Cdk5 inhibitory peptide (CIP) inhibits Cdk5/p25 activity induced by high glucose in pancreatic beta cells and recovers insulin secretion from p25 damage

• Published in: PloS one Vol. 8; no. 9; p. e63332
• Main Authors: Zheng, Ya-Li, Li, Congyu, Hu, Ya-Fang, Cao, Li, Wang, Hui, Li, Bo, Lu, Xiao-Hua, Bao, Li, Luo, Hong-Yan, Shukla, Varsha, Amin, Niranjana D, Pant, Harish C
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 05-09-2013; Public Library of Science (PLoS)
• Subjects: Alzheimer's disease; Animals; Apoptosis; Beta cells; Cell death; Chemical compounds; Chronic exposure; Cyclin-dependent kinase 5; Cyclin-Dependent Kinase 5 - metabolism; Deregulation; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - enzymology; Enzyme Activation; Exposure; Glucose; Glucose - pharmacology; Glucose - physiology; HEK293 Cells; Hospitals; Humans; Hyperactivity; Hypoglycemic Agents - pharmacology; Insulin; Insulin - metabolism; Insulin resistance; Insulin Secretion; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - enzymology; Insulin-Secreting Cells - metabolism; Kinases; Laboratories; Mice; Nephrology; Nerve Tissue Proteins - pharmacology; Neurochemistry; Neurological disorders; Neurons; Obesity; Pancreas; Pancreatic beta cells; Pathogenesis; Peptide Fragments - pharmacology; Peptides; Pharmacology; Phosphorylation; Proteins; Secretion; Stroke; Studies; Transcription factors; Transcriptional Activation; Type 2 diabetes; United States > US; Maryland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0063332

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.