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Biomedical subjects

B A Bengtsson

Publications and source records attributed to B A Bengtsson.

At least 19 recordsLinked to original sources
PubMed1999

Double-blind, placebo-controlled study of growth hormone treatment in elderly patients undergoing chronic hemodialysis: anabolic effect and functional improvement.

Elderly patients with end-stage renal disease often have protein and/or caloric malnutrition that severely affects general well-being and mortality. Uremia is associated with resistance to the action of growth hormone (GH). This resistance could be of clinical importance in elderly dialysis patients. In the present study, the effects of GH treatment were assessed in elderly patients receiving chronic hemodialysis. Twenty hemodialysis patients with a mean age of 71.7 years (range, 53 to 92 years) were included on a 6-month, randomized, double-blind, placebo-controlled trial of GH treatment. The dose of GH was 66.7 microgram/kg, administered subcutaneously three times weekly immediately after each dialysis session. Body composition was measured using total-body potassium levels, computed tomography of the lower leg, and bioelectrical impedance analysis. Serum albumin concentrations and handgrip strength were also measured. GH treatment increased the serum concentration of insulin-like growth factor-I (IGF-I), IGF-I/IGF-binding protein-3 ratio, fat-free mass, and the serum concentration of albumin compared with placebo. The number of patients with serum albumin levels less than 40 g/L was reduced by a factor of three in the GH-treated group. Handgrip strength increased in response to GH treatment compared with placebo. Six months of GH treatment in elderly hemodialysis patients produced anabolic effects, with improved muscle performance. Also, the number of patients with low albumin levels was markedly reduced, indicating improved nutritional status and/or attenuated catabolism. These are all important beneficial effects for individual patient outcomes.

Aged↗
PubMed1999

Discrepancy between serum leptin values and total body fat in response to the oral growth hormone secretagogue MK-677.

OBJECTIVE: Growth hormone (GH) treatment decreases total body fat while this effect has not yet been documented for the oral GH secretagogue MK-677. In the present study, the effects of MK-677 treatment on serum levels of leptin, thyroid hormones and testosterone were determined. DESIGN: This was a randomized, double-blind, and parallel study. Twenty-four healthy obese males, 19-49 years of age, with body mass index (BMI) > 30 kg/m2 and a waist:hip ratio > 0.95, were treated with MK-677 (25 mg/day; n = 12) or placebo (n = 12) for 8 weeks. RESULTS: MK-677 treatment increased serum leptin levels and leptin/body fat ratio at 2 weeks of treatment (P < 0.05 vs. placebo) but no significant change was observed at 8 weeks. An increase in serum free 3, 5, 3'-triiodothyronine (free T3) was not detected until 8 weeks of MK-677 treatment (P < 0.05 vs. placebo). Peak serum thyroid stimulating hormone (TSH) concentration after MK-677 administration was similar to that after placebo administration at initiation of treatment and at 2 weeks. At 8 weeks of MK-677 treatment, mean peak serum TSH concentration was increased (P < 0.05 vs. placebo) although it remained within the normal range. Serum peak values of luteinizing hormone (LH) and follicle stimulating hormone (FSH) were similar after MK-677 and placebo administration. MK-677 treatment reduced serum total testosterone (P < 0.05 vs. placebo) although total testosterone/sex hormone-binding globulin (SHBG) ratio (an index of free testosterone) was not changed. CONCLUSION: Treatment with the oral GH secretagogue MK-677 transiently increased serum leptin levels and leptin/body fat ratio at 2 weeks of treatment, and increased serum free T3 after 8 weeks. These results indicate that MK-677 treatment is able to affect circulating factors of importance for adipose tissue mass and fuel metabolism.

Administration, Oral↗
PubMed1999

GH replacement in 1034 growth hormone deficient hypopituitary adults: demographic and clinical characteristics, dosing and safety.

OBJECTIVE: Long-term experience of growth hormone (GH) replacement therapy in a large population of hypopituitary adults with GH deficiency (GHD) is limited, and safety surveillance is clearly essential. KIMS, the Pharmacia & Upjohn International Metabolic Database, is a long-term, open, outcomes research programme of hypopituitary adult patients with GHD who are treated in a conventional clinical setting. PATIENTS: The present analysis encompasses data from 1034 hypopituitary adult GHD patients treated with GH for a total of 818 patient years. RESULTS: Prior to GH therapy, the KIMS patient population exhibited an increased prevalence of obesity, diabetes mellitus (in females) and hyperlipidaemia, compared with normal populations described in published studies. Quality of life, assessed using a disease-specific questionnaire (QoL-AGHDA), was also reduced in KIMS patients. The maintenance dose of GH was significantly higher in patients who were receiving GH prior to enrolment into KIMS (non-naive patients) compared with patients who commenced GH at the time of enrolment (naive patients). In addition, dose of GH correlated significantly with body weight in the former group of patients. Analysis of serum levels of IGF-I indicated that overtreatment with GH was markedly more common in non-naive than in naive patients. The frequency of adverse events in KIMS patients was no higher than that reported in patients receiving placebo in previous clinical trials. Recurrence of pituitary or CNS tumours was reported in six patients, a rate consistent with data from control series. Three deaths were reported, none of which was obviously associated with GH treatment. CONCLUSIONS: Our data, drawn from a large population of hypopituitary adults treated with GH for a total of more than 800 patient years, confirm previous reports that untreated GHD in hypopituitary adults is associated with a number of important clinical problems. In addition, the results suggest that there has been a shift in recent years from determination of GH dose on the basis of body weight to dose titration of individual patients, and indicate that the latter technique has important advantages. The data provide further evidence that GH replacement therapy is well-tolerated in adults. However, it is possible that some adverse events may not become evident over the time scale covered by the present analysis, and continued surveillance therefore remains mandatory.

Adolescent↗
PubMed1999

Possible protective role of growth hormone in hypoxia-ischemia in neonatal rats.

Perinatal asphyxia still constitutes a clinical hazard associated with considerable neurologic morbidity. Several growth factors, including insulin-like growth factor-I (IGF-I), have been reported to have a neuroprotective effect in experimental models of hypoxic ischemia (HI). In the present study, we have applied solution hybridization for quantification of the time course for mRNA expression of IGF-I, IGF-I receptor, and growth hormone (GH) receptor after HI in 7-d-old rats. There was a significant increase in IGF-I mRNA in the damaged hemisphere 72 h (1.19 +/- 0.28 vs 0.48 +/- 0.02 amol/microg DNA, p < 0.05) and 14 d (0.61 +/- 0.18 vs 0.19 +/- 0.05 amol/microg DNA, p < 0.05) after HI. In the contralateral hemisphere, both IGF-I and GH receptor mRNA had increased by 14 d after the insult (0.36 +/- 0.042 vs 0.13 +/- 0.011, p < 0.05, and 0.31 +/- 0.013 vs 0.11 +/- 0.004 amol/microg DNA, p < 0.001, respectively). There were no changes in IGF-I receptor mRNA throughout the study period. We have also evaluated the neuroprotective effect of GH after HI in neonatal rats. GH administered s.c. after HI in daily doses of 50 and 100 mg/kg provided a moderate neuroprotection of 20%. These results suggest a role for the GH/IGF-I axis in the neurochemical process leading to HI brain injury.

Animals↗
PubMed1999

Responses of the growth hormone (GH) and insulin-like growth factor axis to exercise, GH administration, and GH withdrawal in trained adult males: a potential test for GH abuse in sport.

GH abuse by elite athletes is currently undetectable. To define suitable markers of GH doping, we assessed the effects of acute exercise, GH administration, and GH withdrawal on the GH/insulin-like growth factor (IGF) axis in athletic adult males. Acute endurance-type exercise increased serum GH, GH-binding protein (GHBP), total IGF-I, IGF-binding protein (IGFBP)-3, and acid-labile subunit (ALS), each peaking at the end of exercise. IGFBP-1 increased after exercise was completed. Free IGF-I did not change with exercise. Recombinant human GH treatment (0.15 IU/kg x day) for 1 week increased serum total IGF-I, IGFBP-3, and ALS, exaggerating the responses to exercise. IGFBP-2 and IGFBP-1 were trivially suppressed. After GH withdrawal, the GH response to identical exercise was suppressed. Total IGF-I, IGFBP-3, and ALS returned to baseline over 3-4 days. In summary, 1) acute exercise transiently increased all components of the IGF-I ternary complex, possibly due to mobilization of preformed intact complexes; 2) GH pretreatment augmented the exercise-induced changes in ternary complexes; 3) postexercise IGFBP-1 increments may protect against delayed onset hypoglycemia; 4) serum total IGF-I, IGFBP-3, and ALS may be suitable markers of GH abuse; and 5) differences in disappearance times altered the sensitivity of each marker for detecting GH abuse.

Adult↗
PubMed1999

Growth hormone (GH) therapy in GH-deficient adults influences the response to a dietary load of cholesterol and saturated fat in terms of cholesterol synthesis, but not serum low density lipoprotein cholesterol levels.

An increased dietary load of cholesterol (ch) and saturated fat increases serum low density lipoprotein ch (LDL-ch) levels. GH therapy in GH-deficient adults decreases serum LDL-ch levels. In the rat, GH is important for resistance to dietary cholesterol in terms of serum cholesterol levels. The aim of this study was to investigate the influence of GH on the effects of an increase in the intake of cholesterol and saturated fat on serum lipoproteins and markers for cholesterol synthesis in man. Six GH-deficient adults were given an isocaloric diet enriched in cholesterol and saturated fat for 17 days with and without GH therapy (1-1.5 U/day). Serum cholesterol, LDL-ch, apolipoprotein B (apoB), and apoA1 levels increased during the diet period with GH therapy and tended to increase during the diet period without GH. However, GH therapy did not influence the dietary effect on serum cholesterol, LDL-ch, apoA1, or apoB levels. Serum levels of triglycerides, very low density lipoprotein ch, high density lipoprotein ch, and apoE were not affected by diet or GH therapy. GH therapy increased serum lipoprotein(a) levels, but did not affect the response to diet. The serum total delta7-lathosterol/cholesterol ratio increased less during the diet period with GH therapy than during the diet period without GH. Serum 7alpha-hydroxy-4-cholesten-3-one levels tended to increase during both diet periods, but were not influenced by GH treatment. Serum plant sterol levels did not change. These results indicate that GH counteracts an increase in cholesterol synthesis induced by a high fat diet without affecting bile acid synthesis or sterol absorption. GH therapy did not have any major influence on the dietary effects on serum lipoprotein levels.

Adult↗
PubMed1999

Treatment of obese subjects with the oral growth hormone secretagogue MK-677 affects serum concentrations of several lipoproteins, but not lipoprotein(a).

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.

Adipose Tissue↗
PubMed1999

Growth hormone and the metabolic syndrome.

The association of several risk factors, obesity, dyslipoproteinemia, hepatic steatosis, insulin resistance and hypertension with Type 2 (non-insulin-dependent) diabetes mellitus and myocardial infarction has long been known and has been termed the "metabolic syndrome". In 1988 Reaven introduced syndrome X as the link between insulin resistance and hypertension. It has been suggested that a critical factor in the association between obesity, Type 2 diabetes and cardiovascular morbidity is the mass of intraabdominal fat. Striking similarities exist between the metabolic syndrome and untreated growth hormone (GH) deficiency in adults. The central findings in both these syndromes are abdominal/visceral obesity and insulin resistance. Other features common to both conditions are premature atherosclerosis and increased mortality from cardiovascular diseases. These similarities indicate that undetectable and low levels of GH may be of importance in the metabolic aberrations observed in both these conditions. Recent investigations have found that abdominal/visceral distribution of adipose tissue is associated with endocrine disturbances including increased activity of the hypothalamic-pituitary-adrenal axis and a blunted secretion of GH and sex steroids. Theoretically, these endocrine perturbations can be a consequence of obesity, but the endocrine aberrations may have causal effects. We studied moderately obese, middle-aged men with a preponderance of abdominal body fat. As a group, they had slight to moderate metabolic changes known to be associated with abdominal/visceral obesity. Nine months of GH treatment reduced their total body fat and resulted in a specific and a marked decrease in both abdominal subcutaneous and visceral adipose tissue. Moreover, insulin sensitivity improved and serum concentrations of total cholesterol and triglyceride decreased. Diastolic blood pressure also decreased. The finding that GH replacement in men with abdominal obesity can diminish the negative metabolic consequences of visceral obesity suggests that low levels of this hormone are of importance for the metabolic aberrations associated with visceral/abdominal obesity.

Adult↗
PubMed1998

Serum leptin concentration and insulin sensitivity in men with abdominal obesity.

OBJECTIVE: We have examined the association between generalized adiposity, abdominal adiposity, insulin sensitivity, and serum levels of leptin in a cross-sectional study of abdominally obese men. RESEARCH METHODS AND PROCEDURES: Thirty men, 48 to 66 years of age with a body mass index (BMI) of between 25 kg/m2 and 35 kg/m2 and a waist hip ratio of >0.95, were included in the study. Serum leptin concentration was measured using radioimmunoassay. Total body fat percentage was determined from total body potassium, abdominal adiposity was measured by computed tomography, and the glucose disposal rate (GDR) was measured during an euglycemic, hyperinsulinemic glucose clamp. RESULTS: Significant correlations were found between serum leptin concentration and BMI, percentage body fat, abdominal subcutaneous adipose tissue, serum insulin, GDR, and 24-hour urinary-free cortisol. In a multiple regression analysis, it was shown that abdominal subcutaneous adipose tissue, GDR, and BMI explained 72% of the variability of serum leptin concentration. GDR demonstrated an independent inverse correlation with serum leptin concentration. DISCUSSION: In abdominally obese men with insulin resistance, it was demonstrated that most of the individual variability in serum leptin concentration was explained by the amount of subcutaneous abdominal adipose tissue, insulin sensitivity, and BMI.

Abdomen↗
PubMed1998

Beneficial effects of long-term GH replacement therapy on quality of life in adults with GH deficiency.

OBJECTIVE: Quality of life tends to be adversely affected in adults with GH deficiency. The aim of this study was to examine changes in quality of life in a large group of GH-deficient adults receiving long-term GH replacement therapy. DESIGN: The study was conducted in two stages. The first stage was a prospective, open trial of GH replacement therapy in 71 GH-deficient adults, during which GH was administered for 20-50 months. For the second stage, a further 90 patients were recruited to create a population of 161 GH-deficient adults, all of whom had received GH replacement therapy for more than 12 months. This population was investigated retrospectively, using a questionnaire designed specifically for this study. PATIENTS: All patients were GH deficient and showed a peak GH response of less than 3.0 micrograms/l during an insulin tolerance test in which blood glucose levels dropped to 2.2 mmol/l or below. MEASUREMENTS: The quality of life of patients in the prospective stage was assessed using the Nottingham Health Profile (NHP) parts I and II, and the Psychological General Well-Being (PGWB) index. In the retrospective study patients completed a specially developed questionnaire, designed to determine whether changes in quality of life were sudden or gradual, and whether quality of life continued to change after GH had been administered for more than 12 months. RESULTS: In the prospective stage, mean overall score on the NHP I improved significantly during the first 6 months of GH therapy, and remained at its new level thereafter. Scores in all areas of the NHP II improved significantly between baseline and 20-50 months, as did the total score and five of six area scores on the PGWB index. The total PGWB score and three area scores improved significantly between 6 or 12 months and 20-50 months. In the retrospective stage, 92.7% of the patients reported that they had experienced positive effects of GH therapy. In 30.3% of patients, however, such effects did not become apparent until GH had been administered for more than 6 months. Almost 60% of patients felt that their condition was still improving. CONCLUSIONS: These results indicate that the previously reported beneficial effects of GH therapy on quality of life in GH-deficient adults are sustained during long-term therapy. In addition, they suggest that, once started, GH therapy should be continued for at least 6 months before judgements are made regarding its efficacy in improving quality of life.

Adult↗
PubMed1998

Acromegaly and Cushing's syndrome due to ectopic production of GHRH and ACTH by a thymic carcinoid tumour: in vitro responses to GHRH and GHRP-6.

A 50-year-old male presented with diabetes mellitus and Cushing's syndrome associated with a large mediastinal mass. The levels of serum cortisol were high (1500-1800 nmol/l) without diurnal variation. Plasma ACTH levels (200-250 ng/l) and urinary excretion of cortisol were also increased. The levels of these hormones did not change in response to stimulation with corticotrophin releasing hormone (CRH) or suppression with high doses of dexamethasone. The patient had an elevated baseline GH level (7.3 mU/l), and the levels of immunoreactive GH-releasing hormone (GHRH) in eight plasma samples were markedly increased (600-1500 ng/l). Circulating levels of IGF-1, chromogranin A and neuropeptide Y (NPY) were also increased. Computer-assisted tomography and octreotide scintigraphy revealed a large mediastinal tumour and metastases in the left supraclavicular fossa. During treatment with octreotide, the baseline GH level was decreased (to 4.4 mU/l), while the GH pulse height was unchanged. Surgical removal of most of the tumour tissue resulted in a further decrease in the baseline serum GH level to a value (1.6 mU/l) about 20% of that before treatment, while the pulse height and mean GH were affected to a lesser extent. Postoperatively, circulating levels of cortisol and IGF-1 decreased, and the patient exhibited clinical improvement. Histological examination showed a neuroendocrine tumour with characteristics consistent with a foregut carcinoid of thymic origin. Immunoreactive GHRH, ACTH and NPY, but not immunoreactive GH, were detected in 80-90% of the tumour cells and the three peptides appeared to be co-localized. In primary culture, cells from this tumour displayed calcium influx in response to GHRH or GH releasing peptide-6 (GHRP-6), while there were not such responses by cells from another carcinoid not producing GHRH, ACTH or NPY. These results demonstrate a rare case of ectopic production of GHRH, ACTH and NPY, and indicate that the tumour cells were responsive to GHRH and GHRP-6 as well as octreotide.

Acromegaly↗
PubMed1998

A placebo-controlled study of growth hormone in patients with congestive heart failure.

AIM: Experimental data in heart failure models and an open trial of seven patients with idiopathic dilated cardiomyopathy have suggested beneficial effects of growth hormone on cardiac function. The aim of the present study was to evaluate growth hormone effects on cardiac function in a placebo-controlled study. METHODS: Twenty two patients with congestive heart failure of different aetiologies in NYHA II and III and an echocardiographic ejection fraction <0.45 were studied in a 3 month double-blind placebo-controlled study with growth hormone added to optimal heart failure therapy. Patients received either placebo (n=11) or recombinant human growth hormone (n=11) in an initial dose of 0.1 IU x kg(-1) week(-1) for 1 week, and thereafter 0.25 IU x kg(-1) week(-1) for the rest of the treatment period. Cardiac function was assessed by equilibrium radionuclide angiography and Doppler echocardiography. Functional capacity was evaluated by computerized bicycle exercise electrocardiography. RESULTS: Recombinant human growth hormone had no significant effect on systolic or diastolic cardiac function, exercise capacity or neuroendocrine activation. In addition, there was no overall improvement in functional class or dyspnoea grade. Insulin-like growth factor-I significantly increased demonstrating that the growth hormone had an endocrine effect. CONCLUSION: This is the first double-blind and placebo-controlled study of the administration, over 3 months, of recombinant human growth hormone in patients with congestive heart failure of different aetiologies. The treatment was safe and without serious side effects. However, no beneficial effects on cardiac function or structure could be detected.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Growth hormone and bone.

It is well known that GH is important in the regulation of longitudinal bone growth. Its role in the regulation of bone metabolism in man has not been understood until recently. Several in vivo and in vitro studies have demonstrated that GH is important in the regulation of both bone formation and bone resorption. In Figure 9 a simplified model for the cellular effects of GH in the regulation of bone remodeling is presented (Fig. 9). GH increases bone formation in two ways: via a direct interaction with GHRs on osteoblasts and via an induction of endocrine and autocrine/paracrine IGF-I. It is difficult to say how much of the GH effect is mediated by IGFs and how much is IGF-independent. GH treatment also results in increased bone resorption. It is still unknown whether osteoclasts express functional GHRs, but recent in vitro studies indicate that GH regulates osteoclast formation in bone marrow cultures. Possible modulations of the GH/IGF axis by glucocorticoids and estrogens are also included in Fig. 9. GH deficiency results in a decreased bone mass in both man and experimental animals. Long-term treatment (> 18 months) of GHD patients with GH results in an increased bone mass. GH treatment also increases bone mass and the total mechanical strength of bones in rats with a normal GH secretion. Recent clinical studies demonstrate that GH treatment of patients with normal GH secretion increases biochemical markers for both bone formation and bone resorption. Because of the short duration of GH treatment in man with normal GH secretion, the effect on bone mass is still inconclusive. Interestingly, GH treatment to GHD adults initially results in increased bone resorption with an increased number of bone-remodeling units and more newly produced unmineralized bone, resulting in an apparent low or unchanged bone mass. However, GH treatment for more than 18 months gives increased bone formation and bone mineralization of newly produced bone and a concomitant increase in bone mass as determined with DEXA. Thus, the action of GH on bone metabolism in GHD adults is 2-fold: it stimulates both bone resorption and bone formation. We therefore propose "the biphasic model" of GH action in bone remodeling (Fig. 10). According to this model, GH initially increases bone resorption with a concomitant bone loss that is followed by a phase of increased bone formation. After the moment when bone formation is stimulated more than bone resorption (transition point), bone mass is increased. However, a net gain of bone mass caused by GH may take some time as the initial decrease in bone mass must first be replaced (Fig. 10). When all clinical studies of GH treatment of GHD adults are taken into account, it appears that the "transition point" occurs after approximately 6 months and that a net increase of bone mass will be seen after 12-18 months of GH treatment. It should be emphasized that the biphasic model of GH action in bone remodeling is based on findings in GHD adults. It remains to be clarified whether or not it is valid for subjects with normal GH secretion. A treatment intended to increase the effects of GH/IGF-I axis on bone metabolism might include: 1) GH, 2) IGF, 3) other hormones/factors increasing the local IGF-I production in bone, and 4) GH-releasing factors. Other hormones/growth factors increasing local IGF may be important but are not discussed in this article. IGF-I has been shown to increase bone mass in animal models and biochemical markers in humans. However, no effect on bone mass has yet been presented in humans. Because the financial cost for GH treatment is high it has been suggested that GH-releasing factors might be used to stimulate the GH/IGF-I axis. The advantage of GH-releasing factors over GH is that some of them can be administered orally and that they may induce a more physiological GH secretion. (ABSTRACT TRUNCATED)

Animals↗
PubMed1998

Two-month treatment of obese subjects with the oral growth hormone (GH) secretagogue MK-677 increases GH secretion, fat-free mass, and energy expenditure.

Obesity is associated with blunted GH secretion, unfavorable body composition, and increased cardiovascular mortality. The objective of this study was to investigate the effects of oral treatment with the GH secretagogue MK-677 on GH secretion and body composition in otherwise healthy obese males. The study was randomized, double blind, parallel, and placebo controlled. Twenty-four obese males, aged 18-50 yr, with body mass indexes greater than 30 kg/m2 and waist/hip ratios greater than 0.95, were treated with MK-677 25 mg (n = 12) or placebo (n = 12) daily for 8 weeks. Serum insulin-like growth factor I (IGF-I) increased approximately 40% with MK-677 treatment (P < 0.001 vs. placebo). Serum IGF-binding protein-3 was also significantly increased (P < or = 0.001 vs. placebo). GH and PRL (peak and area under the curve values) were significantly increased after the initial dose of MK-677. Significant increases, with the exception of peak PRL, persisted at 2 and 8 weeks of treatment. The increases in GH and PRL after the initial dose were significantly greater than the increase seen after multiple doses. Serum and urinary concentrations of cortisol were not increased at 2 and 8 weeks (P = NS, vs. placebo). Fat-free mass increased significantly in the MK-677 treatment group when determined with dual energy x-ray absorptiometry (P < 0.01) or using a four-compartment model (P < 0.05). Total and visceral fat were not significantly changed with active therapy. The basal metabolic rate was significantly increased at 2 weeks of MK-677 treatment (P = 0.01) but not at 8 weeks (P = 0.1). Fasting concentrations of glucose and insulin were unchanged, whereas an oral glucose tolerance test showed impairment of glucose homeostasis at 2 and 8 weeks. We conclude that 2-month treatment with MK-677 in healthy obese males caused a sustained increase in serum levels of GH, IGF-I, and IGF-binding protein-3. The effects on cortisol secretion were transient. Changes in body composition and energy expenditure were of an anabolic nature, with a sustained increase in fat-free mass and a transient increase in basal metabolic rate. Further studies are needed to evaluate whether a higher dose of MK-677 or a more prolonged treatment period can promote a reduction in body fat.

Adult↗