ACROMEGALY IS A rare disorder usually caused by a

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1 X/05/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 90(10): Printed in U.S.A. Copyright 2005 by The Endocrine Society doi: /jc Cotreatment of Acromegaly with a Somatostatin Analog and a Growth Hormone Receptor Antagonist Jens Otto Lunde Jørgensen, Ulla Feldt-Rasmussen, Jan Frystyk, Jian-Wen Chen, Lars Østergård Kristensen, Claus Hagen, and Hans Ørskov Medical Department M (Endocrinology and Diabetes) (J.O.L.J., J.F., J.-W.C., H.Ø.), Aarhus University Hospital, DK-8000 C Aarhus, Denmark; Department of Endocrinology, Rigshospitalet (U.F.-R.), DK-2200 Copenhagen, Denmark; Department of Medicine and Endocrinology, Herlev Sygehus (L.Ø.K.), DK-2730 Copenhagen, Denmark; and Department of Endocrinology (C.H.), Odense University Hospital, DK-5000 Odense, Denmark Context: Pegvisomant is a GH receptor antagonist that blocks the peripheral actions of GH in acromegaly. Pegvisomant, in contrast to somatostatin (SMS) analogs, does not suppress the activity of the GH-producing adenoma. Objective: We assessed the effects of cotreatment with pegvisomant and SMS in acromegaly on GH secretion, IGF-I levels, and glucose tolerance. Design, Patients, and Interventions: Eleven patients with persistent disease despite previous therapy underwent the following fixed treatment algorithm: 1) on SMS therapy, 2) off therapy for 2 months, 3) 6-wk treatment with 10 mg/d pegvisomant, 4) 6-wk treatment with 15 mg/d pegvisomant, and 5) 3-month treatment with 15 mg pegvisomant plus SMS. Blood was sampled in the fasting state and during an oral glucose tolerance test. Results: Total serum IGF-I levels (micrograms per liter) decreased ACROMEGALY IS A rare disorder usually caused by a benign pituitary somatotroph adenoma. The clinical features reflect autonomous GH-hypersecretion and the direct mass effects from the tumor. Transsphenoidal adenomectomy remains first-line treatment, which offers decompression of the sellar region, including the optic apparatus, and adequate biochemical remission or cure in 60% of the patients (1). Recent epidemiological data support the need for tight control of GH secretion to lower the excess mortality to that of the background population (2). For this reason, somatostatin (SMS) analogs play an important role in the treatment of residual disease and as primary therapy in patients not eligible for surgery. Although symptom relief and tumor shrinkage are obtained in many cases with SMS analogs, inadequate suppression of GH secretion is encountered in 40 50% of cases (3, 4). Moreover, SMS analogs also suppress insulin secretion (5 7), which may be unfavorable in acromegaly in which glucose intolerance and diabetes mellitus is prevalent. Pegvisomant is a biosynthetic analog of human GH that First Published Online July 26, 2005 Abbreviations: AUC, Area under the curve; IGF-IR, IGF-I receptor; OGTT, oral glucose tolerance test; SMS, somatostatin. JCEM is published monthly by The Endocrine Society ( endo-society.org), the foremost professional society serving the endocrine community after pegvisomant, but the lowest levels were obtained with cotreatment [ (SMS), (active), (10 mg), 269 (15 mg), (combined) (P )]. Free and bioactive IGF-I changed in a similar pattern. Steady-state pegvisomant levels (micrograms per liter) were obtained, but SMS cotreatment increased pegvisomant levels by 20% (P 0.02) [ (10 mg), (15 mg), (combined)]. Pegvisomant increased endogenous GH levels (micrograms per liter), which was countered by SMS cotreatment [ (SMS), (active), (10 mg), (15 mg), (combined) (P 0.01)]. Plasma glucose levels (millimoles per liter) were highest during SMS and lowest during pegvisomant 15 mg [2-h oral glucose tolerance test: (SMS), (active), (10 mg), (15 mg), (combined) (P 0.02)]. Conclusions: Dual blockade of the GH axis with pegvisomant and a SMS analog is feasible in acromegaly. (J Clin Endocrinol Metab 90: , 2005) functions as a GH receptor antagonist (4). A normalization of serum IGF-I, an accepted marker of GH-dependent disease activity (8, 9), with pegvisomant has been reported in publications including 160 patients, of whom many previously had failed to respond to conventional therapy (10, 11). It has been a concern that the combination of low IGF-I levels and GH receptor blockade could stimulate residual pituitary tumor growth. In this context, cotreatment with pegvisomant and a SMS analog would seem an attractive option by combining peripheral GH blockade with suppression of tumor activity. In one anecdotal report, this strategy was associated with a synergistic effect on IGF-I as well as arrest of tumor growth (12). We report here the results of a treatment protocol in which patients with acromegaly were studied during the following conditions: with an SMS analog, without treatment, with pegvisomant in two different doses, and after cotreatment with pegvisomant plus SMS. Patients Patients and Methods As collaboration between four Danish University Hospitals, we screened patients with acromegaly not responding adequately to conventional therapy. Eleven patients (four females, seven males, mean age 46 yr, range yr) were enrolled in the treatment protocol, which was endorsed by the ethics committee system. Nine patients had undergone at least one surgical procedure, and five patients had received conven-

2 5628 J Clin Endocrinol Metab, October 2005, 90(10): Jørgensen et al. Dual Blockade of Acromegaly tional radiotherapy. All patients except one were on SMS analog treatment (Sandostatin LAR; Novartis, Basel, Switzerland) when entering the protocol. Methods The patients were examined on five occasions in the following fixed order: 1) during Sandostatin LAR treatment (SMS), 2) after 2 months discontinuation of SMS analog treatment (active), 3) after 6 wk treatment with pegvisomant 10 mg/d (pegvisomant10), 4) after 6 six wk treatment with pegvisomant 15 mg/d (pegvisomant15), and 5) after 12 wk cotreatment with SMS plus pegvisomant 15 mg/d (combined). Study 1 was performed before the scheduled SMS injection. This injection was skipped and followed by an additional 2 months off therapy. On each of the five occasions, the patients were studied after an overnight fast in the supine position with frequent serum sampling for 3 h. After the first hour, the patients underwent an oral glucose tolerance test (OGTT) (75 g glucose). Serum IGF-I was measured by an in-house noncompetitive, time-resolved immunofluorometric assay (13). Fasting serum levels of free IGF-I were assayed by ultrafiltration (14). IGF-I bioactivity in serum was measured by an in-house IGF-I kinase receptor activation assay, based on human embryonic renal cells (EBNA 293) transfected with the human IGF-I receptor (IGF-IR) gene (15). Briefly, cultured cells are stimulated with either IGF-I standards or unknown serum samples. After 15 min, samples are removed and the cells lysed. The crude cell lysates are transferred to a sandwich assay that detects the concentration of phosphorylated (i.e. activated) IGF-IRs, using a monoclonal antibody against the extracellular domain of the IGF-IR for capture and a europium-labeled monoclonal antiphosphotyrosine antibody (PY20) as tracer. The assay is sensitive (detection limit 0.08 g/liter), specific (IGF-II cross-reactivity is 12%; proinsulin, insulin, and insulin analogs have a cross-reactivity 1%), and precise (mean withinand in-between assay coefficients of variation were 7 and 15%). Endogenous serum GH was measured by an assay (DELFIA) (PerkinElmer, Türku, Finland). In this assay the high pegvisomant contents do not react with the monoclonal anti-gh-coating antibody (directed at or very near binding site 2 for the receptor) but do react with the monoclonal europium-labeled detection antibody (directed at or very near site 1). The original assay procedures were therefore modified slightly: serum (or calibrator) GH was allowed to bind to the coating antibody for 24 h incubation, the pegvisomant containing serum was washed out six times, followed by a second 24-h incubation with the detection antibody. This procedure does not compromise the high performance of the DELFIA. For pegvisomant the cross-reactivity of the detection antibody was exploited in a RIA using pegvisomant and monoiodinated 125 I-GH (15,000 cpm, kindly donated by Novo Nordisk, Copenhagen, Denmark) as competing antigens for a 1% dilution of the concentration of the detection antibody used in the DELFIA. Because the serum samples were diluted 1:200 or 1:400, the endogenous GH contents did not significantly affect the pegvisomant readings. Serum insulin, plasma glucose, and serum nonesterified free fatty acids were analyzed with standard commercial assays. Liver function tests were performed on each occasion. A pituitary magnetic resonance imaging was performed before and at the end of the treatment periods. Statistical analysis Comparison of data among the five treatment periods was performed by one-way repeated-measures analysis. Correction for missing data points (see below) was automatically handled by using a general linear model, in which hypothesis tests are constructed using the marginal sums of squares (also commonly called the type III or adjusted sums of squares), in accordance with the statistical software (SigmaStat 1.0; Systat Software, Inc., Richmond, CA). When the hypothesis of normal distribution of data was rejected, ANOVA on ranks was performed. Where indicated post hoc multiple comparison using the Student-Newman-Keuls method was performed. Where appropriate the area under the curves (AUCs) of individual time series was calculated by the trapezoidal rule. Data are expressed as mean se. Results Eleven patients with acromegaly participated in the study. Ten patients were treated with Sandostatin LAR 30 mg im every 2 4 wk at baseline. This treatment was continued during the first treatment period (SMS). One patient, who had previously failed to respond to SMS analog treatment, participated in only the last four treatment periods. This patient received Sandostatin LAR 30 mg every 4 wk during study 5 (combined). One patient was withdrawn from the last study because of abnormal liver function tests, which subsequently were normalized. The data from these two patients were included in the analysis after correction for missing data points (see above). The remaining nine patients were treated in study 5 with a Sandostatin LAR dose similar to that which they had received in study 1 (30 mg every 2 4 wk). Two patients received insulin at baseline and during all treatment periods. These patients were excluded from analysis of glucose and insulin. Serum total IGF-I levels (micrograms per liter) changed significantly during the study with elevations during study 2 (active) and with the lowest levels during study 5 (combined) [ (SMS), (active), (pegvisomant10), (pegvisomant15), (combined) (P 0.001)]. Post hoc statistics revealed a significant difference between study 2 (active) and studies 3 5 (P 0.05) in addition to a significant difference between study 1 (SMS) and study 5 (combined) (P 0.05) (Fig. 1). Likewise, free IGF-I levels changed significantly (P 0.001), with the lowest levels recorded during combined therapy (P 0.05). Post hoc statistics showed a difference between study 2 (active) and studies 4 and 5 as well as a difference between study 1 (SMS) and studies 4 and 5 (Fig. 1). Serum IGF-I bioactivity decreased significantly during high-dose pegvisomant as well as combined treatment (P 0.01), but there was no difference between the two latter treatments (Fig. 1). The mean free and bioactive IGF-I levels correlated significantly in all studies except during combined treatment (data not shown). Steadystate serum pegvisomant levels (micrograms per liter) were recorded during the three pegvisomant treatment studies (Fig. 2), yielding the following mean levels: (pegvisomant10), (pegvisomant15), (combined) (P ). Interestingly, serum pegvisomant levels were increased by 20% on average when pegvisomant 15 mg was combined with SMS (P 0.02 with a paired t test). Endogenous GH levels (micrograms per liter, mean of 12 measurements over 3 h in each study) changed significantly during the study with lowest levels during SMS and highest levels after pegvisomant15 [ (SMS), (active), (pegvisomant10), (pegvisomant15), (combined) (P 0.01)] (Fig. 2). Post hoc statistics revealed significant differences in GH levels between pegvisomant15 vs. SMS as well as vs. no treatment (active) (P 0.05). Fasting plasma glucose levels (millimoles per liter) were significantly different in the five studies, with highest levels during SMS and lowest levels during treatment with pegvisomant15 [ (SMS), (active), (pegvisomant10), (pegvisomant15), (combined) (P 0.02)]. Post hoc statistics disclosed a difference between studies 1 and 5 (P 0.05) (Fig. 3). Fasting serum insulin levels (picomoles per liter) did not differ among the five studies [45 5 (SMS), 61 9 (active), 63 8 (pegvisomant10), 60 7 (pegvisomant15), (combined) (NS)]. The AUC glucose

3 Jørgensen et al. Dual Blockade of Acromegaly J Clin Endocrinol Metab, October 2005, 90(10): FIG. 1. Mean SE serum levels of total (top panel), free (middle panel), and bioactive (bottom panel) IGF-I at the end of each study period. The P value is derived from ANOVA. For post hoc statistics, please see text. (millimoles l 1 minutes) during the OGTT differed significantly, with the highest levels recorded during SMS and the lowest levels during pegvisomant 15 mg [ FIG. 2. Mean SE serum pegvisomant (upper panel) and GH (lower panel) at the end of each treatment period. The P value is derived from ANOVA. For post hoc statistics, please see text. (SMS), (active), (pegvisomant10), (pegvisomant15), (combined), (P 0.03)]. The AUC insulin (picomoles l 1 minutes) during the OGTT also differed among the five studies (P 0.05), with the lowest levels after SMS and highest levels with 15 mg pegvisomant [20,156 6,294 (SMS), 34,943 7,465 (active), 37,419 7,005 (pegvisomant10), 44,084 6,512 (pegvisomant15), 33,083 7,763 (combined)]. The low AUC insulin during SMS was mainly attributed to low insulin levels for the initial 60 min of the 2-h OGTT (Fig. 3). Moreover, also the 2-h plasma glucose value (millimoles per liter) differed significantly among the five studies, which, according to post hoc statistics, could be attributed to elevated levels during SMS, compared with both pegvisomant10 and pegvisomant15 [ (SMS), (active), (pegvisomant10), (pegvisomant15), (combined) (P 0.02)].

4 5630 J Clin Endocrinol Metab, October 2005, 90(10): Jørgensen et al. Dual Blockade of Acromegaly FIG. 3. Mean SE serum glucose and insulin levels. At the end of each treatment period, an OGTT was performed at t 0. The P value is derived from ANOVA. For post hoc statistics, please see text. Tumor size as assessed by conventional magnetic resonance imaging before and after the study was described as unaltered except for one patient in whom the maximal diameter increased from 14 to 16 mm. Discussion Our protocol aimed to evaluate the effects of cotreatment with SMS and pegvisomant, compared with either treatment modality alone, on biochemical end points in patients with acromegaly. As expected, pegvisomant lowered free and total IGF-I levels in a dose-dependent manner, but a further suppression of total and free IGF-I was observed after subsequent cotreatment with SMS. Treatment with SMS alone was associated with a worsening in glucose tolerance, whereas the opposite was observed with pegvisomant. Failure to obtain acceptable clinical and biochemical remission despite conventional therapy was the inclusion criterion. Six of 11 patients had received conventional pituitary radiotherapy, which potentially may bias our results, inasmuch as the investigation was not conducted in a randomized, parallel manner. On the other hand, our study was conducted over 8 months during which significant and bidirectional IGF-I changes were recorded in all patients. Moreover, five of the six patients had received radiotherapy less than 2 yr before the study. We therefore consider it unlikely that previous radiation therapy has contributed significantly to the observed changes. In study 2 the patients skipped their last scheduled injection and discontinued treatment for an additional 2 months. It is therefore possible that some residual SMS activity prevailed when study 2 was performed, which could influence the biochemical end points and in particular underestimate the IGF-I-lowering effect of SMS. Pegvisomant lowered serum IGF-I in a dose-dependent manner, which is in accordance with previous data (10). The observation that cotreatment with SMS induced a further decrease has previously been reported in a single patient only (12). In fact, with the combined treatment, serum IGF-I was normalized in all but one patient (data not shown). Comparable results were obtained with regard to free and bioactive IGF-I, with the exception that combined treatment failed to show an additional decrease, compared with pegvisomant 15 mg. Our bioassay detects IGF-I accessible to its receptors on the transfected cells, and this IGF-I pool is presumed to comprise free IGF-I plus IGF-I dissociated from its binding proteins during incubation. The mechanisms by which combined treatment affects the dissociable IGF-I fraction and whether this is of clinical significance remain to be investigated. It is also important to recall that combined treatment is not the only way to normalize serum IGF-I because this may be obtained with pegvisomant alone in most patients with a mean daily dose of 19 mg, although some patients may require 40 mg/d (11). Endogenous serum GH levels increased in a dose-dependent manner with pegvisomant treatment followed by a decline during cotreatment with SMS to a level slightly above that measured when no treatment was given. This rise in GH induced by pegvisomant, which has been reported earlier (10, 11), is suggested to be caused by increased secretion from residual tumor tissue as a consequence of lowered IGF-I levels and blockade of autofeedback inhibition by GH itself. It is interesting that GH secretion was markedly reduced by SMS cotreatment despite a further decline in IGF-I. Our study demonstrates for the first time that steady-state levels of pegvisomant in serum are obtained with daily sc administration, which fits well with an estimated half-life of 70 h (3). These pegvisomant concentrations accord with data obtained from dose-response studies in healthy subjects (16). When considering that steady-state levels of pegvisomant were obtained during each study period and that the estimated half-life of total circulating IGF-I is approximately 20 h, we find it likely that the observed IGF-I levels are the results of the different treatment regimens rather than effects of time or carry-over. We therefore suggest that cotreatment with SMS has an additive effect to pegvisomant in terms of IGF-I suppression. It could be speculated that part of this effect is related to the observed 20% increase in pegvisomant levels, which has been observed previously in a single patient

5 Jørgensen et al. Dual Blockade of Acromegaly J Clin Endocrinol Metab, October 2005, 90(10): (12). It is unknown whether this effect of SMS is due to alterations in the clearance rate or the distribution volume of pegvisomant. It has been shown that pegvisomant, like GH, is internalized after binding to the receptor (17). In isolated rat hepatocytes, octreotide (Sandostatin) reduces GH binding to the GH receptor by 81% and also suppressed GH signaling through the Janus kinase/signal transducer and activator of transcription pathway, which resulted in reduced IGF-I production (18). Our study supports the hypothesis that SMS also exerts peripheral effects at the levels of the GH receptor. It has previously been reported that pegvisomant treatment of acromegaly lowers fasting levels of glucose as well as insulin (11), which reflects the insulin antagonistic effects of GH (19). Chronic GH exposure is associated with hyperinsulinemia, which is presumed to be secondary to peripheral insulin resistance (19, 20) and probably also a direct stimulatory effect on the -cell (21). In the present study, the improvement in glucose tolerance with pegvisomant was associated with moderately increased insulin secretion during the OGTT. We consider the most likely explanation to be that pegvisomant treatment predominantly improves insulin sensitivity, which lowers basal glucose levels and reduces chronic -cell stimulation. Improvement of insulin sensitivity with pegvisomant has previously been reported (22, 23), and it is well described in other clinical conditions that a reduction in chronic -cell demand restores the insulin response to acute glucose exposure (24). In summary, this study demonstrates that pegvisomant not only lowers IGF-I levels but also improves glucose tolerance in acromegalic patients who have failed to respond to conventional therapy. Moreover, dual blockade of the GH axis with pegvisomant and a SMS analog is a feasible option in selected patients with acromegaly. This novel therapeutic concept merits to be tested in a randomized clinical trial. Acknowledgments Received March 11, Accepted July 19, Address all correspondence and requests for reprints to: J. O. L. Jørgensen, Medical Department M, Aarhus University Hospital, Norrebrogade 44, DK-8000 C Aarhus, Denmark. jolj@dadlnet.dk. References 1. Swearingen B, Barker FG, Katznelson L, Biller BMK, Grinspoon S, Klibanski A, Moayeri N, Black PM, Zervas NT 1998 Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly. J Clin Endocrinol Metab 83: Holdaway IM, Rajasoorya CR, Gamble GD, Stewart AW 2003 Long term treatment outcome in acromegaly. Growth Horm IGF Res 13: Kopchick JJ, Parkinson C, Stevens EC, Trainer PJ 2002 Growth hormone receptor antagonists: discovery, development, and use in patients with acromegaly. 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