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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-2009
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 4 1972-1978
Copyright © 2005 by The Endocrine Society

Relationship between Disease-Related Morbidity and Biochemical Markers of Activity in Patients with Acromegaly

Jardena J. Puder, Sujatha Nilavar, Kalmon D. Post and Pamela U. Freda

Department of Medicine (J.J.P., S.N., P.U.F.), Columbia University College of Physicians and Surgeons, New York, New York 10032; Division of Endocrinology, Diabetology, and Clinical Nutrition (J.J.P.), University Hospital Basel, 4052 Basel, Switzerland; and Department of Neurosurgery (K.D.P.), Mount Sinai School of Medicine, New York, New York 10029

Address all correspondence and requests for reprints to: Jardena J. Puder, Division of Endocrinology, Diabetology, and Clinical Nutrition, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland. E-mail: puderj{at}uhbs.ch.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
The criteria for biochemical control of acromegaly that will best reduce disease-related morbidity in acromegaly are debated. We therefore studied the relationship of biochemical markers with an important metabolic parameter, insulin sensitivity, and clinical parameters reflecting disease activity in acromegaly.

Newly diagnosed and postoperative patients with acromegaly underwent assessment of fasting IGF-I and fasting and postoral glucose tolerance test GH and insulin levels and completed a numeric signs and symptoms questionnaire. Insulin sensitivity was estimated by the quantitative insulin sensitivity check index (QUICKI) and the composite insulin sensitivity index. Patients were divided into three groups: group I, normal IGF-I and nadir GH less than 0.14 µg/liter (n = 21); group II, normal IGF-I and nadir GH 0.14 µg/liter or more (n = 20); group III (active), elevated IGF-I (n = 25). Age, sex, and body mass index were comparable in these groups.

Insulin sensitivity was reduced in group III (QUICKI: 0.33 ± 0.01 and composite index: 3.44 ± 0.54), compared with group II (0.38 ± 0.01, P = 0.002 and 8.18 ± 1.21, P = 0.0008), group I (0.38 ± 0.01, P = 0.0008 and 8.91 ± 1.34, P = 0.00001), and healthy controls (0.37 ± 0.008, P = 0.009). When other nadir GH cut-offs were analyzed, insulin sensitivity remained relatively reduced in the elevated IGF-I group. IGF-I was a significant predictor for decreasing insulin sensitivity as calculated by QUICKI (r = 0.6, P < 0.0001) independently of nadir GH. Signs and symptom scores were higher in group III (mean 38.5 ± 3.6%), compared with group II (mean 23.5 ± 3.2%, P = 0.004) and group I (mean 20.5 ± 3.7%, P = 0.0008) but not between the latter two groups.

Our data indicate that overall and specifically in the presence of discordant serum IGF-I and nadir GH levels, IGF-I was more predictive than GH levels of insulin sensitivity and clinical symptom score in patients with acromegaly.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
CARDIOVASCULAR DISEASE IS the major cause for the decreased life expectancy observed in acromegaly (1, 2, 3, 4, 5, 6, 7). Disease-specific risk factors for cardiovascular disease in these patients include an increase in insulin resistance with subsequent glucose intolerance (8, 9, 10, 11, 12, 13, 14, 15, 16, 17), an increase in blood pressure (18, 19, 20, 21), and an alteration in procoagulants (22, 23, 24) as well as possible direct effects of GH on the vasculature (25, 26). Although therapy of acromegaly can reduce these risk factors (8, 23, 27, 28), which presumably contribute to reducing the excess mortality of this disease (6, 29, 30, 31, 32), evidence as to how to optimally predict reduction of cardiovascular risk, and in particular insulin resistance, during therapy is lacking.

Biochemical markers for remission of acromegaly include serum IGF-I concentration, suppression of GH after an oral glucose tolerance test (oGTT), or random GH level. Which marker is best, however, is debated. More specifically, the previously proposed threshold for glucose-suppressed GH of 1 µg/liter (33, 34) has been questioned because the introduction of more sensitive GH assays (35) and cut-offs as low as 0.14–0.3 µg/liter have been proposed (17, 36, 37, 38, 39). Also, discordant results for IGF-I and GH testing are not infrequent (34, 36, 38, 39, 40). For example, subtle abnormalities of GH suppression in patients with normal IGF-I levels may increase the risk for postoperative disease recurrence (41), but it is unknown whether such abnormalities are associated with morbidity. Specific criteria for tight control, as assessed with highly sensitive assays, have yet to be validated against important morbidity outcomes in acromegaly. We therefore studied the relationship of random GH, nadir GH after oral glucose, and IGF-I levels to metabolic parameters, in particular insulin sensitivity, and clinical parameters to further refine clinically optimal biochemical goals for therapy of acromegaly.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patient population

Sixty-one patients with acromegaly were evaluated. Fifty-two patients had undergone transphenoidal surgery between 1986 and 2004 and were evaluated at least 3 months postoperatively (mean 52 ± 6.2 months; range 3–176 months). The remainder of the patients were newly diagnosed (n = 9), and five of them were studied twice, both pre- and postoperatively. Eight patients had received radiation therapy 2–16 yr before being studied. One additional patient had undergone gamma knife surgery 6 months before the study. Sixteen patients had hypopituitarism, and all were on stable doses of replacement therapy. The study groups as defined below did not differ significantly in proportions of patients with hypopituitarism: group I (n = 3), group II (n = 8), group III (active) (n = 5, P = 0.13). None of the patients were receiving medical therapy for acromegaly at the time of testing, and none had known liver or kidney disease.

Study design

Patients underwent the following laboratory and clinical assessments. An oGTT was performed in all patients after an overnight fast. Blood was sampled at baseline and then at 60, 90, and 120 min after a 100-g oral glucose ingestion (42). Serum was frozen at –80 C in multiple aliquots. Baseline fasting blood samples were assayed for IGF-I, and blood samples at all time points were assayed for insulin, glucose, and GH. Samples for each patient were run in the same assay and in duplicate. On the same morning, patients had their blood pressure measured in the right arm with a mercury sphygmomanometer sitting in a relaxed position. Patients were questioned about their history of diabetes, hypertension, and their use of anithypertensives. They completed a questionnaire on which they rated the following signs and symptoms of acromegaly: headache, excessive perspiration, fatigue, arthralgias, snoring, and overall health, with scores ranging from 0 (no symptoms) to 10 (severe, incapacitating symptoms). Score results were analyzed as a percentage of the maximal possible score. This protocol was approved by the Institutional Review Board of Columbia-Presbyterian Medical Center (New York, NY), and written informed consent was obtained from all patients.

Patient classification

Patients were classified before the analysis into three groups based on our previously defined criteria for disease status (36). These groups are defined as follows:

Group I (remission group I). Normal serum IGF-I levels and GH less than 0.14 µg/liter [the upper normal limit in healthy control subjects (36) after the oGTT] (n = 21; mean age, 45 ± 2.0 yr).

Group II (remission group II). Normal IGF-I levels but nadir GH after oral glucose 0.14 µg/liter or more, abnormal GH suppression (n = 20; mean age, 48 ± 3.6 yr).

Group III (active group). Elevated serum IGF-I levels (n = 25, mean age, 44 ± 2.0 yr).

Control group. Fasting glucose and insulin levels were measured in 24 healthy subjects as a control group.

The control group and the three acromegaly groups were comparable for age, sex, and body mass index (BMI) (Table 1Go).


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  		TABLE 1. Demographic characteristics, biochemical markers, and QUICKI in patients and controls

 
Patients were also classified according to the newly revised American Diabetes Association criteria (43): those with fasting plasma glucose levels less than 5.6 mmol/liter were classified as normoglycemic and those with fasting 5.6–6.9 mmol/liter as impaired fasting glucose. Diabetes was diagnosed when the fasting glucose was above 7 mmol/liter in two consecutive measurements or if patients had a history of diabetes.

Estimates of insulin sensitivity

In each patient, insulin sensitivity was estimated by calculating homeostasis model assessment (HOMA) scores [fasting serum insulin (microunits per milliliter) x fasting plasma glucose (millimoles per liter)/22.5)] (44) and by calculating the quantitative insulin sensitivity check index (QUICKI) [1/(log[I0] + log[G0])], where I0 is the fasting plasma insulin level (microunits per milliliter), and G0 is the fasting blood glucose level (milligrams per deciliter)] (45). Both of these calculations only assess hepatic insulin sensitivity. Because GH affects both hepatic and peripheral insulin sensitivity (14), we also estimated the whole-body insulin sensitivity by using an index derived from the 75-g oGTT (46). This composite insulin sensitivity index [10,000/square root of (fasting glucose in milligrams per deciliter x fasting insulin in microunits per milliliter) x (mean glucose x mean insulin during oGTT)] has been found to be highly correlated with the rate for whole-body glucose disposal during the euglycemic insulin clamp (46). In our study, 100 g glucose were administered, which, although it may limit the comparison of our index values with those in other studies, does still allow us to compare whole-body sensitivity between groups within our study.

With these indices, insulin sensitivity increases as the composite index or QUICKI increases and as the HOMA score decreases.

Assays

Insulin. Insulin was measured by the Immulite immunoassay (Diagnostic Products Corp., Los Angeles, CA). The intraassay coefficient of variation (CV) is 5.3%, and the interassay CV is 6.1%. The analytical sensitivity is 2 µIU/ml.

Glucose. Serum glucose was measured by the hexokinase method.

GH. GH was measured by a two-site immunoradiometric assay obtained from Diagnostic Systems Laboratories, Inc. (Webster, TX). The standards for this immunoradiometric assay contain 22 K recombinant human GH and are calibrated to World Health Organization reference preparation 88/624. In our laboratory the intraassay CV is 3.1%, the interassay CV is 5.9%, the assay sensitivity is 0.05 µg/liter, and the upper limit of normal for nadir GH level after glucose is 0.14 µg/liter (36).

IGF-I. IGF-I was measured by RIA using a polyclonal rabbit antibody generated against human IGF-I (Nichols Institute Diagnostics, San Juan Capistrano, CA). The intraassay CV is 4%, the interassay CV is 11%, and the assay sensitivity is 13.5 ng/ml. The normal ranges for this assay are: age, 16–24 yr, 182–780 ng/ml; 25–39 yr, 114–492 ng/ml; 40–54 yr, 90–360 ng/ml; and 55 yr or older, 71–290 ng/ml. IGF-I levels for all patients were compared with their age-appropriate normal ranges.

Statistical analysis

All data are described as mean ± SEM unless stated otherwise. Nadir GH was defined as the lowest values at any time after oral glucose ingestion. All variables were compared for significant differences between groups by ANOVA with post hoc testing using Fisher multiple comparison tests. Nonnormally distributed values were log transformed. Pearson’s correlation tests were used to assess the relationship between IGF-I and GH. The differences among the groups of acromegalics for the prevalence of diabetes, impaired fasting glucose, and treated hypertension were evaluated using {chi}2 test. QUICKI and composite insulin sensitivity index between two groups of either concordant GH suppression with discordant IGF-I levels or vice versa were compared using Student’s t test.

Bivariate and multiple linear regression analyses were performed to estimate the effects of different predictors of insulin sensitivity as defined by QUICKI. To normalize widely different scales of candidate predictors, values were transformed into Z-scores before analysis.

Regressions were performed using Intercooled STATA (version 8, StataCorp LP, College Station, TX); the rest of the analysis was analyzed using Statistica for Windows (version 6.0, StatSoft, Inc., Tulsa, OK).

Two-tailed P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
GH and IGF-I levels

The demographic characteristics and mean nadir GH, range of nadir GH, and mean IGF-I for the acromegaly patient groups and healthy controls are shown in Table 1Go. Seven patients in group III (28%) had GH nadir concentrations less than 1 µg/liter. The GH and IGF-I levels were previously reported in 31 of these patients (41, 47).

In patients with acromegaly, IGF-I correlated well with the log-transformed nadir GH (r = 0.72, P < 0.0001) as well as the random log GH values after overnight fasting (r = 0.67, P < 0.001).

Insulin sensitivity

Patients with high IGF-I levels (group III) were less insulin sensitive than all patients with normal IGF-I levels (groups I and II together; data not shown).

Hepatic insulin sensitivity as calculated by the QUICKI was significantly reduced in the patients in group III (0.33 ± 0.009), compared with patients in group II (0.38 ± 0.01, P = 0.002), patients in group I (0.38 ± 0.01, P = 0.0008) (Fig. 1Go), and healthy controls (0.37 ± 0.008, P = 0.009, Table 1Go). Insulin sensitivity as calculated by QUICKI was not different between healthy controls and patients in the two groups (groups I and II) with normal IGF-I concentrations. Whole-body insulin sensitivity as estimated by the composite index was also significantly reduced in the patients in group III (3.44 ± 0.54), compared with patients in group II (8.18 ± 1.21, P = 0.0008) and patients in group I (8.91 ± 1.34, P = 0.0001, Fig. 1Go). The corresponding HOMA scores for the three acromegaly groups were 3.79 ± 0.67 for group III, 2.25 ± 0.99 for group II, and 2.10 ± 0.89 for group I. There were no differences between groups I and II with respect to either of these estimates of insulin sensitivity. Thus, abnormal GH suppression, as defined by a nadir GH 0.14 µg/liter or greater, did not impair insulin sensitivity in patients with normal serum IGF-I levels.



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  		FIG. 1. Estimates of insulin sensitivity (composite insulin sensitivity index and QUICKI) in the three acromegaly groups. *, P < 0.001 vs. groups I and II. **, P < 0.005 vs. groups I and II. The groups are defined as follows: group I, normal serum IGF-I levels and nadir GH after oral glucose less than 0.14 µg/liter; group II, normal IGF-I levels but nadir GH 0.14 µg/liter or more; group III, elevated serum IGF-I levels.

 
In addition, we compared these insulin sensitivity indices in patients with normal or high IGF-I levels and different clinically relevant nadir GH cut-offs (Table 2Go). BMI did not differ between these groups. Again, insulin sensitivity was impaired in patients with high IGF-I levels but not in patients with normal serum IGF-I levels and abnormal GH suppression.


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  		TABLE 2. Estimates of insulin sensitivity (composite insulin sensitivity index and QUICKI) in patients divided by IGF-I level and different GH suppression cut-offs of 0.3 or 1.0 µg/liter

 
When we analyzed insulin sensitivity with regard to nadir GH levels only, patients whose GH suppressed to less than 0.14 µg/liter were more insulin sensitive than those with a GH nadir of more than 0.14 µg/liter (composite index 8.91 ± 1.14 and 5.55 ± 0.70, P = 0.01; QUICKI 0.38 ± 0.01 and 0.35 ± 0.007, P = 0.04, respectively). BMI did not differ between these two groups.

To examine the effect of changes in IGF-I levels within the spectrum of normal on insulin sensitivity, we divided the patients with normal IGF-I values (groups I and II) into age-adjusted IGF-I quartiles. Overall, insulin sensitivity was highest in the first (lowest) quartile of IGF-I and subsequently decreased as estimated by both QUICKI (P < 0.002) and the composite insulin sensitivity index (P = 0.02, Fig. 2Go). Post hoc analysis revealed that insulin sensitivity, as estimated by QUICKI, was significantly higher in all three lower quartiles, compared with the fourth quartile (all P < 0.02), and as estimated by the composite insulin sensitivity index, it was significantly higher in the first quartile, compared with the fourth quartile (P = 0.002).



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  		FIG. 2. Insulin sensitivity (composite insulin sensitivity index and QUICKI) within each quartile of the IGF-I normal ranges in patients with normal IGF-I values (groups I and II). *, P = 0.002 vs. first quartile; **, P < 0.02 vs. first, second, and third quartile (see text).

 
On bivariate linear regression, IGF-I as well as the log-transformed nadir and random GH levels were significant predictors for decreasing insulin sensitivity as calculated by QUICKI (Table 3Go). After transformation into Z-scores, IGF-I had a ß-coefficient of –0.54 (P < 0.0001; mean ± SEM before transformation into Z-scores: 449.8 ± 40.8 ng/ml), meaning that an increase in 1 SD of IGF-I led to a decrease of insulin sensitivity of 0.54 SD. When IGF-I was added to the random or nadir GH as a predictor of insulin sensitivity, the latter two lost their significance but not vice versa (data not shown). IGF-I explained 36% of the variance of the insulin sensitivity (r = 0.6, P < 0.0001). Other potential explanatory variables like age, sex, or BMI were not significant predictors of insulin sensitivity and did not improve the model or change the significance of IGF-I in predicting insulin sensitivity.


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  		TABLE 3. Coefficients of bivariate correlations between IGF-I and log-transformed nadir and random GH and insulin sensitivity as calculated by QUICKI

 
The expression of the IGF-I values as percentage of the upper limit of normal for age only minimally improved the correlations (data not shown).

Before testing, four patients were known to have diabetes, and they were all on pharmacological therapy. The three patients in the active group were receiving insulin and metformin (n = 1), rosiglitazone (n = 1), or metformin with glyburide (n = 1). The one patient in group I was treated with metformin. Removing the diabetic patients from any of the analyses of insulin sensitivity did not significantly alter the results.

The prevalence of impaired fasting glucose, diabetes, or combined impaired fasting glucose and diabetes was slightly but not significantly higher in group III (n = 3, n = 3, n = 6, respectively), compared with group II (n = 3, n = 0, n = 3, respectively) or group I (n = 2, n = 1, n = 3, respectively).

Signs and symptoms

The percentage of the maximal signs and symptoms score was significantly higher in the patients with active disease (group III, mean 38.5 ± 3.6%), compared with patients in group II (mean 23.5 ± 3.2%, P = 0.004) and patients in group I (mean 20.5 ± 3.7%, P = 0.0008) but not between the two latter groups (Fig. 3Go). Changing the cut-off that separated the two remission groups to 0.3 µg/liter yielded comparable results. Overall (in the total acromegalic population), both the nadir GH (r = 0.48, P < 0.01) and IGF-I (r = 0.36, P < 0.01) correlated with the percentage of the maximal signs and symptoms score.



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  		FIG. 3. Sign and symptom score in the three acromegaly groups. *, P < 0.005 vs. groups I and II. The groups are defined as follows: group I, normal serum IGF-I levels and nadir GH after oral glucose less than 0.14 µg/liter; group II, normal IGF-I levels but nadir GH 0.14 µg/liter or more; group III, elevated serum IGF-I levels.

 
Blood pressure

Treated hypertension was found in five patients with active disease (group III, 24%), five patients in group II (30%), and four patients in group I (19%, P = 0.7). There was no difference in either systolic or diastolic blood pressure among group III (121 ± 2.2 and 80 ± 1.6 mm Hg), group II (123 ± 4.2 and 79 ± 2.6 mm Hg), or group I (120 ± 2.4 and 80 ± 1.9 mm Hg).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Using modern assays, we observed for the first time that in the presence of discordant serum GH and IGF-I levels, IGF-I was more predictive of insulin sensitivity and clinical symptoms.

On a molecular level, GH augments insulin resistance in the liver and periphery (14, 48, 49). Thus, insulin resistance is a very common metabolic abnormality in patients with active acromegaly (11, 12, 13, 50) and is likely to be a major contributor to the increased cardiovascular risk associated with this disease (3, 4, 5, 6, 7, 21).

However, reports about the utility of either IGF-I or GH as a marker of insulin resistance in acromegaly are rare and vary in their conclusions. GH has been shown to correlate with insulin resistance as estimated by clamp (11, 51), oGTT (52), and iv glucose tolerance testing (8) but not with fasting measures of insulin resistance in patients before and after transphenoidal surgery (50) or patients treated with bromocriptine (53). Changes in IGF-I levels also correlated with changes in insulin resistance as assessed by clamp after surgical (54) or octreotide (55) therapy or with the decrease in fasting insulin and glucose values during pegvisomant therapy (56, 57). Only two large studies assessed the relationships between GH/IGF-I and insulin resistance without the confounder of patients being on medical therapy. These studies (52, 58) found a strong association between IGF-I levels and fasting glucose as well as 1-h postprandial glucose levels. Interpretation of prior studies is limited by their almost universal use of older, less sensitive and specific polyclonal RIAs for GH or older generation IGF-I assays.

In our study, IGF-I and nadir GH levels, as measured with a highly sensitive assay, were analyzed in relation to quantitative insulin sensitivity indices. We observed that in patients with normal serum IGF-I levels, abnormalities of GH suppression, either nadir GH 0.14 or greater (a very strict criterion) or nadir GH 0.3 µg/liter or greater, were not predictive of impaired insulin sensitivity. Parallel to this observation, in those with elevated IGF-I levels, insulin sensitivity was reduced regardless of whether GH was suppressed after oGTT. Even in the presence of GH suppression to less than 1 µg/liter (considered by other studies to be normal), high IGF-I levels were still associated with impaired insulin sensitivity. This suggests that this degree of GH suppression alone (with this particular GH assay) is not necessarily indicative of remission. Because all our patients with normal IGF-I levels had nadir GH levels of 1 µg/liter or less, we cannot comment on whether higher GH levels, as measured with other GH assays, would influence insulin sensitivity in patients with normal serum IGF-I. Nevertheless, in our multiple regression analysis in our whole study population, including patients with marked elevations of both IGF-I and nadir GH, IGF-I did prove to be a stronger predictor of insulin sensitivity.

The apparently greater prediction power of a serum IGF-I level, over random or nadir GH levels, for the presence or absence of metabolic abnormalities may be explained in part by the known positive relationship between IGF-I levels and integrated GH secretion in acromegaly. IGF-I seems to serve only as a marker for the degree of GH excess and thus insulin resistance because, in fact, IGF-I itself is known to have insulin-sensitizing effects (16, 49). In acromegaly, however, both GH and IGF-I are elevated and although the interaction between these two hormones on insulin sensitivity is complex, clinically, the elevated GH effect predominates, producing the characteristic metabolic abnormalities of this disease (16).

Our analysis also revealed a negative relationship between insulin sensitivity and IGF-I levels across the spectrum of normal IGF-I concentrations in patients with acromegaly. It is not known whether insulin sensitivity is relatively impaired in these patients with acromegaly whose IGF-I levels are in the highest quartile of normal as a reflection of mild GH excess or whether these IGF-I levels are not truly normal for these patients. Patients in our earlier study, with the biochemical profile of those in group II and who went on to recurrence, tended to have IGF-I levels in this highest quartile (41). On the basis of these findings, one could suggest that therapy should aim for an IGF-I level near the middle of the age-adjusted normal range to optimize treatment of metabolic abnormalities. This question warrants further study.

In addition to being more insulin resistant, the prevalence of impaired glucose tolerance and overt diabetes mellitus has been shown in most other studies to be increased in patients with active acromegaly (17, 23). IGF-I and nadir GH greater than 0.25 µg/liter may also be predictive of glucose intolerance (17). In our series, however, despite being more insulin resistant, neither the prevalence of impaired fasting glucose nor diabetes mellitus, as defined by fasting criteria, was increased in the group with active disease. The low prevalence of diabetes mellitus in our series may be accounted for by the fact that at our center many patients with overt diabetes mellitus do not undergo an oGTT for evaluation of disease status because oGTT results can be unreliable in diabetic patients (59).

Insulin resistance may also be an important contributing factor to the development of hypertension in acromegaly (21). Serri et al. (17) found a lower diastolic blood pressure in patients in remission, compared with those with active disease, and others (60) found the resolution of hypertension to directly correlate with GH lowering in a majority of patients. In our study, blood pressure did not differ among our patient groups. The use of effective antihypertensive treatment may have masked potential relationships among insulin resistance, biochemical markers, and hypertension in our patient population.

Few studies have assessed the relationship between IGF-I and GH levels and other specific clinical signs and symptoms of acromegaly. The initial study, performed by Clemmons et al. in 1979 (58), revealed a correlation between IGF-I and heel-pad thickness. In some (38, 58, 61) but not all (62) studies, the improvement in individual clinical symptoms paralleled the normalization of IGF-I values. In agreement with this literature, our study found that patients with high IGF-I levels, regardless of their degree of GH suppression, had a higher disease-related symptom score. Nevertheless, both IGF-I and the GH nadir correlated to the sign and symptom score.

The best criteria for biochemical remission in acromegaly is controversial, especially in the case of discordance between GH and IGF-I values (17, 33, 34, 36, 38, 52, 63, 64). Most arguments in support of one or the other marker are based on retrospectively collected mortality data (5, 7, 29, 31). However, we examined our criteria for tight biochemical control with respect to short-term morbidities that should relate to long-term outcome. Overall, our results support the validity of serum IGF-I levels as the best single predictor of overall disease status. There is also no doubt, however, of the strong negative correlation of GH levels with insulin sensitivity from our data (Table 2Go). Nadir GH levels may also still be more predictive, in some patients, of subtle GH excess or early GH dysregulation that are insufficient to raise serum IGF-I levels or impair insulin sensitivity but that may be a precursor to disease recurrence (41).

In summary, we found that in patients with acromegaly with a wide spectrum of disease activity, GH clearly influenced insulin sensitivity, but IGF-I was superior to both the random and nadir GH in its ability to predict insulin sensitivity. In the presence of apparently discordant results, IGF-I was more predictive. Patients with normal IGF-I levels are more insulin sensitive and have fewer signs and symptoms of acromegaly, compared with patients with elevated IGF-I levels, regardless of their ability to adequately suppress GH in response to a glucose load. IGF-I may be most representative of integrated GH exposure as well as possible differences in GH sensitivity and thus is an optimal predictor of insulin sensitivity and overall disease activity.


   Footnotes
 
This work was supported by National Institutes of Health Grant R01 DK 064720 (to P.U.F.) and RR 00645 (to the Columbia University General Clinical Research Center).

First Published Online January 5, 2005

Abbreviations: BMI, Body mass index; CV, coefficient of variation; HOMA, homeostasis model assessment; oGTT, oral glucose tolerance test; QUICKI, quantitative insulin sensitivity check index.

Received October 13, 2004.

Accepted December 22, 2004.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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