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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 6 2978-2983
Copyright © 2002 by The Endocrine Society

Other Original Articles

Free and Total Insulin-Like Growth Factor (IGF)-I Levels Decline during Fasting: Relationships with Insulin and IGF-Binding Protein-1

Lorraine E. L. Katz, Diva D. DeLeón, Hui Zhao and Abbas F. Jawad

Division of Endocrinology and Diabetes, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104

Address all correspondence and requests for reprints to: Lorraine E. L. Katz, M.D., Division of Endocrinology and Diabetes, Room 8416 Main, Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, Pennsylvania 19104-4399. E-mail: . KatzL{at}email.chop.edu

Abstract

We have previously demonstrated that IGF-binding protein-1 (IGFBP-1) levels rise steadily during fasting, following an inverse relationship with insulin. The function of the IGFBP-1 rise is unknown, but it has been hypothesized that IGFBP-1 serves as a glucose counterregulatory hormone during fasting and hypoglycemia by binding free IGFs, thus inhibiting IGF interactions with IGF receptors. Our objective in this study was to determine levels of free and total IGFs during fasting together with their interrelationships with simultaneous IGFBP-1, insulin, and glucose levels. Our patient population consisted of 22 children, aged 6 months to 15 yr, who underwent diagnostic fasting studies in the General Clinical Research Center. Blood was sampled at baseline and at 6-h intervals for glucose, IGFBP-1, free and total IGF-I, and insulin. The fasting studies lasted 14–40 h and were terminated at a glucose concentration of less than 50 mg/dl (n = 11) or for the completion of the allotted fasting duration (n = 11). Of the children studied, 11 had ketotic hypoglycemia, 8 had no disorder, 2 had steroid-induced adrenal suppression, and 1 had recovered transient hyperinsulinism. During fasting, IGFBP-1 levels rose above mean initial levels of 27.1 ± 13.4 ng/ml to a mean of 318.4 ± 29.9 ng/ml at the end point (P < 0.001). Insulin levels declined from a mean initial level of 7.4 ± 1.3 mU/ml to a mean level of 1.4 ± 0.4 mU/ml at the end point (P < 0.001). Concomitantly, free and total IGF-I levels declined from initial levels of 0.48 ± 0.08 and 180.3± 27 ng/ml, respectively, to mean levels of 0.10 ± 0.02 ng/ml (P < 0.001) and 119.3 ± 22 ng/ml (P = 0.001), respectively, at the end point. Levels of free IGF-I were inversely associated with IGFBP-1 over the course of fasting (P = 0.002). Similarly, total IGF-I was negatively associated with IGFBP-1 (P = 0.01). We conclude that free and total IGF-I levels decline steadily over the course of fasting. This decline in free IGF-I appears to be the result of the steady rise in IGFBP-1 that occurs as insulin declines. We speculate that the decline in IGF levels, controlled by the rise in IGFBP-1, serves to protect against possible insulin-like activity of the IGFs during fasting.

IGF-BINDING PROTEIN-1 (IGFBP-1) is a 28-kilodalton protein produced by the liver, reproductive tissues, and kidney (1, 2, 3). Virtually all of the known actions of IGFBP-1 are related to its ability to specifically bind to and modulate the actions of the IGFs. IGFBP-1 is the only one of the six IGFBPs that appears to have rapid dynamic regulation in human plasma, with levels that may vary more than 10- to 20-fold within a few hours (4). The molecular characteristics of IGFBP-1 are consistent with rapid regulation of IGFBP-1 mRNA production, and in vivo and in vitro studies indicate that plasma IGFBP-1 fluctuations are largely due to insulin regulation of IGFBP-1 transcription (5, 6, 7). At the molecular level, insulin inhibits IGFBP-1 gene transcription via an insulin-responsive element (8). In all of the conditions that have been studied, IGFBP-1 levels are inversely correlated with plasma insulin levels (9, 10, 11).

We have previously demonstrated that IGFBP-1 levels rise with fasting and are elevated at the time of hypoglycemia in fasting children (10) One of the postulated roles of IGFBP-1 is prevention of the potential hypoglycemic effects of high plasma levels of free IGFs, acting as a counterregulatory hormone (12). IGFBP-1 levels are increased in poorly controlled insulin-dependent diabetes mellitus, reflecting a deficiency of insulin or insulin action. These elevated levels may contribute to hyperglycemia by the binding of endogenous IGF-I and subsequently preventing its insulin-like effects (13).

The IGF system is extremely sensitive to metabolic alterations, and changes in IGFs and IGFBPs are believed to play a role in the processes that link nutrition and growth (14). Studies based on nonfasting serum samples have shown an inverse relationship between levels of IGFBP-1 and free IGF-I (15). However, the relationships between IGFBP-1 and total and free IGF-I during fasting remain to be investigated. We hypothesized 1) that the rise in IGFBP-1 during fasting serves as a counterregulatory mechanism during fasting and hypoglycemia; and 2) that IGFBP-1 binding to free IGFs (inhibiting interactions with IGF receptors) prevents the potential hypoglycemia that could rise from high plasma levels of free IGFs. Our objectives in this study were to determine levels of free and total IGF-I during fasting and to study the interrelationships of IGFs with simultaneous IGFBP-1, insulin, and glucose levels.

Materials and Methods

Study design

The patient population consisted of 22 children (age, 6 months to 15 yr) with known or suspected hypoglycemic disorders. One of the children had previously been demonstrated to have transient hyperinsulinism, but was subsequently able to be weaned off medical therapy. After the families gave informed consent, standardized fasting studies were conducted in the General Clinical Research Center at the Children’s Hospital of Philadelphia under an institutional review board-approved protocol. The fasting studies lasted 14–40 h and were terminated for a blood glucose concentration of less than 50 mg/dl or completion of the allotted fasting duration. The allotted time of fasting was determined by the age of the child. Children up to 12 months of age were fasted 12–24 h, children older than 12 months were fasted 24–36 h. At regular 6-h intervals during fasting and at the end of fasting, blood samples were drawn for insulin, glucose, IGFBP-1, and total and free IGF-I measurements. After the final blood drawing, patients were given either oral carbohydrates or iv glucose and were observed until they were back on a full oral diet and had stable blood glucose levels. Children who were not able to fast for a previous defined time according to their age, but whose hormonal response to fasting was normal, in combination with appropriate generation of ketones and FFA, were diagnosed with ketotic hypoglycemia. Patients with normal metabolic and hormonal profiles who fasted for the previously defined time were considered to have no disorder.

Methods

Insulin levels were measured by the IMX insulin microparticle immunoassay (Abbott Laboratories, Abbott Park, IL). IGFBP-1 was measured at Esoterix Laboratories (Los Angeles, CA) by a double-antibody RIA using rabbit anti-IGFBP-1 and IGFBP-1. Total and free IGF-I levels were measured by ELISA from Diagnostic Systems Laboratories, Inc. (Webster, TX) (16, 17).

Statistical analysis

Measurements of IGFBP-1, insulin, glucose, and total and free IGF-I were made repeatedly at different time points after the start of fasting. The effects of insulin, glucose, and IGFBP-1 on total and free IGF-I levels across time were analyzed using the general linear mixed effects models approach (18). This approach to data analysis is similar to the multiple regression approach, but it takes into consideration the repeated measures nature of the design that produces correlated observations measured in the same subject. In addition, we were able to include in the analysis all observed subjects, even when some subjects did not have a complete set of measurements. Separate mixed effects models were used to predict free IGF-I and total IGF-I using PROC MIXED (SAS Institute, Inc., Cary, NC) (19). Subjects and time of measurements were assumed to be the random effects, and the structure of the variance covariance matrix was assumed to be unstructured and to be estimated from the data. The natural logarithm values were used for normalizing the distribution of IGFBP-1, which then was used in the analysis. Time was measured as time since the start of the fasting condition. Values are presented as the mean ± SEM. Paired t tests were used to compare baseline values at the start of fasting to those at the completion of the allowed period of fasting.

Results

Of the total 22 patients studied, 8 were determined to have no disorder, 11 had ketotic hypoglycemia, 2 had steroid-induced adrenal suppression, and 1 had recovered from transient hyperinsulinism (Table 1Go). Hormonal and metabolic profiles for the individual patients are shown in Table 2Go.


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  		Table 1. Characteristics of subjects undergoing fasting studies

 

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  		Table 2. Hormonal and metabolic profile at the end of the fast

 
During fasting, IGFBP-1 levels rose above a mean initial level of 27.1 ± 13.4 ng/ml to 318.4 ± 29.9 ng/ml at the end point (P < 0.001, by paired t test; Fig. 1Go). Insulin levels declined from a mean initial level of 7.4 ±1.3 mU/ml to a mean level of 1.4 ± 0.4 mU/ml at the end point (P < 0.001, by paired t test; Fig. 1Go), and glucose levels declined steadily during fasting. Concomitantly, free and total IGF-I levels declined from baseline levels of 0.48 ± 0.08 and 180.3± 27 ng/ml, respectively, at the start of fasting to mean levels of 0.10 ± 0.02 ng/ml (P < 0.001) and 119.3 ± 22 ng/ml (P = 0.001), respectively, at the end point (Fig. 2, A and BGo). Combined fasting parameters for three representative patients are displayed in Fig. 3Go.



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  		Figure 1. Shown are the mean IGFBP-1 (squares) and mean insulin (circles) ± SE at initial measurements and at the end of a controlled fasting study.

 


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  		Figure 2. Shown are the mean free IGF-I (A) and mean total IGF-I (B) ±SE at initial measurements and at the end of a controlled fasting study.

 


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  		Figure 3. Shown are metabolic parameters over the entire course of fasting for three representative patients (no. 1, 10, and 18; A–C).

 
The relationship between IGFBP-1 and insulin over the course of fasting was examined using SAS PROC MIXED. A log transformation of IGFBP-1 was used to linearize the relationship. The predicted model of ln(IGFBP-1) was 3.51 - 0.07 insulin. The insulin coefficient was statistically significant (P = 0.001), with a negative effect in predicting ln(IGFBP-1) (Fig. 4Go). The predicted values estimated for this model highly correlated (r = 0.96; r2 = 92%) with the observed values, indicating that the model explained 92% of the variability in free IGF-I.



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  		Figure 4. Relationships between levels of IGFBP-1 and insulin at the time of hypoglycemia. Shown are natural logarithm data for IGFBP-1 plotted against insulin. The relationship [ln(IGFBP-1) = 3.51 - 0.07(Insulin)] between IGFBP-1 and insulin levels is statistically significant (P = 0.001).

 
The fitted models predicting free IGF-I and total IGF-I using PROC MIXED of SAS are depicted in Fig. 5Go, A and B. For free IGF-I, the predictive model was 0.61 - 0.001 IGFBP-1 - 0.01 h, and the correlation between the predicted and the observed values was strong (r = 0.84). For total IGFBP-1, the predictive model was 183.9 - 0.11 IGFBP-1 and r = 0.97.



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  		Figure 5. Relationships between levels of free (A) and total (B) IGFBP-1 and IGFBP-1 at the time of hypoglycemia are shown. Free IGF-I = 0.61 - 0.001(IGFBP-1) - 0.01(hours); total IGF-I = 183.9 - 0.11(IGFBP-1) (P = 0.01).

 
Discussion

We have demonstrated in this study that levels of free and total IGF-I during fasting steadily decline and are inversely related to levels of IGFBP-1. It has previously been demonstrated that IGFBP-1 levels rise during fasting under regulation by insulin (20, 21). However, before the present study there were no data correlating IGFBP-1 levels with fasting levels of free and total IGF-I. We have confirmed that IGFBP-1 levels rise with fasting and present novel data demonstrating the inverse relationship between IGFBP-1 and total and free IGF-I levels.

In all of the conditions studied, IGFBP-1 levels are inversely correlated with plasma insulin levels (10, 22, 23). One of the postulated roles of IGFBPs is prevention of the hypoglycemia that could arise from high plasma levels of free IGFs (1, 2, 4). IGFBP-1 is thought to be the primary IGFBP involved in the acute regulation of serum glucose levels (24). Studies based on nonfasting and overnight fasting serum samples have shown an inverse relationship between levels of IGFBP-1 and free IGF-I (25). In the fed state, when IGFBP-1 levels are low, the increased IGF effects may serve to supplement insulin action. Conversely, the elevated IGFBP-1 levels seen under fasting conditions may prevent hypoglycemia in normal individuals by the same mechanism. During acute hypoglycemia the rise in IGFBP-1 may also serve to inhibit the metabolic actions of IGF-I. In poorly controlled diabetics, elevated IGFBP-1, by binding up free IGF-I, may actually promote hyperglycemia, aggravating the dawn phenomenon (13). Bereket et al. (26) demonstrated that untreated newly diagnosed diabetic children had reduced free IGF-I levels, which were inversely correlated with IGFBP-1 levels. Free IGF-I levels were progressively restored during insulin therapy, following a more rapid course than total IGF-I (26). In type I diabetic patients undergoing acute insulin withdrawal, an increase in IGFBP-1 together with a marked reduction in free IGF-I were demonstrated (27); these parameters normalized upon restoration of insulin therapy.

Our previous data during fasting hypoglycemia show that IGFBP-1 secretion is regulated by cortisol together with insulin (12). The rise in IGFBP-1 during fasting and hypoglycemia potentially serves to prevent the additional hypoglycemic effects of free IGFs. The data presented here demonstrating a steady reduction in free IGF-I levels during fasting support the hypothesis that IGFBP-1 functions as a glucose counterregulatory hormone during fasting and hypoglycemia by regulating the availability of IGF-I. Our results differ from those of Bereket et al. (28), who failed to demonstrate changes in free IGF-I after short-term fasting. However, the children in our study underwent more prolonged fasts, typically until the point of hypoglycemia. Thus, our longer study time frame may account for the larger decline in free IGF-I that we observed.

The potential for IGFs to affect blood glucose levels is illustrated by patients with nonislet cell tumor hypoglycemia. Hypoglycemia in these patients has been attributed to an elevation of high mol wt IGF-II combined with alterations in the IGFBPs, resulting in a lower proportion of IGFs being present in the ternary complex and thus greater IGF availability (29). Recently, elevations of free IGFs in nonislet cell tumor hypoglycemia have been demonstrated (30). It is not clear whether these insulin-like actions of IGFs are mediated through the type I IGF receptor or through the insulin receptor. However, it has been demonstrated in vitro that half-maximal IGF-I effects on glucose uptake may occur at concentrations of 10-9–10-8 M (31). Although our mean starting concentration of free IGF-I of 65 pmol/liter is lower than this, circulating free IGF-I levels may not be reflective of tissue levels.

Curiously, we demonstrated a decline in total IGF-I as well as free IGF-I during fasting. Although the total IGF-I levels were also negatively associated with IGFBP-1, it is likely that this effect was due to nutritional regulation. Sustained nutritional deprivation causes significant changes in the IGF axis, especially IGF-I. Thus, IGF-I levels are decreased in situations of chronic caloric and/or protein undernutrition (32, 33). It has been demonstrated that fasting lowers serum IGF-I levels in a few days, and refeeding restores levels. IGF-I is very sensitive to short-term changes in weight and body mass index (34) and correlates with body mass index (35). The changes in IGF-I during fasting appear to be a direct effect on the production of IGF-I by the liver (36), the primary source of circulating IGF-I.

Conclusions

In conclusion, levels of free and total IGF-I decline over the course of fasting. The decline in free IGF-I appears to be a result of the steady rise of IGFBP-1 that occurs as insulin declines, whereas the decline in total IGF-I may be in part nutritionally regulated. These events may protect against the insulin-like activity of IGFs during fasting.

Footnotes

This work was supported in part by an NIH Clinical Associate Physician Award (to L.E.L.K.) and NIH Grant 5T32-DK-07314 (to D.D.D.). This work was presented in part at the Annual Meeting of the Society of Pediatric Research, Baltimore, Maryland, 2001.

Abbreviation: IGFBP-1, IGF-binding protein-1.

Received September 13, 2001.

Accepted March 4, 2002.

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