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.
Highlights
Cdk5 is a cyclin-dependent protein kinase which needs to associate with a regulatory partner, p35 or p39, for activation and maintaining numerous physiological functions in the nervous system including neurite outgrowth and axon patterning [1,2]
We showed that high glucose stimulates the increasing expression of p35 in Min6 cells and overexpressed p35 in HG, revealing the expression of p25, which led to decreased insulin secretion [17]
Our previous study has showed that overexpressing p35 in Min 6 cells treated with high glucose induced p25 expression
Summary
Cdk is a cyclin-dependent protein kinase which needs to associate with a regulatory partner, p35 or p39, for activation and maintaining numerous physiological functions in the nervous system including neurite outgrowth and axon patterning [1,2]. Recent studies have documented the existence of both p35 and p39 in pancreatic beta cells and Cdk regulation of insulin secretion [8,9,10]. There are similarities between neurons and pancreatic beta cells, and between the neural degeneration of Alzheimer’s disease and the deterioration of the beta cell functioning in type 2 diabetes [11,12,13]. Glucotoxicity, which deteriorates functions of insulin on peripheral tissues and the secretion of insulin by beta cells is a critical factor of the pathophysiology of diabetes mellitus. The existence of p25 was clearly observed in our study, the role of Cdk5/p25 in pathogenesis to diabetes remains unclear; and whether inhibition of Cdk5/p25 activity can protect beta cells from pathology as it does with neurons
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