J Clin Endocrinol Metab. 2003 Apr.
Growth Hormone Replacement Therapy Induces Insulin Resistance by Activating the Glucose-Fatty Acid Cycle.
Bramnert M, Segerlantz M, Laurila E, Daugaard JR, Manhem P, Groop L.
Department of Endocrinology, University Hospital, S-205 02 Malmo, Sweden.
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Abstract: The effects of GH replacement therapy on energy metabolism are still uncertain, and long-term benefits of increased muscle mass are thought to outweigh short-term negative metabolic effects. This study was designed to address this issue by examining both short-term (1 wk) and long-term (6 months) effects of a low-dose (9.6 µg/kg body weight·d) GH replacement therapy or placebo on whole-body glucose and lipid metabolism (oral glucose tolerance test and euglycemic hyperinsulinemic clamp combined with indirect calorimetry and infusion of 3-[3H]glucose) and on muscle composition and muscle enzymes/metabolites, as determined from biopsies obtained at the end of the clamp in 19 GH-deficient adult subjects.

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

Growth hormone has marked effects on energy metabolism, influencing all major pathways of substrate metabolism. Many studies have been performed to establish the effect of GH on glucose and lipid metabolism in GH-deficient (GHD) man, but the results have been quite divergent due to differences in dose, route of administration, and duration of treatment. Several placebo-controlled studies using higher doses (12–23 µg/kg·d) of GH have reported constant elevation of fasting blood (B)-glucose and serum (S)-insulin concentrations (1, 2, 3, 4).

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.

Patients and Methods

Patients. 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.

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.

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Results

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).

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).

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.

The AUC of glucose and insulin during the OGTT did not differ before treatment between the placebo and GH groups. In the GH-treated group, the AUC of glucose increased after 1 wk (P = 0.0499) and 6 months (P = 0.036) compared with before treatment and compared with the placebo group (P = 0.0113 and 0.0113, respectively). The AUC of insulin was unchanged after 1 wk and 6 months of treatment in the GH group compared with baseline, but increased after 1 wk (P = 0.0055) compared with the placebo group; at 6 months, there was no difference.

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).

Basal rate of glucose oxidation did not differ between the placebo and GH groups before treatment. During GH treatment, there was a decrease in basal glucose oxidation after 1 wk (P = 0.021), which was sustained after 6 months of treatment (P = 0.016) compared with before treatment and compared with placebo after 1 wk (P = 0.0152). In the placebo group, the basal rate of glucose oxidation was unchanged during the 6-month period.

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.

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).

There was no difference in FFA and leptin levels between the groups before treatment. Neither was there any significant change in FFA or leptin concentrations during GH treatment, compared with before treatment or placebo (Table 3). 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).

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).

Discussion

In the present study, physiological GH replacement (IGF-I SD score, 0.3 ± 0.7 after 6 months of treatment) in GHD adults resulted in persistent impairment of glucose tolerance and insulin sensitivity. This is only partially in agreement with previous studies using higher doses of GH (5, 7), in which fasting glucose returned to baseline after 3–12 months and insulin sensitivity improved. Part of this improvement in insulin sensitivity with time in GH-treated adult subjects with GHD has been ascribed to a GH-induced decrease in body fat and an increase in lean body mass, which is usually accompanied by enhanced insulin sensitivity (6). In contrast to this, Christopher et al. (29) found a persistent decrease in insulin sensitivity despite improved body composition.

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.