Growth Hormone Regulation of Somatomedin C/Insulin-Like Growth Factor I Production and DNA Replication in Fetal Rat Islets in Tissue Culture

Swenne, Ingemar; Hill, David J.; Strain, Alastair J.; Milner, R. D. G.

doi:10.2337/diab.36.3.288

Cited by 100 publications

(60 citation statements)

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“…Similarly, addition of IGF-1 or -2 to the GK isolated islets significantly increased the ␤-cell replication. These effects were obtained with a submaximal IGF-2 concentration and a maximal IGF-1 concentration based in our circulating-levels evaluation and in vitro data, respectively (19,30). Therefore, we can conclude that IGF responsiveness by fetal GK islets is maintained but cannot eliminate the possibility that the sensitivity of the islet to these factors could be altered.…”

Section: Discussionmentioning

confidence: 85%

Fetal Insulin-Like Growth Factor-2 Production Is Impaired in the GK Rat Model of Type 2 Diabetes

Serradas

Goya²,

Lacorne

et al. 2002

Diabetes

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At late fetal age (21.5 days postcoitum [dpc]), GK rats present a severely reduced ␤-cell mass compared with Wistar rats. This anomaly largely antedates the onset of hyperglycemia in GK rats. Thus, the ␤-cell mass deficit could represent the primary defect leading to type 2 diabetes in the adult. The aim of this work was to investigate, in GK fetuses at the end of fetal age (21.5 dpc), whether impaired availability of growth factors such as insulin, growth hormone, and IGFs and their IGF binding proteins (IGFBPs) could be instrumental in this anomaly. Although it confirms that GK fetuses are hypoinsulinemic despite enhanced plasma glucose level due to maternal hyperglycemia, the present study shows for the first time that IGF-2 expression in the liver and pancreas and IGF-2 serum levels are decreased in GK fetuses. Serum level as well as liver and pancreatic mRNA expression of IGFBP-2 were found to be normal in GK fetuses, whereas serum level and liver mRNA expression of IGFBP-1 were increased. Finally, we found that the maximal ␤-cell mitogenic response to IGFs in vitro is kept intact, therefore suggesting that the direct biological action of IGFs on fetal GK ␤-cells is not grossly impaired. In conclusion, in GK fetuses at 21.5 dpc, the defective IGF-2 production appears to be an early landmark in the pathological sequence leading to retardation of ␤-cell growth in the fetal GK rat.

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Section: Discussionmentioning

confidence: 85%

Fetal Insulin-Like Growth Factor-2 Production Is Impaired in the GK Rat Model of Type 2 Diabetes

Serradas

Goya²,

Lacorne

et al. 2002

Diabetes

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“…Exogenous GH has been shown to restore embryonic growth in rats after transplantation of parts of embryos into hypophysectomized hosts (2). A number of fetal tissues has been shown to respond to GH in vitro (3)(4)(5)(6). GH receptor transcripts have been demonstrated in day 12 rat embryos and placentae (7), day 51 sheep embryos (8), and mouse placenta (9).…”

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confidence: 99%

Functional growth hormone (GH) receptors and GH are expressed by preimplantation mouse embryos: A role for GH in early embryogenesis?

Pantaleon

Whiteside

Harvey

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

104

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The results of this study challenge the widely held view that growth hormone (GH) acts only during the postnatal period. RNA phenotyping shows transcripts for the GH receptor and GH-binding protein in mouse preimplantation embryos of all stages from fertilized eggs (day 1) to blastocysts (day 4). An antibody specific to the cytoplasmic region of the GH receptor revealed receptor protein expression, first in two-cell embryos, the stage of activation of the embryonic genome (day 2), and in all subsequent stages. In cleavage-stage embryos this immunoreactivity was localized mainly to the nucleus, but clear evidence of membrane labeling was apparent in blastocysts. GH receptor immunoreactivity was also observed in cumulus cells associated with unfertilized oocytes but not in the unfertilized oocytes. The blastocyst receptor was demonstrated to be functional, exhibiting the classic bell-shaped dose-response curves for GH stimulation of both 3-O-methyl glucose transport and protein synthesis. Maximal stimulation of 40-50% was seen for both responses at less than 1 ng͞ml recombinant GH, suggesting a role for maternal GH. However mRNA transcripts for GH were also detected from the morula stage (day 3) by using reverse transcription-PCR, and GH immunoreactivity was seen in blastocysts. These observations raise the possibility of a paracrine͞autocrine GH loop regulating embryonic development in its earliest stages.Embryonic and fetal growth have long been considered to be independent of pituitary growth hormone (GH). However, this view is challenged by a growing body of evidence which demonstrates a role for GH in the development of the fetus. Newborn Laron dwarfs, lacking a functional GH receptor, are more than 2 SD shorter than normal (1). Exogenous GH has been shown to restore embryonic growth in rats after transplantation of parts of embryos into hypophysectomized hosts (2). A number of fetal tissues has been shown to respond to GH in vitro (3-6). GH receptor transcripts have been demonstrated in day 12 rat embryos and placentae (7), day 51 sheep embryos (8), and mouse placenta (9). Immunoreactive GH receptor was observed in the human fetus from the second trimester (10, 11). Recently GH receptor transcripts and immunoreactivity have been demonstrated in germ-line competent mouse embryonic stem cells, and GH receptor transcripts were also demonstrated in mouse blastocysts (12).Preimplantation stages earlier than the blastocyst, however, were not examined by Ohlsson et al. (12). Furthermore, there was no evidence that these very early embryos were capable of receptor synthesis or of signal transduction after ligand binding to expressed receptor. In this study we demonstrate the presence of GH receptors in the early embryo from fertilization to the blastocyst stage and the ability of GH to influence the metabolism of blastocyst. Moreover, we report the expression of GH by preimplantation blastocysts, raising the possibility of paracrine͞autocrine regulation of embryonic growth by GH. MATERIALS AND METHODSGene Ex...

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“…It has been previously suggested that GH mediates increases in -cell proliferation via local IGF-I production (Swenne et al 1987). However, this is now considered unlikely, as GH predominantly induces -cell proliferation via a JAK2/STAT5 signal transduction pathway (Argetsinger & Carter-Su 1996, Sekine et al 1998, Cousin et al 1999.…”

Section: Glucose-dependent Gh-induced Mitogenesis In -Cellsmentioning

confidence: 99%

IGF-I and GH post-receptor signaling mechanisms for pancreatic beta-cell replication

Rhodes

2000

Journal of Molecular Endocrinology

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Certain nutrients, pharmacological agents and growth factors can stimulate pancreatic -cell proliferation; however, mitogenic signal transduction pathways in -cells have not been particularly well characterized. As a model system we have focussed on characterizing the signal transduction pathways immediately downstream of the IGF-I and GH receptors in -cells. The original idea was to gain an idea of important elements in mitogenic signaling pathways which might then be exploited to generate a marked increase in -cell proliferation. Such an approach could eventually reveal a means to increase the number of human pancreatic endocrine cells in vitro, in order to obtain an abundant source of -cells for routine transplantation therapy of type-I diabetes. However, in the course of our studies, we have also unveiled an unexpected insight into the pathogenesis of obesitylinked type-II diabetes. It has been observed that free fatty acids inhibit glucose-and glucosedependent IGF-I/GH-induced -cell proliferation. We hypothesize that a gradual accumulation of intracellular fat in -cells during obesity can eventually lead to an inhibition of -cell mass expansion and hence failure to compensate for peripheral insulin resistance, so that type-II diabetes ensues.

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Growth Hormone Regulation of Somatomedin C/Insulin-Like Growth Factor I Production and DNA Replication in Fetal Rat Islets in Tissue Culture

Cited by 100 publications

References 0 publications

Fetal Insulin-Like Growth Factor-2 Production Is Impaired in the GK Rat Model of Type 2 Diabetes

Fetal Insulin-Like Growth Factor-2 Production Is Impaired in the GK Rat Model of Type 2 Diabetes

Functional growth hormone (GH) receptors and GH are expressed by preimplantation mouse embryos: A role for GH in early embryogenesis?

IGF-I and GH post-receptor signaling mechanisms for pancreatic beta-cell replication

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