Cdkn2a/p16~(Ink4a) Regulates Fasting-Induced Hepatic Gluconeogenesis Through the PKA-CREB-PGC1α Pathway

摘要

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 patho-genesis in order to improve disease prevention and management. Recent genome-wide association studies have revealed strong associations between the CDKN2A/B locus and T2D risk. The CDKN2A/B locus contains genes encoding cell cycle inhibitors, including p16~(Ink4a), which have not yet been implicated in the control of hepatic glucose homeostasis. Here, we show that p16~(Ink4a) deficiency enhances fasting-induced hepatic glucose production in vivo by increasing the expression of key gluconeogenic genes. p16~(Ink4a) downregulation leads to an activation of PKA-CREB-PGC1α signaling through increased phosphorylation of PKA regulatory subunits. Taken together, these results provide evidence that p16~(Ink4a) controls fasting glucose homeostasis and could as such be involved in T2D development.