A Cdk5 Inhibitor Enhances Induction of Insulin Secretion by Exendin-4 Both in Vitro and in Vivo

Abstract

Exendin-4 (Ex4) is a peptide that is found in the lizard Heloderma suspectum and has high similarity to glucagon-like peptide 1 (GLP-1). Ex4 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, long-term treatment with Ex4 and R-ros significantly improved HbA1c compared with treatment with Ex4 alone. These results suggest that co-application of R-ros and Ex4 may become a promising therapy for the treatment of type 2 diabetes.