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Original Studies |
Section of Endocrinology and Metabolism (C.-M.H., C.F.K., T.-Y.L., L.-C.H., S.-H.L., L.-T.H.) and Section of Internal Medicine (C.-M.H.), Department of Medicine, and Department of Medical Research and Education (V.S.F., L.-T.H.), Veterans General Hospital-Taipei, Taipei, Taiwan 112; Department of Medicine (C.-M.H., C.F.K., L.-T.H.), National Yang-Ming University, Taipei, Taiwan 112; Section of Endocrinology and Metabolism (K.-C.S.), Department of Medicine, 804 General Hospital, Tao-Yuan, Taiwan 330; and Department of Medicine (T.-S.L.), Yuan-San Veterans Hospital, Yi-Lan, Taiwan 266 Republic of China
Address all correspondence and requests for reprints to: Low-Tone Ho, M.D., Department of Medical Research and Education, Veterans General Hospital-Taipei, Shih-Pai, Taipei, Taiwan 112, Republic of China.
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The long-term effect of GH deficiency on glucose metabolism in adults is debatable. Both increased insulin sensitivity and insulin resistance have been proposed in literature (6). Landon et al. (7) have found a normal pattern of decrease of plasma glucose (PG) in response to insulin in GH-deficient adults. Salomon et al. (8) have demonstrated normal fasting PG and increased fasting insulin levels in GH-deficient adults who had indistinguishable adiposity from normal subjects. Johansson et al. (9) claimed that GH-deficient adults, measured by hyperinsulinemic euglycemic clamp, were insulin-resistant despite the fact that fasting plasma insulin levels were normal. However, little study information has been published so far to evaluate the in vivo insulin sensitivity in adults with GH deficiency after long-term replacement of GH. We have previously reported a difference of insulin sensitivity in the morning (AM) vs. the afternoon (PM) in normal nonobese subjects (10). Their steady-state PG (SSPG) levels were lower in the AM than in the PM. In the present study, we intend to assess the changes of body fat composition and insulin sensitivity in GH-deficient adults after 12-month replacement of GH. And, for the first time, we also want to demonstrate the changes of the PM-AM pattern of insulin sensitivity in these patients during the trial.
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Materials and Methods |
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Twenty-one GH-deficient adults, (10 men and 11 women) were included in this study. Their GH deficiency resulted from pituitary tumor, craniopharyngioma, Sheehan’s syndrome, or idiopathic origins. A confirmed diagnosis of GH deficiency was made when maximum peak GH responses after 2 pharmacological stimulation tests were less than 3.33 µg/L (10 mU/L). Acceptable stimulation tests were glucagon, clonidine (4 µg/kg), and insulin-induced hypoglycemia (with blood glucose < 40 mg/dL) tests. The tests had to be performed within 5 yr before inclusion and after 20 yr of age. Their GH deficiency should exist for more than 24 months, if it could be verified from source data. Patients with multiple pituitary deficiency were on stable hormonal replacement therapy for at least 6 months before the study.
The patients did not receive treatment with GH during the last 12
months. Age was limited between 20 and 60 yr. Nor did they have any
acute severe illness during the last 6 months. Pregnant women were
excluded. No participant had chronic liver disease (serum ALT, AST, and
-GT higher than twice upper limits of laboratory normal ranges),
renal disease (serum creatinine > 1.5 mg/dL), hypertension
(supine diastolic pressure > 90 mm Hg), or frank diabetes
mellitus (fasting PG > 140 mg/dL) at the time of inclusion. No
patient had a history of malignancy except that that caused the GH
deficiency. Only the following chronic medications were allowed:
pituitary replacement therapy, bromocriptine, DDAVP, and
contraceptives.
Patients were randomized into a double-blind, placebo-controlled study
of human recombinant GH-replacement therapy (Genotropin, Pharmacia and
Upjohn, Stockholm, Sweden) for 6 months (period 1), followed by an open
phase of GH therapy for another 6 months (period 2). Patients in group
P received placebo for the first 6 months, then received GH for the
following 6 months, whereas patients in group G received GH for 12
months. GH was administered sc every night at 2200–2300 h via a pen
injector. The dose of GH was 0.125 IU/kg·week initially and increased
to 0.25 IU/kg·week 1 month later. Measurements of insulin sensitivity
were carried out at the commencement and at the end of the study.
Anthropometric variables and body composition were measured at baseline
and in months 3, 6, 9, and 12 of the study. Biochemical parameters were
assessed at baseline, in month 6, and in month 12. Nineteen patients
completed the study. One patient (No. 9, group G) was withdrawn 1 month
after his enrollment because of poor compliance and loss of follow-up,
and the other (No. 17, group P) was withdrawn in the placebo period
because of disease-related severe dehydration and renal function
deterioration. Among those who completed the trial, the data from 3
patients could not be used for analysis. Patient No. 3 (group P, a
butcher) was a case of protocol violation. He worked at night and slept
in the PM. We did not discover this until month 6. He also developed
hypertension in month 9 (blood pressure: 140/98 and 152/104 mm Hg at
month 9 and 12, respectively). Considering the diurnal changes and the
development of hypertension (an exclusion criteria), his data were
excluded from analysis. Patients No. 6 (group G) and No. 8 (group P)
were excluded for noncompliance (mainly based on numbers of missed
injection of GH, poor drug account, and low serum IGF-1 levels in the
GH-replacement period). Their data were also excluded from analysis.
The mean age of remainders (6 men and 10 women) was 29.5 yr; the median
age was 29 yr. Other baseline clinical details of the patients were
listed in Tables 1
, 2A, and 3.
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Body composition, anthropometric, and biochemical measurements
After overnight fasting for 12 h, all patients received assessments of body composition at 0800 h at baseline and in months 3, 6, 9, and 12 of the study. BW was measured to the nearest 0.1 kg and BH to the nearest millimeter. BMI was calculated as BW (kg) divided by BH squared (m2). Circumferences of waist (W) and hip were also measured to the nearest millimeter. Whole body bioelectrical impedance (BIA) analysis was performed by a portable impedance analyzer (BIA 101, RJL Systems, Detroit, MI). Measurements were made with subjects in the supine position and with limbs abducted from the body slightly. Current injector electrodes were placed just below the phalangeal-metacarpal joint in the middle of the right hand and just below the transverse arch on the superior side of right foot. Detector electrodes were placed on the posterior side of the right wrist and the ventral side of the right ankle joint. The analyzer provided a 50 kHz, 800-µamp current to the subjects. Resistance (expressed in ohms) and reactance (in ohms) were recorded. Body fat percentages (fat %) and total body fat mass were calculated by Segal’s regression equation (11). After the above measurements, fasting blood samples were collected for further analysis of biochemical parameters at baseline, in month 6, and in month 12.
Assessment of insulin sensitivity
The patients received a modified insulin suppression test (MIST) at baseline and in month 12 of the trial to assess insulin sensitivity. The control group received MIST twice: one in the AM and the other in the PM. The GH-deficient patients also received AM and PM MIST at baseline and in month 12. The AM test started at 0830 h, after finishing the assessment of body composition, and the PM one started at 1400 h on a separated day. All subjects were fasting for 12–14 h. The patients were allocated to AM or PM test randomly. The interval of two MIST was 3–5 days. The MIST was performed according to the procedures described previously (12). In brief, regular insulin (Humulin-R, Lilly, Indiana; 30 mU/min•m2), somatostatin (Stilamin, Serono, Swiss; 500 µg/h), and glucose (6 mg/kg·min) were infused simultaneously to the patient with three separate infusion pumps (Harvard Apparatus, Boston, MA). Blood samples were collected at -10, 0, 30, 60, 90, 100, 110, and 120 min during the procedures. PG and serum insulin concentrations were measured. The mean values of the PG at 90, 100, 110, and 120 min were defined as SSPG, and so was the insulin, as steady-state serum insulin (SSSI).
Measurements
PG was measured by a glucose oxidase method with a glucose analyzer (model 23A, YSI, U.S.A.). Serum immunoreactive insulin was determined by an RIA, as reported previously (13). Serum total cholesterol (TC), triglyceride (TG), and high-density lipoprotein-cholesterol (HDL-C) were measured by enzymatic methods using assay kits (Boehringer Mannheim, GmbH, Mannheim, Germany). The level of low-density lipoprotein-cholesterol (LDL-C) was calculated from TC, TG, and HDL-C. Serum GH was measured with a commercially available immunoradiometric assay kit (Daiichi, Tokyo, Japan). The inter- and intraassay coefficients of variation (CV) were 1.4 % and 1.3 %, respectively. The detection limit of the GH assay was 0.1 ng/dL. Serum IGF-1 was determined by an in-house RIA at a laboratory in Pharmacia and Upjohn. The detection limit in an undiluted sample was 20 ng/mL. The inter- and intraassay coefficients of variation were 3.1 % and 10.0 %, respectively.
Statistics
All values were expressed as mean ± SD. Differences between means were compared by Wilcoxon tests (14). The fat % was transformed by angular transformation, and the W/H ratio was transformed by log-transformation before statistical comparisons (15). Spearman’s procedure was used for the examination of correlation (14). The level of significance chosen was P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Compared with the control group matched for sex, BMI and age, the
patients studied had higher fat % (32.6 ± 5.2 % vs.
24.4 ± 6.35 %,P < 0.05). Table 2A shows the
absolute values of anthropometric and body composition variables, and
Table 2B demonstrates the differences between each period and baseline
data. Increased BH was found in group G patients, as compared with
group P patients in the same period (Table 2B). Significant reductions
in fat % and total fat mass were found in the active arm of period 1
(Table 2B). W circumferences and W/H ratios were reduced in group P
subjects during period 2, as compared with their baseline data (Table 2, A and B). However, BW and BMI did not change throughout the study
(Table 2, A and B). Serum IGF-1 concentrations were low in both groups
of patients at the commencement of the study. The IGF-1 levels
increased to normal ranges during the GH replacement therapy (Table 3).
The levels of fasting PG, TC, TG, HDL-C, and calculated LDL-C remained
unchanged in the study (Table 3). The results of MIST are shown in Fig. 1. There was no difference in SSSI levels
(Fig. 1, left panel). In normal nondiabetic subjects, SSPG was higher
in the PM than in the AM (103 ± 13 vs. 136 ± 20
mg/dL). The GH-deficient adults were relatively insulin resistant in
the AM and in the PM (AM SSPG: 160 ± 50; PM SSPG: 174 ± 39
mg/dL) (Fig. 1, right panel). Though the PM-AM difference of SSPG
(14 ± 33 vs. 33 ± 30 mg/dL in control) did not
reach statistical significance (P = 0.25) (Fig. 2), the normal pattern of SSPG (higher in
PM SSPG) could no longer be demonstrated in these patients (Fig. 1, right panel). After replacement of GH for 12 months, a marked reduction
of AM SSPG to 109 ± 41 mg/dL was found in group G, as compared
with the pooled baseline AM SSPG data (160 ± 50 mg/dL) (Fig. 1B),
and the PM-AM pattern of SSPG was also turned normal (Fig. 2). The
above features could not be uncovered in group P patients, who only
received GH replacement for 6 months. The PM-AM SSPG difference
increased significantly in patients after 12-month GH replacement
(43 ± 23 mg/dL), when compared with those without GH therapy
(14 ± 33 mg/dL) or 6-month GH replacement (-1 ± 31 mg/dL)
(Fig. 2). Finally, we used the Spearman’s procedure to test the
correlation of SSPG and body fat. A positive correlation between SSPG,
no matter AM or PM, and fat % and total body fat mass were
demonstrated in GH-deficient adults, which suggested a positive linear
association between these variables (Fig. 3).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, right panel), demonstrated that the PM
SSPG was higher than AM SSPG in normal subjects. Patients with
GH-deficiency had higher AM SSPG, as compared with the normal control
(Fig. 1, right panel). In addition, the difference of PM-AM SSPG in the
GH-deficient adult reduced to one third of the level in normal control
(Fig. 3). Though it did not reach statistical significance
(P = 0.25), we could still observe a tendency of
reduction in PM-AM SSPG difference in these patients. Five out of 16 of
them showed a reverse pattern of PM-AM SSPG; that is, their PM SSPG was
lower than AM SSPG. After 12-month replacement of GH, both AM SSPG
levels and PM-AM SSPG patterns were normalized in these patients. Our
data supported the conclusion claimed by Johansson et
al. (9) that the GH-deficient adults are insulin-resistant. And,
for the first time, we demonstrated that replacement of GH in these
patients not only reduced the AM SSPG levels but also normalized the
PM-AM SSPG patterns. In summary, GH-deficiency does exert effects on
insulin sensitivity.
In normal nondiabetic subjects, glucose tolerance is impaired in the
PM, as compared with the AM (21, 22). Decreased insulin secretion (23)
and diminished insulin sensitivity (24, 25) are both involved in
glucose intolerance later in the day. Circardian changes in
counter-regulatory hormones, especially cortisol and GH, also are
proposed to contribute to the reduction of glucose tolerance after
breakfast (26, 27, 28, 29). Other possible mechanisms are diurnal variation of
free fatty acid levels (22, 23), a down-regulation of insulin receptors
(10, 30), a higher hypoglycemic power of the AM insulin (31), and a
diurnal rhythm of sympathetic activity (25, 32). Our data supported
deterioration of insulin sensitivity in the PM, because AM SSPG was
lower than PM SSPG in normal subjects (Fig. 1). Lee et al.
(33) have used a cholinergic blocker, methscopolamine, to inhibit GH
secretion in normal healthy nonobese men. In their study, nocturnal GH
secretion did not affect diurnal variation in arginine and
glucose-stimulated insulin secretion in normal subjects. Our
observations provided clues to examine the role of GH in the diurnal
difference of insulin sensitivity. GH deficiency affects the insulin
sensitivity and, at least in some patients, the AM-PM pattern of
insulin sensitivity. Further analysis of pooled SSPG data in these
nonobese patients (BMI 22.7 ± 2.9 kg/m2) disclosed
that SSPG, no matter AM or PM, was positively correlated with fat %
and total fat mass (Fig. 3). We propose that the changes of insulin
sensitivity in GH-deficient adults may be related to the effects of GH
deficiency on body fat composition.
Recently, the effects of GH replacement on insulin sensitivity in
GH-deficient adults were reported by three different groups (17, 34, 35). O’Neal et al. have studied the effects of low doses of
GH (0.24 IU/kg·week) on carbohydrate metabolism and insulin secretion
in 10 GH-deficient adults over a 3-month period (17). They found a
small but significant rise in fasting glucose, insulin, C-peptide, free
fatty acid, and first- and second-phase insulin secretion after 1 week
replacement of GH (assessed by the Bergman minimal model). They also
noticed a decrease of insulin-mediated glucose disposal in the first
week. After 3 months of replacement, fasting insulin and C-peptide
levels remained elevated, whereas other parameters returned to
baseline. Therefore, they concluded that short-term low-dose GH
treatment induced a transient mild hyperinsulinemia and insulin
resistance. Weaver and associates (34) have used homeostatic model
assessment to calculate insulin sensitivity in 22 nondiabetic
hypopituitary subjects who received low-dose (0.2 IU/kg·week) GH for
6–12 months. They found a significant elevation of fasting PG and
specific insulin, in parallel with the reduction of insulin
sensitivity, after 6 months replacement of GH. Beshyah et
al. (35) have observed the effects of GH (0.28 IU/kg·week) on
carbohydrate tolerance (assessed by oral glucose tolerance test) in 40
hypopituitary adults for 18 months. They reported that 6- to 18-month
GH replacement in these subjects produced minor detrimental effects on
carbohydrate tolerance and hyperinsulinemia and found that fasting PG
and insulin increased significantly during GH therapy. In patients
receiving active GH treatment, the areas under curve of PG and insulin
during the oral glucose tolerance test were significantly higher, as
compared with the pretreatment values. However, our data showed a
different picture in glucose metabolism. After replacement of GH for 12
months, AM SSPG was reduced significantly, and the AM-PM pattern of
SSPG became normalized (Fig. 1, right panel). The conflicting results
of our data and previous reports may be related to the heterogeneity of
the patients, the methods used for assessment of insulin sensitivity,
the duration of GH administration, and the status of obesity in
patients. The patients recruited by Weaver et al. (34) were
obese (BMI approximately 28 kg/m2), and after GH therapy,
their BW and BMI increased significantly. The deterioration of insulin
sensitivity in them may therefore not be solely explained by the
administration of GH. Obesity is certainly a confounding factor in
evaluation of insulin sensitivity in GH-deficient adults. Beshyah
et al (35) also did their work on a group of obese patients
(BMI approximately 27–28 kg/m2). Within the GH group,
worsening of glucose tolerance was not significantly different from
improvement (33 % vs. 28 %, X2 =
0.131, P = not significant). Therefore, the response of
glucose tolerance to GH replacement seemed to be heterogeneous. Their
results need to be validated in nonobese GH-deficient patients. In the
study of O’Neal et al. (17), the effects of GH
administration on insulin sensitivity were related to the duration of
therapy. Our data showed significant improvement of AM SSPG after
12-month replacement of GH, as compared with baseline pooled AM SSPG
(Fig. 1, right panel). The improvement could not be achieved by 6-month
GH replacement. The difference of PM-AM SSPG also changed significantly
only after 12-month GH replacement, as compared with baseline data
(Fig. 2). Therefore, with regard to the change of insulin sensitivity,
we suggest that at least 1 yr is needed for observation.
The fat % of our patients was higher than controls, in spite of comparable age, sex, and BMI. This was in agreement with previous reports (36, 37, 38). Because GH has profound lipolytic effects (39), the increased body fat may be related to GH-deficiency. As reported previously (37, 40), we also observed significant reductions in fat % (since month 3) and total body fat mass (in month 6) in the active arm of period 1 without alteration in BW and BMI. Replacement of GH in GH-deficient adults would increase protein synthesis and decrease protein oxidation (41). Harant et al. (42) have noticed GH significantly increase the intrinsic lipolytic activities and potentiate the epinephrine-mediated lypolytic responses of adipose tissues (43) in GH-deficient adults after long-term GH replacement. Because there was minimal net change in BW among our GH-treated patients, we might conclude that the excess body fat was replaced with lean body mass (muscle and fluid). The validity of body composition methods used in the study of GH-deficient adults has been questioned (44). All in vivo body composition methods have underlying assumptions and methodological errors. For BIA, the use of prediction equations derived from normal individuals and the possibility of fluid shift during GH treatment seem to be probable measurement bias. Yet, a recent study in GH-deficient adults reported that BIA showed variation of body fat estimation, compared with dual-energy x-ray absorptiometry, whereas correlation was still quite high (45). And, above all, in the present study, we observe the difference before and after treatment. Because all patients were measured by the same machine, the measurement bias could be disregarded.
Though the patient population in the study is heterogeneous, we use the
inclusion/exclusion criteria and randomization to select the subjects
into two more homogeneous groups. At baseline, subjects in group P and
G were homogeneous in age, anthropometric parameters, body fat
composition, and biochemical variables (Tables 1–3). All patients with
thyroid, adrenal, and ADH deficiency received stable replacement
therapy for at least 6 months before the enrollment. The ratio of sex
hormone replacement was equal in two groups (43 % in group P and 50 %
in group G). We think the randomization is acceptable in this study and
do not attribute the reduction of body fat and normalization of insulin
sensitivity in subjects who received GH replacement to the effects of
sex steroids or glucocorticoids, rather than GH. There were some
subjects in our study who increased their BH after replacement of GH.
It implies that they have open epiphyses. Because we included the
patients by chronological age, instead of bone age, and several
patients did not receive sex hormone replacement, it was not surprising
to observe the increase of BH after GH treatment.
The consequences of GH-deficiency on lipid metabolism and changes
during GH replacement are conflicting (44). In our patients, the serum
TC and LDL-C concentrations before the trial were in the upper limit of
normal ranges, and about 40 % of them (7/16) had serum TG levels above
200 mg/dL. However, GH administration did not change serum lipid
levels, except for slight elevation of HDL-C in group G after GH
replacement for 12 months (38 ± 9 vs. 28 ± 8
mg/dL), as compared with the baseline levels (Table 3). The relatively
small number of patients, the duration of GH therapy, and the
preexisting plasma lipid levels may have contributed to our results in
lipid metabolism.
In conclusion, our study, for the first time, demonstrates that GH replacement has beneficial effects on insulin sensitivity in GH-deficient adults. Normalization of insulin sensitivity may be related to the reduction of total body fat in these patients.
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Acknowledgments |
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Footnotes |
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Received November 12, 1996.
Revised June 27, 1997.
Accepted July 8, 1997.
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, P < 0.05
vs. GH-deficient adults; *, P <
0.05 vs. GH-deficient adults with GH replacement for 6
months.
