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Department of Endocrinology (M.B., M.S., E.L., P.M., L.G.), University Hospital, S-205 02 Malmö, Sweden; and Copenhagen Muscle Research Centre (J.R.D.), Department of Human Physiology, DK-2100 Copenhagen, Denmark
Address all correspondence and requests for reprints to: Margareta Bramnert, Department of Endocrinology, University Hospital MAS, S-205 +2 Malmö, Sweden. E-mail: margareta.bramnert{at}skane.se.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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GH therapy resulted in impaired insulin-stimulated glucose uptake at 1 wk (-52%; P = 0.008) and 6 months (-39%; P = 0.008), which correlated with deterioration of glucose tolerance (r = -0.481; P = 0.003). The decrease in glucose uptake was associated with an increase in lipid oxidation at 1 wk (60%; P = 0.008) and 6 months (60%; P = 0.008) and a concomitant decrease in glucose oxidation. The deterioration of glucose metabolism during GH therapy also correlated with the enhanced rate of lipid oxidation (r = -0.508; P = 0.0002). In addition, there was a shift toward more glycolytic type II fibers during GH therapy.
In conclusion, replacement therapy with a low-dose GH in GH-deficient adult subjects is associated with a sustained deterioration of glucose metabolism as a consequence of the lipolytic effect of GH, resulting in enhanced oxidation of lipid substrates. Also, a shift toward more insulin-resistant type II X fibers is seen in muscle. Glucose metabolism should be carefully monitored during long-term GH replacement therapy.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Similarly, high-dose GH treatment for 6 wk resulted in reduced insulin sensitivity determined by a hyperinsulinemic euglycemic clamp, but after 6 months of treatment, insulin sensitivity returned to pretreatment levels (5). Another study using the modified insulin suppression test did not observe any untoward effects on insulin sensitivity after 12 months of treatment (6). Also, a 50% lower GH dose resulted in an exaggerated insulin response and a decreased insulin-mediated glucose disposal after 1 wk of treatment, but insulin sensitivity returned to baseline after 3 months of treatment (7). In contrast, Weaver et al. (8) reported persistent decreased insulin sensitivity after 6 months of treatment with a physiological (9 µg/kg·d) GH dose. Some of the different temporal effects may be ascribed to the acute lipolytic effect of GH, which later on could be counteracted by positive effects of increased lean body mass on insulin sensitivity.
This study was designed to address some of these controversies, examining short- and long-term effects of physiological GH replacement on different aspects of glucose and lipid metabolism in GHD adults.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Nineteen consecutive patients (7 women and 12 men; mean age, 42 ± 2.6 yr; estimated duration of GHD, 134 ± 25 months) from the outpatient clinic of the Department of Endocrinology, University Hospital, Malmö, Sweden, were included (Table 1
). Inclusion criteria were: an estimated duration of GHD for more than 1 yr; patients were on stable hormonal replacement therapy; and patients did not have impaired glucose tolerance. Informed consent was obtained from all subjects. The diagnosis of GHD was based on a maximal GH peak less than 9 mU/liter (3 µg/liter) after a provocation stimulus such as insulin-induced hypoglycemia, arginine, or clonidine applied within 6 months before inclusion in the study. All patients were hormonally replaced for pituitary insufficiencies, except one premenopausal woman who did not receive estrogens. The hormone substitution therapy had been stable for at least 6 months before inclusion in the study. One patient who had hypercholesterolemia and recurrent thrombosis was treated with simvastatin, cholestyramine, and dicumarol. The treatment was unchanged throughout the study.
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)The patients were randomized in a double-blind manner to either GH substitution (Genotropin, Pharmacia, Stockholm, Sweden), 0.067 mg/kg body weight (BW)·wk divided into daily sc doses at bedtime, or the corresponding volume of the preservatives given as placebo. The study was approved by the Ethics Committee of the Medical Faculty of Lund University; the Isotope Committee, University Hospital MAS; and the Swedish Medical Product Agency.
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OGTT
After an overnight fast, the patients ingested 75 mg glucose (dextrose, Boehringer Mannheim, Mannheim, Germany), and blood samples for determination of glucose and insulin were obtained at -15, 0, 30, 60, 90, and 120 min.
BIA
Total body water (TBW) was estimated from total body resistance using a two-terminal portable impedance analyser (BIA 101, RJL analyser, Akern, Copenhagen, Denmark). Measurements were performed in the morning in the supine position as described by Lusaki et al. (9) after voiding. Electrodes were placed on the left side of the body on the dorsal surface of the hand and foot proximal to the metacarpophalangeal and metatarsophalangeal joints, respectively.
Hepatic glucose production (HGP)
The isotope dilution technique using 3-[3H]glucose (Amersham Bioscience, Uppsala, Sweden) was performed to assess HGP. Before the study, a catheter was inserted into an antecubital vein for infusion of 3-[3H]glucose. A second catheter was inserted retrogradely into a wrist vein for drawing of blood, and the forearm was then inserted in a heated box (70 C) to achieve arterialization of venous blood (10). The catheters were kept patent by a slow infusion of physiological saline infusion. A primed 25 µCi bolus injection of 3-[3H]glucose followed by an infusion of 0.25 µCi/min was given for 4 h. The radiochemical purity of the tracer was 99%, as reported from the manufacturer. Blood samples for the determination of 3-[3H]glucose specific activity were obtained at -20, -10, and 0 min before starting the hyperinsulinemic euglycemic clamp, and after 100, 110, and 120 min during the hyperinsulinemic euglycemic clamp.
Basal HGP was calculated by dividing the 3-[3H]glucose infusion rate at steady state by 3-[3H]glucose infusion rate specific activity achieved during the last 30 min of the basal tracer infusion period. After the administration of insulin and glucose, a non-steady state condition in glucose specific activity exists, and the rate of glucose appearance was calculated as a two compartment model (11). This model is known for negative estimates of HGP in the presence of high levels of insulin. In cases in which negative estimates of HGP were obtained, Steele's equation was used for HGP calculations (12). Negative HGP values are taken to indicate that the endogenous (hepatic) glucose production was totally suppressed. See Table 4 for negative values at different time points.
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Insulin sensitivity was measured using the hyperinsulinemic clamp technique (13). After basal samples of insulin and B-glucose were obtained, a bolus dose of short-acting human insulin (Actrapid, Novo Nordisk, Copenhagen, Denmark) was administered, followed by a continuous infusion at a rate of 322 pmol/m2·min (45 mU/m2/min) for 2 h. A glucose infusion of 20% glucose was started, with the option to maintain B-glucose at 5.5 mmol/liter, and B-glucose was determined every 5 min.
The amount of glucose required to maintain euglycemia equals whole body disposal of glucose, provided that there is no entry of glucose from the liver. The rate of whole-body glucose disposal was calculated by adding HGP to the glucose infusion rate. Nonoxidative glucose metabolism, i.e. storage of glucose as glycogen, was calculated from the difference between total-body glucose disposal and glucose oxidation determined by indirect calorimetry.
Indirect calorimetry
To estimate the net rates of carbohydrate and lipid oxidation, indirect calorimetry was used in the basal state and during the last 45 min of the hyperinsulinemic euglycemic clamp (14). A computerized, open circuit system was used to measure gas exchange through a transparent plastic canopy (Deltatrec, Dartex, Helsinki, Finland; Ref. 15). Protein oxidation was calculated from the urinary urea excretion obtained before and during the clamp and was corrected for urea clearance (16). The constants to calculate glucose, lipid, and protein oxidation from gas exchange data and nitrogen excretion were given by Ferrannini (14).
Muscle biopsies
Muscle biopsies were taken using a Bergström needle at the end of the hyperinsulinemic euglycemic clamp from vastus lateralis of the quadriceps muscle (17) under sc local anesthesia with lidocaine (Xylocaine, Astra USA, Inc., Göteborg, Sweden). The muscle tissue sample was immediately divided into two pieces, one for analysis of muscle enzyme activity and the other for histochemical analysis. The piece for muscle enzyme activity was instantly frozen in liquid nitrogen, whereas the other piece of muscle tissue was embedded in plastic material (Tissue-Tek, Miles Scientific, Naperville, IN).
For histochemical determination of muscle fiber type, a serial transverse section (10 µm) was cut in a cryotome at -20 C from embedded muscle sample. The sections were mounted over coverslips and stained for myofibrillar ATPase at pH 9.4 after both acid (pH 4.3 and 4.6) and alkaline (pH 10.3) preincubations (18) to identify type I, type IIA, type IIB, and type IIC fibers. Because the transcript from the fastest human isoform IIB is homologous to rat type IIX isoform (19) and thus may correspond to rat type IIX fibers (20), IIX was chosen to represent the fastest human isoform in the present manuscript. Quantification and calculation were done using COMFAS image scanner (SbsysCOMFAS, Scan Beam, Hadsund, Denmark). Adequate biopsies for muscle fiber analysis were obtained at baseline and after 1 wk in seven individuals in the placebo group and six individuals in the GH-treated group, and after 6 months in seven individuals in both the GH-treated and placebo groups.
Muscle triglycerides were assayed in freeze-dried muscle fibers dissected free from adipose tissue, connective tissue, and blood. For muscle triglyceride determination, tetra-ethyl-ammonium-hydroxide was added to pool muscle fibers. After an overnight incubation, 3 M perchloric acid was added, and the samples were centrifuged. The supernatant was neutralized with 2 M KHCO3 (21). The glycerol concentration was analyzed fluorometrically (22). Adequate biopsies for analysis of triglyceride measurements were obtained in six patients at baseline and after 1 wk and 6 months in both the GH and placebo groups.
For glycogen synthase (GS) activity determination, the frozen muscle samples were homogenized in ice-cold 50 mM Tris-HCl buffer (pH 7.5) containing 0.05 mM dithiothreitol, 1 mM EDTA, and 2 mM MgCl2. Activity was measured by modification of a fluorometric method (23). This method measures the production of uridine diphosphate (UDP) from the incorporation of UDP-glucose in glycogen. The assay couples the conversion of UDP-glucose to UDP and with the oxidation of nicotinamide adenine dinucleotide phosphate (NADH) by two enzymatic steps, including pyruvate kinase and lactate dehydrogenase. The oxidation of NADH is measured fluorometrically (Transcon 102 FN analyser, Biohit, Helsinki, Finland). Samples and blanks were incubated for 15 min at 37 C with 0.3 and 7.1 mM UDP-glucose concentrations at incubation solutions containing 0.1 and 10 mM glucose-6-phosphate (G-6-P). Heating at 100 C for 2 min stopped the reaction. The assay reagent containing lactate dehydrogenase and NADH was added, and initial fluorescence was read. Pyruvate kinase was added, and final fluorescence was read after the reaction was completed. Protein was assayed from homogenates by BCA Protein assay (Pierce Chemical Co., Rockford, IL), and GS activity was given as nanomoles x minutes-1 x milligrams-1 protein. Fractional velocity (FV) is defined as physiological GS activity at 0.1 mM G-6-P divided by the total GS activity at 10 mM G-6-P at subsaturated (0.3 mM) or saturated (7.1 mM) UDP-glucose concentrations.
The maximal activity of citrate synthase was determined using nicotinamide dinucleotide-NADH enzymatic fluorometric assay according to Lowry and Passonneau (24). Adequate biopsies for analysis of muscle enzyme activities were obtained before treatment in 9 individuals in the placebo group and 7 individuals in the GH group, after 1 wk in 9 individuals in the placebo group and 8 in the GH group, and after 6 months in 10 individuals in the placebo group and 8 in the GH group.
Other biochemical assays
Fasting B-glucose was measured by a hexokinase method with a coefficient of variation (CV) less than 1% (Roche Molecular Biochemicals, Mannheim, Germany). Plasma glucose during the OGTT and hyperinsulinemic euglycemic clamp was measured on duplicates using Hemocue (Hemaocue AB, Ängelholm, Sweden). S-insulin concentrations were analyzed with ELISA (DAKO Diagnostics Ltd., Cambridgeshire, UK) with an interassay CV of 9%. S-free fatty acids (FFAs) were analyzed by a microfluorometric method (25). 3-[3H]glucose radioactivity was measured in duplicates on supernatants of 1 N perchloric acid extracts of serum samples after the radio-labeled water had been evaporated. Dilution aliquots of the tracer infusates were processed in the same way as serum samples had been to determine the tracer infusion rate exactly. The CV for the assay was 5%. S-Leptin was analyzed by RIA (Linco Research, Inc., St. Louis, MO) with an interassay CV of 3–6%. S-IGF-I was measured by RIA after separation of IGFs from IGF binding proteins by acid ethanol extraction (26) and with des(1, 2, 3)-IGF-I as radioligand to minimize interference of IGF binding proteins in the extract. The intra- and interassay CV were 4 and 11%, respectively. The IGF-I values are also expressed as SD scores (27).
Statistical analysis
Values are presented as mean ± SEM. For testing of statistical significance, Friedman’s repeated measures ANOVA on ranks was used. If significant, further nonparametric analyses were carried out using Wilcoxon’s test for paired data, and changes from baseline between the GH and placebo groups were calculated by using Mann-Whitney U test for unpaired data. Correlations were calculated using Spearman’s rank correlation coefficients. The area under the curve (AUC) was calculated using the trapezoidal rule (28). All statistical calculations were performed by Statview software (version 4.5 for Windows, Abacus Concept Inc., Berkeley CA; SAS Institute, Inc., Cary, NC). P values less than 0.05 were considered statistically significant.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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At baseline, there was no difference between the placebo and GH-treated groups with respect to gender, age, and body mass index (BMI; Tables 1 and 2). There was no difference in GH peak after stimulatory testing, estimated duration of GHD, and the number of additional pituitary deficiencies (median, 2.2 vs. 2.7). All subjects were clinically and biochemically euthyroid throughout the study. There was no difference in baseline IGF-I concentrations between the placebo and GH-treated groups. After 1 wk (P = 0.008) and 6 months (P = 0.011) of treatment, IGF-I increased in the GH-treated group compared with before treatment, and also compared with the placebo group (P = 0.0002 and 0.0019, respectively). IGF-I SD score increased compared with before treatment from -4.2 ± 1.1 at baseline to 0.7 ± 0.6 after 1 wk (P = 0.008) and 0.3 ± 0.7 after 6 months (P = 0.011) in the GH-treated group and compared with the placebo group (P = 0.0002 and 0.0015, respectively).
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)BW, BMI, body fat (BF), and lean body mass were similar in the placebo and GH groups before treatment. There was no significant change in body composition during GH treatment in all subjects. After 6 months of GH treatment, there was, however, a decrease in percentage BF in men but not in women. TBW was similar before treatment in the placebo and GH groups. There was no significant change in TBW after 1 wk or 6 months of treatment with GH, compared with before treatment, but TBW increased at 6 months compared with placebo (P = 0.0158).
Glucose tolerance and insulin concentrations (Table 3)
Fasting glucose and insulin did not differ between the placebo and GH groups at baseline. There was, however, a significant increase in fasting B-glucose (P = 0.033) and insulin (P = 0.018) levels after 1 wk on GH replacement therapy compared with before treatment and also between the changes in the GH and placebo groups (P = 0.0042 and 0.0092, respectively). When compared with baseline, the increase in insulin was sustained after 6 months of treatment (P = 0.017), whereas fasting B-glucose had returned to baseline levels. The changes in fasting B-glucose and insulin in the GH-treated group were significantly increased (P = 0.0271 and 0.0415, respectively) compared with placebo after 6 months.
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Glucose metabolism (Fig. 2 and Table 4)
Before treatment, there was no difference in insulin-stimulated glucose disposal between the placebo and GH-treated groups. After 1 wk (P = 0.008) and 6 months (P = 0.008), glucose storage decreased by 52% and 39%, respectively, during GH treatment compared with baseline, but it was unchanged during placebo treatment. Glucose disposal was significantly lower in the GH-treated group compared with the placebo group at both 1 wk and 6 months (P = 0.0008 and 0.0412, respectively). The rate of glucose disposal correlated negatively with the IGF-I concentration (r = -0.493; P = 0.0002) and AUC glucose (r = -0.481; P = 0.0003).
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The rate of insulin-stimulated glucose oxidation was similar in the placebo and GH groups before treatment and decreased after 1 wk (P = 0.015) and 6 months (P = 0.045) of GH replacement compared with baseline and compared with placebo after 1 wk (P = 0.0275).
The rate of nonoxidative glucose metabolism during insulin stimulation was similar in the placebo and GH groups before treatment. During GH treatment, there was a significant decrease in nonoxidative glucose metabolism after both 1 wk (P = 0.008) and 6 months (P = 0.011) compared with before treatment, and also when compared with placebo (P = 0.0019 and 0.0469, respectively). It was unchanged in the placebo group.
Before treatment, basal HGP did not differ between the two groups. Neither was there any effect on basal HGP after 1 wk or 6 months in the GH-treated group, compared with before treatment or compared with the placebo group. There was no difference in residual HGP during the clamp, which was completely suppressed in both groups at baseline, after 1 wk, and after 6 months of GH replacement therapy.
Lipid metabolism (Fig. 3 and Table 4)
The basal rate of lipid oxidation did not differ between the placebo and GH groups before treatment. The basal rate of lipid oxidation increased in the GH-treated group after 1 wk (P = 0.008) and 6 months (P = 0.007), both compared with before treatment and with the placebo group (P = 0.0009 and 0.0269, respectively). Before treatment, there was no difference in insulin-suppressed lipid oxidation in the placebo and GH groups. GH treatment increased the rate of lipid oxidation during the clamp after 1 wk (P = 0.008) and after 6 months (P = 0.011), compared with before treatment and with the placebo group (P = 0.009 and 0.0469, respectively). The rate of lipid oxidation correlated positively with FFA (r = 0.629; P < 0.0001) and IGF-I (r = 0.311; P = 0.001) and negatively with glucose disposal (r = -0.508; P = 0.0002), particularly glucose oxidation (r = -0.648; P < 0.0001). There was also an inverse correlation between lipid oxidation and nonoxidative glucose metabolism (r = -0.473; P = 0.004).
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). There was a negative correlation between leptin levels and glucose disposal (r = -0.313; P = 0.019) and between leptin levels and nonoxidative glucose metabolism (r = -0.306; P = 0.023).
Energy expenditure and protein metabolism (Table 4)
There was no difference in energy expenditure between the placebo and GH groups before treatment. After 1 wk (P = 0.008) and 6 months (P = 0.008) of GH replacement therapy, basal energy expenditure increased compared with before treatment and with placebo (P = 0.0092 and 0.0029, respectively). Basal energy expenditure correlated positively to the basal rate of lipid oxidation (r = 0.667; P < 0.0001), and the change in basal energy expenditure after 1 wk and 6 months was strongly correlated to the change in basal rate of lipid oxidation (r = 0.72; P < 0.0001). There was no difference in insulin-stimulated energy expenditure between the placebo and GH groups, and this did not change after 1 wk and 6 months with either GH or placebo.
Protein oxidation was similar in both groups before treatment and did not significantly change during the insulin clamp. There was no significant change during the 6-month period during either fasting or insulin-stimulated conditions in the placebo and GH-treated groups, compared with before treatment and with the placebo group.
Muscle biopsies
Fiber typing (Table 5).
There was no difference in relative distribution of the mean area type I, IIA, IIX, and IIC fibers between the GH and placebo groups before treatment. After 6 months of GH therapy, the relative distribution of type IIX fibers increased (P = 0.018) compared with before treatment. In the placebo group, fiber type composition did not change. The change in mean area distribution of type IIA fibers correlated with the change in fasting insulin (r = 0.353; P = 0.0255).
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).
There was no difference in muscle triglyceride content between the placebo and GH groups before treatment. After 1 wk and 6 months of treatment, there was no significant change in muscle triglycerides in either the GH-treated or placebo group.
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).
Before treatment, GS activity was lower in the placebo group compared with the GH group. There was no significant effect of GH on GS activity compared with before treatment and with the placebo group. |
Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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We observed impaired insulin-stimulated glucose uptake after both 1 wk and 6 months in the GH-treated subjects, affecting both oxidative and nonoxidative pathways of intracellular glucose metabolism. The most likely explanation for the impairment of insulin-stimulated glucose metabolism was concomitant increase in lipid oxidation, which correlated inversely with glucose uptake (r = -0.508) and oxidation (r = -0.648). This is supported by a recent study in which we found that inhibition of lipolysis with acipimox partially prevented GH-induced insulin resistance (30). The increased rate of lipid oxidation is likely a consequence of the lipolytic action of GH as demonstrated by the close correlation between S-FFA and the rate of lipid oxidation (r = 0.699; P < 0.0001) and the S-IGF-I levels as a measure of GH action and the rate of lipid oxidation (r = 0.311; P = 0.001).
We did not observe any significant change in the rate of HGP, either in the basal state or during insulin clamp. It could be argued that our estimates of residual rate of glucose production during the clamp were not sensitive enough because we used a constant infusion of the 3-[3H]glucose tracer (31, 32). We acknowledge this problem, but do not think that this can explain the difference in insulin-stimulated glucose uptake between GH and placebo, which was in the order of 20 µmol/kg BW·min. Other studies using an insulin dose similar to the dose in this study and a variable infusion of 3-[3H]glucose did not show any effect, or only moderate effect, of GH on residual HGP during the clamp (29, 33). Therefore, it is unlikely that GH exerts a major effect on HGP during these conditions. The situation may be different during prolonged starvation because GH might stimulate glucagon release and thereby gluconeogenesis (34).
We observed a slight but significant increase in basal energy expenditure after both 1 wk and 6 months of GH substitution. No such increase was seen during the clamp. The increase in the rate of energy expenditure can partially be ascribed to the increased rate of lipid oxidation, which correlated with energy expenditure (r = 0.72; P < 0.0001). The lack of stimulation of energy expenditure by insulin (thermogenesis) can probably be ascribed to the insulin resistance induced by GH. A thermogenetic response to insulin is usually lacking in insulin-resistant states (35). Enhanced energy expenditure has previously been demonstrated during short-term (14 h) GH infusion in GHD patients (36), who if untreated are characterized by a low rate of energy expenditure. The mechanism by which GH therapy increases energy expenditure could also involve increased conversion of T4 to T3 (37, 38, 39), an increase in lean body mass (40, 41, 42), which is a strong determinant of energy expenditure (43), and an increase in IGF-I (33, 39).
In contrast to some previous studies, the negative effect of GH on glucose metabolism was not attenuated after 6 months. There is no reason to believe that the lipolytic effect of GH would disappear with time. Instead, in some previous studies the subsequent increase in lean body mass seen during GH therapy has been considered to counterbalance the negative effect of GH on glucose metabolism. In this study, we observed no significant effect of GH on lean body mass. There may be several reasons for this. First, our method for estimating body composition (bioimpedance) is not optimal in GH-treated patients if there is a simultaneous fluid retention. Second, the GH dose used in this study was quite modest. Third, it is possible that the patients included in this study already had more preserved lean body mass than patients in previous studies at the start of the GH therapy. Regardless of this, the untoward effect of GH on glucose metabolism persisted after 6 months. However, we have observed impaired insulin sensitivity even after 2 yr of GH treatment (44). This is also supported by Johnston et al. (45), who found increased fasting insulin levels even after 10 yr of GH treatment.
There may also be another explanation for the absence of improved insulin sensitivity with time. Muscle fiber composition changed after 6 months of GH replacement therapy, resulting in increased fast-twitch glycolytic type IIX fibers. An increased amount of type IIX fibers has been associated with insulin resistance (46), but it is not known whether this represents the cause or the consequence of insulin resistance. Interestingly, in rats 7 d of insulin infusion resulted in a similar switch from type I to type IIX fibers (47). We can therefore not exclude the possibility that hyperinsulinemia associated with GH treatment (possibly in association with increased IGF-I levels) was the cause of the change in fiber type composition observed in these patients.
In conclusion, GH therapy for 6 months in GHD adults results in impaired insulin-stimulated glucose metabolism and a change in muscle fiber type toward glycolytic type IIX fibers. The impairment of glucose metabolism correlates strongly with an increased rate of lipid oxidation and could reflect a switch from using glucose to lipids, i.e. activated glucose fatty acid cycle. It is thus important to monitor glucose tolerance during long-term treatment with even moderate doses of GH.
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Acknowledgments |
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Footnotes |
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Abbreviations: AUC, Area under the curve; B, blood; BIA, bioelectrical impedance; BMI, body mass index; BW, body weight; CV, coefficient(s) of variation; FFA, free fatty acid; FV, fractional velocity of GS activity; G-6-P, glucose-6-phosphate; GHD, GH-deficient or GH deficiency; GS, glycogen synthase; HGP, hepatic glucose production; NADH, nicotinamide adenine dinucleotide phosphate; OGTT, oral glucose tolerance test; S, serum; TBW, total body water; UDP, uridine diphosphate.
Received April 4, 2002.
Accepted January 2, 2003.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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