title: 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.
authors.affiliation: Department of Nephrology, Ningxia People's Hospital, Yinchuan, Ningxia Province, China.
authors.forename: Ya-Li
authors.initials: YL
authors.lastname: Zheng
authors.forename: Congyu
authors.initials: C
authors.lastname: Li
authors.forename: Ya-Fang
authors.initials: YF
authors.lastname: Hu
authors.forename: Li
authors.initials: L
authors.lastname: Cao
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.forename: Xiao-Hua
authors.initials: XH
authors.lastname: Lu
authors.forename: Li
authors.initials: L
authors.lastname: Bao
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Luo
authors.forename: Varsha
authors.initials: V
authors.lastname: Shukla
authors.forename: Niranjana D
authors.initials: ND
authors.lastname: Amin
authors.forename: Harish C
authors.initials: HC
authors.lastname: Pant
mesh_terms: D000818:Animals; D017209:Apoptosis; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology; D004789:Enzyme Activation; D005947:Glucose / Q000494:pharmacology / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D015533:Transcriptional Activation
chemical_list: C000588766:Cdk5 inhibitory peptide, human; D007004:Hypoglycemic Agents; D007328:Insulin; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D005947:Glucose
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