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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 5 1484-1491
Copyright © 1997 by The Endocrine Society

Clinical Studies

Circulating Levels of Insulin-Like Growth Factor (IGF) Binding Protein-1 and -3 in Aging Men: Relationships to Insulin, Glucose, IGF, and Dehydroepiandrosterone Sulfate Levels and Anthropometric Measures1

Carlos A. Benbassat, Kevin C. Maki and Terry G. Unterman

Endocrine Section, Department of Medicine, Veterans Administration Chicago Health Care System: West Side Division, and University of Illinois College of Medicine (C.A.B., T.G.U.), Chicago, Illinois 60612; the Rehabilitation Research and Development Center, Edwards Hines, Jr., Veterans Administration Hospital (K.C.M.), Hines, Illinois 60153; and the Department of Epidemiology and Biostatistics, University of Illinois School of Public Health (K.C.M.), Chicago, Illinois 60612

Address all correspondence and requests for reprints to: Terry G. Unterman, M.D., Endocrine Section (M.P. 115), Veterans Administration West Side Medical Center, 820 South Damen Avenue, Chicago, Illinois 60612.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Reduced secretion of GH and production of insulin-like growth factor I (IGF-I) contribute to altered body composition in human aging. IGF-binding proteins (IGFBPs) are important modulators of IGF action, yet little is known regarding their role and regulation in aging. Accordingly, we measured levels of IGFBP-1, an important short term modulator of IGF bioavailability that is suppressed by insulin, and levels of IGFBP-3, the major circulating IGF carrier protein, and examined their relationships to insulin, glucose, IGF, and dehydroepiandrosterone sulfate levels and anthropometric measures in old (63–89 yr) and young (23–39 yr) men.

Serum levels of IGFBP-1 were increased 3-fold in old vs. young men despite high insulin levels in elders. Nevertheless, IGFBP-1 and insulin levels correlated in old and young men (r = -0.49; P < 0.002 and r = -0.42; P < 0.025), suggesting that insulin continues to play an important role in the regulation of IGFBP-1 in aging. Glucose levels also were significantly inversely related to IGFBP-1 in old and young men (r = -0.37; P = 0.02 and r = -0.49; P < 0.01), and this relationship was not accounted for by the effect of insulin. IGF-I levels were reduced by 33% in elders (P < 0.001) and correlated with IGFBP-1 levels among old (r = -0.40; P < 0.01), but not young, men, indicating that low GH secretion and/or IGF-I production may contribute to the elevation of IGFBP-1 levels in aging.

IGFBP-3 levels were reduced among elders, but not to the same extent as IGF-I, resulting in a relative excess of IGFBP-3 in elders (IGFBP-3/IGF-I ratio, 20.1 ± 0.9 vs. 15.4 ± 1.0; P < 0.001). The IGFBP-3/IGF-I ratio correlated with IGF-I levels in young and old men (r = -0.79; P < 0.001 and r = -0.82; P < 0.001), indicating that diminished GH secretion also may contribute to a relative excess of IGFBP-3 among elders. Dehydroepiandrosterone sulfate levels were low in elders, but did not correlate with IGF, IGFBP, insulin, or glucose levels in either age group.

Serum levels of IGFBP-1 (but not IGF-I or -II or IGFBP-3) correlated with body mass index and upper arm fat and muscle areas in elders. These relationships were accounted for by the effects of insulin, suggesting that regulation of IGFBP-1 by insulin may play a role in determining body composition in aging.

We conclude that insulin remains an important determinant of IGFBP-1 levels in elders, that the fasting glucose level is also a significant determinant of IGFBP-1 in both old and young subjects, and that reduced secretion of GH may contribute to impaired anabolism in aging through multiple mechanisms, including reduced production of IGF-I and alterations in circulating levels of both IGFBP-1 and -3. These findings are consistent with the concept that alterations in IGFBP levels may contribute to changes in IGF bioavailability and body composition in aging.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
REDUCED secretion of GH and production of insulin-like growth factor I (IGF-I) are thought to be important determinants in age-related changes in body composition and function (1, 2, 3). IGFs circulate in association with specific binding proteins (IGFBP) that modulate their biological effects on target tissues (4). Little information is available regarding the role and regulation of IGFBPs in human aging. To date, six distinct IGFBPs have been purified from biological fluids, and their complementary DNAs cloned (5). Recent studies suggest that IGFBP-1, a 30-kDa protein that is produced largely in the liver and regulated by insulin, plays an important role in the short term modulation of IGF bioavailability (6). At the same time, most IGFs circulate as part of a stable, high molecular (~150-kDa) weight ternary complex together with IGFBP-3 and an acid-labile subunit; this complex has a prolonged half-life and is thought to limit the metabolic effects of the large amounts of IGFs found in the circulation (7). Recent studies suggest that IGFBP-3 also may exert direct effects inhibiting cell growth (8, 9). IGF-I has direct effects on circulating levels of IGFBP-3, whereas GH stimulates hepatic production of acid-labile subunit (10, 11). GH also is thought to play a role in the regulation of circulating levels of IGFBP-1 (12).

Factors other that GH also may contribute to the regulation of the IGF-IGFBP system in aging. Insulin is required to maintain normal circulating levels of IGF-I in subjects with normal GH secretion, and normal levels of IGF-I are maintained in hyperinsulinemic conditions where GH secretion is reduced (13, 14). Insulin also plays an important role in the regulation of IGFBP-1 in young adults (6), rapidly suppressing its production by the liver at the level of gene transcription (15, 16, 17). Accordingly, increased circulating levels of insulin in elders (18) might contribute to the regulation of IGFBP-1 and IGF bioavailability during aging. However, Rutanen et al. (19) recently reported that circulating levels of IGFBP-1 are elevated among elders despite the presence of high insulin levels, and they suggested that the ability of insulin to regulate hepatic production of IGFBP-1 may be impaired in human aging. In vitro data indicate that glucose also exerts direct effects on hepatocellular production of IGFBP-1 (20, 21), yet relationships between glucose and IGFBP-1 levels in clinical studies of either old or young subjects have not been previously reported. Studies by Yen and co-workers (22, 23) indicate that alterations in the production of adrenal androgens also may contribute to age-related changes in body composition and circulating levels of IGF-I and IGFBP-1.

As a first step in evaluating the relative importance of these factors in the regulation of IGFBP levels and IGF bioavailability in aging, we examined relationships between fasting blood levels of IGFBP-1 and -3 and levels of IGF-I and -II, insulin, glucose, and dehydroepiandrosterone sulfate (DHEA-S) and anthropometric measures in old and young men.


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

Fasting blood samples were obtained and anthropometric measurements were performed between 0530–0930 h in 38 older men (age range, 63–81 yr; mean ± SEM, 71.2 ± 0.8) participating in the Department of Veteran Affairs National Golden Age Games hosted by the Hines V.A. Hospital in July 1994. Fasting blood samples also were obtained from 28 young male veterans (age range, 20–39 yr; mean ± SEM, 27.1 ± 1.1) enrolled in a broader study regarding hormonal correlates of cardiac risk factors. Subjects with a diagnosis of diabetes mellitus or fasting blood glucose levels above 7.8 mmol/L, recent weight loss, renal insufficiency, or glucocorticoid administration were excluded from the study, and written informed consent was obtained from each subject before his participation. Studies were approved by the human studies subcommittee of the Edward Hines, Jr., V.A. Hospital (Hines, IL).

Assays

Serum and ethylenediamine tetraacetate plasma samples were stored at -20 C until assay. Serum glucose was measured with a Paramax 720 ZX analyzer (Baxter Scientific Instruments, Deerfield, IL) in the Hines V.A. clinical laboratory. The plasma insulin concentration was measured by double antibody immunoassay at SmithKline-Beecham clinical laboratories (St. Louis, MO). Serum levels of IGF-I were measured after acid-ethanol extraction, and IGF-I, IGFBP-3, and IGFBP-1 levels were measured by coated tube immunoradiometric assay kits obtained from Diagnostic System Laboratories (Webster, TX). Intra- and interassay coefficients of variation were below 8.5% for each of these assays at the level tested. Serum levels of IGF-II were measured by RIA after acid-ethanol extraction as a courtesy by J. Frystyk and H. Orskov (24), and serum levels of DHEA-S were measured by RIA in the laboratory of S. Pang, as previously reported (25).

Anthropometric measures

Height and weight were measured on a calibrated balance beam scale (Health-O-Meter, Abacus Scale Co., Chicago, IL). Midupper arm circumference was measured using a nonstretch anthropometric tape, and biceps and triceps skinfold thicknesses were measured on the dominant side with Lange calipers (Beta Technology, Santa Cruz, CA) according to standard procedures (26). Measurements were taken in triplicate, and the average was recorded. As the volume of tests required in a short period of time precluded the use of a single anthropometrist, measurements were completed by a team of five people. Acceptable interrater reliability was demonstrated for each measurement before the start of the study. Body mass index was calculated as weight (kilograms) divided by height (meters) squared. Upper arm muscle and fat area (UAMA and UAFA) were calculated from triceps skin folds and upper arm circumference measurements using standard equations (27).

Statistical analysis

Differences between groups were tested for statistical significance by Student’s t test, and similar results were obtained when loge-transformed values were used to reduce a modest deviation from Gaussian distribution for IGFBP-1 and insulin concentrations. Pearson correlation analysis was performed with the Sigmastat program (Jandel Scientific, San Raphael, CA). Multiple linear regression and analysis of covariance were performed using the JMP3.1 Statistical Analysis package (SAS Institute, Cary, NC). In light of the number of statistical tests run, P values between 0.05–0.01 were considered of borderline statistical significance, whereas P <= 0.01 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Serum levels of IGFs, IGFBPS, insulin, glucose, and DHEA-S

As shown in Table 1Go, serum levels of IGF-I and IGFBP-3 were both significantly lower in old vs. young men, consistent with an age-related decline in GH secretion and IGF-I production. Levels of IGF-II, which is not closely regulated by GH, were not reduced significantly among elders. Circulating levels of IGFBP-1 were increased ~2-fold among old vs. young men, consistent with previous reports (19). Levels of IGFBP-3 were reduced among elders, but not to the same extent as levels of IGF-I, resulting in a higher IGFBP-3/IGF-I ratio among old vs. young men (Table 1Go). In contrast, the IGFBP-3/IGF-II ratio was not significantly different in old vs. young men.


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  		Table 1. Circulating levels in young and old men

 
As shown in Fig. 1Go, serum levels of IGF-I and IGFBP-3 correlated with age among elders, presumably reflecting an age-related decline in GH secretion. The relationship between IGFBP-1 and age also approached, but did not achieve, significance among elders (Fig. 1Go), perhaps due to the limited number of subjects studied. IGF-I, IGFBP-3 and IGFBP-1 levels did not correlate with age among young men (r = -0.13; r = 0.03 and r = -0.03, respectively; not shown), and levels of IGF-II did not correlate with age in either age group (not shown).



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  		Figure 1. Relationships of circulating levels of IGF-I, IGFBP-3, and IGFBP-1 to age in elders. Fasting serum levels of IGF-I, IGFBP-1, and IGFBP-3 were measured by specific RIAs and are shown for each subject. Levels of IGFs and IGFBPs did not correlate with age among young men (not shown).

 
Levels of DHEA-S were reduced among old vs. young men, consistent with previous reports (22). Levels of DHEA-S declined with age among elders (r = -0.40; P < 0.02), but did not correlate with age among young men (not shown). DHEA-S levels did not correlate with levels of IGF-I, IGF-II, IGFBP-1, or IGFBP-3 in either age group, suggesting that factors other than DHEA-S are important in determining the levels of IGF-I, IGFBP-1, and IGFBP-3 in both age groups.

Relationship of IGFBPs to insulin and glucose levels

Univariate analysis showed that insulin was significantly related to IGFBP-1 levels among subjects in both age groups (Fig. 2Go). In contrast, fasting levels of insulin did not correlate with levels of IGF-I or -II or IGFBP-3 (not shown). As shown in the left panel of Fig. 2Go, serum levels of IGFBP-1 correlated with insulin levels in both young and old men (r = -0.42; P < 0.025 and r = -0.49; P < 0.01, respectively), indicating that insulin remains a significant determinant of IGFBP-1 levels in aging men. Because this relationship was not clearly linear, and data points were not evenly distributed around the regression lines, we also analyzed the relationship between loge-transformed insulin and IGFBP-1 values. This resulted in a more homoscedastic distribution of data points and strengthened the relationships in old and young men (r = -0.646; P < 0.001 and r = -0.591; P < 0.001, respectively; Fig. 3Go). Analysis of 95% confidence intervals for the equations relating fasting insulin and IGFBP-1 levels demonstrated that the slopes for these regression lines are nearly identical and that intercepts are significantly different in young vs. older subjects. Similar results were obtained with loge-transformed values. Together, these results indicate that the increase in IGFBP-1 levels in older subjects is probably not due to a change in the ability of increments in insulin to suppress IGFBP-1 levels. Interestingly, we also observed a significant relationship between fasting glucose and IGFBP-1 levels in both young and old men (r = -0.49; P < 0.01 and r = -0.37; P < 0.02). In contrast, glucose levels did not correlate with levels of IGF-I, IGF-II, or IGFBP-3 (not shown). As shown in Fig. 2Go, the slope for the relationship between glucose and IGFBP-1 levels appeared to be less steep among old vs. young subjects. This difference was even more apparent when loge-transformed values were used (not shown), supporting the view that the relationship between fasting glucose and IGFBP-1 levels is altered in old vs. young men.



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  		Figure 2. Relationships between fasting levels of IGFBP-1 and levels of insulin, glucose, and IGF-I. Left panel, Fasting levels of insulin and IGFBP-1 for old (solid circles) and young (open circles) men are shown. Middle panel, Levels of glucose and IGFBP-1 are shown for old and young men. Right panel, Levels of IGF-I and IGFBP-1 in old and young men are shown.

 


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  		Figure 3. Relationship between loge-transformed values for fasting levels of insulin and IGFBP-1 in old (solid circles) and young (open circles) men.

 
Several observations suggested that the relationship between glucose and IGFBP-1 levels may not be due to an effect of insulin. Although fasting insulin and glucose levels were related in young men (r = 0.42; P < 0.02), insulin and glucose levels did not correlate among elders (r = 0.01; P = NS), even after examining loge-transformed values (r = 0.03; P = NS; not shown). Also, multiple linear regression analysis showed that the relationship between glucose and IGFBP-1 levels remained significant after controlling for the effect of insulin in both old and young men, including when loge-transformed values were employed in the analysis (P < 0.005 and P < 0.002 for young and older subjects, respectively).

To more completely evaluate these relationships, we also developed multiple linear regression models for IGFBP-1 using age group plus loge-transformed values for IGFBP-1 and fasting plasma insulin and/or glucose. Modeling results are summarized in Table 2Go. In separate models, fasting plasma glucose and insulin each contributed significantly to the variance in IGFBP-1 explained by age group. When both variables were included, glucose and insulin each contributed independently to the explanatory power of the model. This analysis confirmed the presence of an interaction between age group and fasting plasma glucose such that the slope for IGFBP-1 on glucose concentration was less steep for the older age group and also showed that age group remains an important determinant of the IGFBP-1 level after adjusting for the effects of glucose and the interaction variable. In contrast, no interaction with age group was present for the relationship between fasting plasma insulin and IGFBP-1.


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  		Table 2. Least squares linear regression models for ln IGFBP-1

 
Least squares mean values for loge IGFBP-1 were estimated from the model containing age group plus (loge-transformed) fasting plasma insulin, fasting plasma glucose, and an interaction term for age group with fasting plasma glucose. Using this method to adjust for age-related variations in carbohydrate metabolism increased the mean IGFBP-1 value (back-transformed) for older subjects from 21.2 to 30.3 ng/dL and decreased the value for young subjects from 6.5 to 3.1 ng/dL. Although age group did not reach statistical significance in the model (P = 0.078), this most likely is a reflection of the loss of statistical power due to the larger number of variables in the model, as the difference in IGFBP-1 between age groups grew larger with adjustment. This analysis suggests that the difference in IGFBP-1 level in old and young men is not accounted for by age-related alterations in carbohydrate metabolism.

Because fasting insulin and glucose concentrations both reflect aspects of a feedback loop, an analysis also was completed in which a composite variable, the insulin resistance index generated with the homeostasis model assessment method (HOMA-R) (28, 29), was used in place of fasting insulin and glucose values. HOMA-R is calculated by dividing the product of the fasting insulin and glucose concentrations by 22.5. Age group and ln HOMA-R each contributed to the power of this model, and together they explained 55% of the variance in ln IGFBP-1. No evidence was present for interaction between HOMA-R and age group.

Relationships of IGFBPs to IGF-I levels

As shown in Fig. 2Go, serum levels of IGFBP-1 were inversely related to levels of IGF-I among elders (r = -0.40; P < 0.01), and this relationship remained significant after controlling for the effects of both insulin and glucose by regression analysis (P = 0.006). In contrast, levels of IGFBP-1 did not correlate with levels of IGF-I in young men (r = -0.12; P = NS), perhaps because GH secretion in young adults is adequate to exert a maximal effect on IGFBP-1 production. Analysis of loge-transformed values yielded similar results for old and young men (not shown). IGFBP-1 levels did not correlate with levels of IGF-II in either age group. Analysis of covariance revealed that the difference between IGFBP-1 levels in old and young men was only marginally significant (P = 0.054) after controlling for the effect of IGF-I. Taken together, these findings support the view that reduced secretion of GH and/or production of IGF-I may contribute to the increased IGFBP-1 levels in elders.

The IGFBP-3/IGF-I ratio correlated with serum levels of IGF-I in both young and old men (r = -0.82; P < 0.001 and r = -0.79; P < 0.001, respectively), but did not correlate significantly with levels of insulin, glucose, or IGF-II in either age group (not shown). Both the slope and the intercept for the regression lines between the IGFBP-3/IGF-I ratio and IGF-I levels were similar in young and old subjects (Fig. 4Go), suggesting that differences in GH secretion and/or IGF-I production also contribute to age-related differences in the IGFBP-3/IGF-I ratio.



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  		Figure 4. Relationship between IGFBP-3/IGF-I ratio and IGF-I levels in old and young men.

 
Relationships with anthropometric measures

Serum levels of IGFBP-1 (but not IGF-I, IGF-II, or IGFBP-3) correlated with several anthropometric measures among elders. Initial analysis indicated that levels of IGFBP-1 are inversely related to several measures of adiposity, including body mass index (r = -0.48; P < 0.01) and UAFA (r = -0.45; P < 0.005; not shown). Not surprisingly, insulin levels also correlated with these measures of adiposity, and the relationships with IGFBP-1 were no longer significant after adjusting for the effect of insulin. Fasting levels of IGFBP-1 and insulin also correlated with UAMA (r = -0.51; P < 0.01 and r = 0.59; P < 0.01, respectively; Fig. 5Go), and this relationship remained highly significant even after excluding values for two subjects with high insulin levels (r = -0.44; P < 0.007 for IGFBP-1; r = 0.47; P < 0.004 for insulin). The relationship between IGFBP-1 and UAMA was no longer significant after adjusting for the effect of insulin, suggesting that regulation of IGFBP-1 levels and modulation of IGF bioavailability by insulin may contribute to determining UAMA in elders.



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  		Figure 5. Relationship between UAMA and fasting levels of IGFBP-1 (left panel) or insulin (right panel) in elders.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In the present study, we measured circulating levels of IGFBP-1 and -3 and examined their relationships to fasting levels of IGFs, insulin, glucose, and DHEA-S and anthropometric measures in old vs. young men. Our initial observations confirmed that circulating levels of IGF-I and DHEA-S were significantly reduced, whereas levels of insulin and glucose were increased among elders, consistent with previous studies on aging (1, 22, 30, 31). Circulating levels of IGFBP-3 also were reduced among elders, but not to the extent that IGF-I levels were decreased, suggesting the presence of a relative excess of IGFBP-3 that may further limit the availability of IGF-I in older men. Previous studies have shown that the IGFBP-3/IGF-I ratio is increased in subjects with GH deficiency and increased in patients with GH-secreting tumors (32, 33, 34). In the present study, we found that the IGFBP-3/IGF-I ratio correlated significantly with levels of IGF-I, a marker of GH secretory capacity in elders (35). Taken together, these results suggest that reduced secretion of GH and/or production of IGF-I may contribute to the development of an excess of IGFBP-3 relative to IGF-I in aging.

Our results also indicate that changes in GH secretion contribute to the elevation of IGFBP-1 levels observed in older men. Circulating levels of IGFBP-1 and IGF-I were related in elders, but not in young men, suggesting that the relationship between GH secretion and IGFBP-1 levels may be most apparent when GH secretion is limited, and that maximal effects of GH on IGFBP-1 levels are achieved in young men before the full effect of GH on IGF-I levels is obtained. Laboratory studies have shown that GH rapidly suppresses hepatic IGFBP-1 transcription in hypophysectomized rats (36) and that GH exerts direct effects on hepatic IGFBP-I messenger ribonucleic acid abundance in isolated hepatocytes (37). Hilding et al. (12) recently reported that serum levels of both IGFBP-1 and insulin are elevated and correlate with each other in GH-deficient adults, supporting the view that GH contributes to the regulation of IGFBP-1 in humans without disrupting the effect of insulin on IGFBP-1 levels. Laron and colleagues (38) reported that sustained administration of IGF-I lowers circulating levels of IGFBP-1 in children with GH-resistant dwarfism, indicating that long term differences in the IGF-I level also may contribute to the regulation of IGFBP-1. Studies of elders treated with exogenous GH and/or IGF-I should help to determine the extent to which elevated IGFBP-1 levels reflect reduced secretion of GH and/or production of IGF-I in aging.

Recent studies suggest that changes in adrenal androgen production may contribute to age-related alterations in metabolism and body composition (23, 39, 40). Yen and co-workers (41) recently reported that replacement therapy with DHEA had modest effects on serum levels of IGF-I (increased by ~20%) and IGFBP-1 (decreased by ~20%), but not IGFBP-3, in older men and women. They did not detect any effect of DHEA treatment on integrated GH secretion and suggested that DHEA may exert its effects on the IGF-I and IGFBP-1 levels independent of GH secretion (41). In the present study, we confirmed that blood levels of DHEA-S are markedly decreased in old vs. young men, but failed to detect any relationship between levels of DHEA-S and IGFs or IGFBPs in either age group, suggesting that factors other than adrenal androgens play an important role in the regulation of IGF and IGFBP levels in young and old men. Nevertheless, DHEA-S levels varied strongly with age group, and we cannot exclude the possibility that changes in adrenal androgen production contribute to the differences in IGF and IGFBP levels in old vs. young men. Prospective studies examining relationships among levels of adrenal androgens, IGFs, and IGFBPs during the aging process as well as studies of elderly men treated with individual or combinations of anabolic factors should help to clarify the relative roles of adrenal androgens and GH in the regulation of the IGF-IGFBP system in human aging.

We also analyzed the relationships among circulating levels of IGFBP-1, insulin, and glucose in young and old subjects. Rutanen and co-workers (19) previously reported that levels of IGFBP-1 increased with age in a group of men and women, 24–93 yr old (19). They found that insulin and IGFBP-1 levels were not significantly related when young and old subjects were analyzed together and suggested that this increase in IGFBP-1 levels may reflect reduced effectiveness of insulin in regulating hepatic production of IGFBP-1 (19). In the present study, we analyzed the relationship between insulin and IGFBP-1 levels in old and young men separately and found significant relationships in both age groups. We also found that the slope of the regression lines for the relationship between IGFBP-1 and insulin levels was nearly identical in old and young men. Taken together, these results indicate that insulin remains an important determinant of IGFBP-1 levels among elders and that other factors are likely to contribute to the elevation of IGFBP-1 levels in aging.

We found that both IGFBP-1 and insulin levels correlated with anthropometric measures of adiposity and lean body mass, and that the relationships with IGFBP-1 were accounted for by the effect of insulin. Previous studies have shown that lean body mass is increased in obese subjects (42), yet the mechanism(s) underlying this relationship remains unknown. Based on the results of the present study, it is interesting to speculate that the suppression of IGFBP-1 by insulin may increase the availability of IGFs and help to preserve lean body mass among elders and perhaps other subjects in whom insulin levels are elevated and GH secretion is diminished. Additional studies using more precise measures of body composition, IGF availability, and insulin secretion and sensitivity will be important to assess this intriguing possibility.

We also observed that circulating levels of IGFBP-1 correlate with fasting levels of glucose in old and young men. We are not aware of any previous report demonstrating a correlation between fasting levels of glucose and IGFBP-1 in either old or young subjects. Multivariate analysis suggested that this relationship is not accounted for by the effect of insulin in either age group or when all subjects are combined. However, as glucose and insulin levels are so directly linked in a feedback loop, these studies cannot entirely exclude the possibility that the relationship between glucose and IGFBP-1 levels reflects variations in the ability of insulin to regulate glucose utilization and/or production or the ability of glucose to stimulate ß-cell secretion of insulin. Additional studies that examine the relationship between IGFBP-1 levels and direct measures of glucose production and utilization, insulin sensitivity, and islet secretory responsiveness in old and young subjects will be of great interest.

At the same time, it is important to consider the possibility that there is a more direct relationship between glucose metabolism and IGFBP-1 levels in human subjects. Studies with experimental animals given large amounts of IGFBP-1 and with transgenic mice indicate that excess IGFBP-1 may elevate blood glucose levels by reducing the effect of endogenous IGFs on glucose metabolism (20, 43, 44); however, these findings would not explain the inverse relationship we observed between glucose and IGFBP-1 levels in both young and old subjects. Several laboratories have reported that glucose may suppress hepatocellular production of IGFBP-1 in cell culture (20, 21), and Snyder et al. (45) reported that glucose and fructose may both lower IGFBP-1 levels in vivo through an insulin-independent mechanism. In vitro studies also indicate that glucose may exert insulin-independent effects on fat and muscle, whereas glycemic clamp studies indicate that increased glycemia suppresses hepatic production of glucose, perhaps through an indirect mechanism involving alterations in fatty acid levels (46). Based on these findings, it is interesting to speculate that insulin-independent effects of glucose may contribute to the regulation of multiple aspects of hepatic function, including the production of IGFBP-1. As we also observed an interaction between age group and the relationship between IGFBP-1 and glucose levels, it is also possible that insulin-independent effects of glucose may be altered in aging. Additional studies that directly measure the production of IGFBP-1 and other hepatic functions under conditions where glucose and insulin levels are independently controlled in old and young subjects will be of great interest.

In summary, the results of the present study demonstrate that circulating levels of IGF-I, IGFBP-1, and IGFBP-3 are altered in aging men. Reduced secretion of GH may contribute to changes in IGF bioavailability in aging through multiple mechanisms, including reduced production of IGF-I and alterations in circulating levels of IGFBP-1 and -3. Insulin remains an important determinant of IGFBP-1 levels in elders, as it is in younger subjects. Glucose levels also correlate inversely with levels of IGFBP-1 in both young and old men. This relationship appears to be independent of insulin and is less apparent in older subjects. Additional studies are indicated to understand specific mechanisms regulating the production of IGFBPs and the role they may play in modulating the availability and anabolic effects of IGFs in human aging.


   Footnotes
 
1 Presented in part at the 77th Annual Meeting of The Endocrine Society, Washington, D.C., June 14, 1995. This work was supported in part by the V.A. Merit Review Program and Rehabilitation and Research and Development Service and NIH Grant DK-41430–06. Back

Received March 20, 1996.

Revised November 1, 1996.

Revised February 4, 1997.

Accepted February 5, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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