Growth Hormone is a Growth Factor for the Differentiated Pancreatic β-Cell

Nielsen, Jens Høiriis; Linde, Susanne; Welinder, Benny S.; Billestrup, Nils; Madsen, Ole

doi:10.1210/mend-3-1-165

Cited by 120 publications

(73 citation statements)

References 27 publications

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“…The limited activity of growth hormone, compared with the larger effect of PRL, is in agreement with results obtained with homologous hormones [3]. Although the heterologous human growth hormone can stimulate rat islet cell replication [16], most likely through the PRL receptor, it has only a modest effect on mouse islet cells [17]. The relatively lower mitogenic effect of IGF I in this assay, as compared with that of IGF II, is inconsistent with previous results that showed similar effects of both factors on fetal rat islets [7], and with the action of both factors through the IGF I receptor.…”

supporting

confidence: 87%

Growth Factor‐Dependent Proliferation of the Pancreatic β‐cell Line βTC‐tet: An Assay for β‐cell Mitogenic Factors

Milo-Landesman

Efrat

2001

Journal of Diabetes Research

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The ability to expand normal pancreatic islet β cells in culture would significantly advance the prospects of cell therapy for diabetes. A number of growth factors can stimulate limited islet cell replication, however other factors may exist which are more effective β-cell-specific mitogens. The search for novel β-cell growth factors has been hampered by the lack of a β-cell-specific proliferation assay. We developed a simple and sensitive assay for β-cell growth factors based on a conditionally-transformed mouse β-cell line (βTC-tet). These cells express the SV40 T antigen (Tag) oncoprotein under control of the tetracycline (Tc) operon regulatory system. In the presence of Tc, Tag expression is tightly shut off and the cells undergo complete growth arrest. Here we show that the growth-arrested cells can proliferate in response to growth factors in the absence of Tag. Using this assay, a number of growth factors previously shown to be mitogenic to a mixed islet cell population were found to induce proliferation of pure β cells. We conclude that growth-arrested βTC-tet cells can be employed in a survey of factors from various sources for identifying novel factors with β-cell mitogenic activity.Key words: β-cell lines, cell proliferation, growth factors, mitogenicity, tetracycline-regulated gene expression INTRODUCTIONBeta-cell transplantation represents an attractive approach for replacement of the ____________________ *Corresponding author: tel: 972-3-640 7701; fax. 972-3-640 9950; e-mail: sefrat@post.tau.ac.il Int. Jnl. Experimental Diab. Res., 3:69-74, 2002 © 2002 Taylor and Francis 1560 damaged β cells in type I diabetes. One major obstacle to β-cell therapy is the lack of an abundant cell supply. A number of rodent β-cell lines have been developed by oncogenic transformation, however this approach has proven difficult to adapt to human β cells. Development of efficient ways for in vitro expansion of normal islets would significantly advance the prospects of diabetes cell therapy. Adult islet cells are difficult to propagate in culture, although they maintain a proliferative capacity, as evidenced by a limited mitogenic response to a number of growth factors [1,2]. Members of the growth hormone family, in particular placental lactogen (PL) and prolactin (PRL), induce replication in neonatal rat islet cells [3]. These activities may be responsible for islet mass expansion in pregnancy. Significant mitogenic effects of hepatocyte growth factor (HGF) have been observed on human fetal and adult islets [4] and mouse islets [5]. Insulin-like growth factors (IGF) I and II, and platelet-derived growth factor, affect fetal rat islet cell growth [6,7]. IGF I has also been shown to stimulate replication of cultured rat insulinoma cells [8], and IGF II activates the growth of both normal [9] and transformed [10] mouse β cells in vivo. The Reg protein, produced by pancreatic acinar cells and regenerating islets, is another candidate for a β-cell growth factor [11]. These findings suggest that islet cells possess cell su...

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supporting

confidence: 87%

Growth Factor‐Dependent Proliferation of the Pancreatic β‐cell Line βTC‐tet: An Assay for β‐cell Mitogenic Factors

Milo-Landesman

Efrat

2001

Journal of Diabetes Research

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“…For example, GH increases beta cell proliferation in vitro [9] and protects beta cell lines against IL-1β-, IFN-γ-and TNF-α-induced apoptotic cell death [10]. Increased IGF-1 signalling is thought to play a role in the increase in beta cell mass seen with exercise in 90% pancreatectomised (Px) rats [11,12].…”

Section: Search Strategymentioning

confidence: 99%

The time has come to test the beta cell preserving effects of exercise in patients with new onset type 1 diabetes

et al. 2014

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Type 1 diabetes is characterised by immunemediated destruction of insulin-producing beta cells. Significant beta cell function is usually present at the time of diagnosis with type 1 diabetes, and preservation of this function has important clinical benefits. The last 30 years have seen a number of largely unsuccessful trials for beta cell preservation, some of which have been of therapies that have potential for significant harm. There is a need to explore new, more tolerable approaches to preserving beta cell function that can be implemented on a large clinical scale. Here we review the evidence for physical exercise as a therapy for the preservation of beta cell function in patients with newly diagnosed type 1 diabetes. We highlight possible mechanisms by which exercise could preserve beta cell function and then present evidence from other models of diabetes that demonstrate that exercise preserves beta cell function. We conclude by proposing that there is now a need for studies to explore whether exercise can preserve beta cell in patients newly diagnosed with type 1 diabetes.

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“…One of the target tissues of PRL is the endocrine pancreas where PRL and the related hormones growth hormone (GH) and placental lactogen have been found to be potent growth factors for the pancreatic ␤-cell and to enhance insulin production and glucose sensitivity of these cells (2)(3)(4)(5)(6). The stimulatory effects of PRL, GH, and placental lactogen are thought to play an important role in the adaptive growth and function of the ␤-cells during conditions of increased insulin demands.…”

Section: Prolactin (Prl)mentioning

confidence: 99%

Regulation of Prolactin Receptor (PRLR) Gene Expression in Insulin-producing Cells

Galsgaard¹,

Nielsen²,

Møldrup³

1999

Journal of Biological Chemistry

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Expression of the prolactin receptor (PRLR) gene is increased in pancreatic islets during pregnancy and in vitro in insulin-producing cells by growth hormone (GH) and prolactin (PRL). The 5-region of the rat PRLR gene contains at least three alternative first exons that are expressed tissue-specifically because of differential promoter usage. We show by reverse transcription-polymerase chain reaction analysis that both exon 1A-and exon 1C-containing PRLR transcripts are expressed in rat islets and that human (h)GH, ovine (o)PRL, and bovine (b)GH increase exon 1A expression 6.5 ؎ 0.8-fold, 6.8 ؎ 0.7-fold, and 3.9 ؎ 0.7-fold and exon 1C expression 4.8 ؎ 0.4-fold, 4.4 ؎ 0.6-fold, and 2.5 ؎ 0.7-fold, respectively. Expression of exon 1B was not detectable. The transcriptional activities of reporter constructs containing the 1A, 1B, or 1C promoter were found to be 22.8-fold, 2.7-fold, and 8.0-fold, respectively, above that of a promoterless reporter construct when transfected into the insulin-producing INS-1 cells. The transcriptional activity of the 1A promoter construct was increased 8.9 ؎ 1.9-fold by 0.5 g/ml hGH. Responsiveness to hGH of the 1A promoter was localized to the region from ؊225 to ؉81 with respect to the transcription start site. This region contains the sequence TTCTAGGAA that by gel retardation experiments was shown to bind the transcription factors STAT5a and STAT5b in response to stimulation by hGH, oPRL, or bGH. Mutation of this ␥-activated sequence-like element completely abolished transcriptional induction of the 1A promoter by hGH. Our results suggest that GH and PRL increase the levels of exon 1A-and 1C-containing PRLR mRNA species and furthermore that the transcriptional activity of the 1A promoter is increased via activation of STAT5a and STAT5b.

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Growth Hormone is a Growth Factor for the Differentiated Pancreatic β-Cell

Cited by 120 publications

References 27 publications

Growth Factor‐Dependent Proliferation of the Pancreatic β‐cell Line βTC‐tet: An Assay for β‐cell Mitogenic Factors

Growth Factor‐Dependent Proliferation of the Pancreatic β‐cell Line βTC‐tet: An Assay for β‐cell Mitogenic Factors

The time has come to test the beta cell preserving effects of exercise in patients with new onset type 1 diabetes

Regulation of Prolactin Receptor (PRLR) Gene Expression in Insulin-producing Cells

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