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Biomedical subjects

C J Strasburger

Publications and source records attributed to C J Strasburger.

At least 19 recordsLinked to original sources
PubMed2003

Both fasting-induced leptin reduction and GH increase are blunted in Cushing's syndrome and in simple obesity.

BACKGROUND: Simple obesity and Cushing's syndrome (CS) are two clinical models of leptin hypersecretion coupled with GH hyposecretion. Fasting inhibits leptin while stimulating GH secretion in normal human subjects. OBJECTIVES: To clarify the effect of fasting on leptin and GH secretion in obesity and CS. PATIENTS AND PROTOCOL: We studied six women with CS [age 17-66 years; body mass index (BMI) 28.6 kg/m2], seven women with visceral obesity (OB; 20-41 years; BMI 42.9 kg/m2) and seven normal women (NS; 25-31 years; BMI 19.3 kg/m2). The effects of 36-h fasting on 8-h diurnal mean leptin, GH, insulin and glucose concentrations (mLEPTc, mGHc, mINSc and mGLUc) as well as on the IGF/IGFBP system were studied. RESULTS: Before fasting, mLEPTc in OB and in CS were similar and both were higher (P < 0.01) than in NS. OB and CS showed similar mGHc, which were lower (P < 0.05) than in NS. Fasting induced a reduction in mLEPTc that was significant in NS and CS (P < 0.04) but not in OB. The mLEPTc in OB and CS after fasting remained higher (P < 0.05) than in NS. After fasting, OB and CS showed no increase in mGHc, although this clearly increased (P < 0.02) in NS. IGF-I but not IGFBP-3 levels decreased in all groups (P < 0.05). Fasting reduced mINSc and mGLUc while increasing IGFBP-1 in all groups. After fasting, mINSc in OB and CS remained higher (P < 0.03) than in NS. CONCLUSIONS: Short-term fasting has less inhibitory effect on leptin and no stimulatory effect on GH secretion in patients with Cushing's syndrome as well as simple obesity. After fasting, insulin levels in hypercortisolaemic and also in obese patients remained higher than in normal subjects suggesting that hyperinsulinism could play a role in the altered response of leptin and GH to starvation in these conditions.

Adolescent↗
PubMed2003

Decreasing peripheral resistance during pregnancy monitored at the cubital artery.

BACKGROUND: During the physiological course of pregnancy maternal peripheral vascular resistance decreases. Using the Doppler technique, the decreasing resistance and disappearance of the early diastolic notch in the arterial uterine perfusion can be observed. These changes in the Doppler flow velocity wave form are caused by the trophoblast invasion in which the spiral arteries loose their musculoelastic structure of the arterial wall. The aim of this study was to investigate whether maternal systemic alteration in the Doppler flow velocity waveform and Pulsatility Index (PI) could be monitored at the cubital artery during normal pregnancy. METHODS AND RESULTS: Forty-five patients were investigated in a prospective study in 4-6-week intervals for Dopplersonographic evaluation of the two uterine arteries and the right cubital artery; 20 of the patients were also investigated after delivery. The presence or absence of the early diastolic reverse flow of the cubital artery was analyzed. Furthermore, the PI was calculated for all vessels. With increasing duration of gestation, the reverse flow of the cubital artery disappeared. During the course of gestation a significant decrease in the PI of the cubital artery was observed in addition to a significantly decreased PI of the uterine arteries. The PI of the placental and nonplacental uterine arteries showed a significant correlation to the PI of the cubital artery. CONCLUSIONS: This study demonstrates systemical changes in arterial resistance correlating to those of the uterine arteries during the course of physiological pregnancy.

Female↗
PubMed2003

Association between the GH receptor/exon 3 genotype and the level of exon 3-positive GH-binding protein in human serum.

OBJECTIVE: The human GH-binding protein (GHBP) is derived from the GH receptor (GHR) through proteolytic cleavage of its extracellular domain. Two isoforms of the GHBP exist, differing in the retention or exclusion of exon 3: E3(+)GHBP and E3(-)GHBP. Our study aimed to answer the questions whether the level of E3(+)GHBP in the serum correlates with the GHR exon 3 expression and whether or not the E3 genotype matches the mRNA expression pattern. METHODS: Since exon 3 retention/deletion can be detected at the protein level using epitope-specific antibodies, we were able to quantify the two isoforms by means of specific immunoassays in a total of 37 individuals. Additionally, these persons were also genotyped for exon 3 by genomic PCR and tested for GHR exon 3 mRNA expression by RT-PCR. RESULTS: We found a significant correlation between GHR exon 3 genotype and the ratio of E3(+)GHBP and E3(-)GHBP in the serum. Moreover, the genotype matched exactly the mRNA expression in fibroblasts and/or blood leukocytes in all samples investigated. The levels of E3(+)GHBP are more strongly correlated with body mass index, proinsulin and C-peptide than the levels of the E3(-) isoform. CONCLUSIONS: Our results show that the GHR exon 3 genotype is in accord with the type of GHBP isoforms found in the serum. Our data thus support the idea that the presence of exon 3-retaining and -excluding GHR/GHBP isoforms results from a genomic deletion rather than from alternative splicing.

Adolescent↗
PubMed2002

[Primary hypertrophic osteoarthropathy (Touraine-Solente-Golé syndrome)].

HISTORY: A 29-year-old man had finger clubbing since the age of 15 years, and for the last 10 years his hands and feet had grown disproportionately. In addition he suffered from marked whole-body sweating, especially of the hands and feet, as well as persistent pain in the limbs and joints. INVESTIGATIONS: Biochemical and endocrinological tests were normal. Radiology of the hands and lower legs revealed marked periosteal thickening, while the substantia trabeculosa was unremarkable. Secondary causes having been excluded primary hypertrophic osteoarthropathy was diagnosed. TREATMENT AND COURSE: While there is no causal treatment, physio- and balneotherapy improved the symptoms. CONCLUSION: Early and accurate diagnosis of primary hypertrophic osteoarthropathy is essential, if only because of its favourable long-term prognosis.

Adult↗
PubMed2002

Differential regulation of insulin-like growth factor-(IGF) I and IGF-binding protein (IGFBP) secretion by human peripheral blood mononuclear cells.

BACKGROUND: Recent studies have shown that immunocompetent cells synthesize and express growth hormone (GH), growth hormone receptors (GH-R), insulin-like growth factor I (IGF-I), IGF-I receptors (IGF-I-R) and different insulin-like growth factor binding proteins (IGFBPs). The aim of the current study was to evaluate the regulation of IGFBP and IGF-I secretion from immunocompetent cells by different mitogens. METHODS/RESULTS: We studied the in vitro secretion pattern of IGFBPs and IGF-I from human peripheral blood mononuclear cells (PBMC), derived from 10 normal adults and 8 GH-deficient patients with adult onset. In serum-free conditioned medium of unstimulated PBMC, derived from normal adults, Western ligand blotting (1D-WLB) revealed a 24-kD, a 34-kD and a 39/43-kD doublet band to be most prominent. According to their molecular weight and two-dimensional Western ligand blot analysis (2D-WLB), these bands are deglycosylated IGFBP-4, IGFBP-2 and IGFBP-3, respectively. When the cells were treated with the T-cell mitogen phytohemagglutinin (PHA) (10 microg/ml), a differential stimulation of IGFBPs was found with a 2.57 +/- 0.48-fold increase of IGFBP-4 (p < 0.01), a 1.55 +/- 0.13-fold increase of IGFBP-2 (p < 0.01), and a 1.35 +/- 0.19-fold increase of IGFBP-3 (n.s.). In contrast, treatment with the B-cell mitogen pokeweed mitogen (PWM) (10 microg/ml) caused only a modest 1.40 +/- 0.07-fold increase of IGFBP-4 (p < 0.01). Treatment with rhGH (100 ng/ml) or rhIGF-I (200 ng/ml) caused no significant induction of any specific band, respectively. In contrast to the secretion pattern of IGFBPs, IGF-I secretion of the PBMC was not stimulated by either PHA or PWM, but showed a significant increase after GH incubation (p < 0.01). A similar differentiated secretion pattern of IGFBPs and IGF-I was also observed in the conditioned medium of PBMC, derived from GH-deficient patients. CONCLUSION: In summary, at least three different IGFBPs are secreted by human PBMC. Secretion of IGFBPs by PBMC is differentially regulated by different lymphocyte mitogens. Secretion of IGFBPs by PBMC is independent of GH or IGF-I, whereas the secretion of IGF-I is stimulated by GH. PBMC derived from normal adults and GH-deficient patients show similar patterns of IGF-I and IGFBPs secretion, thus indicating that the paracrine/autocrine IGF-I-IGFBPs interactions of the PBMC are not altered by pituitary GH deficiency.

Adult↗
PubMed2002

Impact of experimental blockade of peripheral growth hormone (GH) receptors on the kinetics of endogenous and exogenous GH removal in healthy women and men.

Organs that respond to and metabolize GH are enriched in cognate high-affinity receptors. However, whether isologous receptors mediate the de facto access of ligand to cellular degradative pathways is not known. To address this query, we assessed the distribution and whole-body elimination kinetics of (endogenous and exogenous) GH before and after administration of a novel, potent, and selective recombinant human (rh) GH receptor antagonist peptide, pegvisomant. Sixteen healthy young adults (nine men and seven women) participated in a double-blind, prospectively randomized, within-subject cross-over study. The intervention comprised a single sc injection of placebo vs. a high dose of pegvisomant (1 mg/kg sc) timed 62 and 74 h before the overnight sampling and daytime infusion sessions, respectively. The half-life, metabolic clearance rate (MCR), and distribution volume of GH were quantitated by way of: 1) deconvolution analysis of serum GH concentration time series collected every 10 min for 10 h; 2) exponential regression analysis of the decay of GH concentrations after a 6-min iv pulse of rhGH (1 and 10 micro g/kg); 3) calculation of the MCR during constant iv infusion of rhGH (0.5 and 5.0 micro g/kg every 2 h); and 4) exponential fitting of the elimination time-course of GH concentrations following cessation of each constant infusion. Concentrations of GH and pegvisomant were measured in separate, noncross-reactive, two-site monoclonal, immunofluorometric assays. Pegvisomant concentrations averaged 4860 +/- 480 micro g/liter (+/-SEM) across the infusion interval, thus exceeding low steady state GH concentrations by 3000-fold. Inhibitory efficacy of the GH receptor antagonist peptide was affirmed by way of a 34% reduction in the serum total IGF-I concentration, i.e., from 257 +/- 37 (placebo) to 170 +/- 24 (drug) micro g/liter (P < 0.001); and a reciprocal 77% elevation of the (10-h) mean GH concentration, i.e., from 1.3 +/- 0.23 (placebo) to 2.3 +/- 0.42 (drug) micro g/liter (P = 0.003). ANOVA disclosed that prior administration of pegvisomant (compared with placebo) did not alter: 1) the calculated half-life (minutes) of secreted GH, which averaged 15 +/- 1.3 (placebo) and 14 +/- 0.69 (drug); 2) the half-time of disappearance (minutes) of an iv pulse of rhGH, 15 +/- 1.0 (placebo) and 13 +/- 0.5 (drug) (for the 10 micro g/kg dose); 3) the distribution volume (milliliters per kilogram) of rhGH, 59 +/- 6.2 (placebo) and 58 +/- 3.5 (drug); 4) the steady state GH concentration (micrograms per liter) attained during constant iv infusion of rhGH (at a rate of 5 micro g/kg every 2 h), 18.2 +/- 2.4 (placebo) and 18.3 +/- 2.3 (drug); 5) the half-life (minutes) of elimination of GH from equilibrium, 16 +/- 0.98 (placebo) and 16 +/- 1.8 (drug); and 6) the steady state MCR (liters per kilogram per day) of rhGH, 3.8 +/- 0.32 (placebo) and 3.5 +/- 0.31 (drug). In ensemble, the present data refute the a priori postulate that vascular-accessible GH receptors determine the in vivo pseudoequilibrium kinetics of GH disappearance in the human.

Adult↗
PubMed2002

Systemic regulation of distraction osteogenesis: a cascade of biochemical factors.

This study investigates the systemic biochemical regulation of fracture healing in distraction osteogenesis compared with rigid osteotomy in a prospective in vivo study in humans. To further clarify the influence of mechanical strain on the regulation of bone formation, bone growth factors (insulin-like growth factor [IGF] I, IGF binding protein [IGFBP] 3, transforming growth factor [TGF] beta1, and basic FGF [bFGF]), bone matrix degrading enzymes (matrix-metalloproteinases [MMPs] 1, 2, and 3), human growth hormone (hGH), and bone formation markers (ALP, bone-specific ALP [BAP], and osteocalcin [OC]) have been analyzed in serum samples from 10 patients in each group pre- and postoperatively. In the distraction group, a significant postoperative increase in MMP-1, bFGF, ALP, and BAP could be observed during the lengthening and the consolidation period when compared with the baseline levels. Osteotomy fracture healing without the traction stimulus failed to induce a corresponding increase in these factors. In addition, comparison of both groups revealed a significantly higher increase in TGF-beta1, IGF-I, IGFBP-3, and hGH in the lengthening group during the distraction period, indicating key regulatory functions in mechanotransduction. The time courses of changes in MMP-1, bone growth factors (TGF-beta1 and bFGF), and hGH, respectively, correlated significantly during the lengthening phase, indicating common regulatory pathways for these factors in distraction osteogenesis. Significant correlation between the osteoblastic marker BAP, TGF-beta1, and bFGF suggests strain-activated osteoblastic cells as a major source of systemically increased bone growth factors during callus distraction. The systemic increase in bFGF and MMP-1 might reflect an increased local stimulation of angiogenesis during distraction osteogenesis.

Adult↗
PubMed2001

Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist.

BACKGROUND: Pegvisomant is a new growth hormone receptor antagonist that improves symptoms and normalises insulin-like growth factor-1 (IGF-1) in a high proportion of patients with acromegaly treated for up to 12 weeks. We assessed the effects of pegvisomant in 160 patients with acromegaly treated for an average of 425 days. METHODS: Treatment efficacy was assessed by measuring changes in tumour volume by magnetic resonance imaging, and serum growth hormone and IGF-1 concentrations in 152 patients who received pegvisomant by daily subcutaneous injection for up to 18 months. The safety analysis included 160 patients some of whom received weekly injections and are excluded from the efficacy analysis. FINDINGS: Mean serum IGF-1 concentrations fell by at least 50%: 467 mg/L (SE 24), 526 mg/L (29), and 523 mg/L (40) in patients treated for 6, 12 and 18 months, respectively (p<0.001), whereas growth hormone increased by 12.5 mg/L (2.1), 12.5 mg/L (3.0), and 14.2 mg/L (5.7) (p<0.001). Of the patients treated for 12 months or more, 87 of 90 (97%) achieved a normal serum IGF-1 concentration. In patients withdrawn from pegvisomant (n=45), serum growth hormone concentrations were 8.0 mg/L (2.5) at baseline, rose to 15.2 mg/L (2.4) on drug, and fell back within 30 days of withdrawal to 8.3 mg/L (2.7). Antibodies to growth hormone were detected in 27 (16.9%) of patients, but no tachyphylaxis was seen. Serum insulin and glucose concentrations were significantly decreased (p<0.05). Two patients experienced progressive growth of their pituitary tumours, and two other patients had increased alanine and asparate aminotransferase concentrations requiring withdrawal from treatment. Mean pituitary tumour volume in 131 patients followed for a mean of 11.46 months (0.70) decreased by 0.033 cm(3) (0.057; p=0.353). INTERPRETATION: Pegvisomant is an effective medical treatment for acromegaly.

Acromegaly↗
PubMed2001

High-dose leptin activates human leukocytes via receptor expression on monocytes.

Leptin is capable of modulating the immune response. Proinflammatory cytokines induce leptin production, and we now demonstrate that leptin can directly activate the inflammatory response. RNA expression for the leptin receptor (Ob-R) was detectable in human PBMCs. Ob-R expression was examined at the protein level by whole blood flow cytometry using an anti-human Ob-R mAb 9F8. The percentage of cells expressing leptin receptor was 25 +/- 5% for monocytes, 12 +/- 4% for neutrophils, and 5 +/- 1% for lymphocytes (only B lymphocytes). Incubation of resting PBMCs with leptin induced rapid expression of TNF-alpha and IL-6 mRNA and a dose-dependent production of TNF-alpha and IL-6 by monocytes. Incubation of resting PBMCs with high-dose leptin (250 ng/ml, 3-5 days) induced proliferation of resting cultured PBMCs and their secretion of TNF-alpha (5-fold), IL-6 (19-fold), and IFN-gamma (2.5-fold), but had no effect on IL-4 secretion. The effect of leptin was distinct from, and additive to, that seen after exposure to endotoxin or activation by the mixed lymphocyte reaction. In conclusion, Ob-R is expressed on human circulating leukocytes, predominantly on monocytes. At high doses, leptin induces proinflammatory cytokine production by resting human PBMCs and augments the release of these cytokines from activated PBMCs in a pattern compatible with the induction of Th1 cytokines. These results demonstrate that leptin has a direct effect on the generation of an inflammatory response. This is of relevance when considering leptin therapy and may partly explain the relationship among leptin, proinflammatory cytokines, insulin resistance, and obesity.

Adult↗
PubMed2001

Monoclonal anti-acid-labile subunit oligopeptide antibodies and their use in a two-site immunoassay for ALS measurement in humans.

Quantification of the acid-labile subunit (ALS) has to date been restricted to immunoassays utilizing polyclonal antibodies. By immunization with N-terminal and C-terminal specific ALS oligopeptides, we generated monoclonal antibodies (mAbs) that target ALS-specific sequences outside the nonspecific leucine-rich repeats in the ALS molecule. For mAb selection, a special screening method was developed. Monoclonal antibody 5C9, which targets the N-terminus of ALS, is immobilized and the anti-ALS mAb 7H3, directed against the C-terminus, is biotinylated and used as tracer Ab. Due to the extreme pH-lability of ALS, changes in immunorecognition of ALS were investigated after acidification for protein unfolding in different pH ranges and in a time-dependent manner. It was determined that acidification of the serum samples to pH 2.7 for 30 min, followed by neutralization and dilution to 1:100 was the optimal acid-neutralization method. For standardization purposes, a serum pool derived from healthy volunteers was assigned the value 1 U/ml ALS. The sandwich assay has a working range with a linear dose-response curve in a log/log system between 0.005 and 10 U/ml. ALS levels in seven acromegalic patients ranged from 2.0 to 4.2 U/ml, and in 12 untreated growth hormone deficient patients from 0.036 to 0.986 U/ml (mean=0.45 U/ml). After 12 months of growth hormone therapy, ALS levels increased significantly to 1.18+/-0.45 U/ml (mean+/-SD; p<0.0006). The increase ranged from 0.48 to 1.4 U/ml. The change in ALS with growth hormone (GH) therapy correlated closer with the change in IGF-I (r=0.798, p=0.0057; Spearman rank correlation) than with the change in insulin-like growth factor binding protein (IGFBP3; r=0.549, p=0.057). This specific sandwich assay for the measurement of ALS provides a potentially valuable indicator of growth hormone secretory status. With this mAb-based immunofluorometric assay, the nonspecific detection of other proteins containing leucine-rich repeat sequences can be excluded.

Acromegaly↗
PubMed2001

Acquired growth hormone resistance in patients with chronic heart failure: implications for therapy with growth hormone.

OBJECTIVES: We aimed to determine whether growth hormone (GH) resistance is present in patients with chronic heart failure (CHF) and whether it may be linked to the biochemical response to GH treatment. BACKGROUND: Acquired GH resistance is a feature of severe illness, in particular, cachexia. In patients with CHF, the response to GH therapy appears to be variable. METHODS: Biochemical markers of the GH-insulin-like growth factor-I (IGF-I) axis were compared in 21 cachectic patients with CHF, 51 noncachectic patients and 26 healthy control subjects. In separate studies, the predictive value of baseline biochemical variables for the IGF-I response to GH treatment was analyzed. RESULTS: Cachectic patients showed an increase of total GH and immunologically intact GH (p < or = 0.0002) and a decrease of GH-binding protein (BP) (p = 0.005), IGF-BP3 (p = 0.01) and IGF-I (p = 0.06), compared with noncachectic patients. Similar changes were found when the cachectic group was compared with the control group. No differences were found between noncachectic patients and control subjects. Levels of GH-BP correlated with the IGF-I/GH ratio in all subgroups (all p < or = 0.002). Baseline GH-BP levels were related to the increase of IGF-I levels in response to GH treatment in patients with CHF after 24 h (r = 0.83, p = 0.005; n = 9; study 2), 44 days (r = 0.52, p = 0.007; n = 25; study 3) and 96 days (r = 0.54, p = 0.006; n = 24; study 3). CONCLUSIONS: Most cachectic and some noncachectic patients with CHF show features of acquired GH resistance. The principal predictors of the biochemical features of GH resistance and of the poor biochemical response to short-term and longer-term GH treatment are GH-BP plasma levels. The presence of GH resistance is potentially a major factor determining the response to GH therapy in patients with CHF.

Biomarkers↗
PubMed2001

Findings and theoretical considerations on the usefulness of the acid-labile subunit in the monitoring of acromegaly.

Growth hormone (GH) action induces a variety of biochemical factors of which insulin-like growth factor I (IGF-I) is conventionally measured for the diagnosis and monitoring of GH-related disorders such as GH deficiency or acromegaly. IGF-I circulates predominantly as a ternary complex with IGF-binding protein 3 (IGFBP-3) and the acid labile subunit (ALS). In the treatment of active acromegaly with the GH receptor antagonist pegvisomant, ALS showed a closer correlation with the change in ring size, measured as a clinical indicator of disease activity, than did IGF-I or IGFBP-3. ALS thus seems to be a clinically useful marker of disease activity in acromegaly.

Acromegaly↗
PubMed2001

Effects of 36 hour fasting on GH/IGF-I axis and metabolic parameters in patients with simple obesity. Comparison with normal subjects and hypopituitary patients with severe GH deficiency.

OBJECTIVE: Reduction of growth hormone (GH) secretion in obesity probably reflects neuroendocrine and metabolic abnormalities. Even short-term fasting stimulates GH secretion and distinguishes normal from hypopituitary subjects with growth hormone deficiency (GHD). Marked weight loss improves GH secretion in obesity but the effect of fasting is controversial. We studied the effects of a 36 h fasting on the GH/IGF-I axis and metabolic parameters in obesity. SUBJECTS: We studied nine obese patients (OB; three male and six female; age, 29.2+/-4.8; range, 18-59 y; body mass index (BMI), 43.4+/-2.7 kg/m(2); WHR, 0.9+/-0.1). Fifteen normal subjects (NS; eight male and seven female 28.9+/-0.6, 25-35 y; 21.6+/-0.4 kg/m(2)) and 10 adult hypopituitary patients with severe GH deficiency (GHD; seven male and three female; 37.6+/-2.3, 29-50 y; 24.5+/-1.0 kg/m(2); GH peak<3 microg/l after ITT and/or<9 microg/l after GHRH+arginine) served as control groups. STUDY DESIGN: We studied the effects of 36 h fasting on 8 h diurnal mean GH, insulin and glucose concentrations (mGHc, mINSc and mGLUc; assay every 30 min from 8.00 am to 4.00 pm) as well as on IGF-I, IGFBP-3, ALS, IGFBP-1, GHBP and free fatty acid (FFA) levels. RESULTS: Before fasting, basal IGF-I and ALS levels in OB were similar to those in NS and both were higher (P<0.001) than those in GHD. IGFBP-3 levels in OB were lower (P<0.01) than in NS but higher (P<0.02) than in GHD. GHBP levels in OB and GHD were similar and both were higher (P<0.01) than in NS. Glucose levels were similar in all groups. FFA levels in OB were higher (P<0.01) than in NS but similar to those in GHD. IGFBP-1 in OB were lower (P<0.05) than in NS and GHD which, in turn, were similar. On the other hand, mINSc in OB was higher (P<0.01) than that in NS and GHD which, in turn, were similar. The mGHc in OB was similar to that in NS but only the latter was higher (P<0.05) than in GHD. The individual mGHc in the three groups overlapped. After fasting, IGF-I levels in GHD were unchanged while they decreased in OB (P=NS) as well as in NS (P<0.01). IGFBP-3 and ALS levels did not change. GHBP levels in OB and GHD were unchanged while they increased in NS (P<0.01). Glucose and FFA levels were reduced and increased, respectively, in all groups (P<0.02 and P<0.01). IGFBP-1 increased while mINSc decreased in all groups (P<0.02 and P<0.01); in OB they persisted lower and higher (P<0.01) respectively, than in NS and GHD. Fasting significantly increased mGHc in NS (P<0.001) but not in OB as well as in GHD. Individual mGHc in OB showed persistent overlap with GHD. CONCLUSIONS: Short-term fasting does not increase GH secretion in obesity and does not distinguish somatotroph function in obese from that in severe GHD adults. Short-term fasting in obesity has attenuated effects on insulin and IGFBP-1 secretion while it normally increases free fatty acids in spite of any change in GH secretion.

Adolescent↗
PubMed2001

The exon 3-retaining and the exon 3-deleted forms of the growth hormone-binding protein (GHBP) in human serum are regulated differently.

Recently, two isoforms of the growth hormone-binding protein (GHBP), which is identical with the extracellular domain of the growth hormone receptor (GHR), have been described. One isoform contains the exon 3 (E3+GHBP) and one excludes the exon 3 (E3-GHBP). The distribution of both isoforms in peripheral blood and their functional relevance is so far unknown. To study the molecular distribution of both species we have analysed sera of 141 subjects with average weight, overweight and obesity by newly developed immunoassays. The relationship between the different molecular forms of GHBP and specific parameters of body composition as well as risk factors of metabolic disturbances, were then examined. The extracellular domain of the exon 3-retaining and -deleted isoforms of the GHR are released as E3+GHBP and E3-GHBP into the peripheral circulation. Furthermore, both molecular species do not show any correlation to each other (r = 0.67) and their relative proportion in blood is gender-dependent with a higher E3-GHBP proportion in females (P < 0.01). E3+GHBP appears to have a considerably stronger correlation to indicators (BMI, fat mass, waist circumference) and metabolic risk factors (fasting insulin, uric acid, triglycerides, apolipoprotein B, diastolic blood pressure) of adiposity than E3-GHBP, indicating differences in their functional significance. The availability of assays for the determination of GHBP isoforms may be very important for the study of the GH receptor and its soluble extracellular domain, GHBP.

Body Constitution↗
PubMed2001

Effects of fasting and pegvisomant on the GH-releasing hormone and GH-releasing peptide-6 stimulated growth hormone secretion.

OBJECTIVE: Pegvisomant is a mutated GH molecule which prevents functional dimerization and subsequent activation of the growth hormone receptor. Pegvisomant and fasting both lead to GH resistance. DESIGN AND PATIENTS: We performed a double-blind placebo-controlled cross-over study comparing the effects of pegvisomant and fasting on the GH-releasing hormone (GHRH)- and GH-releasing peptide-6 (GHRP-6)-stimulated GH-release before and after 3 days of fasting in 10 healthy lean male subjects. We also performed a single-arm open label study under nonfasting conditions in five of these subjects. On day 1, in random order, at 0800 h, a GHRP-6 or GHRH test was performed. At 1600 h, a GHRH (if the first test was a GHRP-6 test) or GHRP-6-test (if the first test was a GHRH test) was done. After the second test either pegvisomant (80 mg as a single subcutaneous injection) or placebo was administered. On day 4, GHRP-6 and GHRH tests were performed in the same order as on day 1. During the cross-over study, subjects fasted from 2400 h on day 1 until the end of the study. MEASUREMENTS: During the GH stimulation tests, blood samples were drawn every 15 min from 15 to 120 min. GH was determined in all samples. Total insulin-like growth factor (IGF)-I and free IGF-I were determined from the samples at 0 min only. RESULTS: Three days of fasting alone and pegvisomant alone as well as in combination increased GH concentrations, whereas a decrease in serum-free, but not total, IGF-I concentrations was observed. On day 4, fasting and pegvisomant, either alone or in combination, significantly increased GH concentrations after GHRH compared to baseline. Pegvisomant alone did not increase GH concentrations after GHRP-6 administration. Fasting alone increased GH levels after GHRP-6 administration. The combination of fasting and pegvisomant had a synergistic effect on GH release after GHRP-6. CONCLUSION: These human in vivo data suggest that: (1) circulating free IGF-I, and not total IGF-I, is the major component in the negative feedback on GH secretion; (2) increased pituitary GHRH receptor expression plays a role in the mechanism whereby fasting leads to increased GH concentrations; (3) in vivo, GHRP-6 sensitivity seems to be regulated primarily by metabolic factors and not by changes in GH-IGF-I axis.

Adult↗
PubMed2001

Normal values of insulin-like growth factor I and their clinical utility in adults.

The concentration of circulating insulin-like growth factor I (IGF-I) is a potential marker for growth hormone (GH) deficiency in adults. Indeed, researchers have shown that IGF-I levels are of greater diagnostic value than other possible markers, such as IGF-binding protein 3 (IGFBP-3) and the acid-labile subunit (ALS). Accurate age-matched normative data are essential to give patient data diagnostic meaning. Such data are assay specific and must exclude those individuals with certain confounding medical conditions. Post-diagnosis, monitoring of IGF-I and IGFBP-3 levels can be used to assess the efficacy and safety of GH replacement therapy. Furthermore, IGF-I levels, and possibly ALS levels, can be used to aid the diagnosis and monitoring of acromegaly. For example, acromegaly can be excluded in patients with normal IGF-I levels if liver failure and malnutrition/malabsorption are ruled out.

Acromegaly↗
PubMed2001

Generation of human soluble leptin receptor by proteolytic cleavage of membrane-anchored receptors.

The leptin receptor (ObR) exists in multiple isoforms. In rodents, a soluble isoform is generated by alternative splicing; but in humans, there is no mRNA encoding soluble receptor (leptin binding protein). We investigated the hypothesis that human leptin binding protein can be generated by proteolytic cleavage of membrane-anchored leptin receptors (ObRb and ObRa). Leptin binding protein of similar size to that previously detected in human serum was detected by HPLC in medium of cells transfected with ObRa. ObRa exhibited higher expression at the cell surface than ObRb and generated greater levels of leptin binding protein. Ligand-mediated immunofunctional and immunofluorometric assays revealed that the leptin binding protein in medium bound both leptin and an ObR-specific antibody and that the level of leptin binding protein correlated with receptor expression at the cell surface. Phorbol 12-myristate-13-acetate and N-ethylmaleimide increased the accumulation of leptin binding protein, an indication that the production of leptin binding protein was up-regulated by PKC and sulfhydryl group activation. The protease inhibitors, TNFalpha protease inhibitor 1 and Immunex compound 2, could inhibit the production of leptin binding protein, indicating that the enzyme responsible for leptin binding protein cleavage belongs to the metalloprotease family. In conclusion, human leptin binding protein is generated by proteolytic cleavage of membrane-anchored leptin receptor by a metalloprotease.

Carrier Proteins↗