J. van Doorn

Plasma levels of insulin-like growth factor binding protein-4 (IGFBP-4) under normal and pathological conditions.

OBJECTIVE Insulin‐like growth factor binding protein‐4 (IGFBP‐4) belongs to a family of six structurally related IGF‐binding proteins that are involved in the modulation of the biological effects of the IGFs. In order to obtain more insight into the clinical significance and regulation of IGFBP‐4 in vivo we determined the levels of this protein by a specific radioimmunoassay in the human circulation under normal and various pathological conditions.

Biochemical markers of growth hormone (GH) sensitivity in children with idiopathic short stature: individual capacity of IGF‐I generation after high‐dose GH treatment determines the growth response to GH

objective and patientsu2002 To assess multiple dose–response relationships between three GH doses (1·5, 3·0 and 6·0 IU/m2) and nine different biochemical markers of GH sensitivity in a well‐defined group of 17 children with idiopathic short stature (ISS).

Effects of maternal thyroid status on thyroid hormones and growth in congenitally hypothyroid goat fetuses during the second half of gestation

Congenital hypothyroidism in Dutch goats is due to a thyroglobulin (TG) synthesis defect that is inherited in an autosomal recessive manner. Minute amounts of mutated TG messenger RNA are translated into glycosylated TG fragments that contain the N-terminal hormonogenic site and are able to form T4, albeit less efficiently. We analyzed the effects of maternal thyroid status on fetal plasma thyroid hormones and growth during the second half of gestation (E90–E150). Maternal hypothyroidism, present from midgestation, resulted in decreased brain and cerebellum weights of affected goitrous fetuses, most evident at term gestation (E150). Brain and cerebellum weights of affected fetuses from unaffected mothers were not decreased. T4 and FT4 levels in affected fetuses were dependent on the maternal phenotype, as was the degree of enlargement of the goiter at E150. Newborn unaffected lambs from affected mothers had plasma T4 levels within the normal range. The present data show that in late gestation, fetal goats...

Differential patterns of insulin‐like growth factor‐I and ‐II mRNA expression in medulloblastoma

Insulin‐like growth factors (IGFs) play an important role in tumour growth and development. We hypothesized that this is also the case for medulloblastomas, which are highly malignant cerebellar brain tumours usually occurring in children. In these tumours the expression patterns of IGF‐I and ‐II mRNA were studied. Tumour specimens obtained from 12 children and two adults at diagnosis were hybridized in situ with digoxigenin‐labelled cRNA probes for hIGF‐I and hIGF‐II mRNAs. In all cases, tumour cells showed abundant expression of IGF‐I mRNA. Nine of the 14 tumours showed variable but significant IGF‐II expression. In these tumours, the hybridization signal almost exclusively colocalized with a subpopulation of Ki‐M1P positive cells that were identified as ramified microglia (RM) cells. In the five tumours without IGF‐II expression, microglia/brain macrophages with a more rounded amoeboid‐like morphology predominated. RM cells in normal cerebellar tissues, residing abundantly in areas of the white and, to a less extent, in the grey matter, were IGF‐II mRNA‐negative. These RM cells showed a thinner and more extensively branched appearance and were more evenly distributed than those encountered in medulloblastoma. Probably, during the transformation from the resting ramified towards the amoeboid morphology (or vice versa) IGF‐II mRNA expression is only temporarily induced. The physiological meaning of the induction of IGF‐II mRNA expression by these cells in medulloblastoma remains unclear but any IGF‐II peptide synthesized could exert unfavourable mitogenic and antiapoptotic effects on adjacent tumour cells. However, in this relatively small number of cases we could not find any indications for a relationship between clinical characteristics of the various cases and the extent of IGF‐II mRNA expression.

Treatment of haemangiopericytoma-associated hypoglycaemia with embolisation

A 48-year-old woman with a known history of metastatic haemangiopericytoma presented with intractable hypoglycaemia. Hypoglycaemia was accompanied by undetectable serum insulin levels with high levels of proforms of insulin-like growth factor-II (big IGF-II). Reduction of tumour load with embolisation resulted in a normal pattern of serum glucose levels throughout the day.

Insulin-like growth factors and leucine kinetics during exercise training in children with cystic fibrosis.

Background Little is known about the metabolic effects of exercise training in children with cystic fibrosis. The hypothesis for the current study was that in patients with declining clinical status, exercise increases circulating insulin-like growth factors (IGFs) and improves protein kinetics. Methods This was a prospective intervention study in 10 children with cystic fibrosis who participated in a structured isoenergetic exercise (cycling) training program for 3 months. Measurements of IGFs, protein kinetics (using intravenous [13C]-1-leucine tracer infusions) and nutritional balance studies were conducted at baseline and after 3 months. Results Standard deviation scores of plasma IGF-I, IGF-II, and IGF binding protein (BP)-3 were all decreased at baseline (mean ± SE: −2.0 ± 0.2, −2.0 ± 0.2, −0.6 ± 0.2, respectively). IGF-I and IGF-II concentrations were significantly higher after exercise training (standard deviation scores −1.4 ± 0.3 and −1.3 ± 0.1, respectively; compared with baseline: one-tailed t-test P = 0.03 and 0.002). The standard deviation score of the IGF-I/IGF BP-3 ratio, an indicator of free IGF-I in the circulation, normalized during exercise training (0.0 ± 0.6 vs. −1.3 ± 0.2 SD units at baseline, one-tailed t-test P = 0.04). There was no significant difference in protein intake and fasting protein breakdown, oxidation, and protein synthesis or in energy balance and fat absorption. Conclusions These results show that isoenergetic exercise training can be safely recommended to patients with cystic fibrosis. It provides a positive anabolic stimulus to IGF status but is not sufficient to adequately augment protein accretion in patients with diminished nutritional status.

Non-islet-cell tumour induced hypoglycaemia: a case report and review of literature

A 54-year-old man presented with a poorly differentiated adenocarcinoma of the rectum with multiple metastases to the liver. During hospitalization the patient developed periods of hypoglycaemia due to production of big IGF-II by the tumour. Possible pathophysiological mechanisms of non-islet-cell tumour-induced hypoglycaemia are discussed.