Deletion of CDKAL1 affects mitochondrial ATP generation and first-phase insulin exocytosis

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Background: A variant of the CDKAL1 gene was reported to be associated with type 2 diabetes and reduced insulin release in humans; however, the role of CDKAL1 in β cells is largely unknown. Therefore, to determine the role of CDKAL1 in insulin release from β cells, we studied insulin release profiles in CDKAL1 gene knockout (CDKAL1 KO) mice. Principal Findings: Total internal reflection fluorescence imaging of CDKAL1 KO β cells showed that the number of fusion events during first-phase insulin release was reduced. However, there was no significant difference in the number of fusion events during second-phase release or high K + -induced release between WT and KO cells. CDKAL1 deletion resulted in a delayed and slow increase in cytosolic free Ca 2+ concentration during high glucose stimulation. Patch-clamp experiments revealed that the responsiveness of ATP-sensitive K + (K ATP ) channels to glucose was blunted in KO cells. In addition, glucoseinduced ATP generation was impaired. Although CDKAL1 is homologous to cyclin-dependent kinase 5 (CDK5) regulatory subunit-associated protein 1, there was no difference in the kinase activity of CDK5 between WT and CDKAL1 KO islets. Conclusions/Significance: We provide the first report describing the function of CDKAL1 in β cells. Our results indicate that CDKAL1 controls first-phase insulin exocytosis in β cells by facilitating ATP generation, K ATP channel responsiveness and the subsequent activity of Ca 2+ channels through pathways other than CDK5-mediated regulation. © 2010 Ohara-Imaizumi et al.




Ohara-Imaizumi, M., Yoshida, M., Aoyagi, K., Saito, T., Okamura, T., Takenaka, H., … Nagamatsu, S. (2010). Deletion of CDKAL1 affects mitochondrial ATP generation and first-phase insulin exocytosis. PLoS ONE, 5(12).

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