Elsevier

Metabolism

Volume 59, Issue 11, November 2010, Pages 1656-1662
Metabolism

Serum fibroblast growth factor–21 concentration is associated with residual renal function and insulin resistance in end-stage renal disease patients receiving long-term peritoneal dialysis

https://doi.org/10.1016/j.metabol.2010.03.018Get rights and content

Abstract

Fibroblast growth factor–21 (FGF-21) is a new metabolic regulator, which is related to antiobesity and insulin sensitivity in vivo. However, the clinical implication of FGF-21 is poorly understood. To investigate whether FGF-21 may play a role as a metabolic regulator in patients with end-stage renal disease, we measured serum concentrations of FGF-21, inflammatory markers, and metabolic parameters in healthy people (n = 63) and nondiabetic patients receiving peritoneal dialysis (PD, n = 72). The patients were treated with angiotensin receptor blocker for 6 months, and the changes in FGF-21 concentration and metabolic parameters were assessed. Compared with controls, serum FGF-21 concentration was 8 times higher in patients undergoing PD (754.2 ± 463.5 vs 86.9 ± 60.2 pg/mL, P < .001). In controls, only lipid parameters correlated positively with FGF-21 concentration. In contrast, inflammatory markers (interleukin-6, fibrinogen, high-sensitivity C-reactive protein) and homeostasis model assessment of insulin resistance (HOMA-IR) correlated positively and residual renal function correlated inversely with serum FGF-21 concentration in PD patients. In a multivariate analysis adjusting these factors, residual renal function, HOMA-IR, and fibrinogen concentration were independent determinants of serum FGF-21 concentration. After 6-month angiotensin receptor blocker treatment, serum FGF-21 concentration declined significantly by 13% and HOMA-IR and inflammatory markers improved in PD patients. These findings suggest that FGF-21 may play a role in insulin resistance in patients with end-stage renal disease.

Introduction

Patients with end-stage renal disease (ESRD) show insulin resistance [1]. Insulin resistance is significantly associated with the progression of atherosclerosis and may predict cardiovascular mortality in this population [2]. High glucose exposure exerts detrimental effects on the peritoneal membrane in patients treated with peritoneal dialysis (PD), and a substantial amount of glucose is absorbed via the peritoneal capillary vessels. This may further aggravate insulin resistance in PD patients, although they are not classified as having diabetes [3].

Fibroblast growth factors (FGFs) are classified into 7 families and are involved in a variety of cellular functions including cell survival, differentiation, mitosis, and angiogenesis. The FGF-19 families (FGF-19, FGF-21, and FGF-23) function as metabolic regulators of glucose metabolism and mineral homeostasis. Fibroblast growth factor–21 is produced in the liver but acts mainly on white adipose tissue because of its receptor specificity for FGF receptors [4]. However, several studies suggest that FGF-21 could be expressed in pancreas, skeletal muscle, and various cells [5], [6]. Recent studies show that FGF-21 increases glucose uptake in adipose tissue, ameliorates diet-induced obesity, and regulates hepatic lipid metabolism in ketotic states by activating peroxisome proliferator-activated receptor–α[7], [8], [9], [10], [11]. Human studies [12], [13], [14] show a potential relationship between FGF-21 level and obesity. However, more studies are needed to clarify the clinical role of FGF-21 in humans.

It is not understood clearly whether serum FGF-21 contributes to the detrimental metabolic status in patients with chronic kidney disease. Only one report has shown that serum FGF-21 concentration correlates with renal function and is elevated markedly in patients receiving hemodialysis, suggesting a possible link between FGF-21 concentration and its renal excretion [15]. Given the potential effects of FGF-21 as an endocrine factor involved in the regulation of glucose homeostasis [8], [9], [10], [13], we hypothesized that this circulating protein plays a role in insulin resistance in nondiabetic, ESRD patients receiving PD. However, the relationship between serum FGF-21 concentration and insulin resistance has not been explored in patients receiving PD. We performed this study to identify which factors are associated with FGF-21 concentration and to elucidate whether FGF-21 plays a role in insulin resistance in nondiabetic ESRD patients undergoing PD.

Section snippets

Study subjects and data collection

The study included 156 regular PD patients at the dialysis clinic of Yonsei University Medical Center, Seoul, Korea, between 2006 and 2007. Because we aimed to investigate the metabolic effects of FGF-21 in ESRD patients who exhibited insulin resistance induced by uremia per se, 55 patients with diabetes were excluded from our study. Patients younger than 18 years or who had been maintained on PD for less than 3 months were also excluded. Patients were considered eligible for this study if they

Comparison of demographic and clinical parameters between healthy subjects and nondiabetic patients undergoing PD

Baseline characteristics of the 72 PD patients and 63 healthy controls with normal renal function were presented in Table 1. Age and sex were well matched between the 2 groups. Among the patients treated with PD, chronic glomerulonephritis was the most common cause of ESRD (48.6%), followed by hypertension (26.4%); and only 5 patients (6.9%) had previous CVD. The PD patients had higher mean systolic BP (132.8 ± 19.8 vs 114.1 ± 12.9 mm Hg, P < .001) and diastolic BP (80.5 ± 9.7 vs 70.0 ± 10.8 mm

Discussion

Although several human studies have investigated the clinical significance of FGF-21 [13], [14], [15], the clinical role of FGF-21 is understood incompletely; and it would be of great value to elucidate the function of this new metabolic regulator in humans. In the present study, we investigated (1) the relationship between metabolic parameters and serum FGF-21 concentrations in people with normal and impaired renal function, (2) whether FGF-21 concentration is related to residual renal

Acknowledgment

This work was supported by grants from the Seoul R&BD program to Choi SH, Republic of Korea (10526).

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    1

    Han SH and Choi SH contributed equally to this work.

    2

    Co-corresponding author.

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