Cdk5 Inhibitory Peptide (CIP) Inhibits Cdk5/p25 Activity Induced by High Glucose in Pancreatic Beta Cells and Recovers Insulin Secretion from p25 Damage

Abstract

Cdk5/p25 hyperactivity has been demonstrated to lead to neuron apoptosis and degenerations. Chronic exposure to high glucose (HG) results in hyperactivity of Cdk5 and reduced insulin secretion. Here, we set out to determine whether abnormal upregulation of Cdk5/p25 activity may be induced in a pancreatic beta cell line, Min6 cells. We first confirmed that p25 were induced in overexpressed p35 cells treated with HG and increased time course dependence. Next, we showed that no p25 was detected under short time HG stimulation (4–12 hrs), however was detectable in the long exposure in HG cells (24 hrs and 48 hrs). Cdk5 activity in the above cells was much higher than low glucose treated cells and resulted in more than 50% inhibition of insulin secretion. We confirmed these results by overexpression of p25 in Min6 cells. As in cortical neurons, CIP, a small peptide, inhibited Cdk5/p25 activity and restored insulin secretion. The same results were detected in co-infection of dominant negative Cdk5 (DNCdk5) with p25. CIP also reduced beta cells apoptosis induced by Cdk5/p25. These studies indicate that Cdk5/p25 hyperactivation deregulates insulin secretion and induces cell death in pancreatic beta cells and suggests that CIP may serve as a therapeutic agent for type 2 diabetes.

CDK2 limits the highly energetic secretory program of mature β cells by restricting PEP cycle-dependent KATP channel closure

“…In addition to CDK2, CDK1 ( Gregg et al, 2019 ), CDK5 ( Wei et al, 2005 ), and CDK8 ( Xue et al, 2019 ) have been found to regulate glucose-stimulated insulin secretion. Additionally, the CDK regulator p16/INK4a ( Helman et al, 2016 ; Zheng et al, 2013 ) and the effector molecule c-MYC ( Puri et al, 2018 ; Rosselot et al, 2019 ) have demonstrated significant control over insulin secretion in addition to established canonical cell cycle control of proliferation. Our results provide further evidence that CDK2 can modify the metabolic and secretory state independent of maturation defects reflected by MAFA, GLUT2, or UCN3 ( Blum et al, 2012 ; Hang et al, 2014 ; van der Meulen et al, 2015 ).…”

Mesenchymal Stem Cells Loaded with p5, Derived from CDK5 Activator p35, Inhibit Calcium‐Induced CDK5 Activation in Endothelial Cells

“…However, kinase inhibitors (such as roscovitine) are not very specific as they inhibit not only CDK5-p25 but also CDK5-p35 and other CDKs, leading to serious side effects and thereby reducing the therapeutic efficacy. In order to overcome this problem, several peptides consisting of amino acid residues of p35, such as CDK5 inhibitory peptide (CIP, a peptide of 125 amino acid residues), p10, and p5 have been generated and proven to specifically reduce CDK5-p25 increased activity without affecting the normal endogenous CDK5-p35 or other CDKs activities [ 9 – 15 ]. In particular, p5 also reduced neuronal apoptosis induced by hypoxia/ischemia brain injury, high glucose-mediated toxicity, or A β stress [ 12 – 14 ].…”

Knockdown of Expression of Cdk5 or p35 (a Cdk5 Activator) Results in Podocyte Apoptosis

“…Adenovirus-p35 and empty vector (EV) were made and infected according to the methods of previous study [ 2 , 18 ].…”