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Endothelial cell signalling supports pancreatic beta cellfunction in the rat
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
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2009 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 52, no 11, 2385-2394 p.Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis The proximity of endothelial cells andbeta cells in islets by necessity means that they are exposedto each other’s products. Whereas islet endothelial cellsrequire signals from beta cells to function properly,endothelin-1, thrombospondin-1 and laminins, amongothers, have been identified as endothelial-derived molecules,although their full effects on beta cells have not beenexplored. We tested the hypothesis that islet endothelialderivedproducts affect beta cell function.Methods Endothelial cells from rat islets were proliferatedand purified. Endothelium-conditioned culture medium(ECCM) was obtained by maintaining the endothelial cellsin culture medium. Islet function was evaluated followingexposure of cultured islets to standard culture medium orECCM. Changes in mRNA levels for key beta cellmetabolic enzymes were also measured in islets afterECCM exposure.Results Glucose-stimulated insulin release and islet insulincontent were markedly enhanced by exposure to ECCM.This was at least partly explained by improved mitochondrialfunction, as assessed by glucose oxidation and anupregulation of the mitochondrial gene for glycerol-3-phosphate dehydrogenase (mGpdh [also known as Gpd2]),combined with upregulation of the rate-limiting enzyme inthe glycolysis, glucokinase, in the islets. The intracellulardegradation of insulin was also decreased in the islets. Isletendothelial cells produced laminins, and the positive effectsof islet endothelial cells were prevented by addition of aneutralising antibody to the β1-chain of laminin. Additionof exogenous laminin stimulated islet function.Conclusions/interpretation This study provides proof ofprinciple that endothelial cells can affect the function of betacells in their vicinity and that this is at least partially mediatedby laminins.

Place, publisher, year, edition, pages
2009. Vol. 52, no 11, 2385-2394 p.
Keyword [en]
Endothelial cells, Beta cells, Laminin
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-109712DOI: 10.1007/s00125-009-1485-6ISI: 000270650600018PubMedID: 19669728OAI: oai:DiVA.org:uu-109712DiVA: diva2:273611
Available from: 2009-10-22 Created: 2009-10-22 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Properties of Endothelium and its Importance in Endogenous and Transplanted Islets of Langerhans
Open this publication in new window or tab >>Properties of Endothelium and its Importance in Endogenous and Transplanted Islets of Langerhans
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Transplantation of insulin producing cells is currently the only cure for type 1 diabetes. However, even though the Edmonton protocol markedly increased the success rate of pancreatic islet transplantation, the long term insulin independence is still very poor. An adequate engraftment is critical for islet graft survival and function.

In the present thesis, isolated islet endothelial cells were found to have a low proliferatory and migratory capacity towards vascular endothelial growth factor (VEGF), but this could be reversed by using neutralizing antibodies to the angiostatic factors thrombospondin-1, endostatin or alpha1-antitrypsin.

In the adult islet endothelial cell, VEGF may act as a permeability inducer more than an inducer of angiogenesis. p38 MAP kinase activity has been shown to serve as a switch between these properties of VEGF. Inhibition of p38 MAP kinase by daily injections of SB203580 in the early posttransplantation phase lead to a redistribution of the islet graft blood vessels from the stroma into the endocrine tissue and this was accompanied by a higher oxygen tension.

Besides transports of oxygen and nutrients, beta-cells may require signals from the endothelial cells for their growth and differentiation. It was demonstrated that islet endothelial cells secrete factors, including laminin, that have positive effects on beta-cell insulin release and insulin content.

Our results suggest that improved revascularization of transplanted islets may be achieved by either inhibition of angiostatic factors, or by blocking p38 MAPkinase activity, in the implanted tissue. Islet endothelial cells have a supportive paracrine role for beta-cells that might be hampered by the normally poor revascularization.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 48 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 492
Keyword
islet transplantation, endothelial cells, engraftment, beta cells
National Category
Endocrinology and Diabetes
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-109713 (URN)978-91-554-7643-4 (ISBN)
Public defence
2009-12-05, B22, BMC, Husargatan 3, Uppsala, 10:15 (English)
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Supervisors
Available from: 2009-11-13 Created: 2009-10-22 Last updated: 2009-11-13

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Magnusson, Peetra

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