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Christian J Strasburger and Wieland Kiess

In the 1960s pharmacotherapy with pituitary-derived human growth hormone (GH) preparations was introduced into clinics for the treatment of children with severely impaired longitudinal bone growth (1). Initially, the generally accepted route of GH administration was deep intramuscular injections. It was not until the advent of recombinant growth hormone preparations in the 1980s that subcutaneous injection of GH proved to be at least equally effective and was propagated widely (2). The less traumatic subcutaneous injection then facilitated investigation of effectiveness as a function of number of injections per week. With respect to the promotion of longitudinal bone growth in children and adolescents, daily subcutaneous injection was shown to be more effective than administration of the same weekly dose by injection thrice weekly. Extrapolation of these findings promoted further studies in animals and humans that unanimously demonstrated the superior effectivity of continuous GH infusion as compared to administration of the same

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Matthias M Weber, Christoph J Auernhammer, Wieland Kiess and Dieter Engelhardt

Abstract

We have identified and characterized insulin-like growth factor (IGF)-I and IGF-II/mannose-6phosphate (IGF-II/M6P) receptors in normal adult human adrenocortical tissue. Furthermore, we investigated the IGF-I receptor concentration and binding characteristics in benign and carcinomatous adrenocortical tumors. Membrane preparations of 14 normal adrenocortical glands showed a mean specific 125I-IGF-I binding (SB) of 5·0±0·5% and a competition by unlabeled ligands which is characteristic of the IGF-I receptor. The Scatchard analysis revealed a single class of high affinity binding sites with a dissociation constant (K d) of 0·16±0·03 nmol/l, and a receptor concentration (RC) of 19·2±2·5 nmol/kg protein. Affinity cross-linking experiments with normal and tumorous adrenocortical tissue displayed a band at an apparent molecular mass of 135 kDa, corresponding to the size of the normal α-subunit of the IGF-I receptor. In agreement, 125I-IGF-II binding to normal adult human adrenocortical membranes was characteristic for the IGF-II/M6P receptor, and the Scatchard analysis revealed the presence of a single class of high affinity binding sites (SB 7·5±0·5, RC 1137±265 nmol/kg protein, K d 2·20±0·46 nmol/l, n=6). The identity of the IGF-II/M6P receptor in adrenocortical tissue was further confirmed by Western blotting showing a specific band at 220 kDa. When 125I-IGF-I binding in adrenocortical hyperplasias (SB 4·1±0·4% RC 19·6± 2·0 nmol/kg protein, K d 0·19±0·04 nmol/l, n=4) and adenomas (SB 4·0±1·1% RC 17·5± 3·1 nmol/kg protein, K d 0·21±0·nmol/l,04 n=4) was compared with the 125I-IGF-I binding in normal adrenocortical tissue, similar IGF-I receptor concentration and binding kinetics were found. In contrast, three out of four hormonally active adrenocortical carcinomas showed a strongly elevated specific 125I-IGF-I binding with a 3- to 4-fold increase in IGF-I receptor concentration, as compared with normal adrenocortical tissue. This resulted in a significantly higher mean specific binding and receptor concentration in adrenocortical carcinomas, while the binding kinetics and the size of the α-subunit of the IGF-I receptor remained unaltered (n =4, SB 13·8±4·2%, RC 72·2 ± 21·3 nmol/kg protein, K d 0·17±0·02 nmol/l). In summary, we show that intact IGF-I and IGF-II receptors are present in normal adult human adrenocortical tissue. While the abundance of the IGF-I receptor in adrenocortical hyperplasias and adenomas was similar to normal tissue, a strong overexpression of the intact IGF-I receptor was found in three out of four adrenocortical carcinomas.

European Journal of Endocrinology 136 296–303

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Wieland Kiess, Linda L. Liu and Nicholas R. Hall

Abstract.

Sex-related differences in immune responsiveness are mediated at least in part by sex steroid hormones. Lymphocyte subset distribution in peripheral blood and natural killer cell function both have been reported to be under hormonal control. In order to gain more insight into sex steroid hormone action on the immune system, we have measured the lymphocyte subset distribution and natural killer cell activity in 18 men with idiopathic hypogonadotropic hypogonadism before treatment, and after hormonal treatment had normalized plasma testosterone levels. In untreated patients, the mean plasma testosterone concentrations were significantly lower than those in the treated men (3.0 ± 0.5 nmol/l vs 16 ± 1.7 nmol/l, p < 0.001). The percentage of peripheral CD3+ lymphocytes, CD8+ cells, the CD4+/CD8+ ratio, and the natural killer cell activity of peripheral mononuclear cells measured in a 51Cr release assay against target K 562 cells did not differ between patients with idiopathic hypogonadotropic hypogonadism and healthy adults, and most importantly, did not change during hormonal treatment which normalized plasma testosterone levels in the patients. In contrast, the percentage of peripheral CD4+ cells was significantly higher in untreated patients compared with normal adult subjects or patients with idiopathic hypogonadotropic hypogonadism after hormonal treatment that resulted in normal plasma testosterone levels (53 ± 2 vs 47 ± 2, p < 0.05). It should be noted that the percentage of peripheral CD 16+ cells was significantly lower in untreated men with low plasma testosterone levels than in normal controls. The percentage of CD16+ cells in peripheral venous blood rose significantly after hormonal treatment restored plasma testosterone levels to normal (6 ± 1 vs 11 ± 1, p < 0.001). In addition, the percentage of peripheral CD16+ cells correlated significantly with the plasma testosterone levels measured in men with idiopathic hypogonadotropic hypogonadism (r = 0.534, p < 0.001). In conclusion, both the percentage of peripheral CD4+ cells (T-helper lymphocytes) and peripheral CD16+ cells (non-T-non-B cells) are related to the plasma testosterone levels in men with idiopathic hypogonadotropic hypogonadism. These data suggest that in vivo human immune cells are under the regulatory influence of endogenous sex steroids.

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Angela Galler, Götz Gelbrich, Jürgen Kratzsch, Nicole Noack, Thomas Kapellen and Wieland Kiess

Objective: Adiponectin plays an important role in pathophysiology of obesity, type 2 diabetes and cardiovascular disease. The aim of this study was to determine adiponectin concentrations in children and adolescents with type 1 diabetes in a longitudinal manner and to study the impact of age, gender, body mass index (BMI) and metabolic control.

Research design and methods: In this study, 88 children and adolescents with type 1 diabetes were followed longitudinally. At baseline and during follow-up, serum levels of adiponectin were measured by enzyme-linked immunoassay and correlated with clinical data, HbA1c and lipids. Healthy children (n = 259) were chosen as a control group.

Results: Serum adiponectin levels were significantly higher in children with type 1 diabetes compared with healthy children (13.1 vs 9.1 μg/ml at baseline, P < 0.001). Adiponectin concentrations inversely correlated with BMI s.d.s (P < 0.001). No significant difference of adiponectin levels regarding gender, diabetes duration or HbA1c was seen. Adiponectin concentrations decreased in males with type 1 diabetes during puberty (P = 0.03) while there was no significant change in females. In a subgroup of patients with new onset type 1 diabetes, adiponectin concentrations were not different from adiponectin levels in control subjects but increased during follow-up (P = 0.007). Stepwise multiple regression analysis showed that most important predictors of adiponectin levels in type 1 diabetes at the end of the study were adiponectin concentration at baseline (β = 0.574, P < 0.001) and BMI s.d.s (β = −0.302, P = 0.001, r 2 = 0.56).

Conclusions: Children and adolescents with type 1 diabetes have BMI-dependent elevated serum concentrations of adiponectin compared with healthy children.

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Barbara Funk, Ulrike Kessler, Wolfgang Eisenmenger, Angela Hansmann, Helmut J Kolb and Wieland Kiess

The insulin-like growth factors (IGFs) are bound to multiple IGF binding proteins (IGFBPs) that are present both in the circulation and in extracellular fluids. There are at least six different IGFBP species that have been fully characterized in terms of molecular structure and amino acid sequence. The tissue distribution and local production of these proteins as well as the regulation of IGFBP production in different tissues have not been elucidated. We have studied the distribution of multiple IGFBP species in protein extracts from human kidney, skeletal muscle, lung, liver and brain by ligand blotting employing [125I]IGF-2 as the radiolabeled hormone. Five distinct IGFBP species with a respective molecular weight of43, 38, 34, 30 and 20 kDa were detected on the ligand blots in tissues from human fetuses and infants (23 weeks of gestation till 24 months of postnatal age). The 34 kDa species and a 30–32 kDa IGFBP species were predominant in brain, whereas a 30 kDa IGFBP species was mainly detected in skeletal muscle. Immunoblotting experiments using an anti IGFBP-2 antiserum showed that the 34 kDa IGFBP species from human brain was presumably related to IGFBP-2. We conclude that IGFBPs are differentially expressed in different tissues throughout human fetal life and early infancy. Local production or accumulation of the different IGFBPs could modulate IGF action at a local level or alternatively have differential functions during development.

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Matthias M Weber, Wieland Kiess, Thomas Beikler, Pia Simmler, Martin Reichel, Barbara Adelmann, Ulrike Kessler and Dieter Engelhardt

Weber MM, Kiess W, Beikler T, Simmler P, Reichel M, Adelmann B, Kessler U, Engelhardt D. Identification and characterization of insulin-like growth factor I (IGF-I) and IGF-II/mannose-6-phosphate (IGF-II/M6P) receptors in bovine adrenal cells. Eur J Endocrinol 1994;130:265–70. ISSN 0804–4643

We have identified and characterized insulin-like growth factor I (IGF-I) and IGF-II/mannose-6-phosphate (IGF-II/M6P) receptors in bovine adrenal cells. Iodine-125-labeled IGF-I ([125I]IGF-I) binding was characteristic of the IGF-I receptor, and binding kinetics as well as receptor densities were similar in cortical and medullary membranes. Scatchard analysis of [125I]IGF-I binding to cultured adrenocortical cells showed a single class of high-affinity binding sites with a Kd of 1.4 nmol/l and an average of 150 000 binding sites/cell. Affinity cross-linking experiments displayed a band at an apparent molecular weight of 135 kD, corresponding to the size of the α-subunit of the IGF-I receptor. In analogy, the binding of [125I]IGF-II to bovine adrenal membranes was characteristic of the IGF-II/ M6P receptor and no differences between cortical and medullary membrane fractions were found. Scatchard analysis revealed a single class of high-affinity binding sites in adrenocortical cells with a Kd of 1.1 nmol/l and an average of 280 000 binding sites/cell. The identity of the IGF-II/M6P receptor was confirmed by western blotting of adrenocortical membranes with an anti-IGF-II/M6P receptor antibody and by affinity cross-linking of adrenocortical cells with labeled IGF-II. In conclusion, we have identified and characterized IGF-I and IGF-II/M6P receptors in bovine adrenocortical as well as medullary cells. In both regions of the bovine adrenal gland the IGF-II/M6P receptor is much more abundant than the IGF-I receptor.

Matthias M Weber, Medizinische Klinik II, Klinikum Groβhadern, Marchioninistraβe 15, 81377 München, Germany

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Andreas Hoeflich, Yi Yang, Wolfgang Rascher, Werner F Blum, Stefan Huber, Gabriele Koepf, Helmut J Kolb and Wieland Kiess

Hoeflich A, Yang Y, Rascher W, Blum WF, Huber S, Koepf G, Kolb HJ, Kiess W. Coordinate expression of insulin-like growth factor II (IGF-II) and IGF-II/mannose-6-phosphate receptor mRNA and stable expression of IGF-I receptor mRNA during differentiation of human colon carcinoma cells (Caco-2). Eur J Endocrinol 1996;135:49–59. ISSN 0804–4643

Insulin-like growth factor II (IGF-II) has been implicated in the differentiation of skeletal muscle cells. In this study the putative role of IGF-II in epithelial cell differentiation was investigated. The expression of IGF-II, IGF-1 receptor and IGF-II/mannose-6-phosphate receptor (IGF-II/M6P receptor) mRNA during spontaneous differentiation of the colon carcinoma cell line Caco-2 was measured. In addition, differentiation of Caco-2 cells during the cell culture period (days 1–21 in culture) was studied in parallel using morphological (light and scanning electron microscopy) and biochemical markers of growth (DNA, RNA and protein content, and β-actin mRNA and glyceraldehyde phosphate dehydrogenase mRNA expression) and differentiation (alkaline phosphatase activity, carcinoembryonic antigen content). A putative correlation between the markers of growth and differentiation and IGF gene expression was studied using linear regression analysis. Expression of IGF-II mRNA and IGF-II/M6P receptor mRNA correlated significantly with the progress of differentiation, while the IGF-I receptor was stably expressed throughout the culture period and exhibited a crucial role for the survival of Caco-2 cells, as shown by blocking experiments employing the monoclonal anti-IGF-I receptor antibody alpha-IR3. We hypothesize that: IGF-II mRNA and IGF-II/M6P receptor mRNA are expressed in a coordinate fashion during the differentiation of Caco-2 cells; coordinate expression of IGF-II and of IGF-II/M6P receptor mRNA might point to a role for IGF-II as a growth stimulant and for the IGF-II/M6P receptor for a regulator of IGF-II bioavailability in differentiating cells; alternatively, high IGF-II/M6P receptor mRNA and protein expression in differentiated cells but low IGF-II binding to the IGF-II/M6P receptor point to an important intracellular role of this receptor type in differentiated colon epithelial cells; the IGF-I receptor mRNA is stably expressed during the differentiation process of Caco-2 cells; the IGF-I receptor protein seems to be a prerequisite for the survival of Caco-2 cells.

W Kiess, Children's Hospital, Justus Liebig University, Feulgenstr. 12, D-35385 Giessen, Germany

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Thomas M K Völkl, Diemud Simm, Antje Körner, Wolfgang Rascher, Wieland Kiess, Jürgen Kratzsch and Helmuth G Dörr

Objective

Congenital adrenal hyperplasia (CAH) patients are at a higher risk to develop obesity. The role of leptin in CAH is still controversial. Our study aimed to evaluate serum levels of leptin, the soluble leptin receptor (sOB-R), and the sOB-R: leptin molar ratios in a cohort of CAH children and adolescents, and their associations with clinical and metabolic parameters.

Methods

We studied 51 CAH patients, aged 5.6–19.6 years (median 11.8, n=30 females) cross-sectionally. All patients had genetically proven CAH and received standard steroid substitution therapy. Blood specimens were taken after overnight fasting between 0800 and 1000 h. For the analyses of leptin and sOB-R, matched pairs were built with healthy Caucasian patients for sex, Tanner stage (TS), chronologic age (CA), and body mass index (BMI).

Results

BMI and SDS were significantly elevated compared with the reference population. Leptin levels were not different between matched pairs, whereas sOB-R levels were significantly lower in CAH. Consequently, the sOB-R: leptin molar ratios were significantly decreased in CAH. Correlation analyses in CAH patients revealed significant relationship between leptin and CA, TS, BMI, and homeostasis model assessment of insulin resistance. Similar results were obtained for the matched control group. For sOB-R, we found no significant correlation for CA, TS, or BMI in CAH, but we did in the controls. There were significant correlations for androgens within the CAH group. Additional analyses revealed no correlation with steroid medication or metabolic control.

Conclusions

Our data show that an altered leptin axis with normal serum leptin concentrations but decreased sOB-R serum levels may contribute to the increased risk of overweight and obesity in CAH.

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Denise Rockstroh, Heike Pfäffle, Diana Le Duc, Franziska Rößler, Franziska Schlensog-Schuster, John T Heiker, Jürgen Kratzsch, Wieland Kiess, Johannes R Lemke, Rami Abou Jamra and Roland Pfäffle

Objective

The IGF/IGF1R axis is involved in the regulation of human growth. Both IGF1 and IGF2 can bind to the IGF1R in order to promote growth via the downstream PI3K/AKT pathway. Pathogenic mutations in IGF1 and IGF1R determine intrauterine growth restriction and affect postnatal body growth. However, to date, there are only few reports of pathogenic IGF2 mutations causing severe prenatal, as well as postnatal growth retardation.

Results

Here we describe a de novo c.195delC IGF2 variant (NM_000612, p.(Ile66Serfs*93)) in a 4-year-old patient with severe pre- and post-natal growth retardation in combination with dystrophy, facial dimorphism, finger deformities, as well as a patent ductus. Cloning and sequencing of a long-range PCR product harboring the deletion and a SNP informative site chr11:2153634 (rs680, NC_000011.9:g.2153634T>C) demonstrated that the variant resided on the paternal allele. This finding is consistent with the known maternal imprinting of IGF2. 3D protein structure prediction and overexpression studies demonstrated that the p.(Ile66Serfs*93) IGF2 gene variation resulted in an altered protein structure that impaired ligand/receptor binding and thus prevents IGF1R activation.

Conclusion

The severity of the phenotype in combination with the dominant mode of transmission provides further evidence for the involvement of IGF2 in growth disorders.

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Jing Jin, Lingfeng Cao, Zhuhui Zhao, Shuixian Shen, Wieland Kiess, Dijing Zhi, Rong Ye, Ruoqian Cheng, Lian Chen, Yi Yang and Feihong Luo

Context

Congenital generalized lipodystrophy (CGL) is a rare and heterogeneous disease of autosomal recessive inheritance. Until now, no genetic findings had been reported in Chinese patients with CGL.

Objective

To analyze Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) and 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) gene variation in a Chinese boy with CGL and his family.

Design, setting, and participants

All exons of BSCL2 and AGPAT2 with adjacent intron–exon junctions were analyzed using direct sequencing.

Main outcome measures

Sequences of each exon and nearby intron of the BSCL2 and AGPAT2 genes of the family members were compared with the gene bank genomic sequences.

Results

DNA sequence analysis of the entire coding regions and surrounding uncoding regions disclosed a novel homozygous G→T mutation at nucleotide 909 in exon 5 of the BSCL2 gene in the affected child. A heterozygous state of the G→T mutation of the BSCL2 gene was also found in other family members. This mutation predicts the substitution of glutamic acid at codon 189 by the stop codon (Glu189X or E189X). No variation was found in the AGPAT2 gene.

Conclusion

E189X is a novel BSCL2 gene mutation that contributes to CGL formation in a family of Chinese origin.