Distinct patterns of heparan sulphate in pancreatic islets suggest novel roles in paracrine islet regulation

Aikaterini Theodoraki; Youli Hu; Subathra Poopalasundaram; Arie Oosterhof; Scott E. Guimond; Petra Disterer; Bernard Khoo; Astrid C. Hauge-Evans; Peter M. Jones; Jeremy E. Turnbull; Toin H. van Kuppevelt; Pierre Marc Bouloux

doi:10.1016/j.mce.2014.09.011

Distinct patterns of heparan sulphate in pancreatic islets suggest novel roles in paracrine islet regulation

Aikaterini Theodoraki^*, Youli Hu, Subathra Poopalasundaram, Arie Oosterhof, Scott E. Guimond, Petra Disterer, Bernard Khoo, Astrid C. Hauge-Evans, Peter M. Jones, Jeremy E. Turnbull, Toin H. van Kuppevelt, Pierre Marc Bouloux

^*Corresponding author for this work

Diabetes

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

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.

Original language	English
Pages (from-to)	296-310
Number of pages	15
Journal	Molecular and Cellular Endocrinology
Volume	399
DOIs	https://doi.org/10.1016/j.mce.2014.09.011
Publication status	Published - 5 Jan 2015

Keywords

Fibroblast growth factor
Heparan sulphate
Islet
Signalling

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10.1016/j.mce.2014.09.011

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Theodoraki, A., Hu, Y., Poopalasundaram, S., Oosterhof, A., Guimond, S. E., Disterer, P., Khoo, B., Hauge-Evans, A. C., Jones, P. M., Turnbull, J. E., Kuppevelt, T. H. V., & Bouloux, P. M. (2015). Distinct patterns of heparan sulphate in pancreatic islets suggest novel roles in paracrine islet regulation. Molecular and Cellular Endocrinology, 399, 296-310. https://doi.org/10.1016/j.mce.2014.09.011

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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.",

keywords = "Fibroblast growth factor, Heparan sulphate, Islet, Signalling",

author = "Aikaterini Theodoraki and Youli Hu and Subathra Poopalasundaram and Arie Oosterhof and Guimond, {Scott E.} and Petra Disterer and Bernard Khoo and Hauge-Evans, {Astrid C.} and Jones, {Peter M.} and Turnbull, {Jeremy E.} and Kuppevelt, {Toin H. van} and Bouloux, {Pierre Marc}",

year = "2015",

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doi = "10.1016/j.mce.2014.09.011",

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Theodoraki, A, Hu, Y, Poopalasundaram, S, Oosterhof, A, Guimond, SE, Disterer, P, Khoo, B, Hauge-Evans, AC , Jones, PM, Turnbull, JE, Kuppevelt, THV & Bouloux, PM 2015, 'Distinct patterns of heparan sulphate in pancreatic islets suggest novel roles in paracrine islet regulation', Molecular and Cellular Endocrinology, vol. 399, pp. 296-310. https://doi.org/10.1016/j.mce.2014.09.011

TY - JOUR

T1 - Distinct patterns of heparan sulphate in pancreatic islets suggest novel roles in paracrine islet regulation

AU - Theodoraki, Aikaterini

AU - Hu, Youli

AU - Poopalasundaram, Subathra

AU - Oosterhof, Arie

AU - Guimond, Scott E.

AU - Disterer, Petra

AU - Khoo, Bernard

AU - Hauge-Evans, Astrid C.

AU - Jones, Peter M.

AU - Turnbull, Jeremy E.

AU - Kuppevelt, Toin H. van

AU - Bouloux, Pierre Marc

PY - 2015/1/5

Y1 - 2015/1/5

N2 - 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.

AB - 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.

KW - Fibroblast growth factor

KW - Heparan sulphate

KW - Islet

KW - Signalling

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DO - 10.1016/j.mce.2014.09.011

M3 - Article

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SN - 0303-7207

VL - 399

SP - 296

EP - 310

JO - Molecular and Cellular Endocrinology

JF - Molecular and Cellular Endocrinology

ER -

Distinct patterns of heparan sulphate in pancreatic islets suggest novel roles in paracrine islet regulation

Abstract

Keywords

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