Identification of the matricellular protein Fibulin-5 as a target molecule of glucokinase-mediated calcineurin/NFAT signaling in pancreatic islets

• Okuyama, Tomoko

• Shirakawa, Jun

• YANAGISAWA, Hiromi

• Kyohara, Mayu

• Yamazaki, Shunsuke

• Tajima, Kazuki

• Togashi, Yu

• Terauchi, Yasuo

Abstract

Glucokinase-mediated glucose signaling induces insulin secretion, proliferation, and apoptosis in pancreatic β-cells. However, the precise molecular mechanisms underlying these processes are not clearly understood. Here, we demonstrated that glucokinase activation using a glucokinase activator (GKA) significantly upregulated the expression of Fibulin-5 (Fbln5), a matricellular protein involved in matrix-cell signaling, in isolated mouse islets. The islet Fbln5 expression was induced by ambient glucose in a time- and dose-dependent manner and further enhanced by high-fat diet or the deletion of insulin receptor substrate 2 (IRS-2), whereas the GKA-induced increase in Fbln5 expression was diminished in Irs-2 -deficient islets. GKA-induced Fbln5 upregulation in the islets was blunted by a glucokinase inhibitor, K ATP channel opener, Ca 2+ channel blocker and calcineurin inhibitor, while it was augmented by harmine, a dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) 1 A inhibitor. Although deletion of Fbln5 in mice had no significant effects on the glucose tolerance or β-cell functions, adenovirus-mediated Fbln5 overexpression increased glucose-stimulated insulin secretion in INS-1 rat insulinoma cells. Since the islet Fbln5 expression is regulated through a glucokinase/K ATP channel/calcineurin/nuclear factor of activated T cells (NFAT) pathway crucial for the maintenance of β-cell functions, further investigation of Fbln5 functions in the islets is warranted.

Journal

• Scientific Reports

  Scientific Reports 7 2364-, 2017-05

  Nature Publishing Group

Keywords

• Multidisciplinary

Details

• CRID: 1050282677603547904
• NII Article ID: 120007134459
• DOI: 10.1038/s41598-017-02535-0
• ISSN: 20452322
• HANDLE: 2241/00151187
• Web Site: https://tsukuba.repo.nii.ac.jp/records/45906
• Web Site: https://www.nature.com/articles/s41598-017-02535-0.pdf
• Web Site: https://www.nature.com/articles/s41598-017-02535-0
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • Crossref
  • CiNii Articles
  • KAKEN