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Mikael Knip, Päivi Tapanainen, Fredrika Pekonen and Werner F Blum

Knip M, Tapanainen P, Pekonen F, Blum WF. Insulin-like growth factor binding proteins in prepubertal children with insulin-dependent diabetes mellitus. Eur J Endocrinol 1995:133:440–4. ISSN 0804–4643

To study the possible role of insulin-like growth factor binding proteins (IGFBPs) in the discrepancy between normal or only slightly retarded growth and substantially reduced concentrations of insulin-like growth factor I (IGF-I) in prepubertal children with insulin-dependent diabetes mellitus (IDDM), we measured the plasma concentrations of IGF-I, IGFBP-1, IGFBP-2 and IGFBP-3 and free insulin in 24 prepubertal diabetic subjects and 12 control children. In addition, the growth hormone response to exercise was evaluated. The diabetic children had significantly decreased peripheral IGF-I levels (8.2 + 1.1 (sem) vs 16.7 + 2.5 nmol/l; p < 0.001), whereas the concentrations of free insulin were increased (217 + 14 vs 103 + 21 pmol/l; p < 0.001). The concentrations of IGFBP-1 and IGFBP-3 were of the same magnitude in both groups. The diabetic children had significantly increased levels of IGFBP-2 (465 + 13 vs 416 + 14 μg/l; p = 0.029), which were inversely related to the circulating IGF-I levels (r = −0.35; p = 0.034). The diabetic and control children had comparable growth hormone responses to exercise. Diabetic children with poor glucose control had even lower IGF-I levels than those with moderate metabolic control (6.0 + 0.8 vs 10.3 + 1.7 nmol/l; p = 0.037). No differences could be observed in the plasma concentrations of various IGFBPs between these two groups of diabetic subjects. The absence in prepubertal diabetic children of increased IGFBP-1 levels observed in adolescent and adult patients with IDDM may contribute to their maintained linear growth, despite definitely decreased IGF-I concentrations. The role of increased IGFBP-2 levels in prepubertal children with IDDM remains open, but the inverse relationship between IGF-I levels and IGFBP-2 concentrations suggests that IGF-I may be involved in the regulation of IGFBP-2.

Mikael Knip, Department of Pediatrics, University of Oulu, FIN-90220 Oulu, Finland

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Werner F. Blum, Michael B. Ranke and Jürgen R. Bierich

Abstract. Six somatomedin-like peptides were purified from human plasma Cohn fraction IV by a six-step procedure which included ethanol precipitation, reversed-phase extraction, gel filtration, chromatofocusing and reversed-phase high pressure liquid chromatography (HPLC). Purification was monitored with a competitive protein binding assay using a crude preparations of somatomedin carrier protein. The peptides isolated were homogeneous by reversed-phase HPLC and sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE). Their apparent isoelectric points determined by chromatofocusing were 9.2 (Sm I), (Sm II), 8.2 (Sm III), 6.7 (Sm IV), 6.3 (Sm V), and 6.15 (Sm VI). SDS-PAGE under reducing conditions revealed that they are composed of a single peptide chain with apparent molecular weights of 6800 for Sm I, II and IV and 6400 for Sm III, V, and VI. They were equally potent in the porcine costal cartilage in vitro bioassay. The basic peptides (Sm I–III) were significantly more active in radioimmunoassays for somatomedin C (SmC) and insulin-like growth factor I C-peptide (IGF-I (30–41)), while only the slightly acidic peptides were active in a radioimmunoassay for insulin-like growth factor II C-peptide (IGF-II (33–40)). When receptor binding was tested with human placental cell membranes and Sm III as tracer, the basic peptides were significantly more potent than Sm IV–VI. With rat liver cell membranes and Sm V as tracer the slightly acidic peptides were more potent.

These findings suggest 1) that human plasma may contain other somatomedin-like peptides besides the major components IGF-I/SmC and IGF-II, and 2) that the basic peptides are structurally related to IGF-I/SmC and the slightly acidic peptides are related to IGF-II.

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Werner F. Blum, Michael B. Ranke and Jürgen R. Bierich

Abstract. A specific antiserum for human IGF-II has been produced by immunizing rabbits against the synthetic peptide IGF-II(33–40). With this antiserum and IGF-II as tracer a radioimmunoassay for IGF-II has been developed. Cross-reactivity with IGF-I was 0.05% and half-maximal displacement occurred at 2.5 μg IGF-II per 1. It was demonstrated that residual IGF-binding protein (IGF-BP) in acid-ethanol extracts interferes with IGF-II measurements and may produce erroneously high values. This interference could be completely blocked by excess IGF-I (25 ng per tube). Utilizing this method IGF-II was measured in subjects at various developmental stages. In newborns, the mean serum level was 237 μg/l (N = 56) with a range of 132–430 μg/l (5- and 95-percentile, respectively). During the first year of life a considerable increase occurred. Thereafter IGF-II increased only slightly with age from 520 μg/l (range 368–735) to 647 μg/l (range 507–823) in adults. In patients with growth hormone deficiency (N = 57) IGF-II levels were significantly (P <0.001) lower than in controls (mean 261 μg/l, range 126–542). It is concluded 1) that residual IGF-binding proteins in acid-ethanol extracts may cause considerable error in IGF-II measurements, and 2) that this interference can be completely blocked by excess IGF-I, if highly specific antisera are used.

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Roman Deyssig, Herwig Frisch, Werner F Blum and Thomas Waldhör

The effect of recombinant GH on strength, body composition and endocrine parameters in power athletes was investigated in a controlled study. Twenty-two healthy, non-obese males (age 23.4±0.5 years; ideal body weight 122±3.1%, body fat 10.1±1.0%; mean±sem) were included. Probands were assigned in a double-blind manner to either GH treatment (0.09U (kg BW)−1 day−1 sc) or placebo for a period of six weeks. To exclude concurrent treatment with androgenic-anabolic steroids urine specimens were tested at regular intervals for these substances. Serum was assayed for GH, IGF-I, IGF-binding protein, insulin and thyroxine before the onset of the study and at two-weekly intervals thereafter. Maximal voluntary strength of the biceps and quadriceps muscles was measured on a strength training apparatus. Fat mass and lean body mass were derived from measurements of skinfolds at ten sites with a caliper. For final evaluation only data of those 8 and 10 subjects in the two groups who completed the study were analyzed. GH, IGF-I and IGF-binding protein were in the normal range before therapy and increased significantly in the GH-treated group. Fasting insulin concentrations increased insignificantly and thyroxine levels decreased significantly in the GH-treated probands. There was no effect of GH treatment on maximal strength during concentric contraction of the biceps and quadriceps muscles. Body weight and body fat were not changed significantly during treatment. We conclude that the anabolic, lipolytic effect of GH therapy in adults depends on the degree of fat mass and GH deficiency. In highly trained power athletes with low fat mass there were no effects of GH treatment on strength and body composition.

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MICHAEL B. RANKE, FRANK HAUG, WERNER F. BLUM, WERNER ROSENDAHL, ANDREA ATTANASIO and JÜRGEN R. BIERICH

ABSTRACT

In 33 patients with Turner's syndrome growth during a one year period of treatment with low doses of estrogens was evaluated (group A: (N=12) PresomenR 5–9 μg/kg d; group B: (N=9) PresomenR 10–21 μg/kg d; group C: (N=12) ethinylestradiol 45–155 ng/kg d) and compared to a group (N=37) of untreated patients. The auxological evaluation was made using SDS derivations based on control data derived from 150 untreated patients. Based on chronological age (CA) SDS levels for height velocity and the increments in height at the end of treatment increased marginally. Compared to untreated patients no effect was seen when calculations were based on bone age (BA) due to an advancement in bone maturity. It is concluded that low doses of estrogens are not suitable to improve the height development in Turner's syndrome.

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Michael B. Ranke, Werner F. Blum, Frank Haug, Werner Rosendahl, Andrea Attanasio, Herbert Enders, Derek Gupta and Jürgen R. Bierich

Abstract. In a total of 56 children and adolescents with Turner's syndrome (41 with karyotype 45,X) basal serum levels of somatomedin bioactivity, Sm-C/IGF-I (RIA), IGF II (RIA), GH response to arginine and GHRH (GRF(1-29)NH2), and spontaneous GH secretion during 5.5 h of deep sleep were determined in a cross-sectional manner. GH responses to GRF and arginine as well as IGF-II levels were found to be in the normal range. Levels of somatomedin bioactivity were higher than normal before a bone age of 10 years, in the low-normal range thereafter, and below normal in some patients. Levels of Sm-C/IGF-I were found normal before and low-normal after a bone age of ten years. There was a trend towards increasing Sm-C/IGF-I levels with age. In contrast to the normal pattern, spontaneous sleep-related GH secretion was declining with age and did not show the puberty-associated rise. These findings suggest a normally functioning growth hormone-somatomedin axis in Turner's syndrome with alterations of its functioning level occurring secondarily as a result of absent gonadal activation. In single patients abnormally low growth hormone and/or somatomedin secretion may be present.

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Miklos Hamori, Werner F. Blum, Attila Török, Ralph Stehle, Eberhard Waibel, Philippe Cledon and Michael B. Ranke

Abstract.

Granulosa cells from human preovulatory follicles were cultured under serum-free conditions to investigate the presence of immunoreactive insulin-like growth factor binding protein-3 (IGFBP-3). IGFBP-3 levels were measured by a radioimmunoassay developed against the acid-stable subunit of the protein. The antiserum had no cross-reactivity to the low molecular weight GH-independent IGFBP-1. Granulosa luteal cells exhibited a continuous release of IGFBP-3 into the culture medium during the whole time (6 days) of the incubation. A dose-dependent increase in IGFBP-3 was observed when the cells were treated by dibutyryl cAMP. Cycloheximide suppressed almost completely both the basal and the stimulated production of IGFBP-3. The smallest effective dose of dibutyryl cAMP enhancing the progesterone release was lower than that for IGFBP-3. The different time course of IGFBP-3 and progesterone secretion to dibutyryl cAMP treatment, as well as the failure of progesterone to elicit IGFBP-3 increase alone, do not support the participation of progesterone in the IGFBP-3 production of granulosa cells. It is concluded that 1. immunoreactive IGFGBP-3 is produced by cultured granulosa luteal cells; 2. its synthesis is regulated by physiological intracellular mechanisms.

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Jens Otto L. Jørgensen, Werner F. Blum, Niels Møller, Michael B. Ranke and Jens S. Christiansen

Abstract.

Knowledge of the circadian patterns of serum IGF-I I and the large molecular weight IGF binding protein, IGFBP-3 might, apart from its physiological relevance, be of clinical interest, inasmuch as measurements of these parameters are being introduced into the evaluation of GH deficiency. We therefore evaluated the 24-h (08.00-08.00 h) patterns of serum IGF-II and IGFBP-3 in 8 GH-deficient patients who were studied during three periods when receiving 1. GH (2 IU) at 20.00 h; 2. GH (2 IU) at 08.00 h and 3. no GH. For comparison, 10 age- and sex-matched untreated healthy subjects were studied once under similar conditions. The serum IGF-II levels of the patients were relatively stable over the 24-h periods, yielding mean levels which were significantly lower during no GH: 553±78 (evening GH), 554±54 (morning GH), and 429±65 μg/l (no GH). The mean IGF-II level in the normal subjects was 635±29 μg/l, which was significantly higher than in either patient study. Similarly, stable 24-h levels of IGFBP-3 were recorded in all studies. The mean IGFBP-3 level of the patients was significantly lower when they received no GH, and the mean level in the healthy subjects was higher than in any of the patient studies: 1853±301 (no GH), 2755 ± 317 (evening GH), 2904±269 (morning GH), and 3856±186 μg/l (healthy subjects). However, minute but significant changes over time, characterised by slight decrements at night, were observed for both parameters in several of the studies. Nevertheless, since both IGF-II and IGFBP-3 display rather stable 24-h levels in the individual, it is concluded that measurements of these parameters in evaluation of growth retardation can be based on a single daytime sample.

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Werner F. Blum, Michael B. Ranke, Brigitte Lechner and Jürgen R. Bierich

Abstract. Human somatomedins (Sm) are heterogeneous on separation by chromatofocussing. Besides the 'classic' insulin-like growth factor I and II (IGF-I/Sm-C and IGF-II), a number of minor peaks emerge which can be classified as IGF-I/Sm-C-like or as IGF-II-like. The aim of the current study was to investigate whether or not polymorphism of somatomedins is present in individuals and whether or not the polymorphic pattern changes during development. Serum extracts from normal healthy children and adults were fractionated by chromatofocussing and the various somatomedin-like peptides were quantitated by specific radioimmunoassays for IGF-I/Sm-C or IGF-II. The results demonstrate 1) that heterogeneity of somatomedins is a common phenomenon existing in all individuals studied, and 2) that the polymorphic patterns of the IGF-I/Sm-C-family and of the IGF-II-family remain rather stable during development, although minor changes are evident.

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Jürgen Kratzsch, Werner F Blum, Manfred Ventz, Thomas Selisko, Gerd Birkenmeyer and Eberhard Keller

Kratzsch J. Blum WF, Ventz M, Selisko T, Birkenmeyer G, Keller E. Growth hormone-binding proteinrelated immunoreactivity in the serum of patients with acromegaly is regulated inversely by growth hormone concentration. Eur J Endocrinol 1994;132:306–12. ISSN 0804–4643

In this report we describe a newly developed radioimmunoassay (RIA) for the determination of the high-affinity growth hormone-binding protein (GHBP) in human blood. Using this RIA for the measurement of GHBP in serum of 29 patients with acromegaly, decreased concentrations were found compared to the normal range, depending on the activity of the disease. Growth hormonebinding protein was correlated inversely to log GH (r = −0.7, p < 0.001). A weaker relationship was shown between the GHBP activity determined in a functional assay based on charcoal separation and log GH (r = −0.51, p< 0.01). While insulin-like growth factor I (IGF-I) and IGF binding protein 3 (IGFBP-3) were correlated directly to log GH (r = 0.77 and r = 0.66, p < 0.001), an inverse and weaker relationship was evident between GHBP measured by RIA and IGF-I or IGFBP-3 (r = −0.61 and r = −0.57,p < 0.01). In contrast, no correlation could be detected between data of the functional GHBP assay and IGF-I or IGFBP-3, These results suggest, that: (1) in patients with acromegaly the GH receptor density in tissue reflected by the GHBP serum levels seems to be down-regulated, depending on the increased GH level; (2) low GHBP concentrations indicate an active disease in acromegaly and may be of diagnostic interest; (3) presuming that the GH receptor density is related to GH sensitivity, the variation of GH sensitivity is less important for IGF-I and IGFBP-3 production than the circulating GH concentration, at least in the situation of acromegaly; (4) because endogenous GH does not interfere in that assay, the RIA provides a valuable tool for the investigation of regulations between GH, GHBP and the GH receptor, especially in patients with acromegaly. The GHBP levels may be used as a sensitive parameter of GH oversecretion and tissue sensitivity to this hormone.

Jürgen Kratzsch, Inst. Clin. Chem., University of Leipzig, Paul-List-Str. 13–15, D-04103 Leipzig, Germany