Exendin-4 regulates GLUT2 expression via the CaMKK/CaMKIV pathway in a pancreatic β-cell line

Ke Chen, Xiao Yu, Koji Murao, Hitomi Imachi, Junhua Li, Tomie Muraoka, Hisashi Masugata, Guo Xing Zhang, Ryoji Kobayashi, Toshihiko Ishida, Hiroshi Tokumitsu

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10 Citations (Scopus)

Abstract

The GLUT2 glucose transporter plays an important role in glucose-induced insulin secretion in pancreatic β-cells by catalyzing the uptake of glucose into the cell. In this study, we investigated whether exendin-4, a long-acting agonist of glucagon-like peptide-1, mediates stimulatory effects on GLUT2 gene expression through the Ca2+/calmodulin (CaM)-dependent protein kinase IV (CaMKIV) cascade. GLUT2 expression was examined by real-time polymerase chain reaction, Western blot analysis, and a reporter gene assay in rat insulin-secreting INS-1 cells incubated with exendin-4. An increased expression level of GLUT2 protein was noted in response to increasing concentrations of exendin-4, with maximal induction at 10 nmol/L. Real-time polymerase chain reaction analysis similarly revealed a significant increase in the amount of GLUT2 messenger RNA by 10 nmol/L exendin-4. Exendin-4 also stimulated GLUT2 promoter activity in response to increasing exendin-4 concentrations, but failed to do so in the presence of STO-609, a CaMKK inhibitor. We also investigated the effect of the constitutively active form of CaMKK (CaMKKc) on GLUT2 promoter activity. The result is consistent with the observations that CaMKKc/CaMKIV enhanced or up-regulated GLUT2 promoter activity in INS-1 cells. Furthermore, exendin-4 induction of GLUT2 protein expression was significantly suppressed in the cells knocking down the CaMKIV. In summary, activation of the CaMKK/CaMKIV cascade might be required for exendin-4-induced GLUT2 gene transcription, indicating that exendin-4 plays an important role in insulin secretion in pancreatic β-cells.

Original languageEnglish
Pages (from-to)579-585
Number of pages7
JournalMetabolism: Clinical and Experimental
Volume60
Issue number4
DOIs
Publication statusPublished - Apr 2011
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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    Chen, K., Yu, X., Murao, K., Imachi, H., Li, J., Muraoka, T., Masugata, H., Zhang, G. X., Kobayashi, R., Ishida, T., & Tokumitsu, H. (2011). Exendin-4 regulates GLUT2 expression via the CaMKK/CaMKIV pathway in a pancreatic β-cell line. Metabolism: Clinical and Experimental, 60(4), 579-585. https://doi.org/10.1016/j.metabol.2010.06.002