title: Deletion of CDKAL1 affects mitochondrial ATP generation and first-phase insulin exocytosis.
abstract: 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.
  
  
  RESULTS
  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, glucose-induced 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
  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.
authors.affiliation: Department of Biochemistry, Kyorin University School of Medicine, Tokyo, Japan.
authors.forename: Mica
authors.initials: M
authors.lastname: Ohara-Imaizumi
authors.forename: Masashi
authors.initials: M
authors.lastname: Yoshida
authors.forename: Kyota
authors.initials: K
authors.lastname: Aoyagi
authors.forename: Taro
authors.initials: T
authors.lastname: Saito
authors.forename: Tadashi
authors.initials: T
authors.lastname: Okamura
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takenaka
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Akimoto
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nakamichi
authors.forename: Rieko
authors.initials: R
authors.lastname: Takanashi-Yanobu
authors.forename: Chiyono
authors.initials: C
authors.lastname: Nishiwaki
authors.forename: Hayato
authors.initials: H
authors.lastname: Kawakami
authors.forename: Norihiro
authors.initials: N
authors.lastname: Kato
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Hisanaga
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kakei
authors.forename: Shinya
authors.initials: S
authors.lastname: Nagamatsu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics* / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005089:Exocytosis; D014644:Genetic Variation; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000737:chemistry; D012359:tRNA Methyltransferases
chemical_list: D007328:Insulin; D009419:Nerve Tissue Proteins; D000255:Adenosine Triphosphate; D012359:tRNA Methyltransferases; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; C559068:CDKAL1 protein, mouse; D005947:Glucose; D011188:Potassium