title: Deletion of CDKAL1 affects high-fat diet-induced fat accumulation and glucose-stimulated insulin secretion in mice, indicating relevance to diabetes.
abstract: OBJECTIVE
  The CDKAL1 gene is among the best-replicated susceptibility loci for type 2 diabetes, originally identified by genome-wide association studies in humans. To clarify a physiological importance of CDKAL1, we examined effects of a global Cdkal1-null mutation in mice and also evaluated the influence of a CDKAL1 risk allele on body mass index (BMI) in Japanese subjects.
  
  
  METHODS
  In Cdkal1-deficient (Cdkal1⁻/⁻) mice, we performed oral glucose tolerance test, insulin tolerance test, and perfusion experiments with and without high-fat feeding. Based on the findings in mice, we tested genetic association of CDKAL1 variants with BMI, as a measure of adiposity, and type 2 diabetes in Japanese.
  
  
  RESULTS
  On a standard diet, Cdkal1⁻/⁻ mice were modestly lighter in weight than wild-type littermates without major alterations in glucose metabolism. On a high fat diet, Cdkal1⁻/⁻ mice showed significant reduction in fat accumulation (17% reduction in %intraabdominal fat, P = 0.023 vs. wild-type littermates) with less impaired insulin sensitivity at an early stage. High fat feeding did not potentiate insulin secretion in Cdkal1⁻/⁻ mice (1.0-fold), contrary to the results in wild-type littermates (1.6-fold, P<0.01). Inversely, at a later stage, Cdkal1⁻/⁻ mice showed more prominent impairment of insulin sensitivity and glucose tolerance. mRNA expression analysis indicated that Scd1 might function as a critical mediator of the altered metabolism in Cdkal1⁻/⁻ mice. In accordance with the findings in mice, a nominally significant (P<0.05) association between CDKAL1 rs4712523 and BMI was replicated in 2 Japanese general populations comprising 5,695 and 12,569 samples; the risk allele for type 2 diabetes was also associated with decreased BMI.
  
  
  CONCLUSIONS
  Cdkal1 gene deletion is accompanied by modestly impaired insulin secretion and longitudinal fluctuations in insulin sensitivity during high-fat feeding in mice. CDKAL1 may affect such compensatory mechanisms regulating glucose homeostasis through interaction with diet.
authors.affiliation: Division of Animal Model, Department of Infectious Diseases, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Okamura
authors.forename: Rieko
authors.initials: R
authors.lastname: Yanobu-Takanashi
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Takeuchi
authors.forename: Masato
authors.initials: M
authors.lastname: Isono
authors.forename: Koichi
authors.initials: K
authors.lastname: Akiyama
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Motohito
authors.initials: M
authors.lastname: Goto
authors.forename: Yi-Qiang
authors.initials: YQ
authors.lastname: Liang
authors.forename: Ken
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Katsuya
authors.forename: Akihiro
authors.initials: A
authors.lastname: Fujioka
authors.forename: Keizo
authors.initials: K
authors.lastname: Ohnaka
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Takayanagi
authors.forename: Toshio
authors.initials: T
authors.lastname: Ogihara
authors.forename: Yukio
authors.initials: Y
authors.lastname: Yamori
authors.forename: Norihiro
authors.initials: N
authors.lastname: Kato
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D000818:Animals; D015992:Body Mass Index; D001835:Body Weight / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D059305:Diet, High-Fat / Q000009:adverse effects*; D005260:Female; D055786:Gene Knockout Techniques; D056426:Genetic Loci / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D000078790:Insulin Secretion; D051379:Mice; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics; D009765:Obesity / Q000209:etiology; D010179:Pancreas / Q000378:metabolism; D010641:Phenotype; D012359:tRNA Methyltransferases
chemical_list: D007328:Insulin; D009419:Nerve Tissue Proteins; D012359:tRNA Methyltransferases; C559068:CDKAL1 protein, mouse; D005947:Glucose