended daily allowance for age.
Serum IGF-1 levels were low, three of the seven subjects had baseline IGF-1 levels that were outside the 95% confidence intervals for age- and gender-matched controls (Table 2). With treatment, mean serum IGF-1 levels increased more than twofold. The T 1/2 for IGF-1 was 10.3 hours. The volume of distribution of IGF-1 was 0.24 L/kg, and clearance of the peptide was 0.30 mL/min/kg. Serum IGFBP3 concentrations were not decreased at baseline compared with normal subjects and did not change with IGF-1 treatment.
Effect of IGF-1 Treatment on Linear Growth Rate and Weight Gain and on Pulmonary Function
We observed no difference in linear growth rate or weight gain during treatment with IGF-1 compared with placebo (Table 3). Because growth is a dynamic process, we also compared the change of height z score. The rate of change of height z score was similar between IGF-1 and placebo treatment phases. The rate of change of lean body mass paralleled that of weight gain and was not different between the two phases. Body mass index at the end of treatment with IGF-1 was similar to that determined at the end of treatment with placebo (16.1 ± 1.2 vs. 16.0 ± 1.4). Attempts to assess dietary intake were unsuccessful, because the dietary records were incomplete. Resting energy expenditure was similar during treatment with IGF-1 compared with placebo (1457 ± 170 vs.1414 ± 98, not significant). The mean FEV 1 for the group was similar after treatment with IGF-1 compared with placebo (Table 4).
Effect of IGF-1 Treatment on Blood Glucose and Serum Insulin
Fasting serum insulin levels were lower when subjects were treated with IGF-1 compared with placebo (Table 5). The differences were more marked when serum insulin levels were compared 2 hours after a standard oral glucose load. When subjects were treated with IGF-1, mean serum insulin levels were 40% lower than during the placebo treatment period. There were no significant differences in fasting and 2-hour blood glucose concentrations during the IGF-1 compared with placebo treatment periods. In contrast, the glucose/insulin ratio, an indirect index of insulin sensitivity, increased with IGF-1 treatment compared with placebo (7.4 ± 5.1 vs 3.6 ± 1.9, P < 0.02).
Complications and Adverse Events
No subject had symptomatic or biochemical hypoglycemia during the study, and patients did not have ketosis develop with intercurrent illnesses. There were no significant differences in the number of illnesses or hospitalizations between the baseline observation period and the placebo or IGF-1 intervention periods.
We performed a double-blind crossover study to assess the effect of treatment with recombinant human IGF-1 on prepubertal children with CF. Linear growth rate and weight gain did not increase with IGF-1 treatment. However, we found that basal and stimulated insulin levels decreased.
The IGF-1 levels were low at baseline as previously described for children with CF (12,17,27,28). Moreover, with treatment we were able to achieve IGF-1 levels that were in the normal range. The half-life for IGF-1 in our subjects was similar to that observed for normal controls in phase 1 studies (29,30). In contrast, the half-life was greater than that for children with growth hormone insensitivity syndrome because of absent GH receptors. The differences between the half-life for children with CF compared with children with GH insensitivity syndrome are likely due to IGF-BP3 levels. IGF-BP3 levels were within the normal range for our subjects. IGF-BP3 is the principal carrier for circulating IGF-1 and protects IGF-1 from degradation (31).
Linear growth rate did not increase when our subjects were treated with IGF-1. The findings contrast with three previous studies examining the effect of GH therapy on linear growth in children with CF. In these three open-labeled studies, prepubertal patients with CF were treated with GH for 1 to 2 years. The investigators reported that GH treatment increased linear growth rate, height standard deviation scores, and IGF-1 levels. (13–15). Multiple explanations exist for the discrepancies. Our study design differed from those previously reported, because we performed a double-blinded study. In contrast, in the previously reported studies all patients received open-label GH. Moreover, the changes in growth rate were modest, and variation in growth rate might have reflected changes in disease activity. Each of the previous studies and our study examined less than 25 patients. Consequently, the power of the studies was low. The power of this study to detect a 1.5-fold increase in linear growth rate compared with baseline was 0.4 and the power to detect a twofold increase in linear growth rate was 0.8. We treated patients for only 6 months, and, consequently, disease exacerbation, limited exposure to rhIGF-1, or the inherent variability in linear growth rate might have masked a growth-promoting effect of IGF-1. The differences between GH and IGF-1 treatment might also reflect the biology of the peptide hormones. Although most of the growth-promoting effects of GH are mediated through IGF-1, GH has biologic effects that occur independently of IGF-1. For example, GH enhances production of IGF-BP3 (32,33). In contrast, with IGF-1 therapy, GH secretion is inhibited, and IGF-BP3 production might decrease, which might decrease the half-life of IGF-1 (31). Finally, we attempted to assess dietary intake, but the dietary records were incomplete. Consequently, we cannot comment on the effect of IGF-1 when given with nutritional supplementation. Moreover, inadequate nutrient intake during the study period may have limited the response to treatment with IGF-1.
Despite our observations that linear growth rate did not increase with IGF-1 treatment, we did observe a consistent biologic effect of treatment with IGF-1. In this study, we found that the glucose/insulin ratio increased during treatment with IGF-1. Because our patients continued to receive IGF-1 or placebo during the measurement of glucose and insulin levels, we cannot exclude the possibility that decreased insulin requirements were the result of the hypoglycemic properties of IGF-1. However, our findings were similar to observations in healthy volunteers in whom IGF-1 improved insulin sensitivity (34,35). Further studies that directly measure insulin sensitivity are needed to determine whether IGF-1 treatment alters insulin sensitivity. Our findings may be of clinical significance, because diabetes is prevalent in patients with CF (36). Approximately 20% of patients older than 18 years have glucose intolerance or diabetes (1). Impaired glucose tolerance and secondary diabetes are associated with clinical deterioration and decreased survival rate (37). Patients with CF who have diabetes develop have decreased insulin production and insulin resistance (37–40). Baseline and postprandial hepatic glucose production are increased, indicating hepatic resistance to insulin (41).
In summary, we performed a double-blind crossover study to determine the effect of IGF-1 on seven prepubertal patients with CF. We found that treatment with IGF-1 for 6 months did not promote linear growth. However, longer duration of treatment and a much larger sample size will be necessary to provide sufficient power to make certain that IGF-1 does not promote linear growth. The glucose/insulin ratio was increased with IGF-1 treatment, suggesting increased insulin sensitivity, perhaps prompting future studies designed to determine whether IGF-1 can serve as adjunctive therapy for patients with CF and glucose intolerance.
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