Search PubMed⌕ Search

Biomedical subjects

G Norstedt

Publications and source records attributed to G Norstedt.

At least 91 records · Page 5Linked to original sources
PubMed1988

Insulin-like growth factor I in the pancreas of normal and diabetic adult rats.

Insulin-like growth factor I (IGF-I, somatomedin C) was mapped by immunocytochemistry in the pancreas of normal and experimentally influenced rats. The polyclonal IGF-I antiserum K 37 was characterized and demonstrated to be specific. In the exocrine pancreas some duct cells showed IGF-I immunoreactivity, other components being negative. The three main endocrine cell types in the islets of Langerhans were IGF-I immunoreactive, most strikingly the D cells. Hypophysectomy resulted in loss of IGF-I immunoreactivity in all three endocrine cell types, i.e. D, A and B cells, while the levels of somatostatin, glucagon and insulin, respectively, remained unchanged. Starvation seemed to increase and feeding to decrease the IGF-I immunoreactivity in the B cells. Cysteamine pre-treatment reduced the normally intense IGF-I and somatostatin immunoreactivities in the D cells. In rats made diabetic with alloxan or streptozotocin, the B cells were irreversibly damaged and lost both their insulin and IGF-I immunoreactivities, while the IGF-I immunoreactivity was increased in A cells; the D cells remained unchanged. The concentrations of IGF-I mRNA in the pancreas were almost equal in normal and alloxan diabetic rats as were the concentrations of extractable IGF-I. We conclude that IGF-I immunoreactive material can be demonstrated in adult animals in all endocrine islet cells, most prominently in the D cells. The expression of IGF-I immunoreactivity is in part under pituitary control. In the adult rat only one islet cell type synthesizes IGF-I immunoreactive material, i.e. the D cells, while, in contrast, the B cells are likely to be a major IGF-I source in fetal and neonatal islets.

Animals↗
PubMed1988

Regulation of insulin-like growth factor messenger ribonucleic acid in rat growth plate by growth hormone.

The mechanism of action for the stimulatory effect of GH on longitudinal bone growth is not yet clarified. Several recent reports indicate that GH has a direct effect at the site of the epiphyseal growth plate, as opposed to the somatomedin hypothesis which holds that the effect of GH is mediated by circulating insulin-like growth factors (IGFs). Using a RNA probe in a solution hybridization assay we investigated the presence of IGF-I mRNA in rat rib growth plate. Hypophysectomy resulted in a decrease in the number of IGF-I mRNA copies compared to that in normal rats. Replacement treatment with GH restored the number of transcripts in a specific and dose-dependent manner. The results show that GH regulates the level of IGF-I mRNA in rat rib growth plate and give further support to the hypothesis that locally produced IGF-I might contribute to the stimulatory effect of GH on longitudinal bone growth.

Actins↗
PubMed1988

Human calpactin II (lipocortin I) messenger ribonucleic acid is not induced by glucocorticoids.

Studies were carried out to examine the effect of glucocorticoids on human calpactin II (lipocortin I) mRNA expression. A cRNA probe for human calpactin II (hCPII) was used in a solution hybridization assay to study the effect of dexamethasone on hCPII mRNA levels in human skin fibroblasts, peripheral lymphocytes, pulmonary alveolar macrophages, and HeLa S3 cells. As a positive control, human metallothionein II (hMTII) mRNA levels were measured since hMTII is known to be regulated by glucocorticoids and heavy metals, both of which induce transcriptional activity of the gene. Dexamethasone treatment of these human cell types caused a dose-dependent increase in hMTII mRNA levels, whereas no effect on hCPII mRNA levels was observed. These findings were confirmed in time course studies, where 10(-6) M dexamethasone treatment caused a maximal 2- to 5-fold increase in hMTII mRNA levels after 6-8 h of treatment but no increase in hCPII mRNA levels was observed at any time point up to 24 h. A human glucocorticoid sensitive lymphoid cell line, CEM C7, and a glucocorticoid resistant mutant, ICR-27, isolated from CEM C7, were included in order to confirm the requirement of a functional glucocorticoid receptor (GR) in the induction of glucocorticoid-regulated genes. Dexamethasone (10(-6) M) induced hMTII but not hCPII mRNA in CEM C7 cells, whereas neither hMTII nor hCPII mRNA was induced in ICR-27 cells. In conclusion, our data suggest that glucocorticoids do not induce calpactin II (lipocortin I) mRNA in the human cell types studied.

Annexins↗
PubMed1988

Cellular distribution of somatogenic receptors and insulin-like growth factor-I mRNA in the rat liver.

Parenchymal and non-parenchymal cell fractions isolated from rat liver were analysed for the distribution of somatogenic receptors and for insulin-like growth factor-I (IGF-I) mRNA. The effect of hypophysectomy either alone or in combination with a single injection of human GH (hGH) on the levels of IGF-I mRNA was also studied in the two cell fractions. The contamination of parenchymal cells in the non-parenchymal cell fraction was in the range of 2-3%. Somatogenic receptors were found only in the parenchymal cell fraction. IGF-I mRNA was detected in both cell fractions, although the level of this mRNA was about fivefold higher in parenchymal cells. When RNA was studied by Northern gel analysis no major differences were observed in the size distribution of IGF-I transcripts in the two cell fractions. In hypophysectomized animals, the IGF-I mRNA level was decreased to 10 and 30% of control values in the parenchymal and non-parenchymal cell fractions respectively. Treatment of hypophysectomized animals with a single dose of hGH restored IGF-I mRNA in parenchymal and in non-parenchymal cells to the extent found in intact animals. In conclusion, our data indicate that somatogenic receptors are exclusively, and IGF-I mRNA predominantly, expressed in liver parenchymal cells compared with a total non-parenchymal cell fraction. The most marked effect of GH, correlating with the presence of somatogenic receptors, was seen in the parenchymal cells. The minor non-GH dependent expression of IGF-I mRNA suggests that this peptide may elicit effects in addition to the well-established GH-dependent activity.

Animals↗
PubMed1987

Induction of prolactin receptors in the liver is more closely related to the growth-promoting than to the lactogenic potency of peptides.

The sex differentiated binding 125I-human prolactin (PRL) to rat liver membranes was studied and the present results extend our previous studies on induction of hepatic PRL receptors by growth hormone (GH). In prepubertal female rats, PRL receptor levels are low compared with those in mature female rat livers. Infusion of hGH during one week to 17-day-old female rats resulted in a receptor level typical of adult female rats. The time course of receptor disappearance in male rats treated with hGH was also studied. When the receptor-inducing hormone was removed, receptor levels in hGH-treated male rats returned to the normal level characteristic of male rats after approximately 96 h. The specificity of various GH-like and PRL-like hormones in PRL receptor induction was studied in hypophysectomized rats. The PRL-like hormones were identified by measuring their potency to displace 125I-hPRL from a receptor preparation obtained from female rat livers, and the GH-like hormones were identified by their potency to increase body weight in hypophysectomized rats. Using similar doses of hormones it was found that in vivo administration of growth-promoting peptides (rGH, hGH, bGH) induced PRL receptors, whereas lactogenic hormones (rPRL, hPL) had a very small or no effect on PRL receptor induction. This suggests that binding to a type of GH receptor is the first step in PRL receptor induction.

Animals↗
PubMed1987

Growth hormone induction of insulin-like growth factor I messenger RNA in primary cultures of rat liver cells.

Primary liver cells from adult rats were used to study the hormonal regulation of mRNA coding for insulin-like growth factor I (IGF-I). IGF-I mRNA could be detected at a low concentration in liver cells prepared from hypophysectomized rats and cultivated for 3 days. When these cells were exposed to GH on the second day, a dose-dependent increase in IGF-I mRNA was observed. The continuous presence of serum was not a prerequisite for this response, since GH also induced IGF-I mRNA in a defined hormone-supplemented medium. It is concluded that GH can induced IGF-I mRNA in the liver by a direct mechanism.

Animals↗
PubMed1986

Regulation of insulin-like growth factor I gene expression by growth hormone.

Recombinant clones containing exon 3 of the insulin-like growth factor I (IGF-I) gene were isolated from a mouse genomic library. These sequences were used to generate an RNA probe, which was used in a solution hybridization assay to quantitate IGF-I mRNA in various murine tissues as a function of growth hormone status. The liver is the major site of IGF-I synthesis and the level of IGF-I mRNA is regulated about 10-fold by growth hormone in the growth hormone-deficient lit/lit mouse. Nuclear run-on assays were used to show that growth hormone regulation is manifested in part at the transcriptional level. Growth hormone also affects the size distribution of hepatic IGF-I mRNAs. Pancreas showed the highest non-hepatic expression, but every tissue analyzed contained some IGF-I mRNA. Expression was not growth hormone-dependent in most non-hepatic tissues.

Animals↗
PubMed1986

Effect of anterior hypothalamic deafferentation and continuous growth hormone infusion on the hepatic synthesis of alpha 2u-globulin in the male rat.

Anterior hypothalamic deafferentation and infusion of human GH (hGH) in the normal male rat caused a marked reduction in the hepatic concentration of alpha 2u-globulin, an androgen-dependent protein. Although s.c. injections of hGH (twice-daily) resulted in more than a 50% reduction in the hepatic level of alpha 2u-globulin, the same dose of hGH when administered continuously through osmotic minipumps caused a threefold greater inhibition. The decreased hepatic concentration of alpha 2u-globulin after hGH administration was associated with corresponding changes in the hepatic level of translatable alpha 2u-globulin messenger RNA. Continuous infusion of hGH through osmotic minipumps and removal of the anterior hypothalamic influence on GH secretion by deafferentation also caused a marked reduction in the cytoplasmic androgen-binding activity of the rat liver. These results suggest that alterations in the level and pattern of GH secretion may influence hepatic androgen-binding activity and alpha 2u-globulin synthesis.

Afferent Pathways↗
PubMed1985

The mode of growth hormone administration is of major importance for the excretion of the major male rat urinary proteins.

Male and female urinary proteins were analysed using chromatofocusing. Male rat urine had a higher protein content (measured as UV absorbance), particularly in the pI range 5.0-5.5, where female rat urine seemed to lack UV-absorbing material. The molecular weight of the major male rat urinary protein(s) is approximately 16 000 according to sodium dodecylsulphate (SDS)-polyacrylamide gel electrophoresis. The regulation of the major male rat urinary protein(s) (pI 5.3; MRUP) was studied in normal male rats and hypophysectomized rats treated for 1 week with various hormones. Urine was collected during the last day of hormone treatment and analysed by chromatofocusing and SDS-polyacrylamide gel electrophoresis. It was found that estrogen treatment of male rats suppressed the appearance of MRUP. This 'feminizing' effect was also observed following continuous infusion for 1 week of human growth hormone (hGH) or rat growth hormone (rGH) in male rats. Single injections of hGH, however, given once daily for 1 week and supplemented with glucocorticoid, thyroid hormone and androgen had an opposite effect and induced MRUP in hypophysectomized male rats. It is concluded that the mode of administration of GH is of great importance for the effects of the hormone and that continuous, as compared to intermittent, administration of GH may result in suppression or induction, respectively, of major male rat urinary protein(s).

Animals↗
PubMed1985

Characterization and subcellular distribution of somatogenic receptor in rat liver.

Binding of [125I]iodobovine GH [( 125I]iodo-bGH) to rat liver microsomes and Golgi/endosomal fractions isolated from male and female rats has been characterized. Binding of bGH to a pure somatogenic site was suggested by the finding that 50% inhibition of [125I]iodo-bGH binding required 5-130 ng bGH, rGH, or hGH/incubation, while around 500 ng rat PRL/incubation were needed to obtain the same effect. Binding of [125I]iodo-bGH to microsomes and Golgi/endosomes was time, temperature, and protein dependent. Maximal specific binding occurred at 15-16 and 15-20 h at 22 C in Golgi and microsomal membranes, respectively. Subcellular distribution studies demonstrated in the Golgi/endosomal fractions compared to the total particulate fraction, while residual microsomes devoid of Golgi/endosomal-derived components were approximately 2-fold enriched. Low levels of somatogenic receptors were detected in lysosome-enriched fractions. Removal of endogenous ligand by treating Golgi/endosomal membranes with 3 M MgCl2 increased specific binding of bGH about 2- to 3-fold. These results indicate that approximately 50% of specific somatogenic binding sites in the low density fractions represent internalized ligand-receptor complexes. The level of rat liver somatogenic receptors did not show a pronounced sex differentiation; however, an endocrine dependence of somatogenic receptor levels is suggested by the finding that livers from rats in the late stages of pregnancy had a level of somatogenic receptors exceeding that of nonpregnant rats.

Animals↗
PubMed1984

Secretory rhythm of growth hormone regulates sexual differentiation of mouse liver.

The secretory pattern of growth hormone (GH) differs between the sexes; in males it is more pulsatile than in females. Experiments were performed to test the hypothesis that differences in the secretory rhythm of GH are responsible for sex-dependent liver functions of mice. Continuous delivery of GH was achieved either by introducing metallothionein-GH fusion genes into the germ line or by implanting minipumps. Pulsatile delivery of GH was mimicked by injection. The effects of these treatments on production of hepatic prolactin/GH receptors, albumin, and major urinary protein (MUP) were monitored. The results suggest that induction of MUP mRNA requires pulsatile occupancy of GH receptors, which is achieved naturally in males or by injection of GH, whereas chronic occupancy of GH receptors is inhibitory. In contrast, induction of prolactin/GH receptors requires chronic stimulation of GH receptors, which is approximated in normal female mice or results from increased GH levels in mice with foreign genes or undergoing infusions from minipumps.

Animals↗
PubMed1984

Effect of growth hormone on prolactin receptors and on estrogen receptors in the liver of prepubertal rats.

The regulation of both the sex-differentiated prolactin (Prl) receptor and the non-sex-differentiated estrogen receptor in rat liver was studied. In prepubertal female rats both liver Prl and estrogen receptors were found at a lower concentration compared to the receptor level present in adult female rats. The effect of growth hormone (GH) treatment on Prl and estrogen receptor levels was investigated. In prepubertal female rats (17 and 22 days old), infusion of human GH using an infusion rate of 0.1 microgram/h per g body weight (BW) over a period of 6 days resulted in an increase in the number of Prl receptors to a level normally found in adult female rats. Human GH also induced Prl receptors in prepubertal male rats to an adult female level. In contrast, the same infusion rate of human GH given to female rats at 17 and 22 days of age did not increase the level of estrogen receptor. Addition of the glucocorticoid dexamethasone, 2.8 ng/h per g BW, to the human GH infusion did not result in estrogen receptor induction. These findings indicate a differential response to human GH administration of Prl receptor and estrogen receptor induction in prepubertal rats. Thus, the so-called 'feminizing effect' of GH (induction of Prl receptors) can be achieved in prepubertal rats whereas a non-sex-differentiated effect of GH (induction of estrogen receptors) could not be evoked in prepubertal rats using the same dose of human GH.

Animals↗
PubMed1984

Regulation, linkage, and sequence of mouse metallothionein I and II genes.

The mouse metallothionein II (MT-II) gene is located approximately 6 kilobases upstream of the MT-I gene. A comparison of the sequences of mouse MT-I and MT-II genes (as well as those of other mammals) reveals that the coding regions are highly conserved even at "silent" positions but that the noncoding regions and introns are extremely divergent between primates and rodents. There are four blocks of conserved sequences in the promoters of mouse MT-I, mouse MT-II, and human MT-IIA genes; one includes the TATAAA sequence, and another has been implicated in regulation by heavy metals. Mouse MT-I and MT-II mRNAs are induced to approximately the same extent in vivo in response to cadmium, dexamethasone, or lipopolysaccharide. Mouse MT-I and MT-II genes are regulated by metals but not by glucocorticoids after transfection into HeLa cells.

Amino Acid Sequence↗
PubMed1984

Growth hormone induction of lactogenic receptors at intracellular sites in male rat liver.

Male and female rat livers were fractionated by density gradient centrifugation into Golgi I (mainly secretory vesicles), Golgi II (mainly cisternal elements), and lysosomes. Estimations of fraction purity and representativity were made by marker enzyme and electron microscopic analyses. The binding of [125I]iodo-human GH ( [125I]iodo-hGH) to different subcellular liver fractions were studied. In Golgi I and II the binding specificity was similar in both sexes and indicated that [125I] iodo-hGH binds to a lactogenic receptor. Scatchard analysis showed a larger number of binding sites in female Golgi I (5600 fmol/mg protein), Golgi II (3400 fmol/mg), and lysosomes (1300 fmol/mg) than in male Golgi I (240 fmol/mg), Golgi II (200 fmol/mg), and lysosomes (230 fmol/mg). The apparent dissociation constant was within a similar range (0.6-0.7 X 10(-9) M) in all fractions. Administration of hGH to male rats by continuous infusion (infusion rate, 5 micrograms/h) resulted, after 5 days of treatment, in an increase in the number of lactogenic binding sites in Golgi I and II to levels similar to the binding in the corresponding female Golgi fractions. When rat GH was given to hypophysectomized male rats (infusion rate, 10 micrograms/h) for 1 week, the binding of [125I]iodo-hGH in lysosomal and Golgi fractions was increased to a female level. The present results suggest that lactogenic receptors are located in the Golgi complex as well as the lysosomal compartment and that these receptors can be induced at these intracellular sites with both a somatotropic-lactogenic hormone (human GH) and a pure somatotropic hormone (rat GH).

Animals↗
PubMed1983

Metallothionein-human GH fusion genes stimulate growth of mice.

The promoter or regulatory region of the mouse gene for metallothionein-I was fused to the structural gene coding for human growth hormone. These fusion genes were introduced into mice by microinjection of fertilized eggs. Twenty-three (70 percent) of the mice that stably incorporated the fusion genes showed high concentrations of human growth hormone in their serum and grew significantly larger than control mice. Synthesis of human growth hormone was induced further by cadmium or zinc, which normally induce metallothionein gene expression. Transgenic mice that expressed human growth hormone also showed increased concentrations of insulin-like growth factor I in their serum. Histology of their pituitaries suggests dysfunction of the cells that normally synthesize growth hormone. The fusion genes were expressed in all tissues examined, but the ratio of human growth hormone messenger RNA to endogenous metallothionein-I messenger RNA varied among different tissues and different animals, suggesting that expression of the foreign genes is influenced by site of integration and tissue environment.

Animals↗
PubMed1983

Regulation of sexually dimorphic hepatic steroid metabolism by the somatostatin-growth hormone axis.

Lesions in the periventricular hypothalamic area in male rats results in a "feminization" of steroid metabolizing enzymes in the liver. These lesions also resulted in a decrease of somatostatin levels in the median eminence. Since blockade of somatostatin by in vivo administration of an antiserum also caused "feminization" of the liver, it is possible that at least one hypothalmic factor responsible for "feminization" is related to somatostatin. Also extrahypothalmic areas seem to influence sexually differentiated functions in the liver. The neuroendocrine control of the "feminizing factor" secretion from the pituitary bears several resemblances to the central control of GH. The hypothesis that the plasma pattern of GH regulates hepatic steroid metabolism in the rat was studied in two different animal models: (1) Different plasma patterns of GH were achieved by administration of human GH (hGH) at different frequencies or by infusing the hormone continuously by means of Alzet osmotic minipumps to hypophysectomized female rats. (2) The plasma pattern of GH in animals with an intact pituitary gland was investigated under conditions which lead to "feminization" of hepatic steroid metabolism. The results demonstrate that the plasma pattern of GH influences hepatic steroid metabolism. Increased trough plasma GH values or absence of time periods with undetectable plasma levels of GH appears to be a major determinant for "feminization" of hepatic steroid metabolism. Since sex steroids were found to influence the plasma pattern of GH it seems as if differences in the plasma pattern of GH between male and female rats explain the sex-differentiated hepatic steroid metabolism.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1983

Sex steroid induced changes in hepatic enzymes.

Sex differences exist in steroid and xenobiotic metabolism in the liver of a number of species. In the rat, the differences are regulated through the hypothalamo-pituitary axis. The previously postulated "feminizing factor" responsible for a female-type liver metabolism appears to be identical to growth hormone. The different effects of this peptide on hepatic metabolism in male and female rats may be related to the sexual dimorphism of the growth hormone secretory pattern; serum levels of growth hormone do not fluctuate as markedly in female as in male rats and may be simulated by administration of the hormone via osmotic minipumps, a procedure resulting in "feminization" of liver metabolism of male or hypophysectomized rats. This newly discovered system, the hypothalamo-pituitary-liver axis, represents a novel concept in endocrinology.

Androgens↗