The History of the Insulin-Like Growth Factor System.

The growth hormone (GH)-insulin-like growth factor (IGF) cascade is central to the regulation of growth and metabolism. This article focuses on the history of the components of the IGF system, with an emphasis on the peptide hormones, IGF-I and -II, their cell surface receptors, and the IGF binding proteins (IGFBPs) and IGFBP proteases that regulate the availability of the peptide hormones for interaction with their receptors in relevant target tissues. We describe landmark events in the evolution of the somatomedin hypothesis, including evidence that has become available from experiments at the molecular and cellular levels, whole animal and tissue-specific gene knockouts, studies of cancer epidemiology, identification of prismatic human cases, and short- and long-term clinical trials of IGF-I therapy in humans. In addition, this new evidence has expanded our clinical definition of GH insensitivity (GHI) beyond growth hormone receptor mutations (classic Laron syndrome) to include conditions that cause primary IGF deficiency by impacting post-receptor signal transduction, IGF production, IGF availability to interact with the IGF-I receptor (IGF-1R), and defects in the IGF-1R, itself. We also discuss the clinical aspects of IGFs, from their description as insulin-like activity, to the use of IGF-I in the diagnosis and treatment of GH deficiency, and to the use of recombinant human IGF-I for therapy of children with GHI.

Collaborative rewiring of the pluripotency network by chromatin and signalling modulating pathways.

Reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) represents a profound change in cell fate. Here, we show that combining ascorbic acid (AA) and 2i (MAP kinase and GSK inhibitors) increases the efficiency of reprogramming from fibroblasts and synergistically enhances conversion of partially reprogrammed intermediates to the iPSC state. AA and 2i induce differential transcriptional responses, each leading to the activation of specific pluripotency loci. A unique cohort of pluripotency genes including Esrrb require both stimuli for activation. Temporally, AA-dependent histone demethylase effects are important early, whereas Tet enzyme effects are required throughout the conversion. 2i function could partially be replaced by depletion of components of the epidermal growth factor (EGF) and insulin growth factor pathways, indicating that they act as barriers to reprogramming. Accordingly, reduction in the levels of the EGF receptor gene contributes to the activation of Esrrb. These results provide insight into the rewiring of the pluripotency network at the late stage of reprogramming.

Effect of recombinant hGH (rhGH) replacement on gonadal function in male patients with organic adult-onset GH deficiency.

OBJECTIVE: Previous evidence indicated that, in adults with organic hypopituitarism, GH deficiency (GHD) may mask the presence of other pituitary deficits, in particular central hypothyroidism and hypoadrenalism. Little and conflicting information is available about the relationship between GHD, rhGH therapy and gonadal function in males. The aim of the present study was to investigate the hypothalamic-pituitary-gonadal axis (HPG) in male adults with organic GHD and normal HPG axis. PATIENTS: Twelve male adults (mean age 48 +/- 7 years) with organic GHD and normal HPG axis. MEASUREMENTS: Serum levels of testosterone, LH and FSH (basal and after GnRH stimulation test), SHBG and IGF-I and percentage body fat (BF%) were evaluated before and during rhGH (mean dose 0.24 +/- 0.02 mg/day for 13 +/- 1 months) treatment. RESULTS: Serum IGF-I levels normalized during rhGH treatment and BF% significantly decreased. Serum testosterone levels significantly decreased (from 18.1 +/- 1.7 to 14.2 +/- 1.6 nmol/l, P = 0.01), with a parallel and significant decrease of serum SHBG (from 31.1 +/- 3.6 to 24.3 +/- 2.3 nmol/l, P < 0.05). Thus, calculated free testosterone (cFT) did not change (from 0.39 +/- 0.17 to 0.33 +/- 0.14 nmol/l, P = ns). Finally, no difference was found in basal and GnRH stimulated gonadotrophins levels. CONCLUSIONS: In conclusion, the condition of GHD does not seem to mask central hypogonadism, in contrast to what is observed for central hypothyroidism and hypoadrenalism. However, the significant decrease in serum testosterone levels, strictly related to SHBG decrease, suggests that evaluation of the HPG axis during rhGH treatment cannot be based on the measurement of total testosterone levels, but should mainly rely on calculation of cFT and a careful clinical evaluation, in order to avoid unnecessary replacement therapy.

Therapeutic applications of the insulin-like growth factors.

The potential therapeutic applications of the insulin-like growth factors (IGFs) are broad. This review focuses on treatment of humans with recombinant human IGF-I (rhIGF-I), and with a rhIGF-I/IGF binding protein-3 (IGFBP-3) complex. Several groups of patients have been treated effectively, including individuals with growth hormone insensitivity syndrome (GHIS) secondary to GH receptor deficiency, to IGF-I gene deletion, or to defects in GH signal transduction pathways, patients with type 1 and type 2 diabetes mellitus, or individuals with severe insulin resistance syndromes. In each of these conditions rhIGF-I therapy has been demonstrated to be of clear clinical benefit. Other conditions, which may potential targets for therapy with rhIGF-I or rhIGF-I/IGFBP-3, include chronic inflammatory or nutritional disorders such as Crohn's disease, juvenile chronic arthritis, or cystic fibrosis. Therapy with IGFs has not been attempted in these disorders yet, in part because of lack of adequate supplies. Recently, the newly developed rhIGF-I/IGFBP-3 complex has been used in early clinical studies. Pharmacokinetic analyses in patients with diabetes mellitus and GHIS have suggested that a more physiological profile of serum IGF-I results. Improved glycaemic control has been reported in type 1 and type 2 diabetes in adults. A therapeutic trial in naïve children with GHIS is currently under way.

Genetic defects of the growth hormone-insulin-like growth factor axis.

Our understanding of the physiology of the growth hormone-insulin-like growth factor (GH-IGF) axis has been characterized by remarkable advances in the past decade, with clarification of genetic defects in the development of somatotropes, GH secretion and action, and IGF synthesis and action. Combined efforts of research in this area and the development of animal models of growth retardation have also indicated new genetic abnormalities that might prove to cause short stature in humans. Genetic defects, both established and hypothetical, are reviewed, and a pragmatic clinical approach to the genetic investigation of short-statured patients is presented.

[Dwarfism in the Alagille syndrome caused by somatomedin C deficiency?]. / Kleinwuchs bei Alagille-Syndrom durch Somatomedin-C-Mangel?

Alagille syndrome (= arterio-hepatic dysplasia) is a rare congenital syndrome consisting of cholestasis with paucity of intrahepatic bile ducts, pulmonary artery stenosis, skeletal anomalies and typical facies. Growth retardation, which is not correlated with vertebral anomalies or the degree of cholestasis, occurs in about two thirds of patients. We report on hormonal aspects of growth retardation in an 8 year old Austrian boy with the typical features of arteriohepatic dysplasia. Thyroid function and a cortisol profile were normal and we found normal HGH response to insulin stimulation. The Somatomedin C-activity was well below the age-adjusted normal range. Even after test-induced HGH peaks no increase in Somatomedin C-activity could be observed. A six month course of phenobarbital-, cholestyramine- and D-penicillamine-therapy led to significant improvement of cholestasis, however Somatomedin C values and growth velocity remained unchanged. Results in our patients show that Somatomedin C-deficiency might be an important cause of growth retardation in children with chronic liver disease, at least in arteriohepatic dysplasia.

Histopathological features of the skin in hypopituitarism and Laron-type dwarfism.

Skin biopsies from children and adolescents with various syndromes of somatomedin deficiency revealed changes in structure and in distribution of the dermal elastin fibers as compared with a group of seven healthy control subjects. In 18 patients with isolated growth hormone deficiency (IGHD) and in 11 with multiple pituitary hormone deficiencies (MPHD), the number of elastin fibers was reduced; the individual fibers were shorter and slimmer than usual, and frequently arranged in groups dispersed in various directions. Skin biopsies from six patients with Laron-type dwarfism (LTD) revealed mostly thickened elastin fibers, frequently arranged in irregular bundles, but the number of elastin fibers was normal in prepubertal patients and reduced only in postpubertal patients. The reduction of elastin fibers in these patients was less prominent than in IGHD. The finding of more numerous elastin fibers in LTD than in IGHD is suggestive of a direct nonsomatomedin-mediated effect of human growth hormone on skin elastogenesis.

Resistance to subcutaneous and intramuscular insulin associated with deficiency of insulin-like growth factor (IGF) 2.

A diabetic patient is described whose serum was deficient in IGF 2. The patient responded appropriately to intravenous insulin but was resistant to subcutaneous and intramuscular insulin. His serum degraded insulin in vitro. This degradation was inhibited by IGF 2 and to a lesser extent by IGF 1 and insulin. We propose that this patient inactivated insulin at the injection site because of an insulin protease in his tissues that would normally be inhibited by serum IGF 2.

Monoclonal antibodies directed to human insulin-like growth factor I (IGF I). Use for radioimmunoassay and immunopurification of IGF.

Mouse hybridomas secreting antibodies to human insulin-like growth factor I (IGF I) were produced by fusion of spleen cells of hyperimmunised mice with FO mouse-myeloma cells. Eight clones producing antibodies against human IGF I have been isolated, two of which have been characterised. One was used in a radioimmunoassay, the other for immunopurification of IGF.

Dwarfism in the pygmy. An isolated deficiency of insulin-like growth factor I.

Insulin-like growth factors (IGFs) I and II, which are present in normal human beings, were measured in serum samples from 11 pygmies from the Central African Republic, 31 controls, and 12 patients with growth hormone deficiency. The mean serum concentration of IGF-I (+/- S.E.M.) was 68.6 +/- 8 ng per milliliter in pygmies, as compared with 193 +/- 10 ng per milliliter in controls (P less than 0.001) and 24 +/- 4 ng per milliliter in patients with growth hormone deficiency (P less than 0.05). Mean serum concentrations of IGF-II in controls, pygmies, and growth hormone-deficient patients were 647 +/- 22, 503 +/- 37, and 252 +/- 29 ng per milliliter, respectively. The serum IGF-I concentration was within the normal range in only one pygmy, whereas IGF-II values were within the normal range in 10 of 11. Pygmies appear to have a major defect in the production of IGF-I.

[Somatomedins (author's transl)]. / Somatomédines.

Research on somatomedins (insulin-like growth factors) has progressed greatly over the past few years. In the present review we summarize, in addition to our own results, some recent findings concerning the structure of these factors, their carrier protein, their biosynthesis and hormonal regulation. We also stress the interest of specific assays for their use in clinical investigation.

The inhibition of the transplacental blastomogenic effect of nitrosomethylurea by postnatal administration of buformin to rats.

N-Nitrosomethylurea (NMU) (20 mg/kg) was i.p. administered to rats on the 21st day of pregnancy. A decrease of glucose utilisation in the oral glucose tolerance test was found in 3 month old female progeny of NMU-treated rats. The serum insulin level did not differ from control, but serum cholesterol level was higher in offspring of NMU-treated rats. The ability of diethylstilboestrol to inhibit compensatory ovarian hypertrophy was decreased in female hemicastrated 3 month old rats whose mothers were treated with NMU. Postnatal administration of the antidiabetic drug buformin decreased the malignant neurogenic tumor incidence 3.5 times (to rats transplacentally treated with NMU).