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Exendin-4 regulates glucokinase expression by CaMKK/CaMKIV pathway in pancreatic β-cell line.
- Source :
-
Diabetes, Obesity & Metabolism . Oct2009, Vol. 11 Issue 10, p939-946. 8p. 1 Chart, 5 Graphs. - Publication Year :
- 2009
-
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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 14628902
- Volume :
- 11
- Issue :
- 10
- Database :
- Academic Search Index
- Journal :
- Diabetes, Obesity & Metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 44154878
- Full Text :
- https://doi.org/10.1111/j.1463-1326.2009.01067.x