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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-2276
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 5 1724-1728
Copyright © 2007 by The Endocrine Society

The Impact of Pegvisomant Treatment on Substrate Metabolism and Insulin Sensitivity in Patients with Acromegaly

Rune Lindberg-Larsen, Niels Møller, Ole Schmitz, Søren Nielsen, Marianne Andersen, Hans Ørskov and Jens O. L. Jørgensen

Medical Department M (Endocrinology and Diabetes) and Institute of Clinical Experimental Research (R.L.-L., N.M., S.N., H.Ø., J.O.L.J.) and Department of Clinical Pharmacology (O.S.), Aarhus University Hospital, DK-8000 Aarhus, Denmark; and Department of Endocrinology (M.A.), Odense University Hospital, DK-5000 Odense, Denmark

Address all correspondence and requests for reprints to: Dr. J. O. L. Jørgensen, Medical Department M, Aarhus Sygehus, Norrebrogade 44, DK-8000 C, Aarhus, Denmark. E-mail: jolj{at}dadlnet.dk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Pegvisomant is a specific GH receptor antagonist that is able to normalize serum IGF-I concentrations in most patients with acromegaly. The impact of pegvisomant on insulin sensitivity and substrate metabolism is less well described.

Patients and Methods: We assessed basal and insulin-stimulated (euglycemic clamp) substrate metabolism in seven patients with active acromegaly before and after 4-wk pegvisomant treatment (15 mg/d) in an open design.

Results: After pegvisomant, IGF-I decreased, whereas GH increased (IGF-I, 621 ± 82 vs. 247 ± 33 µg/liter, P = 0.02; GH, 5.3 ± 1.5 vs. 10.8 ± 3.3 µg/liter, P = 0.02). Basal serum insulin and plasma glucose levels decreased after treatment (insulin, 54 ± 5.9 vs. 42 ± 5.3 pmol/liter, P = 0.001; glucose, 5.7 ± 0.1 vs. 5.3 ± 0.0 mmol/liter, not significant), whereas palmitate kinetics were unaltered. During the clamp, the glucose infusion rate increased after pegvisomant (3.1 ± 0.5 vs. 4.4 ± 0.6 mg/kg·min, P = 0.02), whereas the suppression of endogenous glucose production tended to increase (0.7 ± 0.0 vs. 0.5 ± 0.1 mg/kg·min, not significant). Total resting energy expenditure decreased after pegvisomant treatment (1703 ± 109 vs. 1563 ± 101 kcal/24 h, P = 0.03), but the rate of lipid oxidation did not change significantly.

Conclusions: 1) Pegvisomant treatment for 4 wk improves peripheral and hepatic insulin sensitivity in acromegaly. 2) This is associated with a decrease in resting energy expenditure, whereas free fatty acid metabolism is unaltered. 3) The data support the important direct effects of GH on glucose metabolism and add additional benefits to pegvisomant treatment for acromegaly.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ACTIVE ACROMEGALY IS a hypermetabolic condition characterized by elevated resting energy expenditure (REE), increased lipolysis, and hepatic as well as peripheral insulin resistance with respect to glucose metabolism (1). An increased prevalence of impaired glucose tolerance and overt diabetes mellitus is also well documented (2). It is assumed, albeit not formally demonstrated, that these abnormalities contribute to the observed increase in cardiovascular morbidity and mortality (2). In indirect support of this, successful surgery, which has been shown to normalize the mortality rate, is also associated with a correction of the metabolic aberrations (1). However, surgery is not always an option, and approximately 50% of operated patients are not adequately controlled by this treatment (3). Therefore, medical therapy with somatostatin analogs is justified in many cases and has proven effective regarding control of GH hypersecretion and symptom relief in 60% of patients. The impact of somatostatin analogs on glucose homeostasis in acromegaly is unpredictable (4, 5), which may be explained by the concomitant inhibition of insulin secretion.

Pegvisomant is a newly developed GH receptor (GHR) antagonist, which competes with native GH for the GHR and prevents its functional dimerization and thereby also GH signal transduction (6). When administered in high doses, pegvisomant is able to normalize IGF-I concentrations in virtually all acromegalic patients (7). Theoretically, pegvisomant treatment compared with surgery or administration of a somatostatin analog would allow a more specific examination of the effects of GH hypersecretion in acromegaly on substrate metabolism and insulin sensitivity. Indeed, long-term pegvisomant treatment significantly lowers fasting blood glucose levels in acromegalic patients (8), and there is also evidence of improvement in glucose tolerance (9, 10). The impact of pegvisomant on insulin sensitivity remains unclear, because an improvement was observed as judged by a short insulin test but not when employing the homeostatic model assessment (HOMA) (9). A detailed evaluation of substrate metabolism during pegvisomant treatment has so far not been reported.

This paper describes the effect of pegvisomant treatment in acromegaly on substrate metabolism and insulin sensitivity by means of indirect calorimetry, isotopical assessment of glucose and palmitate turnover, and a euglycemic-hyperinsulinemic glucose clamp.


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

Seven patients with active acromegaly participated in the study (two women and five men; mean ± SE age, 49 ± 5 yr). Two patients were newly diagnosed, four patients had residual disease despite previous surgery, and one patient received pegvisomant beforehand (15 mg/d). Apart from one patient, who continued treatment with tiamazol 5 mg/d for hyperthyroidism, none of the patients received any medication. All patients were normotensive and had normal liver function tests at baseline, and none of the patients had overt diabetes mellitus. All subjects gave their informed consent after receiving oral and written information according to the Declaration of Helsinki II. The study was approved by the Ethics Committee System of Aarhus County.

Design

The study was an open, nonrandomized trial. Each patient was investigated on two occasions: 1) in the active phase (pretreatment) and 2) after 4 wk pegvisomant therapy (15 mg/d). The one patient on current pegvisomant treatment was first studied on this treatment and then after 4 wk of discontinuation. The studies commenced at 0730 h after a 10-h overnight fast and were conducted in the supine position. An iv cannula was inserted in an antecubital vein for iv infusions. For blood sampling, a wrist vein on the contralateral hand was cannulated and kept in a heating box to provide arterialized blood.

At 0800 h, a priming dose of [3-3H]glucose (20 µCi; NEN Life Science Products, Boston, MA) was given, followed by a continuous infusion of [3-3H]glucose (20 µCi/h) for 5 h, with 2.5 h allowed for the tracer to equilibrate. At 0930 and 1230 h, infusion of [9,10-3H]palmitate (0.3 µCi/min; Laegemiddelstyrelsen, Bronshoj, Denmark) was started and maintained for 1 h, respectively.

At 1030 h, a 2.5-h constant (0.6 mU/kg·min) infusion of human insulin (Actrapid; Novo Nordisk, Copenhagen, Denmark) was started; based on measurements every 5 min, plasma glucose concentrations were clamped at 5.0 mmol/liter by infusion of variable amounts of 20% glucose solution.

Analytic methods

All samples were analyzed in duplicate. Plasma glucose was measured immediately after sampling on a glucose analyzer (Beckman Instruments, Palo Alto, CA). Serum free fatty acid (FFA) concentrations were determined by a colorimetric method using commercial kit (Wako Chemicals, Neuss, Germany). RIAs were employed to measure plasma glucagon, serum insulin, and serum total IGF-I. The assay for measurement of GH and pegvisomant in serum has been described previously (10). Serum C-peptide was analyzed by a commercial kit (Immunonuclear Corp., Stillwater, MN).

The non-steady-state equation of Steele as modified by DeBodo et al. (11) was used for calculation of glucose appearance/disposal rates (Ra/Rd). A pool fraction of 0.65 was used. Net nonoxidative glucose disposal (NGD) was calculated by subtracting oxidative glucose disposal (GOX) from whole-body glucose disposal (WGD). During the clamp, endogenous glucose production (EGP) was calculated by subtracting the glucose infusion rate (GIR) from WGD. To minimize rapid dilution of the labeled glucose pool with unlabeled glucose, [3-3H]glucose was added to the glucose infused during the clamp (200 µCi/liter glucose, 20%) (12). The specific activity (SA) of [3-3H]glucose was measured as previously described (13). Systemic palmitate flux was measured with the isotope dilution technique and steady-state equations. Blood samples for measurements of palmitate concentration and SA were drawn before the infusion and after 30, 40, 50, and 60 min of infusion. Plasma palmitate concentration and SA were determined by HPLC (14) by use of [2H31]palmitate as internal standard (15). Systemic palmitate flux was calculated using the [9,10-3H]palmitate infusion rate divided by the steady-state palmitate SA.

Indirect calorimetry (Deltatrac monitor; Datex Instrumentarium, Helsinki, Finland) was performed for 30 min at the end of the basal period and at the end of the clamp period, allowing measurements of REE and the respiratory exchange ratio. The initial 5 min of calorimetry were used for acclimatization, and calculations were based on mean values of 25 1-min measurements. Net lipid and glucose oxidation rates (GOX) were calculated by using the nonprotein respiratory quotient from the above measurements. Protein oxidation rates were estimated from the urinary excretion of urea collected over the first 5 h of the study (16). To estimate total body water, body fat percentage, and lean body mass, bioelectrical impedance analysis (BIA) was performed.

Statistics

Values are presented as means ± SE. Either Student’s t test for paired comparisons or Wilcoxon signed rank matched pairs test was used after testing for normal distribution by Kolmogorov-Smirnov. A P value of <0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Circulating hormones and metabolites

During the basal period, total IGF-I decreased significantly after pegvisomant treatment (IGF-I, 621 ± 82 vs. 247 ± 33 µg/liter, P = 0.02). GH increased after treatment (GH, 5.6 ± 1.8 vs. 14.4 ± 4.2 ng/ml, P = 0.02). Neither GH nor IGF-I levels changed significantly during the clamp (data not shown). A mean ± SE serum pegvisomant level of 6795 ± 1247 µg/liter was reached after treatment. Basal serum insulin decreased after treatment (insulin, 54 ± 5.9 vs. 42 ± 5.3 pmol/liter, P = 0.001), whereas the decline in serum C-peptide levels failed to reach statistical significance [C-peptide, 852 ± 78 vs. 795 ± 81 pmol/liter, not significant (NS)]. During the clamp, serum insulin increased to comparable steady-state values [225 ± 13 (active) vs. 230 ± 13 pmol/liter (pegvisomant), NS], whereas serum C-peptide levels remained unchanged [555 ± 120 (active) vs. 536 ± 89 pmol/liter (pegvisomant), NS]. Neither basal nor insulin-stimulated plasma glucagon levels changed after pegvisomant treatment (data not shown). Circulating FFA levels did not differ in the two experiments and decreased to the same extent during the clamp [basal, 383 ± 41 (active) vs. 361 ± 40 µmol/liter (pegvisomant), NS; clamp, 41 ± 10 (active) vs. 52 ± 10 µmol/liter (pegvisomant), NS].

Glucose metabolism and insulin sensitivity

Fasting plasma glucose concentrations decreased insignificantly after pegvisomant treatment (5.7 ± 0.1 vs. 5.3 ± 0.0 mmol/liter). The SA of the glucose tracer was checked during the last 20 min in each period for steady state. The values were 83 ± 8, 86 ± 8, 87 ± 8 (basal before pegvisomant), 111 ± 9, 111 ± 9, 114 ± 9 (clamp before pegvisomant), 89 ± 5, 90 ± 6, 92 ± 6 (basal after pegvisomant), 111 ± 7, 109 ± 7, and 111 ± 6 (clamp after pegvisomant) dpm/µmol. The slope of the regression line does not differ significantly from zero in either situation, indicating achievement of near steady state. The isotopically determined basal rates of glucose appearance (Ra) and disposal (Rd) were comparable before and after pegvisomant [Ra, 1.74 ± 0.09 (before) vs. 1.81 ± 0.07 mg/kg·min; Rd, 1.82 ± 0.07 (before) vs. 1.89 ± 0.07 mg/kg·min]. Basal GOX tended to decrease after pegvisomant treatment (1.7 ± 0.2 vs. 1.3 ± 0.2 mg/kg·min, P = 0.05). The GIR (mg/kg·min) necessary to maintain euglycemia during the clamp increased after treatment (Fig. 1Go). During the clamp, GOX rate remained unchanged after treatment, whereas NGD increased (Table 1Go). EGP during the clamp tended to be more suppressed after pegvisomant treatment (NS) (Table 1Go).


Figure 1
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  		FIG. 1. Mean ± SE levels of glucose (upper panel), insulin (middle panel), and the GIR (lower panel) before ({circ}) and after (•) pegvisomant treatment.

 

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  		TABLE 1. Glucose metabolism during the euglycemic hyperinsulinemic clamp before and after pegvisomant treatment

 
REE, lipid oxidation, and palmitate turnover

Total REE decreased both in the basal period and during the clamp after pegvisomant treatment as compared with nontreatment levels (basal, 1703 ± 109 vs. 1563 ± 101 kcal/24 h, P = 0.03; clamp, 1700 ± 174 vs. 1580 ± 109 kcal/24 h, P = 0.03).

Basal and insulin-stimulated lipid oxidation rates were comparable before and after treatment (basal, 632 ± 134 vs. 503 ± 101 mg/kg·min, P = 0.35; clamp, 238 ± 65 vs. 123 ± 109 mg/kg·min). Basal and insulin-stimulated palmitate concentrations and fluxes did not change significantly after treatment (basal palmitate, 106 ± 16 vs. 101 ± 22 µM, NS; clamp, 21 ± 7 vs. 19 ± 4, NS; basal palmitate flux, 134 ± 12 vs.112 ± 14 µmol/min, NS; clamp, 42 ± 14 vs. 32 ± 5 µmol/min, NS) (Fig. 2Go). The rate of protein oxidation increased after treatment (0.6 ± 0.1 vs. 1.0 ± 0.2 mg/kg·min, P = 0.03).


Figure 2
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  		FIG. 2. Mean ± SE basal and insulin-stimulated (clamp) palmitate turnover before (untreated) and after 4 wk of pegvisomant therapy.

 
Body composition

The percentage of total body weight accounted for by fat increased after treatment (17 ± 5 vs. 19 ± 4%, P = 0.04). Total body water decreased after treatment (55 ± 5 vs. 52 ± 4 kg, P = 0.02). Lean body mass decreased after treatment (88 ± 6 vs. 86 ± 6 kg, P = 0.02).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study reports that short-term specific suppression of GH activity by means of the GHR antagonist pegvisomant increases hepatic and peripheral insulin sensitivity with respect to glucose metabolism in patients with acromegaly. This was accompanied by unaltered FFA kinetics and lipid oxidation. Insulin sensitivity was assessed by the euglycemic glucose clamp technique in combination with infusion of a glucose tracer, which is considered the gold standard.

The increase in insulin sensitivity after suppression of GH activity is in accordance with data obtained before and after successful surgery (1, 17, 18), but the use of pegvisomant provides a more specific model for measuring the metabolic impact of GH, which rules out the potential contribution of non-GH-related effects such as surgery-induced abnormalities of other pituitary hormones. Our data support the observations that pegvisomant treatment in acromegaly improves glycemic control as judged by fasting levels of glucose and insulin (8, 9, 19). In addition, Drake et al. (9) recorded an increase in insulin sensitivity measured by a short insulin tolerance test but not when using HOMA. It should, however, be recognized that HOMA is a measure of basal insulin sensitivity, whereas the clamp technique yields a measure of insulin sensitivity in the maximally stimulated state.

The molecular mechanisms subserving GH-induced insulin resistance have not been elucidated, but studies using glucose tracers (20) and the euglycemic clamp (13, 21) have documented resistance to the actions of insulin on hepatic as well as peripheral glucose metabolism. Glucose intolerance during prolonged GH exposure is also well documented despite a several-fold increase in prehepatic insulin secretion (22). Interestingly, the study by Rosenfalck et al. (22) observed a more pronounced GH-induced clearance of C-peptide compared with insulin, which is compatible with our data. The explanation for this is unknown, but GH increases the glomerular filtration rate and renal plasma flow, and the kidney is largely responsible for the clearance of both C-peptide and insulin. Bak et al. (23) have documented unchanged insulin binding and insulin receptor kinase activity in muscle biopsies from healthy subjects after GH infusion during a glucose clamp, whereas glycogen synthase activity was reduced by 41%. We have recently reported activation of the signal transducer and activator of transcription 5b (STAT5b) pathway in muscle and fat biopsies in human subjects in vivo shortly after exposure to an iv GH bolus (24), which indicates acute and direct effects of GH in these tissues. We have also previously observed that suppression of FFA levels with a nicotinic acid derivative reversed the GH-induced decline in insulin sensitivity in GH-deficient adults (25). That observation is in accordance with experimental studies demonstrating that FFA infusion causes insulin resistance in healthy subjects and in patients with type 2 diabetes mellitus . This effect is associated with suppression of insulin signaling proteins involved in the translocation of glucose transporters (GLUT4) in skeletal muscle (26). A study by Jessen et al. (27) however, failed to record an effect of GH on insulin-stimulated insulin receptor substrate-1-associated phosphatidylinositol-3-kinase activity in muscle biopsies obtained from healthy subjects. In the present study, pegvisomant treatment was not associated with significant changes in FFA levels or lipid oxidation, which suggests that GH also induces insulin resistance via FFA-independent mechanisms.

It is also noteworthy, albeit predictable, that pegvisomant treatment caused a moderate increase in total body fat and a decrease in lean body mass assessed by BIA. It is well known that GH also increases extracellular volume, which will overestimate any dry weight changes in fat and lean body mass recorded by BIA (28); for this reason, BIA-derived data on changes in body composition induced by GH must be interpreted with caution. But it is predictable that control of GH hypersecretion in acromegaly will result in a reduction in lean body mass and an increase in total body fat. The increase in fat mass after pegvisomant treatment may, in turn, explain why FFA levels were similar in the two settings, if assuming that the lipolytic effect of GH in the active phase and the increased fat mass after 4 wk pegvisomant treatment yield the same amount of FFA release although via different mechanisms.

We have previously observed that discontinuation of GH replacement in adolescent GH-deficient patients improved insulin sensitivity concomitantly with an increase in fat mass (29). The latter observation in conjunction with the present data emphasizes that GH in certain conditions causes insulin resistance despite changes in body composition, which per se would favor an improvement in insulin sensitivity.

The reduction in REE and protein oxidation after pegvisomant treatment are compatible with the calorigenic and protein anabolic actions of GH, but it is important to underline that our study did not include a standardized diet or corrections for changes in physical activity.

Our data support that insulin resistance is prevalent in patients with active acromegaly (1, 30). Successful surgery improves insulin sensitivity (1, 30), and the same seems to be true regarding pegvisomant. The impact of somatostatin analogs, which effectively lowers GH and IGF-I levels in 50–60% of patients, on insulin sensitivity and glucose tolerance is more ambiguous. In an open design, glucose tolerance was studied in 90 patients with acromegaly before and 6 months after thrice-daily octreotide treatment (31). The peak glucose concentrations during the oral glucose tolerance test (OGTT) were increased and delayed after octreotide treatment, which was associated with a relative decrease in stimulated insulin levels. A deterioration of glucose tolerance was recorded in 34%, whereas an improvement occurred in 15% (5). Ho et al. (4) performed an OGTT as well as a euglycemic clamp in seven patients with acromegaly before and after 7–14 months of thrice-daily octreotide treatment. Each study was performed after an overnight fast after omission of the morning dose of octreotide. With this design, a significant improvement in glucose tolerance as well as insulin sensitivity was observed (4). In a study involving 24 patients on sustained-release formulations of somatostatin analogs, a worsening of glucose tolerance and glycemic control was observed after 6 months, whereas insulin sensitivity, assessed by a glucose clamp in 12 patients, improved (9). Drake et al. (9) compared insulin sensitivity (HOMA and short insulin tolerance test) in seven patients, who were studied while treated with depot octreotide and subsequently after 8 months of pegvisomant treatment. Serum IGF-I levels decreased insignificantly, whereas insulin sensitivity, assessed by the short insulin tolerance test, and the pancreatic ß-cell secretory function (HOMA) improved significantly. In a recent study of 11 patients with acromegaly, who had not responded adequately to depot octreotide, glucose tolerance improved after treatment with pegvisomant (10). This improvement was associated with a higher and more rapid increase in insulin secretion during the OGTT, which is in accordance with the study by Baldelli et al. (32) in which octreotide treatment induced a reduced and delayed insulin response during the OGTT. These observations suggest that somatostatin analog treatment tends to worsen glucose tolerance secondary to a direct suppression of insulin (33) and perhaps also via inhibition of gut-derived insulinotropic hormones. At the same time, however, somatostatin analog treatment seems to improve hepatic and peripheral insulin sensitivity as assessed by the glucose clamp proportionally with its ability to reduce GH secretion (4, 32). It remains to be investigated whether the potentially unfavorable effects of somatostatin analogs on glycemic control may affect the long-term outcome in terms of morbidity and mortality. At this stage, it seems fair to conclude that pegvisomant therapy compared with somatostatin analogs confers a theoretical advantage regarding glucose tolerance and insulin sensitivity. In addition, pegvisomant is also able to normalize IGF-I levels in a larger proportion of patients compared with somatostatin analogs (7, 8, 10). On the other hand, the clinical experience with pegvisomant is still limited, and the costs as well as the lack of suppression of tumor activity and size by this treatment remain a concern. In this regard, combined treatment with a somatostatin analog and pegvisomant could prove to be a promising option, which may even be cost effective compared with monotherapy with pegvisomant (8, 10).

In summary, this study demonstrates that short-term pegvisomant treatment of patients with acromegaly lowers energy expenditure and improves insulin sensitivity with respect to glucose metabolism without altering circulating FFA kinetics or lipid oxidation. This adds to our understanding of the pathophysiology of active acromegaly, and at the clinical level, the data indicate that the possibilities of medical treatment of this condition continue to expand.


   Acknowledgments
 
We are grateful for the skillful technical assistance of Annette Mengel. Pegvisomant was generously supplied by Pfizer Inc.


   Footnotes
 
The study was supported in part by an unrestricted research grant from Pfizer Inc.

Disclosure Statement: J.O.L.J. has received an unrestricted research grant and lecture fees from Pfizer Inc. and lecture fees from Novartis and Ipsen. The other authors have nothing to declare.

First Published Online March 6, 2007

Abbreviations: BIA, Bioelectrical impedance analysis; EGP, endogenous glucose production; FFA, free fatty acid; GHR, GH receptor; GIR, glucose infusion rate; GOX, oxidative glucose disposal; HOMA, homeostasis model assessment; NGD, nonoxidative glucose disposal; NS, not significant; OGTT, oral glucose tolerance test; REE, resting energy expenditure; SA, specific activity; WGD, whole-body glucose disposal.

Received October 18, 2006.

Accepted February 26, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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S. J. C. M. M. Neggers, M. O. van Aken, J. A. M. J. L. Janssen, R. A. Feelders, W. W. de Herder, and A.-J. van der Lely
Long-Term Efficacy and Safety of Combined Treatment of Somatostatin Analogs and Pegvisomant in Acromegaly
J. Clin. Endocrinol. Metab., December 1, 2007; 92(12): 4598 - 4601.
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