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Title: Patterns of heparan sulfate and FGF ligand expression in pancreatic islets and roles in paracrine regulation
Author: Theodoraki, A.
ISNI:       0000 0004 5352 1280
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2014
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Heparan sulfate 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. This work shows that distinct spatial distribution of HS domains is present in islets in the adult, that intra-islet HS domains 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- sulfated moieties, whereas HS in alpha cells is N-acetylated, N-, and 2-O sulfated 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. Immunoelectron microscopy localized the alpha cell HS epitopes in alpha cell intracellular granules. Furthermore, 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. Intra-islet FGF21 was shown in beta cells with low levels of expression, bound mainly to the co-receptor ╬▓Klotho in unstimulated conditions and FGF21 gene expression was down-regulated by hyperglycaemia in vitro. In contrast, islet and beta cell FGF1 was constitutively expressed in vitro, in leptin resistant Zucker rats and in insulinopenic, hyperglycaemic rats. FGF1 induced signalling was dependent on 2-O, and 6-O HS sulfation in beta cells, and HS desulfation 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 a 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. The intracellular alpha cell HS that localises in vesicles, suggests a role for HS in the regulation of vesicle trafficking and/or hormone secretion.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available