Search PubMed⌕ Search

Biomedical subjects

E R Froesch

Publications and source records attributed to E R Froesch.

At least 19 recordsLinked to original sources
PubMed1996

1 alpha,25-dihydroxyvitamin D3 increases IGF binding protein-5 expression in cultured osteoblasts.

Rat osteoblasts produce insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs). Expression of IGFBP-5, an IGFBP which stimulates DNA synthesis of osteoblasts, was studied in vitro under the influence of 1 alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) and parathyroid hormone (PTH). These two calcium-regulating hormones stimulated the expression of IGFBP-5 mRNA in cultured rat osteoblasts at low concentrations (10 pM) and in a dose- and time-dependent manner. Intact IGFBP-5 was not detected in the culture medium, but was found attached to the cell layer. IGFBP-5 may thus direct IGFs to the sites of bone remodeling.

Animals↗
PubMed1996

Reduced ob mRNA in hypophysectomised rats is not restored by growth hormone (GH), but further suppressed by exogenously administered insulin-like growth factor (IGF) I.

To examine whether GH and IGF-I participate in the regulation of obese (ob) mRNA expression we determined ob mRNA levels in epididydimal fat pads of hypophysectomised (hypox) rats, hypox rats treated with recombinant human (rh) GH or rhIGF-I and normal, weight-matched controls. We found that 1. ob mRNA was markedly suppressed after hypophysectomy (37 +/- 25% of controls), 2. GH infusion had no effect on ob mRNA, but stimulated IGF-I mRNA in fat pads, 3. IGF-I treatment further suppressed ob mRNA (3.5% +/- 0.6% of controls) and 4. serum insulin levels were decreased in all hypox groups (11.2 to 15.9% of controls). In conclusion, exogenous and GH-induced IGF-I differ in their effects on ob mRNA expression and GH is unable to restore ob mRNA towards normal at low insulin levels.

Adipose Tissue↗
PubMed1996

A novel point mutation in the translation initiation codon of the pre-pro-vasopressin-neurophysin II gene: cosegregation with morphological abnormalities and clinical symptoms in autosomal dominant neurohypophyseal diabetes insipidus.

Autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) is a rare variant of idiopathic central diabetes insipidus. Several different mutations in the human vasopressin-neurophysin II (AVP-NP II) gene have been described. We studied nine family members from three generations of an ADNDI pedigree at the clinical, morphological, and molecular levels. AVP concentrations were measured during diagnostic fluid restriction tests. Coronal and sagittal high resolution T1-weighted images of the pituitary were obtained from affected and healthy family members. PCR was used to amplify the AVP-NP II precursor gene, and PCR products were directly sequenced. Under maximal osmotic stimulation, AVP serum levels were close to or below the detection limit in affected individuals. Magnetic resonance imaging studies revealed the characteristic hyperintense ("bright spot") appearance of the posterior pituitary in two healthy family members. This signal was absent in all four ADNDI patients examined. The coding sequences of AVP and its carrier protein, neurophysin II, were normal in all family members examined. Affected individuals showed a novel single base deletion (G 227) in the translation initiation codon of the AVP-NP II signal peptide on one allele. The mutation in the AVP-NP II leader sequence appears to be responsible for the disease in this kindred, possibly by interfering with protein translocation. The absence of the hyperintense posterior pituitary signal in affected individuals could reflect deficient posterior pituitary function.

Adolescent↗
PubMed1996

Insulin-like growth factor I alters peripheral thyroid hormone metabolism in humans: comparison with growth hormone.

Insulin-like growth factor I (IGF-I) is considered to mediate some of the growth-promoting and metabolic effects of growth hormone (GH). Growth hormone treatment of healthy and GH-deficient subjects is accompanied by increased conversion of thyroxine (T4) to triiodothyronine (T3) in peripheral tissues. Whether these effects are mediated by IGF-I is unknown. To assess the respective roles of these hormones on thyroid hormone metabolism we have treated two groups of subjects. The first group consisted of eight healthy subjects who were treated with IGF-I (10 micrograms.kg-1.h-1 sc for 5 days). The second group consisted of eight subjects with combined GH and thyrotropin (TSH) deficiency due to acquired pituitary disease. They were treated with IGF-I (10 micrograms.kg-1.h-1 sc for 7 days), GH (2 IU m-2 sc q.i.d.) or both hormones together. The IGF-I treatment in healthy subjects led to an increase in free T3 (FT3) and a reduction in TSH levels, whereas FT4 and total T4 (TT4) levels remained unchanged. In the second group-in which all subjects were substituted with oral L-thyroxine-treatment with IGF-I led to an elevation of FT3 in the face of unchanged T4 levels. Growth hormone alone and GH plus IGF-I resulted in a more pronounced elevation in T3 level. The results suggest that IGF-I partially mediates the well-known effects of GH on peripheral conversion of T4 to T3. However, GH has more pronounced effects on thyroid hormones that apparently are not mediated by IGF-I.

Adult↗
PubMed1996

Insulin-like growth factor-I in the therapy of non-insulin-dependent diabetes mellitus and insulin resistance.

Recombinant DNA technology has made large amounts of insulin-like growth factor-I (IGF-I) available for studies in animal models and humans. It has been shown that treatment with IGF-I is associated with increased insulin sensitivity in normal subjects as well as in patients with growth hormone deficiency, Type 1 and Type 2 diabetes mellitus and type A insulin-resistance. The metabolic effects of IFG-I appear to be beneficial in these conditions. The reported side effects of IGF-I, which may be largely due to overdosage, have limited its use to small and mostly short-term clinical studies.

Diabetes Mellitus, Type 2↗
PubMed1995

[From research of non-suppressible serum insulin activity to the clinical application of recombinant insulin-like growth factor (rhIGF-I)].

The meandering and sometimes painful journey from the discovery of non-suppressible insulin-like activity in serum to the chemical, biological and physiological characterization and biotechnological production of the two peptide hormones which are responsible for this plasma activity, i.e. IGF-I and IGF-II, is described. IGF-I is the major mediator of most activities of pituitary growth hormone and is therapeutically used for the stimulation of growth in growth hormone-insensitive (Laron) dwarfs and for the treatment of type A insulin-resistant diabetics with non-functional insulin receptors. IGF-I and -II are not only endocrine hormones but also important locally produced peptides that act on cell differentiation during embryogenesis and on the regeneration of tissues during adult life via the autocrine/paracrine pathway. IGF research, chiefly in Zürich, serves as a basis on which to discuss more general aspects of the training of medical doctors and research structures in Switzerland.

Amino Acid Sequence↗
PubMed1995

Effects of insulin-like growth factor (IGF) binding proteins (BPs) -3 and -6 on DNA synthesis of rat osteoblasts: further evidence for a role of auto-/paracrine IGF I but not IGF II in stimulating osteoblast growth.

IGFBP-3 and IGFBP-6 were used to study whether both IGF I and IGF II play a role in auto-/paracrine stimulation of rat osteoblast growth. Both IGFBPs decreased basal DNA synthesis in neonatal rat calvaria cells but with different potencies. Consistent with their IGF binding affinities, IGFBP-3 blocked both IGF I- and IGF II-stimulated DNA synthesis, whereas IGFBP-6 preferentially blocked IGF II-stimulated DNA synthesis. These inhibitory effects of the two IGFBPs can be fully explained by the sequestration of IGFs. Because IGFBP-6 preferentially binds IGF II and is much less potent than IGFBP-3 in decreasing basal DNA synthesis in calvaria cells, IGF I but not IGF II appears to be an important auto-/paracrine stimulator of DNA synthesis.

Animals↗
PubMed1995

Expression, effects, and fate of IGFBP-5 are different in normal and malignant osteoblastic cells.

Normal osteoblasts from newborn rat calvaria and human osteosarcoma (Saos-2) cells express IGFBP-5 mRNA. IGF I increases IGFBP-5 mRNA levels in both cell types, whereas retinoic acid stimulates IGFBP-5 mRNA expression in calvaria but suppresses it in Saos-2 cells. IGFBP-5 mRNA expression is stimulated in normal bone cells by parathyroid hormone. 30 nM IGFBP-5 stimulates 3H-thymidine incorporation in calvaria (which produce IGF I contributing to basal proliferation in serum-free medium) but not in Saos-2 cells which produce little IGF I and IGF II. Among the 5 rhIGFBPs tested (IGFBP-2 to -6), only IGFBP-5 stimulates DNA synthesis in calvaria cells, and only IGFBP-6 in Saos-2 cells. RhIGFBP-5 displays a short half-life (approximately 30 min) in serum-free medium of calvaria cells and a long half-life (approximately 15 h) in the medium of Saos-2 cells. Fragments of 20 and 14 kDa accumulate in the media of both cell types. Intact (31 kDa) IGFBP-5 is associated and remains with the extracellular matrix of mature calvaria osteoblasts but not of Saos-2 cells. Among the IGFBPs produced IGFBP-5 is unique with regard to its marked affinity to matrix of normal bone cells, its short half-life when released, and its stimulatory effects on DNA synthesis.

Animals↗
PubMed1995

Intravenously injected insulin-like growth factor (IGF) I/IGF binding protein-3 complex exerts insulin-like effects in hypophysectomized, but not in normal rats.

Insulin-like growth factor (IGF) circulates in blood in two large molecular mass forms of 150 and 40 kD. Under normal conditions, most of the IGF is bound to the 150-kD complex by which it is retained in the circulation and therefore unable to exert acute insulin-like actions. The aim of this study was to answer the question whether or not IGF in the 40-kD complex is bioavailable to insulin target tissues and thus can cause acute insulin-like effects in vivo. Intravenously injected 1:1 molar recombinant human (rh) IGF I/rhIGF binding protein (BP)-3 complex lowered blood glucose and stimulated glycogen synthesis in diaphragm of hypophysectomized, but not of normal rats. The serum half-lives of the two components of the complex were similar to each other, but considerably shorter in hypox than in normal rats. On neutral gel filtration of serum both components of the injected complex appeared predominantly in the 150-kD region in normal rats. In hypox rats which lack the 150-kD complex they were found in the 40-kD region and disappeared rapidly from the circulation. We conclude that in the absence of the 150-kD complex, IGF associated with the 40-kD complex can rapidly leave the vascular compartment, reach insulin or type 1 IGF receptors and exert acute insulin-like effects.

Animals↗
PubMed1995

Treatment with insulin-like growth factor I alters capillary permeability in skin and retina.

Treatment with insulin-like growth factor I (IGF-I) is accompanied by mild generalized and reversible edema. These changes may be due to increased capillary permeability. Therefore, we studied the effects of subcutaneous IGF-I treatment in healthy subjects on capillary permeability of the skin and the retina. Eight healthy subjects were treated with saline or recombinant human IGF-I (rhIGF-I) (10 micrograms.kg-1.h-1 s.c.) in a randomized crossover fashion. Transcapillary diffusion of sodium fluorescein (NaF) was quantitated by video densitometry in the skin in all subjects on the 4th treatment day. In seven subjects, plasma penetration of NaF at the blood-retinal barrier was investigated using vitreous fluorometry (VF) on days 3 and 5. Fluorescent light intensities of the skin and plasma penetration determined by VF were significantly higher during the IGF-I treatment as compared with those during the control situation. In conclusion, IGF-I treatment at the above dose is accompanied by increased transcapillary diffusion of NaF in skin and in retinal vessels.

Adult↗
PubMed1994

Functional properties of a heterozygous mutation (Arg1174-->Gln) in the tyrosine kinase domain of the insulin receptor from a type A insulin resistant patient.

We analysed the biochemical properties of insulin receptors of a Type A insulin resistant patient with a single heterozygous point mutation substituting Gln for Arg1174. Insulin binding capacity and affinity to Epstein-Barr virus transformed lymphocytes was normal. Quantitative analysis of autophosphorylation and substrate phosphorylation of soluble insulin receptors isolated from patient cells revealed no differences in the basal state whereas in the presence of insulin autophosphorylation activity was only 30% of control receptors. The stimulation of substrate phosphorylation and down-regulation of receptors on patient cells after chronic exposure to insulin was diminished when compared to controls. We conclude that the heterozygous Arg1174 mutation does not perturb basal kinase activity but specifically interferes with the kinase activation by insulin and that the mutation has a dominant negative effect on the wild type kinase.

Adult↗
PubMed1994

Insulin-like growth factor I stimulates myofibril development and decreases smooth muscle alpha-actin of adult cardiomyocytes.

Adult rat cardiomyocytes in long-term culture express type 1 insulin-like growth factor (IGF) receptors. In contrast to insulin receptors, type 1 IGF receptors are up-regulated during culturing. IGF-I added to the cells at plating increased granular density and pseudopodia number per cell after 7 days. After 16 days, IGF-I-treated cells showed, as compared with controls, a dramatic increase of the number of newly built sarcomeres and were packed with myofibrils. At the same time, IGF-I suppressed the accumulation of smooth muscle alpha-actin (sm-alpha-actin) in a dose-dependent manner. Under the conditions of this in vitro system, growth hormone had no effect on cell morphology or sm-alpha-actin. sm-alpha-Actin, a nonsarcomeric isoform of actin expressed in early fetal cardiac development, reappears both during long-term culture of adult rat cardiomyocytes and during heart hypertrophy. This study shows that type 1 IGF receptors are up-regulated in adult rat cardiomyocytes in long-term culture and that IGF-I enhances myofibril development and concomitantly down-regulates sm-alpha-actin. This protein forms stress-fiber-like structures and may temporarily serve as a scaffold for the formation of new sarcomeres until myofibrils have developed throughout the cell and the scaffold is no longer needed. Our findings thus allow us to propose another hypothesis for the mechanism leading to overload heart hypertrophy.

Actins↗
PubMed1994

Recombinant human insulin-like growth factor-I: a therapeutic challenge for diabetes mellitus.

Insulin-like growth factor I (IGF I) is an endocrine hormone that mediates most of the effects of pituitary growth hormone. Other important regulatory factors of serum IGF I levels are insulin and nutrition. Most of the circulating IGF I is bound to three IGF binding proteins (BP), mostly IGFBP-3, BP-2 and BP-1. IGF I is also produced by many cells in the body where it exerts autocrine and/or paracrine effects. IGF I has a specific receptor on most cells, the so-called type 1 IGF receptor. When IGF I is administered intravenously as a bolus it leads to acute hypoglycaemia in a similar way to insulin and mainly with the insulin receptor. Chronic administration of IGF I to hypophysectomized or diabetic rats leads to prominent anabolic effects and growth. In this manuscript, metabolic and endocrine effects of recombinant IGF I are discussed. Recombinant IGF I therapy increases energy expenditure and lipid oxidation and decreases proteolysis and protein oxidation. These effects occur despite a partial inhibition of insulin and growth hormone secretion. The therapeutic spectrum of recombinant IGF I, consisting of inhibition of catabolism, stimulation of anabolism, decreases of triglyceride and cholesterol levels and a striking increase in insulin sensitivity, renders IGF I a very interesting, powerful tool for insulin-resistant states such as non-insulin-dependent diabetes mellitus.

Animals↗
PubMed1994

Growth hormone and parathyroid hormone stimulate IGFBP-3 in rat osteoblasts.

Osteoblast-like cells prepared from calvaria of newborn rats produce insulin-like growth factor (IGF) I and several insulin-like growth factor binding proteins (IGFBPs) in vitro. Among the IGFBPs found in conditioned cell culture medium, IGFBP-3 is the most abundant. Intact IGFBP-3, as assessed by 125I-labeled IGF-II ligand blot analysis, is more abundant in culture media of cells exposed to growth hormone (GH) or to parathyroid hormone (PTH), both at 5 x 10(-9) mol/l, for 24 h. At the same time, concentrations of IGF-I are increased in media of cells exposed to PTH but not to GH, compared with hormone-free control cultures. IGFBP-3 mRNA is increased in osteoblasts exposed to PTH or to GH but not in response to 5 x 10(-9) mol/l IGF-I. PTH exerts a rapid (within 2 h) stimulatory effect on IGF-I and IGFBP-3 production, both at the message and peptide levels, whereas GH increases only IGFBP-3, both at the message and peptide levels (after 24 h). We conclude that IGF-I does not mediate increased IGFBP-3 production by rat osteoblasts in response to GH and PTH.

Animals↗