title: Distinct patterns of heparan sulphate in pancreatic islets suggest novel roles in paracrine islet regulation.
abstract: Heparan sulphate proteoglycans (HSPGs) exist in pancreatic beta cells, and HS seems to modulate important interactions in the islet microenvironment. However, the intra-islet structures of HS in health or altered glucose homeostasis are currently unknown. Here we show that distinct spatial distribution of HS motifs is present in islets in the adult, that intra-islet HS motifs are mostly conserved between rodents and humans, and that HS is abundant in glucagon producing islet alpha cells. In beta cells HS is characterised by 2-O, 6-O and N-sulphated moieties, whereas HS in alpha cells is N-acetylated, N-, and 2-O sulphated and low in 6-O groups. Differential expression of three HS modifying genes in alpha and beta cells was observed and may account for the different HS patterns. Furthermore, we found that FGF1 and FGF2 were present in alpha cells, whereas functional FGFRs exist in beta cells, but not in the alpha cell line aTC1-6, or in primary alpha cells in islets. FGF1 induced signalling was dependent on 2-O, and 6-O HS sulphation in beta cells, and HS desulphation reduced beta cell proliferation and potentiated oxidant induced apoptosis. In leptin resistant animals and in islets from streptozotocin treated rats there was a reduction in alpha cell HS expression. These data demonstrate the distinct HS expression patterns in alpha and beta islet cells and propose a novel role for alpha cells as a source of paracrine FGF ligands to neighbouring beta cells with specific cell-associated HS domains mediating the activation and diffusion of paracrine ligands.
authors.affiliation: Centre for Neuroendocrinology, Royal Free Campus, UCL, London NW3 2QG, UK. Electronic address: aikaterini.theodoraki@nhs.net.
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Theodoraki
authors.affiliation: Centre for Neuroendocrinology, Royal Free Campus, UCL, London NW3 2QG, UK.
authors.forename: Youli
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Centre for Neuroendocrinology, Royal Free Campus, UCL, London NW3 2QG, UK.
authors.forename: Subathra
authors.initials: S
authors.lastname: Poopalasundaram
authors.affiliation: Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands.
authors.forename: Arie
authors.initials: A
authors.lastname: Oosterhof
authors.affiliation: Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZE, UK.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Guimond
authors.affiliation: Centre for Neuroendocrinology, Royal Free Campus, UCL, London NW3 2QG, UK.
authors.forename: Petra
authors.initials: P
authors.lastname: Disterer
authors.affiliation: Centre for Neuroendocrinology, Royal Free Campus, UCL, London NW3 2QG, UK.
authors.forename: Bernard
authors.initials: B
authors.lastname: Khoo
authors.affiliation: Diabetes and Nutritional Sciences Division, School of Medicine, King's College London, Guy's Campus, London SE1 1UL, UK.
authors.forename: Astrid C
authors.initials: AC
authors.lastname: Hauge-Evans
authors.affiliation: Diabetes and Nutritional Sciences Division, School of Medicine, King's College London, Guy's Campus, London SE1 1UL, UK.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Jones
authors.affiliation: Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZE, UK.
authors.forename: Jeremy E
authors.initials: JE
authors.lastname: Turnbull
authors.affiliation: Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands.
authors.forename: Toin H
authors.initials: TH
authors.lastname: van Kuppevelt
authors.affiliation: Centre for Neuroendocrinology, Royal Free Campus, UCL, London NW3 2QG, UK.
authors.forename: Pierre-Marc
authors.initials: PM
authors.lastname: Bouloux
mesh_terms: D000818:Animals; D016220:Fibroblast Growth Factor 1 / Q000235:genetics / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D050416:Glucagon-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D006497:Heparan Sulfate / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D019899:Paracrine Communication / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker
chemical_list: D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2; D006497:Heparan Sulfate
keywords: Fibroblast growth factor; Heparan sulphate; Islet; Signalling