Cdkn2a/p16^sup Ink4a^ Regulates Fasting-Induced Hepatic Gluconeogenesis Through the PKA-CREB-PGC1[alpha] Pathway

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 have revealed strong associations between the CDKN2A/B locus and T2D risk. The CDKN2A/B locus contains genes encoding cell cycle inhibitors, including p16..., which have not yet been implicated in the control of hepatic glucose homeostasis. Here, we show that p16... deficiency enhances fasting-induced hepatic glucose production in vivo by increasing the expression of key gluconeogenic genes. p16... 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... controls fasting glucose homeostasis and could as such be involved in T2D development. (ProQuest: ... denotes formulae/symbols omitted.)