Exendin-4 regulates glucokinase expression by CaMKK/CaMKIV pathway in pancreatic β-cell line

K. Murao, J. Li, H. Imachi, T. Muraoka, H. Masugata, G. X. Zhang, R. Kobayashi, T. Ishida, H. Tokumitsu

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25 Citations (Scopus)

Abstract

Aim: Glucokinase (GK) in pancreatic β cells is thought to be involved in insulin secretion and glucose homeostasis. This study investigates whether the long-acting agonist of the glucagon-like peptide 1, namely exendin-4, mediates stimulatory effects on GK gene expression through the Ca2+/calmodulin (CaM)-dependent protein kinase (CaMK) cascade. Methods: : GK expression was examined by real-time PCR, western blot analysis and reporter gene assay in rat insulin-secreting INS-1 cells incubated with exendin-4. CaMKIV activity was assessed by detection of activation loop phosphorylation (Thr196) of CaMKIV. We investigated the effect of the constitutively active form (CaMKIVc) of CaMKIV on GK promoter activity. Results: Increased expression level of GK protein was noted in response to rising concentrations of exendin-4 with maximum induction at 10 nM. Real-time PCR analysis showed a significant increase in the amount of GK mRNA in response to rising concentrations of exendin-4. Exendin-4 also stimulated GK promoter activity but failed to do so in the presence of STO-609, a CaMKK inhibitor. This result is consistent with the observations that the upregulation of CaMKIV phosphorylation (at Thr196) peaked after 15 min of exposure to exendin-4 and that CaMKIVc enhanced or upregulated GK promoter activity in INS-1 cells. Furthermore, STO-609 significantly suppressed the exendin-4 - upregulated the expression of the GK protein. Conclusion: Activation of the CaMKK/CaMKIV cascade might be required for exendin-4-induced GK gene transcription, indicating that exendin-4 plays an important role in insulin secretion in pancreatic β cells.

Original languageEnglish
Pages (from-to)939-946
Number of pages8
JournalDiabetes, Obesity and Metabolism
Volume11
Issue number10
DOIs
Publication statusPublished - Oct 2009
Externally publishedYes

Keywords

  • CaMKK/CaMKIV
  • Exendin-4
  • GLP-1
  • Glucokinase

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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  • Cite this

    Murao, K., Li, J., Imachi, H., Muraoka, T., Masugata, H., Zhang, G. X., Kobayashi, R., Ishida, T., & Tokumitsu, H. (2009). Exendin-4 regulates glucokinase expression by CaMKK/CaMKIV pathway in pancreatic β-cell line. Diabetes, Obesity and Metabolism, 11(10), 939-946. https://doi.org/10.1111/j.1463-1326.2009.01067.x