A Cdk5 inhibitor enhances the induction of insulin secretion by exendin-4 both in vitro and in vivo

Kohsuke Kitani, Shigeo Oguma, Tei-ichi Nishiki, Iori Ohmori, Hervé Galons, Hideki Matsui, Laurent Meijer, Kazuhito Tomizawa

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18 Citations (Scopus)

Abstract

Exendin-4 (Ex4) is a peptide found in the lizard Heloderma suspectum, and it has a high similarity to glucagon-like peptide 1 (GLP-1). It induces insulin secretion without the risk of hypoglycemic episodes. Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase that is predominantly expressed in neurons. Recent studies have shown that this kinase regulates glucose-stimulated insulin secretion. Cdk5 inhibition enhances insulin secretion under conditions of stimulation by high glucose, but not low glucose. In the present study, we examined whether R-roscovitine (R-ros), a Cdk5 inhibitor, enhances insulin secretion induced by Ex4. R-ros induced Ex4-dependent insulin secretion under conditions of high glucose, but not low glucose in MIN6B1 cells. The enhancement by R-ros was also observed in db/db mice, a mouse model of type 2 diabetes. Moreover, longterm treatment with Ex4 and R-ros significantly improved HbA1c compared with treatment using only Ex4. These results suggest that a co-application of R-ros and Ex4 may become a promising therapy for the treatment of type 2 diabetes.

Original languageEnglish
Pages (from-to)235-239
Number of pages5
JournalJournal of Physiological Sciences
Volume57
Issue number4
DOIs
Publication statusPublished - Aug 2007

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Keywords

  • Beta cell
  • Cdk5
  • GLP-1
  • Insulin secretion
  • Signal transduction

ASJC Scopus subject areas

  • Physiology

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