Mice overexpressing dominant negative Cdk5 in the pancreatic beta-cells show the phenotype of type 1 diabetes mellitus

Abstract

Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase. Cdk5 and its activators, p35 and p39, are enriched in neuron and regulate neurotransmission, synaptic plasticity and neural development. Recently studies have shown that a high Cdk5 activity is also detected in pancreatic beta cells and Cdk5 regulates glucose-stimulated insulin secretion. A number of very recent studies showed single-nucleotide polymorphisms in cdk5 regulatory subunit-associated protein 1-like 1 (CDKAL1) gene in type 2 diabetes mellitus. CDKAL1 shares considerable protein domain and amino acid homology with cdk5 regulatory subunit associated protein 1 (Cdk5RAP1) gene, a known inhibitor of cdk5 activation. In the present study, we produced transgenic mice overexpressing dominat-negative Cdk5 in the pancreatic beta cells. Cdk5 activity in the pancreatic islets of the mice was 48% of that of wild-type islets. The mice showed higher HbA1c than wild-type mice in the age of 6-weeks and 12-weeks. Intraperitoneal glucose tolerance test (IPGTT) revealed the glucose-stimulated insulin secretion was impaired in the transgenic mice. Moreover, the number of pancreatic beta cell was decreased in the transgenic mice through the development. These results suggest that Cdk5 may be involved in the development of pancreatic islets, and the transgenic mouse may be a new model of the patients with type 1 diabetes mellitus. [J Physiol Sci. 2008;58 Suppl:S137]