Lack of circulating bioactive and immunoreactive IGF-I changes despite improved fitness in chronic kidney disease patients following 48 weeks of physical training

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Abstract

Objective

As known abnormalities exist in the insulin-like growth factor (IGF) system in chronic kidney disease (CKD) patients, the measurement of bioactive IGF-I may provide further insight into the therapeutic potential of long-term exercise training.

Design

Patients (N = 21) with stages 3 and 4 CKD were recruited from a local nephrology practice in Springfield, MA and randomized into matched treatment and control groups. The treatment group participated in 48 weeks of supervised, progressive exercise training and dietary counseling, while the control group received only usual care. Treadmill testing, anthropometric measurements, and blood samples for analysis of immunoreactive IGF-I, IGF-II, IGFBP-1 and -2, and bioactive IGF-I were taken at baseline, 24 weeks, and 48 weeks.

Results

There were no significant differences in any of the components of the IGF system (all p-values > 0.05). Immunoreactive IGF-I levels correlated significantly with bioactive IGF-I at baseline (r = 0.50, p = 0.02) and at 48 weeks (r = 0.64, p = 0.01). There was a significant interaction between group and time for both V̇O2peak (p = 0.03) and total treadmill time (TT) (p < 0.01).

Conclusions

Despite improvements in physical performance, a 48-week training program did not affect any of the circulating IGF system measurements. Disparities between these findings and those of other researchers reporting a biphasic response to long-term training may be explained by differences in study groups and exercise programs.

Introduction

The insulin-like growth factor (IGF) system involves IGF-I and six binding proteins that interact with IGF-I to either increase or decrease its bioavailability, thus determining the ability of IGF-I to interact with the IGF-I receptor (IGF-IR) on the cell membranes of target tissues. Of the total circulating IGF-I, ~ 75% is bound in a 150 kDa complex composed of IGF-I, IGFBP-3, and acid labile subunit (ALS), while 20 to 25% is bound in smaller 35 kDa binary complexes, and the remainder (~ 1–2%) is in a free form [1], [2], [3], [4]. When IGF binds to the IGF-IR, a conformational change is induced that stimulates the intracellular kinase domain of the receptor. As a result, tyrosine residues are phosphorylated and the intracellular signal cascade is initiated [5], [6], [7]. The receptor activation may be quantified by an IGF-I bioassay, termed a kinase receptor activation (KIRA) assay, which assesses the ability of serum to activate the receptor in cultured cells at physiological conditions by measuring the phosphorylation of tyrosine residues on the activated receptor [1].

The assessment of bioactive IGF-I is relevant for individuals with chronic kidney disease (CKD) because of the known abnormalities associated with the growth hormone (GH)-IGF-I axis in this patient population [2], [8]. Elevated GH and a concomitant resistance to GH action have been reported in individuals with kidney disease [3]. As IGF-I is known to have anabolic and mitogenic effects [9], reduced bioavailability of IGF-I may be related to impaired muscle protein synthesis and muscle wasting in this population [10]. Interestingly, immunoreactive IGF-I levels have been reported to be in the normal range, while free and bioavailable IGF-I have been reported to be reduced in these individuals [2], [3], [8], [11], [12]. Diminished levels of free and bioactive IGF-I in patients with CKD have been attributed to increased circulating levels of IGFBPs due to reduced clearance with impaired kidney function [2], [8].

Progressive exercise training has been prescribed for individuals with kidney disease in hopes of attenuating or ameliorating the muscle wasting and impaired physical function associated with the condition [13]. The benefits of exercise training may be mediated via alterations and improvements in the IGF system. However, the response of circulating IGF-I to exercise training appears to be variable [9]. As an explanation some studies have suggested that circulating IGF-I exhibits a biphasic response to exercise [4], [14]. Thus in some studies, circulating levels of IGF-I have been reported to decrease following short term exercise training programs, and to increase following longer term programs (> 12 weeks) [12], [14]. It appears, however, counter-intuitively that short-term exercise reduces circulating IGF-I levels and at the same time improves muscular strength, aerobic fitness, and muscle volume. The measurement of bioactive IGF-I using the KIRA method may provide further insight into the response of the IGF-I system to chronic exercise training in CKD patients. Measurement of bioactive IGF-I provides information regarding the interaction between IGF-I and IGFBPs that determines its ability to interact with the IGF-IR. Thus, the purpose of the present study was to assess changes in total IGF-I, IGFBPs, and bioactive IGF-I, as determined by the KIRA method, in stages 3 and 4 CKD patients following a 48-week supervised, progressive physical training program.

Section snippets

Subjects

Patients were recruited and enrolled in the study by physicians and staff at a local nephrology practice based on eligibility criteria, which included being in stage 2 to 4 of the disease (i.e. glomerular filtration rate (GFR) of 0.25 to 1.5 mL s 1 1.73 m 2) and taking angiotensin converting enzyme (ACE) inhibitors or angiotensin-receptor blockers. No patient had been participating in a physical training program prior to study commencement. Patients were excluded if they had any contraindications

Results

Baseline clinical and demographic characteristics of the treatment and control groups are presented in Table 1, Table 2. There were no significant differences between treatment and control group for age (p = 0.32), GFR (p = 0.23), or serum creatinine (p = 0.9) at baseline. The average endurance exercise session attendance for the entire 48 weeks was 79.4 ± 16.0% for the treatment group. Energy expenditure during aerobic exercise training sessions was approximately 504.6 ± 352.4 kcal/week at baseline, and

Discussion

The major finding of the present study was that 48 weeks of regular physical exercise training did not result in significant changes in immunoreactive IGF-I, IGF-II, bioactive IGF-I, IGFBP-1, or IGFBP-2 concentrations in stages 3 and 4 CKD patients. Total circulating IGF-I levels correlated positively with measurements of bioactive IGF-I both before and after the 48 week intervention. Despite any significant changes in the IGF-I system, improvements in physical performance measurements were

Acknowledgements

We would like to acknowledge the effort and commitment of the subjects who participated in the study, the student trainers who supervised the training sessions, and the staff at the Springfield College Wellness Center and at Western New England Renal and Transplant Associates (WNERTA) for their accommodation and assistance. We would like to thank Mrs. Lone Kvist, Elsebeth Horneman, Kirsten Nyborg, and Susanne Sørensen for skilled laboratory measurements with the IGF-measurements. This study was

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