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

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.

Cyclin-dependent kinase 5 activity is required for allogeneic T-cell responses after hematopoietic cell transplantation in mice

“…An emerging body of data implicate Cdk5 activity in processes and conditions as diverse as neurodegenerative disease, 11,17 inflammation, 13,22,23,31 cancer biology, 47,50-52 and tumor invasiveness. 48,49 Cdk5 was the top hit of 37 genes that when silenced synergistically potentiate effects of proteosome inhibition in myeloma cells, 47 and a cell-based, high-content, screening assay determined that Cdk5 was the biologic target of several cyclin-depending kinase inhibitors that could modulate cancer cell invasion capacity.…”

“…Rather, Cdk5 interacts with its obligate partner proteins, p35 and p39, [10][11][12][13] whose constitutive expression in postmitotic neurons is essential for the many known functions of Cdk5 in the regulation of cytoarchitecture, synaptic function, and dopamine signaling in the central nervous system. Physiologic Cdk5 activity is essential in neuronal development, [14][15][16][17] memory, and neurogenesis, 16 whereas aberrant hyperactivity of Cdk5 has been linked with neurodegenerative disorders 11,[18][19][20][21] Data from our laboratory and others have implicated Cdk5 in immune dysregulation 13,22,23 and inflammatory pain signaling activated by tumor necrosis factor a (TNFa) through mechanisms that include transcriptional upregulation of p35. 24,25 We recently demonstrated a role for Cdk5 in posttranslational modification of proteins triggered by T-cell receptor (TCR) and chemokine receptor signaling and required for optimal immune synapse formation, cellular activation, and migratory capacity.…”

Cdk5, the multifunctional surveyor

“…299 The observation that roscovitine enhances insulin secretion induced by the peptide Exendin-4 under high-glucose conditions supports the finding that Cdk5 inhibits insulin secretion in response to highglucose. 300 It is noteworthy that Cdk5 not only targets two proteins that bind Stx (L-VDDC and Munc18a), but also has opposite effects on insulin secretion. It would be important to know if under basal conditions Munc18a inhibits the interaction between the Stx/Snap25 complex and the L-VDDC channel and also if Cdk5 acts sequentially, first through Munc 18a to stimulate insulin secretion allowing the interaction between Stx and α 1C L-VDDC and then through phosphorylation of α 1C to turn off secretion.…”

Cyclin-Dependent Kinases as Drug Targets for Cell Growth and Proliferation Disorders. A Role for Systems Biology Approach in Drug Development. Part II—CDKs as Drug Targets in Hypertrophic Cell Growth. Modelling of Drugs Targeting CDKs

“…cDK9 inhibition contributes to the anticancer activity of most cDK inhibitors currently under clinical investigation (25,33,46). in addition, the activity of cDK9 is up-regulated in myocardial hypertrophy.…”

“…it is possible that the antiinflammatory properties of Roscovitine and CDK inhibitors as a whole may find a significant clinical application. There has already been some experimental proof that the inhibition of cDK5 by Roscovitine enhances the induction of insulin secretion and exerts a protective effect against glucotoxicity in pancreatic beta cells (25,41,50). Therefore, inflammatory diseases such as diabetes type 2 turn out to be network diseases as well, which opens new vistas of therapeutic opportunities as well as of potential downsides.…”