A Cdk5 inhibitor enhances the induction of insulin secretion by exendin-4 both in vitro and in vivo.
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, long-term 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.
Kitani
Kohsuke
K
Department of Physiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, 700-8558 Japan.
Oguma
Shigeo
S
Nishiki
Tei-ichi
T
Ohmori
Iori
I
Galons
Herv
H
Matsui
Hideki
H
Meijer
Laurent
L
Tomizawa
Kazuhito
K
D000367:Age Factors; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002460:Cell Line; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D000077270:Exenatide; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000032:analysis; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D010455:Peptides / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology*; D000077546:Roscovitine; D014688:Venoms / Q000494:pharmacology*
D001786:Blood Glucose; D051360:Cyclin-Dependent Kinase 5; D000077270:Exenatide; D005947:Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; D014688:Venoms; C495906:Cdk5 protein, mouse