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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 9 2832-2835
Copyright © 1997 by The Endocrine Society

Original Studies

Impaired Postprandial Regulation of Insulin-Like Growth Factor Binding Protein-1 in Children with Chronic Renal Failure

Dieter Haffner, Werner F. Blum, Udo Heinrich, Otto Mehls and Burkhard Tönshoff

Divisions of Pediatric Nephrology (D.H., O.M., B.T.), and Pediatric Endocrinology (U.H.), University Children’s Hospital, Heidelberg;University Children’s Hospital Gießen (W.F.B.),Gießen, Germany

Address correspondence and requests for reprints to: Burkhard Tönshoff, M.D., Division of Pediatric Nephrology, University Children’s Hospital, Im Neuenheimer Feld 150, 69120 Heidelberg, Germany.E-Mail: Burkhard–Toenshoff@krzmail.krz.uni-heidelberg.de.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Patients with chronic renal failure (CRF) have elevated plasma levels of insulin-like growth factor-1 (IGFBP-1). We sought to determine the dynamics of plasma IGFBP-1 in response to an endogenous insulin pulse during an oral glucose tolerance test (oGTT) in 12 prepubertal children with advanced CRF [glomerular filtration rate (GFR) 12.5 ± 4 mL/min/1.73 m2] and in 9 age-, gender-, and body size-matched controls with normal renal function. Glucose and insulin responses to oGTT were significantly elevated in CRF (P < 0.01), indicating decreased sensitivity to the hypoglycemic action of insulin. Fasting plasma IGFBP-1 levels in CRF (235 ± 40 ng/mL) were 2.5-fold increased compared with controls (94 ± 11.6 ng/mL, P < 0.0001). In controls, plasma IGFBP-1 levels rapidly decreased with time by 52%, to a level of 45 ± 6.7 ng/mL 180 min after the oral glucose load. In contrast, plasma IGFBP-1 levels in CRF patients slowly decreased with time by 25%, to a level of 176 ± 28 ng/mL (P < 0.001 vs. controls) 180 min after the oral glucose load. For the group as a whole, the percent decrease in IGFBP-1 at 180 min was positively correlated with GFR (r = 0.85, P < 0.0001). Plasma GH concentrations were not statistically different at baseline, but showed a paradoxical increase in CRF patients thereafter. Plasma IGF-I concentrations at baseline were comparable in CRF patients and controls and similarly decreased by about 10% (P < 0.01) after the oral glucose load. In summary, our study shows that the decline of plasma IGFBP-1 in response to an oral glucose load is impaired in children with CRF despite increased insulin levels. This impaired postprandial decline of plasma IGFBP-1 might interfere with glucose homeostasis by blocking insulin-like activity of free IGFs in vivo and thereby contribute to glucose intolerance in uremia.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
INSULIN-LIKE growth factor binding proteins (IGFBP) are a group of six structurally related proteins that specifically bind insulin-like growth factors I and II (IGF-I and -II) and modulate their anabolic and insulin-like effects. IGFBP-1 is a 28 kDa nonglycosylated protein that is primarily produced by liver and female reproductive tissue (1). IGFBP-1 is regulated acutely in a manner similar to known glucose counterregulatory hormones with substantially fluctuating diurnal plasma levels. Insulin appears to be the principal suppressive regulator of hepatic IGFBP-1 production mainly at the level of hepatic transcription (2). In various clinical studies, circulating IGFBP-1 levels were inversely correlated with insulin, with elevated levels in insulin-dependent diabetes mellitus and decreased levels in the immediate postprandial period (3, 4, 5).

Because of its high turnover rate IGFBP-1 probably accounts for most of the unsaturated IGF-binding activity in normal adult plasma (1). There is strong evidence from both in vivo and in vitro studies that IGFBP-1 is a potent inhibitor of IGF action (6, 7). That seems to be particularly relevant for its regulatory role in carbohydrate metabolism (7, 8).

IGFBP-1 plasma concentrations are markedly elevated in children with chronic renal failure (CRF) in relation to the degree of renal dysfunction (9, 10, 11, 12). Increased IGFBP-1 levels contribute to the increased IGF inhibitory activity in uremic plasma, which is thought to play a pathogenic role for catabolism and growth failure in children with CRF (13, 14). The question arises if the insulin-mediated postprandial suppression of IGFBP-1 is preserved in CRF in view of the decreased sensitivity to the action of insulin in uremia (15). We therefore investigated the response of plasma IGFBP-1 concentrations to an endogenous insulin pulse in children with CRF and age- and gender-matched controls by use of oral glucose tolerance tests (oGTT) mimicking postprandial conditions.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients and controls

Twelve prepubertal children with CRF were examined. Patient characteristics are listed in Table 1Go. All patients were growth-retarded. Adequate spontaneous energy and caloric intake was monitored in all subjects by written dietary diaries. As a consequence of this close dietary supervision, patients were in a good nutritional status, as indicated by serum albumin levels of more than 35 g/L. Moreover, the body mass index (BMI) was normal in all patients (Table 1Go), although this parameter may not accurately reflect body fat in CRF given the relatively large shifts in body water which occur in this condition. The patients had the following primary renal diseases: renal dysplasia/hypoplasia (n = 4), obstructive or reflux uropathy or both (n = 3), nephronophthisis (n = 2), focal segmental glomerulosclerosis (n = 1), perinatal renal venous thrombosis (n = 1) and perinatal asphyxia (n = 1). Eight patients had end-stage renal disease, treated by continuous cycling peritoneal dialysis (n = 6) or intermittent hemodialysis (n = 2). Four patients had preterminal CRF with a residual glomerular filtration rate (GFR) of 10, 11, 21, and 52 mL/min/1.73 m2, respectively. Patients with CRF received medications consisting of oral phosphate binders, 1,25-dihydroxy-vitamin D3, water-soluble vitamins, and recombinant human erythropoietin for treatment of renal anemia. No patients received clonidine or glucocorticoids. Patients were investigated before enrollment into a study for treatment of CRF-related growth retardation with recombinant human growth hormone (rhGH). Inclusion- and exclusion criteria for this study have been published previously (16).


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  		Table 1. Characteristics of patients and controls

 
For comparison, nine age- and gender-matched prepubertal children with comparable body size and normal renal function were examined (Table 1Go). Controls were investigated before an intended GH therapy of idiopathic short stature. There were no identifiable endocrine, metabolic, genetic, systemic, or psychological causes of short stature. Specifically, the children had normal assessments of serum electrolytes, serum creatinine, blood urea nitrogen, creatinine clearance, erythrocyte sedimentation rate, complete blood count, serum thyroxin, free thyroxin, triiodothyronine, and thyroid-stimulating hormone, plus normal urinalysis. In patients and controls, GH-deficiency had been excluded by serum GH levels equal or above 10 ng/mL during spontaneous nocturnal GH secretion profiles and/or in a GH stimulation test with arginine.

Study protocol

All subjects were investigated after informed parental consent. The protocol had been approved by the Ethics Committee of the University of Heidelberg. The children were admitted to the hospital one day before the test was performed. After an overnight fast (in patients on peritoneal dialysis at least 6 h after the last dialysis fluid exchange, in hemodialysis patients on a day between the dialysis sessions), a standard oGTT (1.75 g glucose/kg body weight; maximum 75 g) was performed. Blood samples were obtained from an antecubital vein by an iv cannula immediately before and at 15, 30, 60, 90, 120, and 180 min after oral glucose administration for measurement of plasma glucose, insulin, GH, IGF-I, and IGFBP-1 concentrations. Impaired glucose tolerance was defined according to the Pediatric standards proposed by the National Diabetes Group of the National Institutes of Health: fasting venous plasma glucose concentration of less than 140, but 2-h glucose level of more than 140 mg/dL (17).

Methods

Height and weight were measured in all subjects with standardized equipment and techniques. To estimate the nutritional status of the patients, BMI was calculated using the formula: weight (kg)/height2 (m2) (Quetelet index). To obtain age-independent estimates of body size and mass, height and BMI (after logarithmic transformation to obtain normally distributed data) were converted to standard deviation ([sd]) score values related to age- and gender-specific means and [sd] of European reference populations (18, 19). Glomerular filtration rate (GFR) was calculated with the formula given by Schwartz et al. (20): GFR = 0.55 x height (cm)/serum creatinine concentration (mg/dL). In patients with end stage renal disease on dialysis treatment, no attempt was made to measure residual GFR, which is usually in the very low range between 5 and 10 mL/min/1.73 m2. Therefore, a value of 7 mL/min/1.73 m2 was arbitrarily entered.

Assays

Plasma glucose concentration was measured in duplicate with the glucose oxidase method by an autoanalyser. Plasma insulin was determined using a solid phase RIA (Biermann, Bad Nauheim, Germany). The intra- and interassay coefficients of variation (CV) were 3.7% and 8.5%, respectively. Plasma GH concentration was determined using a polyclonal antibody-based IRMA (Pharmacia & Upjohn, Stockholm, Sweden) and the World Health Organization First International Reference Preparation hGH 66/127 as standard. Intra- and interassay CV were 10.3%, 5.7%, 3.6%, or 2.9% at GH concentrations of 2, 5, 15, or 40 ng/mL and 5.0% or 2.7% at 10 or 40 ng/mL, respectively. IGF-I (CV, 3.5% and 11%) was measured by RIA with an IGFBP-blocked assay, as described previously (21). IGFBP-1 (CV, 3% and 11%) in plasma was measured by a specific RIA developed with placental protein 12 (kind gift of Dr. Hans Bohn, Behringwerke, Marburg, Germany) that does not cross-react with IGFBP-3 (22).

Statistical analyses

Data are expressed as mean ± [sem]. Data within one group were analyzed by one-way ANOVA for repeated measurements. Comparisons between CRF and controls were carried out by unpaired Student’s t test as normality and equal variance results did not fail. Associations between variables were assessed using univariate linear regression analysis. P < 0.05 was taken to indicate a significant difference.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Glucose and insulin plasma levels in response to the oGTT were significantly increased in CRF patients compared with controls (Fig. 1Go), but none of the CRF patients showed an impaired oral glucose tolerance according to the NIH criteria (17).



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  		Figure 1. Plasma glucose (left panel) and insulin (right panel) levels after an oral glucose load in CRF patients (closed symbols) and controls (open symbols). Data are mean ± SEM. #, Significant difference between patients and controls.

 
Fasting plasma IGFBP-1 levels were increased 2.5-fold in CRF compared with controls (235 ± 40 ng/mL vs. 94 ± 11.6 ng/mL, P < 0.0001). The individual response of plasma IGFBP-1 to an oral glucose load in CRF patients and controls is shown in Fig. 2Go. In controls, plasma IGFBP-1 levels decreased rapidly with time to a level of 45 ± 6.7 ng/mL 180 min after the oral glucose load. In contrast, plasma IGFBP-1 levels in CRF slowly decreased with time to a level of 176 ± 28 ng/mL 180 min, after the oral glucose load. The impaired decline of plasma IGFBP-1 in CRF patients became most apparent when the IGFBP-1 data during the oGTT were expressed as percent of baseline (Fig. 3Go A). The percent decrease in IGFBP-1 below baseline at 90 min up to 180 min after the oral glucose load was significantly reduced in CRF compared with controls. At 180 min, IGFBP-1 levels had decreased by 25% of baseline in CRF vs. 52% in controls (P < 0.001) (Fig. 3Go A). For the group as a whole, the percent decrease in IGFBP-1 below baseline at 180 min was positively correlated with GFR (r = 0.85, P < 0.0001). Figure 3Go B shows the absolute fall in IGFBP-1 180 min after the oral glucose load as a function of baseline IGFBP-1 levels. In both groups, the insulin-induced decline in IGFBP-1 serum levels was closely related to baseline IGFBP-1 levels (CRF, r = 0.89, P < 0.0001; controls, r = 0.94, P < 0.001). However, the slope of the regression line in CRF patients (0.34 ± 0.06) was significantly less steep than in controls (0.69 ± 0.10, P < 0.005), indicating that the IGFBP-1 levels in CRF patients respond less to the oral glucose load than those in controls.



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  		Figure 2. Individual plasma IGFBP-1 levels in CRF patients (left panel) and controls (right panel) after an oral glucose load. Note the different scale of the y-axis.

 


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  		Figure 3. Left panel: Fractional decrease in plasma IGFBP-1 levels after an oral glucose load in CRF patients (closed symbols) and controls (open symbols). *, Significant vs. baseline; #, significant vs. controls. Right panel: Fall in IGFBP-1 at 180 min after the oral glucose load as a function of baseline IGFBP-1. The slope of the regression line in CRF patients (0.34 ± 0.06) (closed symbols) was significantly (P < 0.005) less steep than in controls (0.69 ± 0.10) (open symbols).

 
Fasting plasma GH concentrations were not statistically different between patients and controls (Fig. 4Go). After the oral glucose load plasma GH concentrations decreased (P < 0.01) similarly in patients and controls during the first 30 min. Thereafter, there was a paradoxical increase in plasma GH levels in CRF patients, whereas in controls plasma GH remained persistently decreased (P < 0.05 vs. baseline values) up to 120 min after the glucose load.



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  		Figure 4. Plasma GH levels after an oral glucose load in CRF patients (closed symbols) and controls (open symbols). *, Significant vs. baseline; #, significant vs. controls. Plasma GH concentrations decreased (P < 0.01) similarly in patients and controls during the first 30 min. Thereafter, there was a paradoxical increase in CRF patients, whereas in controls plasma GH remained persistently decreased (P < 0.05 vs. baseline) up to 120 min after the glucose load.

 
Fasting plasma IGF-I concentrations were not significantly different between CRF patients and controls (152 ± 17.2 ng/mL vs. 132 ± 20.5 ng/mL). There was a similar decrease in plasma IGF-I concentrations by about 10% in both groups at 30 min to 180 min after the oral glucose load (P < 0.01).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study shows for the first time that the postprandial regulation of IGFBP-1 is impaired in patients with CRF. Despite an enhanced insulin response to the oral glucose load, there was a slow and diminished decline of plasma IGFBP-1 levels in CRF patients (25% of baseline) compared with controls with normal renal function (52% of baseline).

Increased fasting IGFBP-1 levels and their diminished postprandial decline in CRF patients could theoretically result from an increased production rate, a reduced transcapillary movement, a reduced elimination by the diseased kidneys, or a combination of these factors. We have recently demonstrated in a rat model of moderate CRF that IGFBP-1 messenger RNA at steady state in liver tissue was increased 3-fold compared with pair-fed controls (23). Insulin is the main regulator of IGFBP-1 production by binding to an insulin responsive element on the IGFBP-1 promoter region (2). The increased hepatic IGFBP-1 production in CRF despite normal or elevated insulin levels points to a reduced hepatic sensitivity to the suppressive effect of insulin. Indeed, there is other evidence for a decreased sensitivity to the action of insulin in uremia, such as diminished insulin-mediated suppression of hepatic gluconeogenesis and insulin-stimulated glucose uptake in peripheral tissues (15). It is obvious to assume that reduced renal clearance also contributes to the diminished postprandial decline of plasma IGFBP-1 in CRF. Retention of low molecular weight proteins in the circulation as a consequence of reduced renal filtration is a well known feature of CRF (24). However, our data do not allow us to determine the relative contribution of increased production vs. reduced filtration to the diminished postprandial decline of IGFBP-1 in CRF patients.

We observed a paradoxical increase in plasma GH levels after the oral glucose load in CRF patients in agreement with a previous report (25). It is unlikely that this rise in plasma GH levels played a role for the impaired postprandial decline of IGFBP-1 in CRF, because GH is a potent inhibitor of IGFBP-1 synthesis both in vivo (26) and in vitro (27).

Other hormones besides insulin regulate plasma IGFBP-1 levels in humans (1). Cortisol stimulates IGFBP-1 production in humans only when the circulating insulin levels are low (28). Cortisol is unlikely to play a role for the impaired postprandial decline of IGFBP-1 in CRF, because circulating cortisol levels are reported to be normal in the setting of clinical (29) and experimental CRF (23). Counter regulatory hormones acting through cAMP, such as glucagon, stimulate IGFBP-1 in vitro (30) and in vivo (31). The IGFBP-1 response to glucagon in humans was inversely correlated to the preceding insulin peak, indicating that the suppressive effect of insulin overcomes the stimulatory effect of both cortisol and glucagon (31). In CRF, the biologically active 3.5 kDa moiety of glucagon is increased 3-fold (32) and might therefore contribute to the impaired postprandial decline of IGFBP-1 plasma levels observed in the present study.

The increased fasting IGFBP-1 plasma levels and the diminished postprandial decline might contribute to the disturbed carbohydrate metabolism in uremia. Circulating IGFs represent an important pool of potential hypoglycemic activity, which is largely inhibited by their sequestration in the ternary complex comprising IGF, IGFBP-3, and the acid-labile subunit (8). Less than 1% of total IGFs circulate in the free form (33). The hypoglycemic activity of IGFs in the circulation not sequestered in the ternary complex is thought to be modulated by rapidly fluctuating IGFBP-1 plasma levels (8). It has been suggested that, in response to glucose ingestion, the acute suppression of plasma IGFBP-1 concentration would allow the insulin-like activity of free IGFs to be expressed, complementing the activity of released insulin. In CRF, the markedly increased fasting IGFBP-1 plasma levels and their impaired decline after an oral glucose load might transiently block insulin-like IGF activity in vivo and thereby interfere with glucose homeostasis.

In summary, plasma IGFBP-1 levels in CRF patients show decreases in response to an oral glucose load that are qualitatively similar to but quantitatively less than for a non-CRF comparison group. This impaired postprandial decline of plasma IGFBP-1 might be the result of a reduced hepatic sensitivity to the suppressive effect of insulin, a reduced clearance of IGFBP-1, or a combination of these factors.

Received February 20, 1997.

Revised May 29, 1997.

Accepted June 6, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Lee PDK, Conover CA, Powell DR. 1993 Regulation and function of insulin-like growth factor-binding protein-1. Proc Soc Exp Biol Med. 204:4–29.[Abstract]
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  20. Schwartz GJ, Haycock GB, Edelmann CM. 1976 A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics. 58:259–263.[Abstract/Free Full Text]
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  23. Tönshoff B, Powell DR, Zhao D, et al. 1997 Decreased hepatic insulin-like growth factor (IGF)-I and increased IGF binding protein-1 and -2 gene expression in experimental uremia. Endocrinology. 138:938–946.[Abstract/Free Full Text]
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