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Endocrine Care |
Research Centre for Endocrinology and Metabolism (J.S., K.L., B.-Å.B., J.-O.J.), Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden; and Department of Internal Medicine (J.F.), Mölndal Hospital, SE-431 80 Mölndal, Sweden
Address all correspondence and requests for reprints to: Johan Svensson, M.D., Research Centre for Endocrinology and Metabolism, Gröna Stråket 8, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden. E-mail: . johan.svensson{at}medic.gu.se
Abstract
The few trials in GH-deficient (GHD) adults that have investigated the long-term effects of GH-replacement therapy on insulin sensitivity have shown conflicting results. In this study, insulin sensitivity was determined using the hyperinsulinemic, euglycemic clamp technique in 11 GHD adults at baseline and after 6 months, 1 yr, 2 yr, and 7 yr of GH-replacement therapy. Furthermore, insulin sensitivity in the GHD patients was compared with that in 11 matched control subjects at baseline and with that in 11 other matched controls at study end.
The mean initial GH dose was 1.10 mg/d. The dose was gradually lowered; and after 7 yr, the mean dose was 0.61 mg/d. A sustained reduction in body fat and a sustained increase in fat-free mass were observed. Serum high-density lipoprotein-cholesterol (HDL-C) increased, and serum low-density lipoprotein-cholesterol (LDL-C) decreased, after 7 yr of treatment. Fasting blood glucose was transiently increased during the first year of GH replacement. The glucose infusion rate/body weight (GIR/BW), as measured using the hyperinsulinemic, euglycemic clamp technique, was unaltered during GH-replacement therapy. The comparisons with the control subjects revealed that GIR/BW in the GHD patients was 45% of that in the control subjects at baseline; whereas, at study end, the GIR/BW was 71% of that in the control subjects (P = 0.06 vs. baseline). This could suggest that GH-replacement therapy may prevent the age-related decline in insulin sensitivity in GHD patients.
ADULT GH-DEFICIENCY (GHD) is characterized by an increase in the amount of total and visceral fat, a decrease in lean mass, and a disturbed lipoprotein pattern (1). Cardiovascular morbidity (2) and mortality (3) are increased. Furthermore, adult GHD is associated with insulin resistance (4, 5).
GH treatment for 6 wk in GHD adults further deteriorated insulin sensitivity, whereas insulin sensitivity returned to baseline values after 6 months of GH treatment (6). The long-term effect of GH substitution on insulin sensitivity in GHD adults is still debatable. Studies have shown that 6 months to 4 yr of GH replacement in GHD adults do not affect (6, 7, 8) or impair (9, 10) glucose tolerance, as measured by oral and/or iv glucose tolerance tests. The results of one study, using the hyperinsulinemic, euglycemic clamp technique, suggest that the decrease in baseline insulin sensitivity, as well as the decrease in baseline skeletal muscle glycogen synthase activity, persists during 2 yr of GH treatment (11). However, in a study by Hwu et al. (12), 1 yr of GH treatment normalized insulin sensitivity, as measured using a modified insulin suppression test. In a study by Jørgensen et al. (13), insulin sensitivity was similar in GHD patients to that in controls, after 5 yr of GH treatment.
In this study, the effect of 7 yr of GH-replacement therapy on insulin sensitivity was determined using the hyperinsulinemic, euglycemic clamp technique. The glucose infusion rate (GIR) values obtained by this technique primarily reflect peripheral glucose utilization and are therefore principally an index of skeletal muscle insulin sensitivity (6, 14). However, by determining the rates of glucose appearance (Ra) and disposal (Rd) using the primed-continuous infusion of tritiated glucose [D-(3-H3)-glucose], as in this study, it is also possible to estimate the hepatic glucose output (6, 15, 16). The GIR values in the 11 GHD patients were compared with the GIR values in 11 healthy subjects at baseline and with those of 11 other healthy subjects at study end. The patients and the controls were matched in terms of age, gender, body mass index (BMI), and waist-to-hip ratio on each occasion.
Subjects and Methods
Patients
Eleven patients (seven men and four women; mean age, 48.0; range, 20–62 yr), who regularly visited the out-patient clinic at the Division of Endocrinology, Sahlgrenska University Hospital, were asked to participate in the study. Nine patients had complete adult onset pituitary deficiency (pituitary adenoma, n = 7; meningioma, n = 1; Sheehan’s syndrome, n = 1), including the thyroid, adrenal, and gonadal function, which had been present for at least 1 yr before this study. Two men had childhood onset, isolated GHD (pituitary stalk interruption, n = 1; idiopathic, n = 1). The patient with idiopathic GHD had been treated with GH during childhood, from the age of 5–17. This treatment had ended 3.5 yr before our study. The diagnosis of GHD was based on a peak GH response of less than 5 mU/liter (<1.7 µg/liter) during an insulin tolerance test (blood glucose < 2.2 mM).
Four men were being treated with bromocriptin (2.5–10 mg/d). All the nine patients with multiple anterior pituitary deficiencies were receiving adequate, stable replacement therapy with glucocorticoids (cortisone acetate, 25 mg daily), thyroid hormones (levothyroxine, 0.1–0.2 mg daily), and sex hormones when required. However, after 6 yr of therapy, the glucocorticoid treatment was changed in one female patient, from cortisone acetate (25 mg daily) to hydrocortisone (20 mg daily). The dose of levothyroxine was increased by 0.05 mg daily in two patients during the study and decreased by 0.025 mg daily in one patient. The replacement with sex steroids was unchanged in all patients. Three of the four female patients (59, 62, and 62 yr old at study start, respectively) did not receive estrogen-replacement therapy at any time during the study.
Two men, 54 and 57 yr old at study start, respectively, developed diabetes mellitus (DM) type 2 during the study. One of these patients received dietary instructions after 8 months of GH replacement and, in addition, oral medication with glipizide after 2.5 yr of GH treatment. The other patient received dietary advice after 3 yr of GH replacement, and oral medication with glibenclamide at 6 yr. All the data obtained from these two patients have been included in the statistical analyses.
One man died of pulmonary edema caused by a probable myocardial infarction after 7 yr of GH-replacement therapy (before the clamp at 7 yr was performed). All values obtained from this patient have been included in the statistical analyses. Two-year values were carried forward to 7 yr in accordance with the intention-to-treat-analysis used.
Control subjects
The GHD patients were compared with 11 healthy control subjects at baseline and with 11 other healthy control subjects at study end. The control subjects were recruited by advertisements in the local newspapers. The criteria for being healthy, in addition to subjective well-being, were: a history of no hospital visits, no diabetes or hypertension, and no medical treatment for any disease during the past 2 yr. The patients and the healthy control subjects were matched for age, sex, BMI, and waist-to-hip ratio on each occasion (Table 1
).
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This was a prospective, open-label treatment trial. The initial target dose of GH was 11.9 µg/kg·d (0.25 IU/kg·wk). The mean dose of GH is given in Table 2. After 1–2 yr GH-replacement therapy, the dose was gradually lowered and individualized when the weight-based dose regimen was abandoned (17). However, in 7 of the 11 GHD patients, the dose was lowered during the first year of therapy because of side effects related to water retention. The individualization of the dose of GH was performed with the aim of normalizing serum IGF-I concentration and body composition (17).
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Ethical considerations
The study was approved by the Ethical Committee at the University of Göteborg and the Swedish Medical Products Agency, Uppsala, Sweden. Informed written consent was obtained from all subjects before study start.
Body composition
Body weight (BW) was measured in the morning, to the nearest 0.1 kg, using a 6800 Digital Indicator (Detecto Scale, Webb City, MO), after the subjects had voided. Body height was measured barefoot and to the nearest 0.5 cm. BMI was calculated using the formula: BMI = BW/height2 (kg/m2).
Waist circumference was measured with a soft tape, midway between the lowest rib margin and the iliac crest, in the standing position. Hip circumference was measured over the widest part of the gluteal region, and the waist-to-hip ratio was calculated.
Body composition was estimated using bioelectrical impedance analysis (BIA) (BIA-101; RJL System, Detroit, MI) and using measurements of total body potassium (TBK). TBK was assessed using a whole-body counter with a coefficient of variation (CV) of 2.2%. Fat-free mass (FFM) was estimated by assuming a potassium content of 64.7 mmol/kg FFM (18), and body fat (BF) was calculated as: BW - FFM.
Clamp technique
All the experiments were begun at 0800 h, after an overnight fast. The patients were given their morning medication (including hormone replacement) after the clamp had been performed. Infusions were administered via a catheter placed in a cubital vein, and arterialized blood samples were drawn from a dorsal hand vein in the contralateral arm. Insulin (Actrapid Human; Novo-Nordisk A/S, Copenhagen, Denmark) was dissolved in NaCl (154 mM), to a concentration of 0.2 U/ml, with 4 mg/ml of albumin added to prevent adhesion, and infused at a rate of 40 mU/m2·min during the euglycemic clamps. Glucose (200 mg/ml; Baxter Chemicals, Oslo, Norway) was infused at variable rates, in the same catheter as the insulin. Potassium chloride (100 mM) was infused at a rate of 7 mmol/h to prevent hypokalemia during clamps.
The Ra and Rd were determined by the infusion of D-(3-H3)-glucose (NEN Life Science Products, Boston, MA) dissolved in NaCl, as described previously (6). The method described by Finegood et al. (15) was used. A primed infusion of 10 µCi was administered, followed by a constant infusion of 6 µCi/h for 125 min. Determinations of Ra and Rd were not performed in the control subjects.
After the 2-h equilibrium period, the euglycemic clamp was initiated with a primed insulin infusion for 10 min, followed by a constant infusion during the following 2 h, as reported previously (4, 6). The infusion rate of glucose [200 mg/liter, including labeled glucose to maintain the constant specific activity in the basal state, as described previously (6)] was adjusted to keep the glucose level constant at 4.5 mM. During the clamp, arterialized venous blood samples were drawn every 5 min for determination of blood glucose with an automatic glucose analyzer (YSI, Inc., Yellow Springs, OH).
The GIR was calculated from the steady-state during the last 60 min of the 2-h clamp.
Ra and Rd were calculated using the non-steady-state equations of de Bodo et al. (16), with modifications, as described previously (6).
Biochemical assays
Serum IGF-I concentration was determined by a hydrochloric acid-ethanol extraction RIA using authentic IGF-I for labeling (Nichols Institute Diagnostics, San Juan Capistrano, CA). Interassay and intraassay CVs were 5.4 and 6.9%, respectively, at a mean serum IGF-I concentration of 126 µg/liter, and 4.6 and 4.7%, respectively, at a mean serum IGF-I concentration of 327 µg/liter.
The individual serum IGF-I values were compared with age- and sex-adjusted values obtained from a randomly selected reference population comprising 197 men and 195 women, 25–64 yr old (19). The following formulae for the calculation of the predicted IGF-I values were used (20): men, 292.7 - (2.1 x age); women, 375.7 - (3.7 x age).
The SD score for IGF-I was then calculated from the formulae (20): men, SD score = (observed IGF-I - predicted)/48; women, SD score = (observed IGF-I - predicted)/54.7.
Blood glucose was measured using an automatic glucose analyzer (YSI, Inc.). Serum insulin was determined by RIA (Phadebas, Pharmacia Biotech, Uppsala, Sweden). FFA levels were determined using an enzymatic colorimetric method (NEFAC; Wako Pure Chemical Industries Ltd., Neuss, Germany).
Serum total cholesterol (TC) and triglyceride (TG) concentrations were determined using enzymatic methods (Roche Molecular Biochemicals, Mannheim, Germany). The interassay CVs for TC and TG determinations were 2.9% and 3.8%, respectively; and the intraassay CVs were 0.9% and 1.1%, respectively. Serum HDL-C concentration was determined after the precipitation of apoB-containing lipoproteins with MgCl2 and heparin (21). Serum LDL-C concentration was calculated according to Friedewald’s formula, adjusted to Systeme International units (22).
Statistical analysis
All the descriptive statistical results are presented as the mean (SEM). Within-group differences were calculated using the Wilcoxon signed-rank test. Between-group differences were evaluated using the Mann-Whitney U test. Correlations were calculated using the Spearman rank-order correlation test. All analyses were calculated using an intention-to-treat approach based on the carry-forward principle. A two-tailed P < 0.05 was considered significant.
Results
The patients and the control subjects were matched for age, sex, and BMI, both at baseline and at study end (Table 1
). In the GHD patients, BMI and waist-to-hip ratio were similar at study end, as compared with baseline (Table 1).
GH dose and IGF-I SD score (Table 2)
The dose of GH was gradually lowered during the first 2 yr of the study. Serum IGF-I concentration was increased by GH-replacement therapy throughout the study period. The mean IGF-I SD score was -2.94 at baseline and 3.54 after 6 months of GH therapy. After 6 months, the mean IGF-I SD score gradually decreased. The mean IGF-I SD score was 1.89 after 7 yr of GH-replacement therapy.
Body composition (Table 3)
BW was unchanged during 7 yr of GH-replacement therapy. The TBK and BIA measurements showed sustained reductions in BF and sustained increases in FFM.
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Lipids (Table 4)
Serum concentrations of TG and TC were unchanged, as compared with baseline, throughout the study. At study end, serum HDL-C concentration was increased, and serum LDL-C concentration was reduced, as compared with baseline.
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Blood glucose, plasma insulin, and plasma FFA (Table 5)
Fasting blood glucose concentration was transiently increased during the first year of GH replacement. Blood glucose concentrations during clamps, fasting and clamp plasma insulin concentrations, and fasting and clamp plasma FFA concentrations were unchanged during 7 yr of GH-replacement therapy.
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Clamp data
The GIR/BW was unchanged throughout the study period, whereas the GIR/FFM decreased transiently during the first year of GH-replacement therapy (Fig. 1).
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). Ra and Rd, during the clamps, were unaltered throughout the study period (Fig. 2, B and C).
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The GIR/BW in the controls at study end was 71% of that in the controls at baseline (P = 0.07; data not shown). The GIR/FFM in the controls at study end was 73% of that in controls at baseline (P = 0.08; data not shown).
The GIR/BW in the GHD patients was lower than that in controls, both at baseline and at study end (P < 0.001 and P < 0.05, respectively; data not shown). The GIR/BW in GHD patients was 45% that of controls at baseline and 71% of controls at study end (P = 0.06 vs. baseline; Fig. 3A).
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). Ra and Rd were not determined in the control subjects.
Correlations
At baseline, the GIR/BW in GHD patients correlated negatively with fasting serum insulin (r = -0.76, P < 0.01) and BF assessed using TBK measurements (r = -0.64, P < 0.05). The baseline GIR/FFM correlated negatively with BMI (r = -0.73, P < 0.05) and serum insulin concentration (r = -0.63, P < 0.05). No baseline correlation was found between GIR/BW or GIR/FFM and other variables.
At study end, the change in GIR/BW or GIR/FFM in the GH treatment group did not correlate with the changes in body composition or in fasting concentrations of variables reflecting glucose and lipid metabolism, respectively.
Discussion
Seven years of GH-replacement therapy induced a sustained reduction in BF and a sustained increase in FFM. The beneficial changes in serum concentrations of HDL-C and LDL-C were maintained, and even progressed, throughout the 7 yr of treatment. This is in line with the few other trials investigating the effects of more than 5 yr of GH-replacement therapy (23, 24) and suggests that the effects observed in short-term trials are maintained during prolonged GH treatment.
Insulin sensitivity in the GHD patients was unchanged after 7 yr of GH-replacement therapy. In the controls, there was a tendency for insulin sensitivity to be higher at baseline than at study end. The comparisons with the controls, therefore, displayed a tendency toward an improvement in insulin sensitivity in the GHD patients at study end. At baseline, insulin sensitivity (GIR/BW) in the GHD patients was 45% of that in the controls; whereas, at study end, insulin sensitivity in the patients was 71% of that in the controls. It is well known that insulin sensitivity decreases with increasing age (25, 26). The present results could therefore suggest that the GH-replacement therapy prevented the age-related decline in insulin sensitivity in the GHD patients.
The Ra during the clamp (60–120 min) displayed low values, suggesting that glucose production was suppressed during the clamp throughout the study. Ra during equilibrium increased after 6 months and 7 yr of GH replacement. The increased Ra at equilibrium suggests that insulin was less effective in restraining hepatic glucose output (6). We have previously observed a similar increase in Ra at equilibrium during short-term GH treatment (6). Ra was not measured in the controls. However, the suppression of glucose production by insulin tends to decrease with increasing age (27). It could therefore be speculated, although not measured, that an increase in Ra at equilibrium could also have been found in the controls after 7 yr.
Glucose metabolism was transiently decreased during the first year of GH treatment, with an increase in fasting blood glucose. The beneficial changes in body composition during GH replacement, with a sustained reduction in BF and a sustained increase in FFM, are probably of importance for the return of glucose concentrations toward baseline values after 1 yr. Furthermore, increased physical activity improves insulin sensitivity (28). GH replacement has previously been shown to increase well-being and therefore probably also physical activity (1, 29). Although physical activity was not measured in this study, it could be speculated that an increase in physical activity during the first years of GH-replacement therapy could have a positive influence on blood glucose concentrations.
Two of the present 11 patients (18%) developed DM type 2. This did not significantly affect the results, because all the results of the statistical analyses would be unchanged if the 2 patients with DM were excluded from the analysis (data not shown). The incidence of DM in this study is not representative of our total cohort of GHD adults. In the total population of GHD adults at Sahlgrenska University Hospital, 10 of 289 patients (3.5%) have developed DM type 2 during GH replacement. One reason for the increased incidence of DM in the present study could be that all the patients initially received a high dose of GH, based on BW; whereas, in our total cohort of GHD patients, most patients have received a lower, individualized dose of GH from the start of treatment. Insulin sensitivity is reduced in both untreated adult GHD (4, 5) and in acromegaly (30). Optimized GH replacement from the start of treatment may therefore minimize the development of DM type 2 during treatment.
In the present study, the weight-based dose regimen was abandoned after 1–2 yr of therapy. In some studies (9, 10), a decrease in insulin sensitivity has been observed during long-term GH replacement. The gradual lowering and individualization of the dose of GH in the present study could contribute to the lack of decrease in mean insulin sensitivity in the 11 GHD adults.
There was a large range (-56% to +204%) in the response in insulin sensitivity in this study. It is important to identify patients who are likely to improve/deteriorate in terms of insulin sensitivity. In this relatively small study, we were not able to find any significant correlation between the change in insulin sensitivity and changes in other variables at study end. However, the two subjects who developed DM had the lowest and the third lowest, respectively, insulin sensitivity at baseline. Therefore, we cannot exclude the possibility that GH-replacement therapy can precipitate DM in GHD patients with very low baseline insulin sensitivity.
In conclusion, insulin sensitivity was unchanged after 7 yr of GH-replacement therapy. Blood glucose concentrations were transiently increased during the first year. There was a tendency for insulin sensitivity in the GHD patients, as compared with that in the controls, to be higher at study end than at baseline. This could suggest that GH-replacement therapy may prevent the age-related decline in insulin sensitivity in GHD patients. Two patients developed DM type 2 during the study. Further, and larger, studies are needed to explore whether GH-replacement therapy is associated with an increased incidence of DM type 2.
Acknowledgments
We are indebted to the staff at the Lundberg Laboratory, especially Margareta Landén, and at the Research Center for Endocrinology and Metabolism for their skillful technical support.
Footnotes
This work was supported by grants from the Swedish Medical Research Council (No. 11621). Results were presented in part at the Fourth International Conference of The Growth Hormone Research Society, Göteborg, Sweden, 2000.
Abbreviations: BF, Body fat; BIA, bioelectrical impedance analysis; BMI, body mass index; BW, body weight; CV, coefficient of variation; DM, diabetes mellitus; FFM, fat-free mass; GHD, GH-deficient; GIR, glucose infusion rate; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; Ra, rate of glucose appearance; Rd, rate of glucose disposal; TBK, total body potassium; TC, total cholesterol; TG, triglyceride.
Received April 11, 2001.
Accepted February 7, 2002.
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