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Original Studies |
Department of Internal Medicine and Endocrinology (A.M.R., S.M., J.H., S.M.), Hvidovre University Hospital, Copenhagen 2650 Hvidovre; Department of Endocrinology M (S.F., J.O.L.J., J.S.C.), Aarhus University Hospital 8000 Aarhus C; and Novo Nordisk A/S (A.V.), 2880 Bagsværd, Denmark
Address all correspondence and requests for reprints to: Anne Mette Rosenfalck, M.D., Department of Internal Medicine and Endocrinology 541, Hvidovre University Hospital, Kettegaard Alle 30, DK 2650 Hvidovre, Denmark. E-mail: amro{at}dadlnet.dk
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Abstract |
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Glucose metabolism was evaluated by an oral glucose tolerance test and an iv (frequently sampled iv glucose tolerance test) glucose tolerance test, and body composition was estimated by dual-energy x-ray absorptiometry.
Treatment with rhGH induced persistent favorable changes in body composition, with a 10% increase in lean body mass (P < 0.001) and a 12% reduction of fat mass (P < 0.002); however, the glucose tolerance deteriorated significantly, and three patients developed impaired glucose tolerance. Fasting insulin level (P < 0.003) and the homeostasis model assessment insulin resistance score increased significantly, indicating a deterioration in insulin sensitivity; whereas the insulin sensitivity index, calculated from the frequently sampled iv glucose tolerance test, only decreased slightly. The clearance of C-peptide and insulin increased 100% and 60%, respectively, and the prehepatic insulin secretion was tripled during rhGH treatment; but related to the impairment in glucose tolerance, ß-cell response was still inappropriate.
Our conclusion is that long-term rhGH-replacement therapy in GH deficiency adults induced a significant deterioration in glucose tolerance, profound changes in kinetics of C-peptide, and insulin and prehepatic insulin secretion, despite an increase in lean body mass and a reduction of fat mass. Therefore, rhGH treatment may precipitate diabetes in some patients already susceptible to the disorder.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Initial studies of rhGH replacement treatment in hypopituitary adults used high doses of rhGH [23 µg/kg BW (=5 IU/day)], based on experience from children (8). This induced an insulin-like growth factor (IGF)-I serum level clearly above physiological level and a high incidence of side effects. Since then, it has been demonstrated that new titration systems allow markedly lower doses to be used [2.5–5.0 µg/kg·day (=0.6–1.2 IU/day)], with satisfactory clinical responses and IGF-I levels within the physiological range, and side effects attenuated or lacking (19).
As rhGH replacement therapy for GH deficiency (GHD) adults becomes more accepted, the importance of long-term surveillance of adverse events is apparent. Therefore, the aim of the present study was to evaluate the long-term effects of rhGH treatment on body composition, SI, glucose effectiveness (SG), and ß-cell function in adult GHD patients receiving rhGH replacement therapy titrated to physiological IGF-I levels. In our previous short-term study, we observed that rhGH treatment seems to change the kinetics of insulin or C-peptide (15). Therefore, the kinetics of insulin and C- peptide were estimated during an oral glucose load, and the kinetic parameters were then applied to calculate prehepatic insulin secretion using the combined model (20). In addition, insulin secretion was related to the ambient glucose level, to quantify ß-cell secretory response to glucose and the gut incretins before and after rhGH treatment.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Of the 24 adults with known pituitary pathology who participated in our study on short-term effects of rhGH on glucose metabolism (15), 20 continued on rhGH replacement therapy after the initial protocol and were invited to participate in the follow-up study. Eleven patients accepted the invitation to participate. Nine refused (1 because of pregnancy, 1 because of severe angina pectoris, 1 had moved, 1 had ongoing radiotherapy because of recurrence of adenoma, and 5 just did not wish to participate). Of the 11 subjects who were retested, 8 were treated with placebo and 3 with active hormone during the initial 4-month study period. The pathology of GHD was 5 nonsecreting adenoma, 1 prolactinoma, 2 craniopharyngeoma, and 3 other. Eight of the patients had adult onset disease, and 3 were diagnosed during childhood. GHD was ultimately defined as a peak GH < 5 µg/L after 2 of the following provocative tests: 1) insulin-induced hypoglycemia (BG < 2.2 mmol/L); 2) clonidine test; 3) arginine test; or 4) heat test. All patients had GHD for at least 1 yr; and, if present, other hormonal insufficiencies had been adequately substituted for at least 1 yr before the start of the study. Three patients were treated with cortisone acetate, T4, testosterone, or ethinylestradiol and antidiuretic desmopressin; 5 patients with (cortisone acetate + T4 + ethinylestradiol); 1 with ethinylestradiol; 1 with desmopressin; and one patient with no replacement therapy. The study was approved by the national (5312–289 -1993) and the local ethical committee (1993–2700).
Experiments
As earlier described (15), the initial protocol had a randomized placebo-controlled double-blind design. Patients were randomized to four-month treatment with either human recombinant GH (rhGH, Norditropin, Novo Nordisk A/S) or placebo in a parallel design. rhGH was administered as a daily, evening sc self injection. During the initial 6 weeks, the dose of rhGH (or placebo) was gradually increased to a daily target dose of 2 IU/m2 (= 16.4 µg/kg·day). Finishing the initial protocol, patients were offered the opportunity to continue on rhGH therapy, with the dose of rhGH titrated according to repetitive IGF measurements.
At baseline, after 4 months, and after 30 months, the patients underwent an oral glucose tolerance test (OGTT) and an iv glucose tolerance test (FSIGT). Body composition was estimated by dual-energy x-ray absorptiometry (DXA) whole-body scanning at baseline and after 4, 12, and 30 months of treatment. rhGH was taken in the evening before the studies, and no patients were given hormone replacement therapy on the study days.
OGTT. Patients were admitted to the hospital at 0800 h, after an overnight fast of 10 h. A venous cannula was inserted into the antecubital vein for blood sampling. Baseline blood samples were drawn at -5, -10, and -5 min. At 0 min, 75 g glucose monohydrate was given orally, diluted in 300 mL water. Venous blood was sampled at 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 135, 150, and 180 min for measurements of plasma glucose, insulin, and C-peptide.
Frequently sampled iv glucose tolerance test (FSIGT). Patients were admitted to the hospital at 0800 h, after an overnight fast of at least 10 h. Two venous cannulas were inserted into the antecubital veins bilaterally for blood samples, and injections of glucose and tolbutamide, respectively. Baseline blood samples were drawn at -15, -10, and -5 min. At 0 min, 0.3 g/kg body weight of 50% glucose was injected iv, over 60 sec. At 20 min after glucose injection, a bolus of 300 mg tolbutamide (Orinase Diagnostic, The Upjohn Company, Kalamazoo, MI) was injected, in 30 sec. Venous blood was sampled at 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 19, 22, 23, 24, 25, 27, 30, 35, 40, 50, 60, 70, 80, 90, 105, 120, 135, 150, and 180 min for measurements of plasma glucose, insulin, and C-peptide.
Body composition. Body composition was estimated by an XR36 DXA scanner (Norland Medical Systems, Inc., Fort Atkinson, WI). Software version Norland 2.5 was used for data acquisition and analysis. A whole-body scan was made that separately measures three of the principal compartments of the body, i.e. total body bone mineral content (BMC), total lean body soft tissue mass (LBM), and total FM. In addition, data on the regional distribution of the different body components were obtained for arms, legs, abdomen, trunk (thorax + abdomen), and head. Furthermore, bone mineral status in the lumbar columna LII-LIV was estimated by a DXA lumbar scanning expressed as total BMC and bone mineral density (BMD). The in vivo precision and accuracy errors are 1–5% (21).
Assays. Plasma glucose was measured, in duplicate, by a glucose oxidase method with a glucose analyzer (Beckman Coulter, Inc. Instruments, Fullerton, CA). Blood samples for plasma insulin and C-peptide were centrifuged, at 3000 rpm for 20 min at 4 C, immediately and were stored at -20 C until analysis. C-peptide and insulin were determined by commercial immunoassays (DAKO Corp., Diagnostics Ltd., Cambridgeshire, UK) (22). Serum IGF-I was measured by a noncompetitive time-resolved immunofluorometric assay (23).
Calculations
Individual data on body composition were compared with a population of healthy subjects living in the same area and were scanned with the same DXA scanner (24). For each body composition compartment, the SD score, Z score, was calculated. Z score is defined as the difference between the individual value and the mean value in a normal population, expressed as the number of SDs from the mean value.
SI was estimated, in the basal state, by use of the homeostasis model assessment (HOMA), which is a structural computer model of the glucose/insulin feedback system, and also during dynamic changes in glucose and insulin using the iv glucose tolerance test analyzed by the minimal model (MINMOD approach).
The HOMA model derives an estimate of SI from the mathematical modeling of fasting glucose and insulin concentrations (25). Fasting glucose and insulin concentrations were calculated as the mean of the -15-, -10-, and -5-min values from the oral glucose tolerance day. The formula for the HOMA model is as follows: insulin resistance (HOMA IR) = fasting insulin (µU/ml) x fasting glucose (mmol/L)/22.5, as described by Matthews and co-workers (25). HOMA IR was reported to be 1.0 in young healthy subjects in the original formulations of the HOMA model, and high HOMA IR scores denote low (25). HOMA IR = 1.0 should not be interpreted as normal values but as a reference value obtained by a particular assay in the Diabetes Research Laboratories in Oxford (25). The SI and the index of noninsulin-dependent glucose uptake (or SG) were calculated using the MINMOD computer program (26) on data from the FSIGT. Furthermore, as a measure of ß-cell function, the acute insulin (first phase) response to glucose (AIRg) was calculated by means of the trapezoidal rule, as total area under the curve, 0–10 min after the glucose bolus injection. In normal subjects, AIRg will increase as SI is reduced. The product of these two parameters is approximately a constant, DI (disposition index) = SI x AIRg. Thus, the relation between SI and secretion is a hyperbola (26).
Insulin secretion rates were calculated by simultaneous kinetic analyses of the measured peripheral concentrations of insulin and C-peptide using the combined model (20). In this model, separate determination of C-peptide kinetic is not necessary. Instead, both plasma insulin and C-peptide measurements are used simultaneously to estimate parameters of insulin and C-peptide kinetics, which are described by first-order kinetics, where KI and KC are the elimination rate constants for the two peptides (20). The fraction of insulin not taken up at first pass by the liver (F) cannot be identified explicitly. Instead the quantity, f = F x VC/VI, i.e. the fraction not taken up multiplied by the ratio between the distribution volumes of C-peptide (VC) and insulin (VI), was estimated. The insulin secretion rates expressed as picomoles per minute per liter of distribution volume of C-peptide (20). This one-compartment model has been described in detail previously and extensively validated, i.e. during an oral glucose load with slow changes in portal insulin appearance and in subjects with major changes in kinetics of insulin and C-peptide (20, 26, 27, 28).
ß-cell secretion, in response to changes in glucose during an oral glucose load, expresses the efficacy with which changes in plasma glucose concentration and the gut incretins stimulate insulin secretion. Therefore, the correlation between the ambient glucose concentration and the insulin secretion rate during the OGTT was evaluated by cross-correlation. The relationship was linear in all subjects, and the slope of the line was used as an index of ß-cell response to oral glucose and denotes ß-cell secretory capacity. Thus, a change in plasma glucose by 1 mmol/L results in a change in the insulin secretion rate by pmol/min. Furthermore, an index of basal insulin secretion was estimated at a reference glucose concentration of 5.0 mmol/L employing the regression line between blood glucose and insulin secretion rate in the individual subject.
Because of the study design, without a placebo-treated group after 4 months of the study, we calculated the kinetics of C-peptide and insulin, basal insulin secretion rate, maximal secretion rate, and total and incremental insulin secretion at 0 and 4 months during the oral glucose tolerance test in the eight patients treated with placebo. No statistically significant differences were found between the 0- and 4-months results (data not shown). Also the slope of the regression line between insulin secretion rate and blood glucose concentration was similar, indicating no major changes in kinetics of C-peptide and insulin and amount of insulin secreted, with time, in GH deficient adults.
Statistical analysis
All calculations were performed with Statgraphics version 7.0 (STSC, Rockville, MD). Data are expressed as means ± SD. The Wilcoxon matched-pairs test was used to compare data before and after treatment.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Dose of rhGH
During the initial placebo-controlled 4-month period, the target dose of rhGH was 2 IU/m2 (=16.4 µg/kg·day). In the following open period, the rhGH dose was gradually decreased, aiming at a serum IGF-I level in the normal physiological range, mean daily dose = 6.7 ± 1.7 (5.2–8.3) µg/kg [=1.6 ± 0.4 (1.3–2.0) IU].
IGF I
Serum IGF-I concentrations were low in all subjects at the commencement of the study and increased with rhGH therapy from 101.3 ± 59.7 (48–230) µg/L at baseline, to 309.7 ± 63.8 (230–392) µg/L at 30 months, P < 0.00001.
Body composition
The patients were characterized by overweight (Table 1
), with a relative BW of 116.8 ±
20.1 (89.5–139.4)% of ideal body weight and a body mass index of
27.1 ± 5.3 (20.8–39.7) kg/m2. The weight
was increased primarily because of an FM that was 1.5 SDs
above age- and sex-matched mean values. Furthermore, a central fat
accumulation was observed (Table 2).
During the first year with rhGH treatment for 8 and 12 months,
respectively, patients achieved a mean reduction of body weight of
2.0 ± 4.5 (-10.6 to 3.4) kg (NS). However, after 30
months of rhGH treatment, weight loss was regained, and body weight had
increased to 1.3 ± 3.0 (-4.5 to 6.0) kg (NS) above
baseline.
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). Bone mineral data
Data on bone mineral status are shown in Table 1. Compared with
baseline, no significant changes were observed after the first year,
whereas 30 months of rhGH treatment induced significant increments in
total BMC content (P < 0.03), total body BMD
(P < 0.03), and lumbarII-Iv BMD
(P < 0.001).
Glucose tolerance, insulin secretion, and kinetics of C-peptide and insulin
In Table 3, the metabolic data from
the OGTT and FSIGT are summarized.
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Figure 1 shows the results from the
OGTT. At baseline, all patients had a normal glucose tolerance. It
seems that rhGH treatment induced a significant upward displacement of
the glucose curve. Fasting blood glucose remained unchanged, but
the incremental area under the glucose curve
(AUCglucose) (P < 0.003) and the
2-h blood glucose value increased significantly (P <
0.008). Three patients developed impaired glucose tolerance.
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Table 4 summarizes the kinetic parameters
for insulin (f and KI) and C-peptide
(KC) obtained from the combined model analyses.
The estimate of f = F x
VC/VI, where F is the
fraction of insulin that is not taken up by passage of the liver, and
VC and VI are the apparent
distribution volumes of insulin and C-peptide, showed no significant
variation from time 0–30 months. The fractional clearances of insulin
(KI) and C-peptide (KC)
both significantly increased after 30 months, compared with basal
values. The change was most pronounced for C- peptide, where clearance
was doubled from 0–30 months.
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shows the mean insulin secretion
profiles during the OGTT at 0 and 30 months. It seems that insulin
secretion becomes markedly increased after 30 months. The mean basal
and maximal secretion rates, the time of maximal secretion, and the
total and incremental (above basal) secretion from 0–180 min are given
in Table 4. Both basal and maximal secretion rates double from 0–30
months, whereas total and incremental insulin secretion triple during
treatment with rhGH.
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. There was a significant increase, of about 60%,
in the slope from 0–30 months. The secretion rate at the basal
reference blood glucose level of 5 mmol/L, determined from the
individual regression lines, doubled from 0–30 months
(P < 0.05). The time to maximal glucose concentration
and to maximal insulin secretion increased in parallel during rhGH
treatment (Figs. 1 and 2). SI, SG, and disposition index
FSIGT. Figure 3 shows the
results from the FSIGT. In contrast to results during the OGTT, only
small increments in AUCglucose,
AUCinsulin, and
AUCC-peptide occurred, although statistically
significant for AUCC-peptide (Table 3). By means
of Bergmann’s minimal model, SI was
calculated. SI index decreased significantly
(Table 3). SG tended to increase, but it failed
to reach statistical significance (P = 0.09). The
insulin disposition index was constant before and after treatment.
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shows the coherent values for
SI and ß-cell function, expressed as
first-phase insulin response. The values show a hyperbolic coherence,
at baseline and during rhGH treatment, with a sufficient compensatory
displacement in insulin secretion at shift in
SI.
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Basal blood glucose was 5.1 ± 0.4 and 5.2 ± 0.5 mmol/L (NS), and fasting plasma insulin was 30.2 ± 9.3 and 53.4 ± 19.9 (P < 0.01) before and after rhGH treatment, respectively. The corresponding HOMA IR was 1.2 ± 0.1 and 2.1 ± 0.09, indicating a deterioration in SI during rhGH treatment, P < 0.01.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several studies have demonstrated beneficial effects of rhGH replacement therapy in GHD adults, evaluated by exercise capacity, body composition, and BMC, motivating long-term treatment (1, 2, 4, 5, 7, 8, 9, 13, 29, 30, 31). However, the negative effect of rhGH on glucose metabolism, demonstrated in short-time studies, may argue against long-time use of the drug (12, 13, 15, 32).
The present population had, at baseline, a body weight of 116% of ideal weight and a FM that was 1.5 SD above age and sex-matched values. We confirmed the known desirable, both acute (1, 2, 7, 8, 32) and prolonged (6, 9, 17, 33, 34, 35, 36, 37) effects on body composition, with a 22.5% reduction in FM and an 7.5% increase in lean body mass during the first year with rhGH treatment. This is in accordance with previous results demonstrating between 8 and 23% reduction of FM and 5–11% increase in LBM during the first year (1, 2, 7, 8, 15, 17, 32, 35, 37). As previously demonstrated, the most pronounced changes occurred during the initial months of treatment, however, still resulting in a persistent 14% reduction in FM and 10% increase in lean body mass after 30 months. Other long-term studies, with observation time up to 10 yr, have reported similar 2–22% reduction of FM and 3–11% increase in LBM (6, 9, 14, 17, 33, 34, 35, 37). The considerable reduction in FM can be explained by the lipolytic effect of rhGH, which has also been demonstrated in normal obese subjects (1, 38).
Data on bone mineral metabolism showed no changes in total BMC content or total body BMD after the first 8–12 months; whereas after 30 months, significant increments in both total BMC content and total body BMD and lumbar BMD were observed. These findings are consistent with an early GH-mediated increase in bone remodeling (39).
In our previous 4-month study in the same subjects (15), treatment with rhGH seemed to change the kinetics of insulin and C-peptide; for which reason, use of the raw insulin and C-peptide concentrations as an index of insulin secretion might be misleading. To circumvent this pitfall in the present study, we estimated the kinetics of both insulin and C- peptide and subsequently used the kinetic data to derive the prehepatic insulin rate during the OGTT by means of the combined model (20). This approach allows insulin secretion rates to be derived independently of changes in clearance of either insulin or C-peptide. The fractional clearance of both insulin and C-peptide showed significant increases during rhGH treatment, compared with basal values. The increase was most pronounced for C-peptide, where clearance doubled, from 0–30 months, whereas the increase was approximately 60% for insulin. The explanation for the changes in kinetics of insulin and C-peptide is unknown from the present data, but rhGH treatment increases both glomerular filtration rates and renal blood flow (7), and the kidney is a predominant site of both C-peptide and insulin clearance from the peripheral circulation (40). Fasting C-peptide decreased 8%, whereas the incremental C-peptide response at OGTT increased 36% during rhGH treatment. When the effect of altered clearance of C-peptide was factored out, the calculated basal insulin secretion rate after rhGH treatment, during 30 months, was approximately doubled; and the incremental insulin secretion during the OGTT increased by a factor of 3. The maximal insulin rate doubled during GH treatment. Our results demonstrate the limitations of using insulin or C-peptide concentrations as an index of insulin secretion before and during rhGH treatment and indicate that the C-peptide and insulin concentrations underestimate the increase in insulin secretion during rhGH treatment.
Despite an increase in ß-cell sensitivity to changes in glucose of about 60%, a deterioration in glucose tolerance was observed after 30 months of therapy, with unchanged fasting blood glucose values but significantly higher 2-h values. Three patients developed impaired glucose tolerance. Therefore, it seems that, during rhGH treatment, the ß-cell was unable to respond adequately to an OGTT and to prevent postprandial hyperglycemia. The precise explanation of the ß-cell dysfunction is poorly understood; but in a previous study, we have demonstrated that treatment with rhGH was accompanied by a blunted GLP-1 response of about 40% during an OGTT (41). GLP-1 is the most important incretin hormone; and therefore, an attenuated GLP-1 response may, in part, explain the inappropriate ß-cell response to glucose during the OGTT (42).
Using Bergmann’s minimal model, we calculated SI, which decreased from baseline to 30 months but failed to reach statistical significance. A parallel increase in SG was observed. The insulin disposition index was constant during the study period. In contrast, we found, after 4 months of rhGH treatment with a greater daily rhGH dose, both a reduction in SI and an inadequate enhancement of insulin secretion, leading to a diminished disposition index during FSIGT (15). We also evaluated SI in the fasting state, by use of the HOMA model, and found a significant deterioration in SI after rhGH treatment. This was in accordance with the results during the OGTT, where elevated plasma insulin, in the face of a normal or supranormal plasma glucose pattern, gives evidence for diminished overall tissue sensitivity to insulin. Recently, other studies have shown that the minimal model underestimates SI in some situations, compared with the glucose clamp technique (42, 43, 44, 45, 46).
It is well known that adult GHD patients, before treatment with rhGH, exhibit both body compositional and metabolic disturbances associated with the insulin resistance syndrome, with an increased centrally accumulated FM (8, 46), an increase in fasting insulin level (8), and an increased occurrence of abnormal glucose tolerance, compared with matched obese controls (43). Furthermore, several studies (13, 32, 45, 47) have demonstrated that GHD patients are severely insulin-resistant, because of a defect in the peripheral insulin-stimulated glucose uptake (45, 47). Estimated by Bergmann’s minimal model or euglycemic-hyperinsulinemic clamp, SI has shown to be reduced by 45% in GHD patients, compared with healthy subjects (17).
Despite the sustained advantageous of rhGH treatment on body composition, only neutral or negative influence on the carbohydrate metabolism has been demonstrated. Already, in the early studies on rhGH replacement therapy in GHD adults, an increase in fasting blood glucose (2, 8), insulin, C-peptide, and the ratio of insulin to C-peptide was demonstrated (8) during rhGH treatment. Since then, several short-term studies (<12 months) have indicated at least temporary reduction in SI after a few weeks with rhGH treatment (12, 13, 15, 32), with partly or fully restoring of pretreatment SI after continued treatment during 3–9 months (12, 32, 48). Only a few long-term studies (>12 months) evaluating body composition, glucose metabolism, and insulin secretion have been published. Estimated by the OGTT and the insulin clamp technique, unaltered glucose tolerance (9, 16, 18) not differing from that in healthy controls (18) has been demonstrated after 3–5 yr of treatment, and unaltered fasting glucose and insulin after up to 10-yr treatment duration (34). However, other authors have shown persistently increased insulin levels after 12 months and 4 yr (9, 13, 16). In the comprehensive study of Christopher et al. (17), no alteration in insulin resistance was found after 24 months of rhGH therapy, with a mean dose of 10.5 µg/kg·day (=2.4 IU/day) despite the fact that fasting insulin level rose 50% and C-peptide 37% at 24 months, compared with baseline values. In the Australian Multicenter Trial of Growth Hormone treatment, in GHD adults, 166 patients were included. After a titration period, a mean dose of 11.9 µg/kg·day (=2.4 IU/day) was used. Thirty-eight percent and 68.9%, respectively, of the subjects had above or normal IGF-I levels at 12 months (4). Fasting serum glucose increased significantly with rhGH treatment from 4.5 mmol/L at baseline, to 4.7 mmol/L after 12 months. Hwu et al. treated their patients at a normal IGF-I level for 12 months and found a normalization of SI, which is in conflict with all previous reports. The discrepant results from different studies may reflect rhGH dose, preexisting SI, and age of the patients.
The dose of rhGH used in the present study was titrated to produce IGF-I values in the normal range, which resulted in a mean dose of 6.7 µg/kg·day (=1.6 IU/day), which is significantly lower than the dose used in our initial short-term study and in many other studies. This may also, in part, explain the fact that the effects on body composition and glucose metabolism were most pronounced for the first 4 months (15). Nevertheless, the adequacy of therapy was confirmed by the fact that IGF-I level increased, by a factor of 3 (15), to the normal age-adjusted adult range. In a previous dose-response study, we have demonstrated that the optimum dose of rhGH was in the range of 8:2–16.5 µg/kg·day (=1.7–3.5 IU/day) (49).
In conclusion, despite the use of relatively low-dose GH replacement therapy in adult GH-deficient patients, the treatment induced significant changes in body composition with an increase in lean body mass and a reduction in body fat. In spite of these favorable changes, a deterioration in glucose tolerance was observed, resulting in development of impaired glucose tolerance in about a quarter of the patients . Furthermore, rhGH treatment had a profound influence on insulin secretion and kinetics of insulin and C-peptide. Therefore, rhGH treatment may precipitate diabetes in some patients already susceptible to the disorder (50).
Received May 12, 2000.
Revised July 18, 2000.
Accepted July 21, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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N. Jessen, C. B. Djurhuus, J. O. L. Jorgensen, L. S. Jensen, N. Moller, S. Lund, and O. Schmitz Evidence against a role for insulin-signaling proteins PI 3-kinase and Akt in insulin resistance in human skeletal muscle induced by short-term GH infusion Am J Physiol Endocrinol Metab, January 1, 2005; 288(1): E194 - E199. [Abstract] [Full Text] [PDF]
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K. Yuen, J. Frystyk, M. Umpleby, L. Fryklund, and D. Dunger Changes in Free Rather Than Total Insulin-Like Growth Factor-I Enhance Insulin Sensitivity and Suppress Endogenous Peak Growth Hormone (GH) Release following Short-Term Low-Dose GH Administration in Young Healthy Adults J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3956 - 3964. [Abstract] [Full Text] [PDF]
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 Q. Zhang, M. Kohler, S.-N. Yang, F. Zhang, O. Larsson, and P.-O. Berggren Growth Hormone Promotes Ca2+-Induced Ca2+ Release in Insulin-Secreting Cells by Ryanodine Receptor Tyrosine Phosphorylation Mol. Endocrinol., July 1, 2004; 18(7): 1658 - 1669. [Abstract] [Full Text] [PDF]
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S. G. Albert and A. D. Mooradian Low-Dose Recombinant Human Growth Hormone as Adjuvant Therapy to Lifestyle Modifications in the Management of Obesity J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 695 - 701. [Abstract] [Full Text] [PDF]
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J. Svensson and B.-A. Bengtsson Growth Hormone Replacement Therapy and Insulin Sensitivity J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1453 - 1454. [Full Text] [PDF]
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T. O'Connell and D. R. Clemmons IGF-I/IGF-Binding Protein-3 Combination Improves Insulin Resistance By GH-Dependent and Independent Mechanisms J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4356 - 4360. [Abstract] [Full Text] [PDF]
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 W. L. Isley Growth Hormone Therapy for Adults: Not Ready for Prime Time? Ann Intern Med, August 6, 2002; 137(3): 190 - 196. [Abstract] [Full Text] [PDF]
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K. Yuen, K. Ong, S. Husbands, P. Chatelain, L. Fryklund, P. Gluckman, M. Ranke, D. Cook, R. Rosenfeld, J. Wass, et al. The Effects of Short-Term Administration of Two Low Doses Versus the Standard GH Replacement Dose on Insulin Sensitivity and Fasting Glucose Levels in Young Healthy Adults J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 1989 - 1995. [Abstract] [Full Text] [PDF]
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J. Svensson, J. Fowelin, K. Landin, B.-A. Bengtsson, and J.-O. Johansson Effects of Seven Years of GH-Replacement Therapy on Insulin Sensitivity in GH-Deficient Adults J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2121 - 2127. [Abstract] [Full Text] [PDF]
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) and after 30 months
(•) of GH replacement therapy in GHD adults (mean ±
SE).
