Deletion of CDKAL1 affects high-fat diet-induced fat accumulation and glucose-stimulated insulin secretion in mice, indicating relevance to diabetes

PLoS One. 2012;7(11):e49055. doi: 10.1371/journal.pone.0049055. Epub 2012 Nov 16.

Abstract

Background/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.

Principal findings: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / metabolism*
  • Adult
  • Animals
  • Body Mass Index
  • Body Weight / genetics
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetes Mellitus, Type 2 / pathology
  • Diabetes Mellitus, Type 2 / physiopathology
  • Diet, High-Fat / adverse effects*
  • Female
  • Gene Knockout Techniques*
  • Genetic Loci / genetics
  • Glucose / metabolism*
  • Homeostasis / genetics
  • Humans
  • Insulin / metabolism*
  • Insulin Resistance / genetics
  • Insulin Secretion
  • Mice
  • Middle Aged
  • Nerve Tissue Proteins / deficiency*
  • Nerve Tissue Proteins / genetics
  • Obesity / etiology
  • Pancreas / metabolism
  • Phenotype
  • tRNA Methyltransferases

Substances

  • Insulin
  • Nerve Tissue Proteins
  • tRNA Methyltransferases
  • CDKAL1 protein, mouse
  • Glucose

Grant support

This study was supported by the Program for Promotion of Fundamental Studies in Health Sciences of NIBIO (the National Institute of Biomedical Innovation Organization); the grant of National Center for Global Health and Medicine; and Grant-in-Aid from the Ministry of Health, Labour and Welfare. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.