Cdkn2a/p16Ink4a regulates fasting-induced hepatic gluconeogenesis through the PKA-CREB-PGC1α pathway.

  1. Bart Staels1,2,3,4,+
  1. 1Univ Lille 2, F-59000, Lille, France
  2. 2Inserm, U1011, F-59000, Lille, France
  3. 3European Genomic Institut for Diabetes (EGID), FR 3508, F-59000 Lille, France
  4. 4Institut Pasteur de Lille, F-59019, Lille, France
  1. Corresponding author: Bart Staels. E-mail: bart.staels{at}pasteur-lille.


Type 2 diabetes (T2D) is hallmarked by insulin resistance, impaired insulin secretion and increased hepatic glucose production. The worldwide increasing prevalence of T2D calls for efforts to understand its pathogenesis in order to improve disease prevention and management. Recent genome wide association studies (GWAS) have revealed strong associations between the CDKN2A/B locus and T2D risk. The CDKN2A/B locus contains genes encoding cell cycle inhibitors, including p16Ink4a, which have not yet been implicated in the control of hepatic glucose homeostasis. Here we show that p16Ink4a-deficiency enhances fasting-induced hepatic glucose production in vivo by increasing the expression of key gluconeogenic genes. p16Ink4a down-regulation leads to an activation of PKA-CREB-PGC1α signalling through increased phosphorylation of PKA regulatory subunits (PKAR2). Taken together, these results provide evidence that p16Ink4a controls fasting glucose homeostasis and could as such modulate in T2D development.


  • * contributed equally

  • + Senior authors

  • Received December 20, 2013.
  • Accepted April 23, 2014.

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