Pituitary cotransplantation significantly improves the performance, insulin content, and vascularization of renal subcapsular islet grafts.

Davalli, Alberto M.; Scaglia, L.; Brevi, Marco; Sanvito, Francesca; Freschi, Massimo; Cavallaro, Ugo; Parlow, Albert F.; Pontiroli, Antonio E.

doi:10.2337/diabetes.48.1.59

Cited by 5 publications

(3 citation statements)

References 37 publications

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“…Preconditioning islets with protein kinase Ce (PKCe) activator improves islet graft function (46). Cotransplanting pituitary cells or bone marrow cells with islets also significantly improves the performance of islet grafts (47,48). It has been reported that administration of GH increases proliferation of β cells in transplanted islets (49).…”

Section: Discussionmentioning

confidence: 99%

Beneficial effects of growth hormone-releasing hormone agonists on rat INS-1 cells and on streptozotocin-induced NOD/SCID mice

Zhang

Cui

et al. 2015

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

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Agonists of growth hormone-releasing hormone (GHRH) have been previously reported to promote growth, function, and engraftment of islet cells following transplantation. Here we evaluated recently synthesized GHRH agonists on the proliferation and biological functions of rat pancreatic β-cell line (INS-1) and islets. In vitro treatment of INS-1 cells with GHRH agonists increased cell proliferation, the expression of cellular insulin, insulin-like growth factor-1 (IGF1), and GHRH receptor, and also stimulated insulin secretion in response to glucose challenge. Exposure of INS-1 cells to GHRH agonists, MR-356 and MR-409, induced activation of ERK and AKT pathways. Agonist MR-409 also significantly increased the levels of cellular cAMP and the phosphorylation of cAMP response element binding protein (CREB) in INS-1 cells. Treatment of rat islets with agonist, MR-409 significantly increased cell proliferation, islet size, and the expression of insulin. In vivo daily s.c. administration of 10 μg MR-409 for 3 wk dramatically reduced the severity of streptozotocin (STZ)-induced diabetes in nonobese diabetic severe combined immunodeficiency (NOD/SCID) mice. The maximal therapeutic benefits with respect to the efficiency of engraftment, ability to reach normoglycemia, gain in body weight, response to high glucose challenge, and induction of higher levels of serum insulin and IGF1 were observed when diabetic mice were transplanted with rat islets preconditioned with GHRH agonist, MR-409, and received additional treatment with MR-409 posttransplantation. This study provides an improved approach to the therapeutic use of GHRH agonists in the treatment of diabetes mellitus.GHRH agonists | diabetes | INS-1 | signaling pathways | transplantation

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Section: Discussionmentioning

confidence: 99%

Beneficial effects of growth hormone-releasing hormone agonists on rat INS-1 cells and on streptozotocin-induced NOD/SCID mice

Zhang

Cui

et al. 2015

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

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“…For example, GH treatment does not affect GH release in rat pituitary cells (16) and enriched rat somatotrophs (17). Pituitary transplanted under the renal capsule has been used as a model to study GH release in the absence of hypothalamic influences (18) and has been recently adopted as a means to prolong the survival of cotransplanted islets for diabetic therapy (19). In these in vivo studies, a normal range of GH levels in blood can be detected after grafting of pituitary fragments into the renal capsule.…”

mentioning

confidence: 99%

Novel Aspects of Growth Hormone (GH) Autoregulation: GH-Induced GH Gene Expression in Grass Carp Pituitary Cells through Autocrine/Paracrine Mechanisms

Zhou

et al. 2004

Endocrinology

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GH feedback on its own secretion at the pituitary level has been previously reported, but the mechanisms involved have not been elucidated. Here we examined the autocrine/paracrine effects of GH on GH synthesis using grass carp pituitary cells as a cell model. GH receptors were identified in carp somatotrophs, and their activation by exogenous GH increased steady-state GH mRNA levels and GH production. Removal of endogenous GH by immunoneutralization using GH antiserum inhibited basal as well as stimulated GH mRNA expression induced by GH-releasing factors in fish, including GnRH, apomorphine, and pituitary adenylate cyclase-activating polypeptide-38. Cytosolic mature GH mRNA levels were elevated by GH treatment and reduced by GH antiserum, whereas nuclear GH primary transcripts were almost undetectable after GH immunoneutralization. Inhibition of Janus kinase-2 (JAK2), phosphoinositide 3-kinase, and MAPK also abolished GH-induced steady-state GH mRNA expression. GH immunoneutralization in pituitary cells pretreated with actinomycin D induced a marked decrease in the half-life of GH mRNA, indicating that the clearance of GH transcripts could be enhanced by removing endogenous GH. These results provide evidence that GH can serve as a novel intrapituitary autocrine/paracrine factor maintaining GH gene expression in somatotrophs, and this action is mediated by JAK2/MAPK and JAK2/phosphoinositide 3-kinase cascades coupled to GH receptors.

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“…At the time of sacrifice grafts were retrieved and RNA was extracted for the analysis of proinsulin trans gene expression by Northern blotting analysis. Naive pancreases were also harvested and immunostained for insulin as previously described (9) in order to detect re sidual P cells. Finally, blood samples were collected for the measurement of circulating mature human insulin levels.…”

Section: Transplantation Experimentsmentioning

confidence: 99%

Insulin-Secreting Pituitary GH3 Cells: A Potential β-Cell Surrogate for Diabetes Cell Therapy

et al. 2000

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In a companion article, we describe the engineering and characterization of pituitary GH3 cell clones stably transfected with a furin-cleavable human insulin cDNA (InsGH3 cells). This article describes the performance of InsGH3 (clones 1 and 7) cell grafts into streptozotocin (STZ)-induced diabetic nude mice. Subcutaneous implantation of 2 x 10(6) InsGH3 cells resulted in the progressive reversal of hyperglycemia and diabetic symptoms, even though the progressive growth of the transplanted cells (clone 7) eventually led to glycemic levels below the normal mouse range. Proinsulin transgene expression was maintained in harvested InsGH3 grafts that, conversely, lose the expression of the prolactin (PRL) gene. Elevated concentrations of circulating mature human insulin were detected in graft recipients, demonstrating that proinsulin processing by InsGH3 cells did occur in vivo. Histologic analysis showed that transplanted InsGH3 grew in forms of encapsulated tumors composed of cells with small cytoplasms weakly stained for the presence of insulin. Conversely, intense insulin immunoreactivity was detected in graft-draining venules. Compared to pancreatic betaTC3 cells, InsGH3 cells showed in vitro a higher rate of replication, an elevate resistance to apoptosis induced by serum deprivation and proinflammatory cytokines, and significantly higher antiapoptotic Bcl-2 protein levels. Moreover, InsGH3 cells were resistant to the streptozotocin toxicity that, in contrast, reduced betaTC3 cell viability to 50-60% of controls. In conclusion, proinsulin gene expression and mature insulin secretion persisted in transplanted InsGH3 cells that reversed hyperglycemia in vivo. InsGH3 cells might represent a potential beta-cell surrogate because they are more resistant than pancreatic beta cells to different apoptotic insults and might therefore be particularly suitable for encapsulation.

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Pituitary cotransplantation significantly improves the performance, insulin content, and vascularization of renal subcapsular islet grafts.

Cited by 5 publications

References 37 publications

Beneficial effects of growth hormone-releasing hormone agonists on rat INS-1 cells and on streptozotocin-induced NOD/SCID mice

Beneficial effects of growth hormone-releasing hormone agonists on rat INS-1 cells and on streptozotocin-induced NOD/SCID mice

Novel Aspects of Growth Hormone (GH) Autoregulation: GH-Induced GH Gene Expression in Grass Carp Pituitary Cells through Autocrine/Paracrine Mechanisms

Insulin-Secreting Pituitary GH3 Cells: A Potential β-Cell Surrogate for Diabetes Cell Therapy

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