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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-1239
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 4 2290-2296
Copyright © 2005 by The Endocrine Society

Adiponectin, Leptin, and Erythrocyte Sodium/Lithium Countertransport Activity, But Not Resistin, Are Related to Glucose Metabolism in Growth Hormone-Deficient Adults

Johan Svensson, Hans Herlitz, Per-Arne Lundberg and Gudmundur Johannsson

Research Centre for Endocrinology and Metabolism (J.S., G.J.), and Departments of Nephrology (H.H.) and Clinical Chemistry (P.-A.L.), Sahlgrenska University Hospital, SE-413 45 Göteborg, 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
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
In a randomized, placebo-controlled, crossover study under metabolic ward conditions, 10 GH-deficient adults received 1-wk GH replacement therapy (9.5 µg/kg·d). The effect of this treatment on the erythrocyte sodium/lithium countertransport (SLC) activity and on serum levels of adiponectin, resistin, leptin, IGF binding protein-1 (IGFBP-1) and IL-6 was determined.

The 1-wk GH replacement impaired glucose homeostasis determined from an oral glucose tolerance test. The other measured variables in serum were unchanged by GH replacement. At baseline, serum adiponectin level was inversely correlated and serum leptin level was positively correlated with measures of glucose tolerance and insulin sensitivity. The changes in serum leptin level and erythrocyte SLC activity were positively correlated, and the change in serum IGFBP-1 level was negatively correlated, correlated with changes in measures of glucose metabolism.

In conclusion, short-term GH treatment induced glucose intolerance but did not significantly change the erythrocyte SLC activity and the serum levels of adipokines, arguing against direct effects of GH on these measures. However, baseline values or changes in erythrocyte SLC activity, adiponectin, leptin, and IGFBP-1 correlated with glucose metabolism. This suggests that these factors are of importance for glucose homeostasis in GH-deficient adults, most likely through GH-independent mechanisms.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THE EFFECT OF GH replacement in adults on insulin sensitivity appears to be biphasic. Short-term (<6 months) GH replacement decreases insulin sensitivity (1), which is followed by an improvement and a return toward baseline values after 3–6 months of therapy (1, 2). During long-term GH replacement, most studies report unchanged insulin sensitivity as compared with baseline (3, 4) although there are reports of both decreased (5, 6) and increased (7) insulin sensitivity. Studies using the hyperinsulinemic, euglycemic clamp technique suggest that the decreased baseline insulin sensitivity persists during 2–7 yr of GH replacement therapy (8, 9), although, in one study, GH replacement provided protection from the age-related decline in insulin sensitivity (9).

The response to GH in terms of insulin sensitivity is not fully understood. Direct effects of GH and increased free fatty acids through GH-induced lipolysis are likely mechanisms for the transient, rapidly reversed decrease in insulin sensitivity (10). The response in insulin sensitivity also differs considerably among patients (9), and at present, there is no clinically useful marker available to predict the patients in whom insulin sensitivity will deteriorate the most during GH therapy (9). During the last years, however, the modulating effects of adipokines, factors produced by adipocytes, on glucose homeostasis, have been pointed out (11). The adipokines could be important for the effects of GH on glucose metabolism because GH has a profound effect on the metabolism of adipocytes. Furthermore, the adipokines could be of value for predicting the response to GH in terms of glucose homeostasis.

The adipokine leptin was cloned in 1994 (12) and has been shown to regulate energy intake and energy expenditure in rodents. In humans with severe lipodystrophy and, therefore, very low serum levels of leptin, administration of recombinant human leptin improved insulin sensitivity (13, 14). Adiponectin is an adipokine reported to have a positive effect (15), and resistin is an adipokine reported to have a negative effect (16) on insulin sensitivity.

In the general population, several factors besides classical adipokines have been related to glucose tolerance. Circulating IL-6 level has been positively associated with increased body fat and insulin resistance (17, 18), and serum IGF binding protein-1 (IGFBP-1) level has been inversely related to circulating insulin concentration (19). The activity of the erythrocyte transport system, the sodium/lithium countertransport (SLC), has been linked to the insulin resistance and the compensatory hyperinsulinemia in the metabolic syndrome (20).

In this randomized, placebo-controlled, crossover study, we determined the effect of 1-wk GH replacement therapy in 10 GH-deficient (GHD) adults on serum concentrations of adiponectin, resistin, leptin, IGFBP-1, and IL-6, and also on erythrocyte SLC activity. Furthermore, we determined whether baseline values or changes in these hormones were related to glucose metabolism.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

Ten adults (nine males/one female) with adult-onset hypopituitarism were recruited consecutively among patients being considered for GH replacement therapy. The mean age was 55 yr (range 48–69 yr) and their mean body mass index at entry was 26.2 kg/m2 (range 18.9–30.2). The hypopituitarism was a result of nonfunctional pituitary adenoma or its treatment in seven patients, whereas in two patients it was due to empty sella syndrome and idiopathic hypopituitarism. In one of the patients, the hypopituitarism was due to previous Cushing’s disease, which had been cured for more than 5 yr before the start of this study. Three of the 10 patients had panhypopituitarism and two had isolated GH deficiency. A GH peak of less than 3 µg/liter during insulin-induced hypoglycemia was used to confirm the GH deficiency. Subjects with renal disease, hypertension, diabetes mellitus, previous stroke, or polyneuropathy were not eligible for the study.

Study protocol

This was a 7-d randomized, double blind, placebo-controlled, crossover study with a 4-wk washout period. Randomization to GH or placebo was performed at the Clinical Trial section at the Sahlgrenska University Hospital Pharmacy. The dose of GH was 9.5 µg/kg·d. Five patients were randomly allocated to receive GH in the first period and placebo in the second period, whereas five patients were randomized to receive treatment in the reverse order. Other hormonal replacement therapy for hypopituitarism, such as glucocorticoids, L-thyroxine, and gonadal steroids, was kept stable for at least 3 months before entering the trial. Other medication was not allowed.

Before and at the end of each treatment period, the patients spent 3 d in a metabolic ward unit. On the second of these days, multifrequency bioelectrical impedance analysis (BIA) and an oral glucose tolerance test (OGTT) using an oral glucose load of 75 g were performed. Venous blood samples were drawn for glucose and insulin determinations during the OGTT at 0, 30, 60, 90, and 120 min. Area under curve (AUC) values for blood glucose and serum insulin during the OGTT were calculated using the trapezoidal rule. Furthermore, on the third day of the metabolic ward regimen, after an overnight fast and before leaving bed, blood samples were collected.

Body weight was measured daily in the morning to the nearest 0.1 kg. Body height was measured barefoot to the nearest 0.01 m. Body mass index (BMI) was calculated as the weight in kilograms divided by the height in meters squared. Waist circumference was measured in the standing position with a flexible plastic tape placed midway between the lower rib margin and the iliac crest, and hip girth was measured at the widest part of the hip. All measurements of waist to hip ratio were performed by the same investigator. Body fat and fat-free mass were determined using multifrequency BIA as previously described (21).

Ethics

After oral and written information, informed consent was obtained from all the patients. The Ethics Committee at the University of Göteborg approved the study.

Metabolic ward regimen

Three days before each metabolic ward period, the patients were given sodium chloride capsules to keep the sodium intake constant. The metabolic ward dietician made a food history interview to customize the metabolic ward menu for each patient. During the 3 d at the metabolic ward the patients were given a strictly controlled menu with the same food items. Only the food on the menu was allowed. The metabolic ward conditions were arranged to estimate renal and other functions (22, 23).

SLC

SLC measurements were carried out in the fasting state, using a modification of the method described by Canessa et al. (24). Briefly, packed erythrocytes were incubated in medium containing 140 mmol/liter LiCl and 10 mmol/liter Li2CO3. After washing three times in choline buffer to eliminate external sodium, a 20% suspension of the cells was incubated either in sodium-free or in sodium-enriched medium also containing 0.1 mmol/liter ouabain. Samples for analysis of lithium in the supernatant were taken after 15, 30, 60, and 90 min incubation. Before the incubation period, a sample was taken for determination of hematocrit to estimate the volume of erythrocytes. The lithium concentration in the flux medium was measured by means of atomic absorption spectrophotometry (AAS 3100; Perkin-Elmer, Göteborg, Sweden). Lithium efflux (millimoles per liter of erythrocytes) was calculated from the linear regression of lithium loss as a function of time.

Biochemical assays

All blood samples for analysis of adipokines, IGFBP-1, and IL-6 were, after an overnight fast and before leaving bed, drawn in the morning at 0730 h at baseline and after 7 d of GH replacement therapy. Blood samples were then stored at –70 C until analysis. All blood sampling and handling of the blood samples were performed according to the instructions from the manufacturers of the different assays. All analyses of adipokines, IGFBP-1, and IL-6 were performed together in a single run.

The serum concentration of IGF-I was determined by a hydrochloric acid-ethanol extraction RIA using authentic IGF-I for labeling (Nichols Institute Diagnostics, San Juan Capistrano, CA). Intra-assay coefficient of variation (CV) was 6.9% at a mean serum IGF-I concentration of 126 µg/liter and 4.7% at a mean serum IGF-I concentration of 327 µg/liter. The detection limit of the assay was 13.5 µg/liter. The individual serum IGF-I values were compared with age- and sex-adjusted values obtained from a reference population of 197 males and 195 females (25). The individual IGF-I SD scores could then be calculated (26).

Serum adiponectin level was measured using RIA (LINCO Research, Inc., St Charles, MO), with an intraassay CV of 3.6%. Serum resistin concentration was analyzed using an ELISA (BioVendor, Brno, Czech Republic), with an intraassay CV of 4.3%. Serum leptin level was determined by RIA (LINCO Research, Inc), with an intra-assay CV of 6.3%. Serum IGFBP-I concentration was analyzed using ELISA (Hybritech, Marseille, France) with an intraassay CV of 4.5%. Serum IL-6 was determined using ELISA (IL-6 Quantikine HS; R&D Systems Europe LTD, Abingdon, UK), with an intraassay CV of 3.8%.

Serum insulin was determined by RIA (Pharmacia, Phadebas, Sweden) and blood glucose was measured with the glucose-6-phosphate dehydrogenase method (Kebo Lab, Stockholm, Sweden). Blood hemoglobin A1c (HbA1c) was determined by high-pressure liquid chromatography (Millipore AB, Waters, Sweden). The homeostasis model assessment of insulin resistance (HOMA IR) was calculated as previously described by Matthews et al. (27), insulin resistance (HOMA IR) = fasting insulin x fasting glucose/22.5.

Statistical analysis

All descriptive statistical results are presented as the mean and SEM. The Wilcoxon’s matched pairs signed rank sum test was used to compare the effects of GH treatment with the effects of placebo. A carry-over effect was sought for by comparing baseline values of the GH period with baseline values in the placebo period in the five subjects who were first randomized to GH treatment. Correlations were sought by calculating the Spearman rank coefficient. A two-tailed P value less than or equal to 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
All patients completed the study without any detectable side effects. No carry-over effect was detected in the five subjects who were randomized to GH during the first treatment period. The dose of GH of 9.5 µg/kg·d resulted in a mean daily GH dose of 0.78 (SEM, 0.04; range, 0.50–1.00) mg during the 1-wk GH replacement therapy.

Serum IGF-I, glucose homeostasis, and body composition

The serum concentration of IGF-I as well as IGF-I SD score increased in response to 1-wk GH replacement (Table 1Go). The GH replacement therapy impaired all variables reflecting glucose metabolism (Table 1Go).


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  		TABLE 1. Serum IGF-I concentration, IGF-I SD score, and variables reflecting glucose homeostasis in a 1-wk, randomized, double-blind, crossover study in 10 GHD adults1

 
There was no significant difference between GH and placebo treatment in terms of changes in body weight, waist to hip ratio, and body fat and fat-free mass as determined using BIA (Table 2Go).


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  		TABLE 2. Body composition, serum concentrations of adipokines, IGFBP-1, and IL-6, and the activity of the SLC in erythrocytes in a 1-wk, randomized, double-blind, crossover study in 10 GHD adults1

 
Adipokines, IGFBP-1, IL-6, and erythrocyte SLC activity

There was a tendency to a decrease in circulating IGFBP-1 concentration (P = 0.07 vs. placebo, Table 2Go). The trend to an increase in IGFBP-1 marginally remained after correction for body fat (IGFBP-1 to body fat ratio, P = 0.09), whereas it lost statistical importance after correction for serum insulin concentration (P = 0.51) (data not shown). There was no change in serum levels of adiponectin, resistin, leptin, and IL-6, or in the erythrocyte SLC activity, during 1-wk GH replacement therapy (Table 2Go).

Correlations

Baseline correlations between circulating levels of adipokines, IGFBP-1, and IL-6, as well as erythrocyte SLC activity, and body composition and glucose metabolism are given in Table 3Go. The inverse baseline correlation between serum adiponectin concentration and serum insulin AUC during OGTT (r = –0.72, P < 0.05), and the positive baseline correlation between serum leptin concentration and blood glucose concentration (r = 0.82, P < 0.01), are shown in addition in Fig. 1Go, A and B, respectively.


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  		TABLE 3. Baseline correlations between circulating adipokines, IGFBP-1, and IL-6, and the erythrocyte SLC activity, and body composition as measured using BIA and glucose metabolism in a 1-wk, randomized, double-blind, crossover study in 10 GHD adults1

 


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  		FIG. 1. A, The inverse baseline correlation between serum adiponectin concentration and serum insulin AUC during OGTT (r = –0.72, P < 0.05). B, The positive baseline correlation between serum leptin concentration and blood glucose level (r = 0.82, P < 0.01). Correlations were sought by calculating the Spearman rank coefficient.

 
Correlations between changes in adipokines, IGFBP-1, and IL-6, as well as erythrocyte SLC activity, and changes in body composition and glucose homeostasis after 1 wk of GH replacement therapy are shown in Table 4Go. The positive relationship between the change in the erythrocyte SLC activity on one hand and the changes in serum insulin AUC during OGTT (r = 0.81, P < 0.01) and 2-h blood glucose during OGTT (r = 0.67, P < 0.05) are shown in Fig. 2Go, A and B, respectively.


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  		TABLE 4. Correlations between the changes in circulating adipokines, IGFBP-1, IL-6, and the erythrocyte SLC activity, and the changes in body composition as measured using BIA and glucose metabolism in a 1-wk, randomized, double-blind, crossover study in 10 GHD adults1

 


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  		FIG. 2. Positive correlations between the change in the erythrocyte SLC activity after 1-wk GH replacement therapy and the changes in serum insulin AUC during OGTT (A; r = 0.81, P < 0.01) and 2-h blood glucose value during OGTT (B; r = 0.67, P < 0.05). Correlations were sought by calculating the Spearman rank coefficient.

 
Finally, baseline serum adiponectin concentration correlated negatively with the change in blood glucose AUC during OGTT (r = –0.81, P < 0.01), 2-h blood glucose value during OGTT (r = –0.77, P < 0.01) and insulin AUC during OGTT (r = –0.62, P ≤ 0.05). Baseline serum leptin concentration correlated positively with the changes in body fat (r = 0.70, P < 0.05), basal serum insulin concentration (r = 0.67, P < 0.05), and HOMA IR (r = 0.67, P < 0.05), and negatively with the change in fat-free mass (r = –0.67, P < 0.05). Baseline values of other variables were not correlated with the change in any variable reflecting glucose homeostasis.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
One-week GH replacement therapy in GHD adults impaired glucose homeostasis, whereas it did not affect erythrocyte SLC activity and serum concentrations of adipokines and IL-6. At baseline, serum levels of adiponectin and leptin correlated with measures of glucose tolerance and insulin sensitivity. Moreover, changes in serum leptin and IGFBP-1 levels and erythrocyte SLC activity were found to correlate with changes in measures of glucose metabolism.

The relatively high dose of GH (9.5 µg/kg·d) used ensured an impairment of glucose tolerance. The short duration of treatment (1 wk) was chosen because we aimed to study effects of GH/IGF-I before there were detectable changes in body composition in response to the GH replacement. This could be confirmed by unchanged waist to hip ratio, body fat, and fat-free mass at the end of the study. Furthermore, the study was performed under a metabolic ward regimen, minimizing the influence of diet and physical activity. Still, it cannot be fully excluded that the lack of direct effect of GH on circulating adipokines and IL-6 were due to the short duration of GH replacement, the supraphysiological GH dosing, or the relatively small study population.

Serum adiponectin level correlated negatively with serum insulin AUC during OGTT at baseline. In the general population, insulin resistance is associated with low circulating adiponectin level (28). In acromegaly, characterized by GH excess, low body fat mass and insulin resistance, increased circulating adiponectin levels have been observed (29, 30). Nine months of GH replacement increased serum adiponectin levels in GHD women only (31). In another study, however, 1-yr GH replacement did not affect serum adiponectin level (32). The present results, showing no effect on serum adiponectin level after 1-wk GH replacement, may indicate that the increased adiponectin levels in acromegalic patients (29, 30) and after 9-month GH replacement in GHD women (31) are secondary to indirect effects of GH, such as changes in glucose metabolism or body composition.

There was no significant baseline correlation between serum leptin level and body fat. This is most likely due to the small study population in this study, because in both the normal population (33, 34) and in GHD adults (35), serum leptin level is positively related to body fat mass (33, 34, 35). Leptin is also of importance for insulin sensitivity because leptin treatment improves insulin sensitivity in patients with severe lipodystrophy (13, 14). In the present study at baseline, serum leptin concentration correlated positively with basal and stimulated glucose and insulin values, and the change in serum leptin concentration correlated positively with the changes in measures of insulin sensitivity. Therefore, serum leptin levels appear to be more strongly related to insulin sensitivity than body fat mass in GHD adults. In line with this, previous studies have shown that short-term GH replacement does not affect, or even increase, serum leptin concentration despite a reduction in body fat (36). During long-term GH replacement in adults, however, serum leptin level has decreased, possibly due to a combined effect of a gradual return of insulin sensitivity toward baseline values and a reduction in body fat (35, 37, 38).

The serum levels of resistin were not related with glucose tolerance in this study whereas it correlated inversely with waist to hip ratio and fat-free mass at baseline. In mice, circulating resistin level is strongly negatively associated with glucose tolerance (16, 39, 40). In humans, however, several studies have not been able to detect any clear relation between circulating resistin levels and glucose homeostasis (41, 42, 43). In acromegalic patients, who have impaired glucose tolerance, circulating resistin levels were similar as in controls (29) and in a 1-yr GH treatment trial, no significant change in serum resistin concentration occurred in GHD adults (32). The results of the present study support the concept that GH does not affect circulating resistin levels, and it provides further support that resistin may have a different role in humans than in mice.

In this short-term trial, the serum level of IL-6 was unchanged. Baseline serum IL-6 level was not correlated with glucose tolerance, whereas it correlated negatively with body weight and fat-free mass. In a previous study, an increased baseline circulating IL-6 concentration was observed in GHD adults as compared with healthy controls (44). In another study, 18 months of GH replacement reduced serum IL-6 level (45). These findings suggest that the increased serum IL-6 level in GHD adults without GH replacement, and the reduction seen during more prolonged GH replacement, is related to changes in body composition.

In the general population, erythrocyte SLC activity has been linked to insulin resistance and the compensatory hyperinsulinemia in the metabolic syndrome (20). Enhanced SLC activity may not have a pathophysiological role in insulin resistance, but could reflect genetic traits linked to disease or membrane properties caused by disease (20). Changes in SLC activity may be caused by a stimulatory effect of insulin, decreased viscosity of the membrane lipid core, or elements of the cytoskeleton, or associated extrinsic membrane protein may modify ion transport. In this study, the change in the erythrocyte SLC activity correlated positively with the changes in several measures of glucose metabolism. Therefore, the erythrocyte SLC activity could be of some value as a marker for changes in glucose tolerance induced by GH replacement in GHD adults although the mechanism for this interaction is unclear.

Baseline serum adiponectin level was inversely related and baseline serum leptin level was positively related to changes after 1 wk in fasting and stimulated levels of glucose and/or insulin. These correlations suggest that the patients with highest baseline serum adiponectin levels and lowest baseline serum leptin levels experienced the smallest impairment in glucose tolerance. This could merely reflect that the GHD patients with the most impaired glucose homeostasis at baseline had the least favorable response in glucose tolerance. However, it could be hypothesized that a high adiponectin concentration at baseline provides protection from the transient impairment of glucose tolerance induced by GH replacement therapy. Therefore, future studies should explore the possibility that baseline measurements of serum adiponectin and leptin concentrations can help to predict which patients will transiently deteriorate the most in glucose tolerance during GH replacement.

In conclusion, the present results suggest that GH administration in adults does not directly regulate circulating adipokines and IL-6. However, this study suggests that, although not directly regulated by GH, serum levels of adiponectin and leptin are of importance for glucose tolerance in GHD adults. Also, adiponectin and leptin may be of value in predicting the patients that will have the most adverse effect on glucose metabolism in response to GH. Serum levels of resistin and IL-6 were not related with glucose metabolism. Finally, the change in erythrocyte SLC activity was associated with the change in glucose tolerance induced by GH replacement therapy.


   Acknowledgments
 
We are indebted to dietician Birgitta K. Lundgren at the Metabolic Ward for her excellent contribution to this study and the personnel at the Endocrine Ward, the Research Centre for Endocrinology and Metabolism, and the Research Laboratory of Nephrology at Sahlgrenska University Hospital for their skilful technical support. Pharmacia kindly provided the GH and placebo preparations.


   Footnotes
 
This work was supported by grants from the Swedish Medical Research Council (Project Nos. 11621, 12170, and 13192), the Swedish Society for Medical Research, and the Swedish Heart and Lung Foundation.

First Published Online January 5, 2005

Abbreviations: AUC, Area under curve; BIA, bioelectrical impedance analysis; BMI, body mass index; CV, coefficient of variation; GHD, GH-deficient; HOMA IR, homeostasis model assessment of insulin resistance; IGFBP-1, IGF binding protein-1; OGTT, oral glucose tolerance test; SLC, sodium/lithium countertransport.

Received June 30, 2004.

Accepted December 22, 2004.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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