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Biochem Biophys Res Commun. 2018 May 15;499(3):688-695. doi: 10.1016/j.bbrc.2018.03.213. Epub 2018 Apr 3.

Heparan sulfate in pancreatic β-cells contributes to normal glucose homeostasis by regulating insulin secretion.

Author information

1
Department of Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan.
2
Department of Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan. Electronic address: tyoshikawa@med.tohoku.ac.jp.
3
Department of Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan; Division of Pharmacology, Tohoku Medical and Pharmaceutical University Faculty of Medicine, Sendai, Japan.
4
Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Japan.
5
Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.

Abstract

Heparan sulfate (HS), a linear polysaccharide, is involved in diverse biological functions of various tissues. HS is expressed in pancreatic β-cells and may be involved in β-cell functions. However, the importance of HS for β-cell function remains unknown. Here, we generated mice with β-cell-specific deletion of Ext1 (βExt1CKO), which encodes an enzyme essential for HS synthesis, to investigate the detailed roles of HS in β-cell function. βExt1CKO mice decreased body weights compared with control mice, despite increased food intake. Additionally, βExt1CKO mice showed impaired glucose tolerance associated with decreased insulin secretion upon glucose challenge. Glucose-induced insulin secretion (GIIS) from isolated βExt1CKO islets was also significantly reduced, highlighting the contribution of HS to insulin secretion and glucose homeostasis. The gene expression essential for GIIS was decreased in βExt1CKO islets. Pdx1 and MafA were downregulated in βExt1CKO islets, indicating that HS promoted β-cell development and maturation. BrdU- or Ki67-positive β-cells were reduced in βExt1CKO pancreatic sections, suggesting the involvement of HS in the proliferation of β-cells. Moreover, insufficient vascularization in βExt1CKO islets may contribute to central distribution of α-cells. These data demonstrate HS plays diverse roles in β-cells, and that loss of HS leads to insufficient insulin secretion and dysregulation of glucose homeostasis.

KEYWORDS:

Exostosin1; Heparan sulfate; Insulin secretion; Pancreatic β-cell

PMID:
29605295
DOI:
10.1016/j.bbrc.2018.03.213
[Indexed for MEDLINE]

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