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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 6 2028-2033
Copyright © 1999 by The Endocrine Society

Original Studies

Treatment of Obese Subjects with the Oral Growth Hormone Secretagogue MK-677 Affects Serum Concentrations of Several Lipoproteins, But Not Lipoprotein(a)1

J. Svensson, J.-O. Jansson, M. Ottosson, G. Johannsson, M.-R. Taskinen, O. Wiklund and B.-Å. Bengtsson

Research Center for Endocrinology and Metabolism (J.S., J.O.J., G.J., B.-Å.B.), Wallenberg Laboratory (M.O., O.W.), Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden; and the Department of Medicine, Helsinki University Central Hospital (M.-R.T.), Helsinki, Finland

Address all correspondence and requests for reprints to: Johan Svensson, M.D., Research Center for Endocrinology and Metabolism, Gröna Strket 8, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Obesity is associated with blunted GH secretion and an unfavorable lipoprotein pattern. The objective of this study was to investigate the effects of treatment with the oral GH secretagogue MK-677 on lipoproteins in otherwise healthy obese males. The study was randomized, double blind, and parallel. Twenty-four obese males, aged 18–50 yr, with body mass index greater than 30 kg/m2 and waist/hip ratio above 0.95 were treated with 25 mg MK-677 (n = 12) or placebo (n = 12) daily for 8 weeks.

MK-677 treatment did not significantly change serum lipoprotein(a) [Lp(a)] levels. Serum apolipoprotein A-I and E (apoA-I and apoE) were increased at 2 weeks (P < 0.001 and P < 0.01 vs. placebo, respectively), but were not changed at study end. Serum total cholesterol and low density lipoprotein (LDL) cholesterol (LDL-C) levels were not significantly changed by MK-677 treatment. Serum high density lipoprotein (HDL) cholesterol (HDL-C) was increased at 2 weeks of MK-677 treatment (P < 0.01 vs. placebo), but not at 8 weeks. The LDL-C/HDL-C ratio was reduced after 8 weeks of MK-677 treatment (P < 0.05 vs. placebo). Mean LDL particle diameter was decreased at 2 weeks (P < 0.05 vs. placebo), but was unchanged compared with baseline values at 8 weeks (P = NS vs. placebo). The level of serum triglycerides was increased at 2 (P < 0.05 vs. placebo), but not at 8, weeks. Lipoprotein lipase activity in abdominal and gluteal sc adipose tissue was not affected by active treatment.

In conclusion, treatment with the oral GH secretagogue MK-677 affected circulating lipoproteins. The effects on serum apoA-1, apoE, triglycerides, and mean LDL particle diameter were transient. At study end, the LDL-C/HDL-C ratio was decreased. MK-677 treatment did not significantly affect serum Lp(a) concentrations at the present dose and administration protocol.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PULSATILE GH release from the anterior pituitary is regulated by the stimulatory peptide GHRH and the inhibitory peptide somatostatin (1). A new class of GH secretagogues has recently been developed, including GH-releasing peptides (GHRPs) such as GHRP-6, GHRP-1, GHRP-2, and hexarelin (2, 3), and nonpeptidyl GH secretagogues, such as orally active MK-677 (4, 5, 6). Recently, a cell membrane G protein-coupled receptor was cloned and shown to be a target for these GH secretagogues (7), although the natural ligand for this receptor remains to be identified. By acting on the GHRP receptor, MK-677 increases serum GH levels with retained pulsatility (6). MK-677 administration to humans has improved sleep quality in young and elderly subjects (8) and reversed diet-induced catabolism in healthy volunteers (9). In obesity, 2-month treatment with MK-677 increased serum insulin-like growth factor I (IGF-I) and fat-free mass, whereas no effect on total body fat was documented (10).

GH influences lipoprotein metabolism at several different levels. GH up-regulates the low density lipoprotein (LDL) receptor in the human liver (11), thereby increasing the clearance of LDL cholesterol (LDL-C). GH also modulates the secretion from the rat liver of apolipoprotein B (apoB) (12) and apoE (13), two apolipoproteins that function as ligands for the LDL receptor (12, 13). In in vitro assays using rat liver hepatocytes, GH stimulates the esterification of oleic acid into triglycerides (TG) and phospholipid (14), thereby increasing the secretion of very low density lipoproteins (VLDLs) (15). In humans, increased levels of serum VLDL-TG have been observed after GH administration (16).

In obesity, pulsatile GH secretion is blunted with a decrease in the amount of GH secreted per burst (17). In obese males, as in GH-deficient (GHD) adults, lipoprotein balance is disturbed with increased serum concentrations of LDL-C in relation to high density lipoprotein (HDL) cholesterol (HDL-C), increased levels of serum TG, and an increased proportion of small, dense LDL particles (18, 19, 20, 21, 22). After GH treatment of GHD adults, total cholesterol (TC) decreased or was unchanged, and HDL-C increased or was unchanged (20). LDL-C decreased (20), although this decrease has often been less marked during GH treatment of 6 months or less (23, 24). In obese subjects, GH treatment has produced similar results on cholesterol levels as in GHD adults, often accompanied by an initial increase in serum TG (25, 26).

Lipoprotein(a) [Lp(a)], composed of lipid, apoB, and apo(a), is a strong independent risk factor for cardiovascular disease in the general population (27, 28, 29, 30). GH treatment has been found to increase this atherogenic lipoprotein in GHD adults (23, 31, 32, 33, 34) as well as in non-GHD males (25, 35). The relative importance of this effect of GH, compared with the other, more favorable effects of GH, is not known.

In the present study, we investigated whether a 2-month treatment of obese males with the oral GH secretagogue (MK-677) affects serum lipoproteins in a way similar to GH treatment. The effect of MK-677 on Lp(a) is of special interest, as MK-677 releases GH more physiologically than a sc injection of GH (6). It has been suggested that the mode of GH administration, which causes a nonphysiological rise in GH levels, contributes to the increase in Lp(a) observed during GH treatment (16).


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

Twenty-four males, 19–49 yr of age, with body mass index (BMI) greater than 30 kg/m2 and waist/hip ratio above 0.95, were studied. The mean age of the study population was 37.8 ± 1.8 yr, the mean BMI was 32.2 ± 0.3 kg/m2, and the mean waist/hip ratio was 1.02 ± 0.01. The subjects were recruited using advertisements in local newspapers. Except for obesity, all subjects were in good general health, and none used concomitant medication.

Two subjects were discontinued from the study after approximately 1–2 weeks. One subject had a 3-fold increase in serum alanine aminotransferase and aspartate aminotransferase, both of which decreased spontaneously to prestudy values after discontinuation of the study drug (MK-677). Of note, this subject had violated the protocol by ingesting alcohol around the time of the elevation of aspartate aminotransferase and alanine aminotransferase. The other subject in the placebo group was discontinued when hypothyroidism was diagnosed based on a prestudy T4 value, and the subject was placed on appropriate T4 replacement therapy. The two discontinued subjects were replaced with two new subjects who received the same treatment as the subjects they replaced.

Study design

This was an 8-week, randomized, double blind, parallel, placebo-controlled trial of the oral administration of MK-677 in healthy obese subjects. Subjects were randomized to receive oral MK-677 (25 mg) or matching placebo daily for 8 weeks (n = 12/group). The dose was administered with 150 mL water between 0800–0900 h. Compliance was checked by weekly tablet counts. The study was approved by the ethics committee at the University of Goteborg and by the Swedish Medical Products Agency (Uppsala, Sweden). Informed consent was obtained from each subject before study start.

Study protocol

The subjects were studied as out-patients and were instructed not to change their ordinary physical activity or dietary intake during the study. The dietary questionnaires used in this study did not show any change in food intake (10). The extent to which the subjects complied with the instruction of an unchanged physical activity was not recorded. Before study start, subjects were examined to assure that they met all inclusion criteria. At baseline, 2 weeks, and 8 weeks, blood samples were drawn predose for measurement of serum Lp(a), TC, HDL-C, LDL-C, TG, apoA-I, apoB, apoE, LDL particle diameter, and other parameters [effects on GH secretion and body composition have previously been reported (10)]. Predose, at baseline, and at 8 weeks, abdominal and gluteal sc adipose tissues were obtained by needle aspiration for determination of total LPL activity. The adipose tissue samples were rapidly frozen in liquid nitrogen and stored at -80 C until assay.

Analytic methods

Blood samples were drawn, and adipose tissue needle aspirations were performed after an overnight fast.

The serum concentration of Lp(a) was determined by RIA (Pharmacia Biotech, Uppsala, Sweden) standardized against an electroimmunoassay (36). The within-assay coefficient of variation (CV) for the Lp(a) assay was 4.4%. The detection limit of the Lp(a) assay was 12 mg/L. TC and TG concentrations were determined using enzymatic methods (Boehringer Mannheim, Mannheim, Germany). The within-assay CVs for TC and TG determinations were 0.9% and 1.1%, respectively. HDL-C levels were determined after the precipitation of apoB-containing lipoproteins with MgCl2 and heparin (36). LDL-C was calculated according to Friedewald’s formula adjusted to Systeme International units (37). ApoA-I and apoB concentrations were determined using an immunoturbidometric assay (Unikit Roche, Hoffmann-LaRoche, Inc., Nutley, NJ), and the apoE concentration was determined using an electroimmunoassay (38). The within-assay CVs for the apoA-I, apoB, and apoE assays were 2.3%, 1.9%, and 4.8%, respectively.

LDL particle diameter was determined by LDL gradient gel electrophoresis. Nondenaturing gradient gel electrophoresis was performed from frozen serum samples using the method described previously (39). The gels with a polyacrylamide gradient from 2–12% were cast in the laboratory of M.-R.T. according to the method of Margolis and Kenrick (40) with slight modifications. Stock solution A contained 12.0% acrylamide (5.0% bisacrylamide), 5.0% sucrose, 0.012% ammonium persulfate, and 0.085% tetraethylenediamine (TEMED), and stock solution B contained 2.0% acrylamide (bisacrylamide 5.0%), 0.019% ammonium persulfate and 0.120% tetraethylenediamine. Both stock solutions were made in 1.0 mol/L Tris-HCl buffer (pH 8.3). Gels were cast by using Gradient Mixer GM-1 (Pharmacia Biotech), Gel Slab Casting Apparatus GSC-8 (Pharmacia Biotech), and Peristaltic Pump P-1 (Pharmacia Biotech) as described previously (41). Gels were stained with Sudan Black B lipid stain and scanned with a computer-assisted laser scanning densitometer (Personal Densitometer, Molecular Dynamics, Inc., Sunnyvale, CA) using a 50-µm pixel size and 12-bit signal resolution. The mean particle diameter of the major LDL peak was determined by comparing the mobility of the sample with the mobility of a calibrated reference LDL preparation run on each gel. CVs for intragel and intergel precisions for the used control sample were 1.2% and 3.5%, respectively.

Total LPL activity in abdominal and gluteal adipose tissues was determined after homogenization of the tissue in a detergent-containing buffer as described previously (42). Bovine skim milk was used as a standard to correct for interassay variation. The amount of TG in the tissue was measured after extraction (43) and weighed after the evaporation of solvents. Activity was expressed in milliunits (1 mU = 1 nmol free fatty acids released/min) per g adipose tissue and per g TG. Control experiments showed that the assay was linear with the amount of sample and incubation time over the range used. The within-assay CV was 3.0%.

Statistical analysis

The descriptive statistical results are presented as the mean and SEM. Where appropriate, a logarithmic transformation was performed before statistical analysis. Logarithmically transformed data (Lp(a), LDL particle diameter, and LPL) are presented as the geometric mean ± SEM. Lp(a) values below the detection limit of the assay were, when logarithmically transformed, given a value of 12 mg/L [the detection limit of the Lp(a) assay]. Unpaired t tests were used to assess between-group differences. Differences in baseline were accounted for by analyzing the percent change from baseline for all variables. Within-group differences were analyzed with paired t tests. Correlations were calculated using Pearson’s linear regression coefficient. A two-tailed P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The treatment groups were comparable with regard to mean age, weight, height, BMI, and waist/hip ratio (10). Compliance data (pill counts) were available for all 24 subjects and indicated greater than 99% compliance. MK-677 treatment was generally well tolerated. Five subjects had clinical and/or laboratory adverse experiences with MK-677 administration, which the investigator considered drug related; all were of mild intensity, and none demanded medical treatment.

As previously reported (10), MK-677 treatment induced a sustained increase in serum GH levels. Serum IGF-I was significantly increased by approximately 40% at both 2 and 8 weeks of MK-677 treatment. Body weight was increased by MK-677 treatment at 2 and 8 weeks of treatment (P < 0.001 and P < 0.01 vs. placebo, respectively). At 2 weeks, mean body weight was 1.6 kg higher than baseline in the MK-677 treatment group and 0.6 kg lower than baseline in the placebo group. At 8 weeks, mean body weight was 2.7 kg higher than baseline in the MK-677 group and 0.3 kg lower than baseline in the placebo group.

Lp(a) (Table 1Go and Fig. 1Go)

In the MK-677 treatment group, Lp(a) was unchanged at 2 and 8 weeks compared with baseline values, whereas in the placebo group, Lp(a) tended to decrease at 8 weeks compared with baseline (Table 1Go and Fig. 1Go). Compared with placebo, Lp(a) in the MK-677 group tended to increase at 8 weeks (P < 0.08 vs. placebo; Table 1Go and Fig. 1Go). No correlation was found in the MK-677 treatment group between the changes in Lp(a) and serum IGF-I at 8 weeks (r = 0.47; P = 0.13).


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  		Table 1. Effects of 2-month treatment with MK-677 (25 mg) or placebo daily in obese males on serum concentrations of Lp(a), apoA-1, apoB, and apoE

 


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  		Figure 1. Individual Lp(a) concentrations during 2 months of treatment of obese males with MK-677 (25 mg) or placebo daily in the MK-677 treatment group (a) and the placebo group (b). Note that the lowest line in a represents three different subjects, all of whom had Lp(a) levels below the assay detection limit of 12 mg/L.

 
Apos (Table 1Go)

ApoA-I and apoE were significantly increased at 2 weeks of MK-677 treatment (P < 0.001 and P < 0.01 vs. placebo, respectively), whereas no changes were observed at 8 weeks (Table 1Go). ApoB tended to an increase at 2 weeks (P < 0.08 vs. placebo), but was not changed at study end (Table 1Go).

Cholesterol (Fig. 2Go)

Serum TC tended to increase at 2 weeks of MK-677 treatment (P < 0.06 vs. placebo), but was unchanged from baseline at 8 weeks (Fig. 2aGo). LDL-C was not changed compared with placebo throughout the study period even though a 10% reduction was found in the treatment group at 8 weeks (note that LDL-C was excluded in one subject in the MK-677 group because the values could not be determined at 2 and 8 weeks due to high serum TG values; Fig. 2bGo). HDL-C was increased at 2 weeks of MK-677 treatment (P < 0.01 vs. placebo), but not at 8 weeks (Fig. 2cGo). The LDL-C/HDL-C ratio was decreased at 8 weeks of MK-677 treatment (P < 0.05 vs. placebo; Fig. 2dGo).



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  		Figure 2. Mean (±SEM) serum TC (a), LDL-C (b), HDL-C (c), and LDL-C/HDL-C (d) ratio during 2 months of treatment with MK-677 (25 mg) or placebo daily in obese males. Note that LDL-C was excluded in one subject in the MK-677 group because the values could not be determined at 2 and 8 weeks due to high serum TG values. *, P < 0.05; **, P < 0.01; #, P < 0.06 (vs. placebo).

 
LDL particle size and triglycerides (Table 2Go)

Mean LDL particle diameter in the major LDL peak was decreased by MK-677 treatment at 2 weeks (P < 0.05 vs. placebo), but was not changed compared with baseline values after 8 weeks (P = NS vs. placebo; Table 2Go). The percentage of LDL particles with a diameter more than 25.5 nm (large, buoyant LDL), as well as the percentage of LDL particles with a diameter less than 25.5 nm (small, dense LDL), was not changed throughout treatment (data not shown). Serum TG were increased at 2 weeks of MK-677 treatment (P < 0.05 vs. placebo), but not at 8 weeks (Table 2Go).


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  		Table 2. Effects of 2-month treatment with MK-677 (25 mg) or placebo daily in obese males on mean LDL particle diameter, serum triglycerides, and sc adipose tissue LPL activity expressed as milliunits per g adipose tissue

 
At baseline in the total study population, the mean LDL particle diameter correlated negatively with serum TG (r = -0.58; P < 0.01) and positively with serum HDL-C (r = 0.63; P < 0.001). In the MK-677 treatment group at 2 weeks of treatment, the percent change in the mean LDL diameter correlated negatively both with the percent change in serum TG (r = -0.67; P < 0.05) and with the percent change in serum HDL-C (r = -0.59; P < 0.05). At 8 weeks of treatment, the percent change in the mean LDL particle in the MK-677 treatment group did not correlate with the percent change in serum TG, TC, LDL-C, or HDL-C.

LPL activity (Table 2Go)

Total LPL activity in sc abdominal and gluteal adipose tissues, expressed as mU/g adipose tissue, did not change with MK-677 treatment (Table 2Go). LPL activity, expressed as milliunits per g TG, was also unchanged (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We have shown that 2 months of treatment with the oral GH secretagogue MK-677 did not significantly increase Lp(a). Serum TG, HDL-C, apoA-I, and apoE transiently increased at 2 weeks of MK-677 treatment. Serum TC and apoB tended to increase at 2 weeks, whereas mean LDL particle diameter was decreased at 2 weeks. After 8 weeks of treatment, the LDL-C/HDL-C ratio was decreased.

The tendency for an increase in Lp(a) at 8 weeks compared with the level with placebo was due to the slight decrease in Lp(a) levels in the placebo group and not to significant changes in the MK-677 treatment group. The reason for this slight decrease in serum Lp(a) in the placebo group is unknown. In GHD adults, one study did not show any change in Lp(a) (44), whereas other studies have shown clear and significant increases up to 85% over baseline (23, 31, 32, 33, 34). In a previous study of middle-aged, moderately obese males, GH treatment increased Lp(a) by 42% after 2 weeks (25). The present, nonsignificant increase in Lp(a) is somewhat difficult to compare with these previous results from GH therapy, as most of the previous GH treatment studies have used high GH doses (23, 31, 32, 33, 34), presumably raising serum GH levels to or above the normal upper range. However, in a recent study of GHD adults (45), a low starting dose of GH and individualized GH dosing induced a similar increase in Lp(a) as a conventional, high dose of GH, suggesting that the response of Lp(a) will occur even with optimized, lower dose GH therapy.

The enhancement of pulsatile GH release by MK-677 may be of importance to the lack of a significant effect on Lp(a) in the present study. MK-677 enhances the preexisting pulsatile pattern of GH secretion (6), whereas GH concentrations are high, demonstrating a bell-shaped curve, for more than 12 h after a sc injection of GH (46). Furthermore, the assumption that a prolonged presence of GH in serum induces a more marked increase in Lp(a) is supported by the finding that continuously infused GH increased Lp(a) to an even higher degree than sc injections of GH (16). Moreover, the continuously high GH secretion in acromegaly is associated with high Lp(a) levels (47). In contrast, the results of the present study indicate that the disadvantageous effect of GH treatment on Lp(a) may be avoided through the use of MK-677, which maintains the physiological pulsatile pattern of GH secretion.

At the end of the present study, serum concentrations of LDL-C and HDL-C were not affected by MK-677 treatment compared with placebo. However, MK-677 treatment appears to have induced meaningful changes in these parameters, as the LDL-C/HDL-C ratio was significantly decreased. GH treatment up-regulates the LDL receptor in the human liver (11), and it is likely that MK-677, through increased GH levels, would act by a similar mechanism. In a previous 18-month GH treatment study in GHD adults, GH decreased LDL-C over time (24), and further studies are needed to evaluate whether a prolonged MK-677 treatment can significantly reduce total LDL-C concentrations. MK-677 treatment decreased mean LDL particle diameter at 2 weeks of treatment, whereas at 8 weeks, mean LDL particle diameter was not affected by active treatment. In the present study as well as in other studies (48, 49), baseline mean particle size diameter correlated negatively with serum TG, and it is likely that the transient decrease in LDL particle size was due to the transient increase in serum TG at 2 weeks. MK-677 treatment increased body weight and fat-free mass, whereas body fat was unchanged (10). An increase in body weight due to increased body fat has been associated with decreased LDL size (50), whereas little is known of the importance of an increase in body weight due to an increase in fat-free mass. The effects of GH therapy on LDL particle size are not fully known, although there is one report (51) of a tendency for an increase in LDL particle diameter after 6 months of GH substitution to GHD adults. On the other hand, chronic exposure to high, continuous GH secretion in acromegaly may instead increase the proportion of small, dense LDL particles (52).

The transient increases in serum HDL-C, TG, apoA-I, apoE and the tendency to transient increases in TC and apoB at 2 weeks of MK-677 treatment may have several explanations. Usually, there is an inverse relation between serum HDL-C and TG (18). However, the present finding that MK-677 transiently increased both serum HDL-C and TG is not unexpected, as GH treatment has increased serum HDL-C and/or TG in some studies (23, 25, 26, 32). GH may modulate the liver secretion of apoB (12, 53) and apoE (13, 16), whereas the effect of GH on apoA-I is less clear. GH treatment has generally not affected serum apoA-I concentrations in adults (23, 24, 25, 32), but in some studies in GHD children, an increase in serum apoA-I has been found during GH therapy (54, 55). GH increases VLDL secretion (14, 15), and in a previous study, daily sc injections of GH increased VLDL-TG more than a continuous infusion of GH (16). Therefore, an enhancement of pulsatile GH release by MK-677 (6) probably increases VLDL secretion, which could explain the transient increase in serum TG at 2 weeks of MK-677 treatment. Possibly, the MK-677-induced changes in circulating lipoproteins at 2 weeks reflect direct GH effects on lipoprotein formation and secretion.

The results at 2 weeks of MK-677 treatment may also be influenced by a MK-677-induced increase in insulin resistance at 2 weeks (10), as serum TG and apoB are increased with increased insulin resistance (56). Furthermore, in addition to GH release, MK-677 elicits a transient cortisol response (10) that is not evident at 1 (57) and 2 (6, 10) weeks of MK-677 treatment. Although glucocorticoids may affect lipoprotein concentrations (58), it seems less likely that the rapidly down-regulated cortisol response to MK-677 influences lipoproteins as late as at 2 weeks of MK-677 treatment.

In the present study, LPL activity in abdominal and gluteal adipose tissue was unchanged from baseline and not different from that in the placebo group after 8 weeks of MK-677 treatment. Previous GH studies have found unchanged (25) or decreased (16, 59) adipose tissue LPL activity during short term GH treatment. In acromegalic patients, plasma LPL activity is reduced (60, 61). Therefore, the effect of GH on LPL activity may be dose dependent. The treatment period may also be of importance, as in a 9-month GH treatment study of obese males, an initial tendency for a decrease in LPL activity was followed by a tendency for an increase at study end (26).

In conclusion, 2 months of treatment with the GH secretagogue MK-677 influenced circulating lipoprotein concentrations. Several of the effects were transient and only observed at 2 weeks. However, at 8 weeks a beneficial effect was found, with a decreased LDL-C/HDL-C ratio. The lack of significant effect on Lp(a) as well as part of the stimulatory effects on serum TG and possibly VLDL at 2 weeks of treatment may be related to the enhancement of pulsatile GH secretion by MK-677. Future long term (>8 weeks) studies are needed to investigate whether the effect on the LDL-C/HDL-C ratio remains and whether prolonged MK-677 treatment can decrease total LDL-C concentrations.


   Acknowledgments
 
We are indebted to Lena Wirén, Anne Rosén, Ingrid Hansson, and Annika Reibring at the Research Center for Endocrinology and Metabolism for their skillful technical support.


   Footnotes
 
1 Presented in part at the 80th Annual Meeting of The Endocrine Society, New Orleans, LA, June 1998. This study was supported by grants from the Swedish Medical Research Council (no. 11621 and 9894) and from Merck Research Laboratories (Rahway, NJ). Back

Received January 14, 1999.

Revised March 12, 1999.

Accepted March 17, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Frohman LA, Jansson J-O. 1986 Growth hormone-releasing hormone. Endocr Rev. 7:223–253.[Abstract]
  2. Bowers C, Sartor A, Reynolds G, Badger T. 1991 On the actions of the growth hormone-releasing hexapeptide, GHRP-6. Endocrinology. 128:2027–2035.[Abstract]
  3. Korbonits M, Grossman A. 1995 Growth hormone-releasing peptide and its analogues. Novel stimuli to growth hormone release. Trends Endocrinol Metab. 6:43–49.
  4. Smith R, Cheng K, Schoen WR, et al. 1993 A non-peptidyl growth hormone secretagogue. Science. 260:1640–1643.[Abstract/Free Full Text]
  5. Jacks T, Smith R, Judith F, et al. 1996 MK-0677, a potent, novel, orally active growth hormone (GH) secretagogue: GH, insulin-like growth factor I, and other hormonal responses in beagles. Endocrinology. 137:5284–5289.[Abstract]
  6. Chapman IM, Bach MA, Van Cauter E, et al. 1996 Stimulation of the growth hormone (GH)-insulin-like growth factor-I axis by daily oral administration of a GH secretagogue (MK-677) in healthy elderly subjects. J Clin Endocrinol Metab. 81:4249–4257.[Abstract]
  7. Howard A, Feighner S, Cully D, et al. 1996 A pituitary gland and hypothalamic receptor that functions in growth hormone release. Science. 273:974–977.[Abstract]
  8. Copinschi G, Leproult R, Van Onderbergen A, et al. 1997 Prolonged oral treatment with MK-677, a novel growth hormone secretagogue, improves sleep quality in man. Neuroendocrinology. 66:278–286.[Medline]
  9. Murphy MG, Plunkett LM, Gertz BJ, et al. 1998 MK-677, an orally active growth hormone secretagogue, reverses diet-induced catabolism. J Clin Endocrinol Metab. 83:320–325.[Abstract/Free Full Text]
  10. Svensson J, Lönn L, Jansson J-O, et al. 1998 Two-month treatment of obese subjects with the oral growth hormone (GH) secretagogue MK-677 increases GH secretion, fat-free mass, and energy expenditure. J Clin Endocrinol Metab. 83:362–369.[Abstract/Free Full Text]
  11. Rudling M, Norstedt G, Olivecrona H, Reihnér E, Gustafsson J-Å, Angelin B. 1992 Importance of growth hormone for the induction of hepatic low density lipoprotein receptors. Proc Natl Acad Sci USA. 89:6983–6987.[Abstract/Free Full Text]
  12. Sjöberg A, Oscarsson J, Boström K, Innerarity T, Edén S, Olofsson S-O. 1992 Effects of growth hormone on apolipoprotein-B (ApoB) messenger ribonucleic acid editing, and ApoB48 and ApoB100 synthesis and secretion in the rat liver. Endocrinology. 130:3356–3364.[Abstract]
  13. Sjöberg A, Oscarsson J, Edén S, Olofsson S-O. 1994 Continuous but not intermittent administration of growth hormone to hypophysectomized increases apolipoprotein-E secretion from cultured hepatocytes. Endocrinology. 134:790–798.[Abstract]
  14. Elam M, Simkevich C, Solomon S, Wilcox HG, Heimberg M. 1988 Stimulation of in vitro triglyceride synthesis in the rat hepatocyte by growth hormone treatment in vivo. Endocrinology. 122:1397–1402.[Abstract]
  15. Elam M, Wilcox H, Salomon S, Heimberg M. 1992 In vivo growth hormone treatment stimulates secretion of very low density lipoproteins by the perfused rat liver. Endocrinology. 131:2717–2722.
  16. Oscarsson J, Ottosson M, Johansson J-O, et al. 1996 Two weeks of daily injections and continuous infusion of recombinant growth hormone (GH) in GH-deficient adults. II. Effects on serum lipoproteins and lipoprotein and hepatic lipase activity. Metabolism. 45:370–377.[CrossRef][Medline]
  17. Veldhuis JD, Liem AY, South S, et al. 1995 Differential impact of age, sex steroid hormones, and obesity on basal vs. pulsatile growth hormone secretion in men as assessed in an ultrasensitive chemiluminescence assay. J Clin Endocrinol Metab. 80:3209–3222.[Abstract]
  18. Reaven GM. 1995 Pathophysiology of insulin resistance in human disease. Physiol Rev. 75:473–486.[Abstract/Free Full Text]
  19. Björntorp P. 1993 Visceral obesity: a "civilization syndrome." Obesity Res. 1:206–222.[Medline]
  20. De Boer H, Blok G-J, Van Der Veen E. 1995 Clinical aspects of growth hormone deficiency in adults. Endocr Rev. 16:63–86.[CrossRef][Medline]
  21. Rosén T, Edén S, Larsson G, Wilhelmsen L, Bengtsson B-Å. 1993 Cardiovascular risk factors in adult patients with growth hormone deficiency. Acta Endocrinol (Copenh). 129:195–200.[Medline]
  22. O'Neal D, Hew FL, Sikaris K, Ward G, Alford F, Best JD. 1996 Low density lipoprotein particle size in hypopituitary adults receiving conventional hormone replacement therapy. J Clin Endocrinol Metab. 2448–2454.
  23. Edén S, Wiklund O, Oscarsson J, Rosén T, Bengtsson B-Å. 1993 Growth hormone treatment of growth hormone-deficient adults results in a marked increase in Lp(a) and HDL cholesterol concentrations. Arterioscler Thromb. 13:296–301.[Abstract/Free Full Text]
  24. Beshyah S, Hendersson A, Niththyananthan R, et al. 1995 The effects of short and long term growth hormone replacement therapy in hypopituitary adults on lipid metabolism and carbohydrate tolerance. J Clin Endocrinol Metab. 80:356–363.[Abstract]
  25. Oscarsson J, Ottosson M, Wiklund O, et al. 1994 Low dose continuously infused growth hormone results in increased lipoprotein(a) and decreased low density lipoprotein cholesterol concentrations in middle-aged men. Clin Endocrinol (Oxf). 41:109–116.[Medline]
  26. Johannsson G, Mrin P, Lönn L, et al. 1997 GH treatment of abdominally obese men reduces abdominal fat mass, improves glucose and lipoprotein metabolism, and reduces diastolic blood pressure. J Clin Endocrinol Metab. 82:727–734.[Abstract/Free Full Text]
  27. Rosengren A, Wilhelmsen L, Eriksson E, Risberg B, Wedel H. 1990 Lipoprotein(a) and coronary heart disease: a prospective case-control study in a general population sample of middle aged men. Br Med J. 301:1248–1251.
  28. Uterman G. 1989 The mysteries of lipoprotein(a). Science. 246:904–910.[Abstract/Free Full Text]
  29. Scott J. 1991 Lipoprotein(a). Br Med J. 303:663–664.
  30. Scanu A. 1992 Lipoprotein(a). A genetic risk factor for premature coronary heart disease. JAMA. 267:3326–3329.[Abstract]
  31. O'Halloran DJ, Wieringa G, Tsatsoulis A, Shalet SM. 1996 Increased lipoprotein(a) concentrations after growth hormone (GH) treatment in patients with isolated GH deficiency. Ann Clin Biochem. 33:330–334.
  32. Johannsson G, Oscarsson J, Rosén T, et al. 1995 Effects of 1 year of growth hormone therapy on serum lipoprotein levels in growth hormone-deficient adults; influence of gender and apo(a) and apoE phenotypes. Arteriosler Thromb Vasc Biol. 15:2142–2150.[Abstract/Free Full Text]
  33. Weaver JU, Monson JP, Noonan K, et al. 1995 The effect of low dose recombinant human growth hormone replacement on regional fat distribution, insulin sensitivy, and cardiovascular risk factors in hypopituitary adults. J Clin Endocrinol Metab. 80:153–159.[Abstract]
  34. Garry P, Collins P, Devlin, JG. 1996 An open 36-month study of lipid changes with growth hormone in adults: lipid changes following replacement of growth hormone in adult acquired growth hormone deficiency. Eur J Endocrinol. 134:61–66.[Abstract]
  35. Olivecrona H, Ericsson S, Berglund L, Angelin B. 1993 Increased concentrations of serum lipoprotein (a) in response to growth hormone treatment. Br Med J. 306:1726–1727.
  36. Wiklund O, Fager G, Craigh I, et al. 1980 Alphalipoprotein cholesterol in relation to acute myocardial infarction and its risk factors. Scand J Clin Lab Invest. 40:239–247.[Medline]
  37. Friedewald W, Levy R, Fredrickson D. 1972 Estimation of low-density lipoprotein in plasma, without use of the preparative ultracentrifuge. Clin Chem. 18:499–502.[Abstract]
  38. Johansson S, Bondjers G, Fager G, et al. 1988 Serum lipids and apolipoprotein levels in women with acute myocardial infarction. Arteriosclerosis. 8:742–749.[Abstract/Free Full Text]
  39. Nichols AV, Krauss RM, Musliner TA. 1986 Nondenaturing polyacrylamide gradient gel electrophoresis. In: Segrest JP, Albers JJ, eds. Methods in enzymology: plasma lipoproteins. London: Academic Press; 128:417–431.
  40. Margolis J, Kenrick KG. 1967 Elecrophoresis in polyacrylamide concentration gradient. Biochem Biophys Res Commun. 27:68–73.[CrossRef][Medline]
  41. Pharmacia. 1984 Polyacrylamide gel elecrophoresis; laboratory techniques. Uppsala: Pharmacia, Laboratory Separation Division; 16.
  42. Bengtsson-Olivecrona G, Olivecrona T. 1992 Lipoprotein analysis–a practical approach. In: Converse CA, Skinner ER, eds. Practical approach series. Oxford: Oxford University Press; 169–185.
  43. Dole VP, Meinertz H. 1960 Microdetermination of long-chain fatty acids in plasma and tissues. J Biol Chem. 235:2595–2599.[Free Full Text]
  44. Russell-Jones DL, Watts GF, Weissberger A, et al. 1993 The effect of growth hormone replacement of serum lipids, lipoproteins, apolipoproteins and cholesterol precursors in adult growth hormone deficient patients. Clin Endocrinol (Oxf). 41:345–350.
  45. Johannsson G, Rosén T, Bengtsson B-Å. 1997 Individualized dose titration of growth hormone (GH) during GH replacement in hypopituitary adults. Clin Endocrinol (Oxf). 47:571–581.[CrossRef][Medline]
  46. Oscarsson J, Johannsson G, Johansson J-O, Lundberg P-A, Lindstedt G, Bengtsson B-Å. 1997 Diurnal variation in serum insulin-like growth factor (IGF)-I and IGF binding protein-3 concentrations during daily subcutaneous injections of recombinant human growth hormone in GH-deficient adults. Clin Endocrinol (Oxf). 46:63–68.[CrossRef][Medline]
  47. Oscarsson J, Wiklund O, Jakobsson K-E, Petruson B, Bengtsson B-Å. 1994 Serum lipoproteins in acromegaly before and 6–15 months after transsphenoidal adenomectomy. Clin Endocrinol (Oxf). 41:603–608.[Medline]
  48. Lahdenperä S, Groop P-H, Tilly-Kiesi M, et al. 1994 LDL subclasses in IDDM patients: relation to diabetic nephropathy. Diabetologia. 37:681–688.[Medline]
  49. Lahdenperä S, Syvänne M, Kahri J, Taskinen M-R. 1996 Regulation of low-density lipoprotein particle size distribution in NIDDM and coronary disease: importance of serum triglycerides. Diabetologia. 39:453–461.[Medline]
  50. Markovic TP, Campbell LV, Balasubramanian S, et al. 1998 Beneficial average lipid levels from energy restriction and fat loss in obese individuals with or without type 2 diabetes. Diabetes Care. 21:695–700.[Abstract]
  51. Hew FL, Alford FP, Christopher M, et al. 1996 Effects of growth hormone deficiency and therapy in adults on skeletal muscle glucose metabolism, lipid profiles and regional body composition. Endocrinol Metab. 3(Suppl A):55–60.
  52. Tan KC, Shiu SW, Janus ED, Lam KS. 1997 LDL subfractions in acromegaly: relation to growth hormone and insulin-like growth factor-I. Atherosclerosis. 129:59–65.[CrossRef][Medline]
  53. Cummings MH, Christ E, Umpleby AM, et al. 1997 Abnormalities of very low density lipoprotein apolipoprotein B-100 metabolism contibute to the dyslipidaemia of adult growth hormone deficiency. J Clin Endocrinol Metab. 82:2010–2013.
  54. Boot AM, Engels MA, Boerma GJ, Krenning, EP, De Muinck Keizer-Schrama SM. 1997 Changes in bone mineral density, body composition, and lipid metabolism during growth hormone (GH) treatment in children with GH deficiency. J Clin Endocrinol Metab. 82:2423–2428.[Abstract/Free Full Text]
  55. Kuromaru R, Kohno H, Ueyama N, Hassan HM, Honda S, Hara T. 1998 Long-term prospective study of body composition and lipid profiles during and after growth hormone (GH) treatment in children with GH deficiency: gender-specific metabolic effects. J Clin Endocrinol Metab. 83:3890–3896.[Abstract/Free Full Text]
  56. Howard B, Howard W. 1994 Dyslipidemia in non-insulin-dependent diabetes mellitus. Endocr Rev. 15:263–274.[CrossRef][Medline]
  57. Copinschi G, Van Onderbergen A, L’Hermite-Balériaux M, et al. 1996 Effects of a 7-day treatment with a novel, orally active growth hormone (GH) secretagogue, MK-677, on 24-hour GH profiles, insulin-like growth factor-I, and adenocortical function in normal young men. J Clin Endocrinol Metab. 81:2776–2782.[Abstract]
  58. Berg A-L, Nilsson-Ehle P. 1994 Direct effects of corticotropin on plasma lipoprotein metabolism in man-studies in vivo and in vitro. Metabolism. 43:90–97.[CrossRef][Medline]
  59. Richelsen B, Pedersen SB, Børglum JD, Møller-Pedersen T, Jørgensen J, Jørgensen JO. 1994 Growth hormone treatment of obese women for 5 wk; effect on body composition and adipose tissue LPL activity. Am J Physiol. 266:E211–E216.
  60. Murase T, Yamada N, Oshawa N, Kosaka K, Morita S, Yoshida S. 1980 Decline of postheparin plasma lipoprotein lipase in acromegalic patients. Metabolism. 29:666–672.[CrossRef][Medline]
  61. Takeda R, Tatami R, Ueda K, Sagara H, Nakabayashie H, Mabushi H. 1982 The incidence and pathogenesis of hyperlipidaemia in 16 consecutive acromegalic patients. Acta Endocrinol (Copenh). 100:358–362.[Medline]



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