Activation of cAMP signaling attenuates impaired hepatic glucose disposal in aged male p21-activated protein kinase-1 knockout mice

P21-activated protein kinase-1 (Pak1) plays a role in insulin secretion and glucagon-like peptide-1 (GLP-1) production. Pak1^-/- mice were found to carry a defect in ip pyruvate tolerance test (IPPTT), leading us to speculatewhetherPak1represses hepatic gluconeogenesis.Weshowherethat the defect in IPPTT became more severe in aged Pak1^-/- mice. In primary hepatocytes, 2,2β-dihydroxy-1,1β-dinaphthyldisulfide, a potent inhibitor of group I Paks, reduced basal glucose production (GP), attenuated forskolin- or glucagon-stimulated GP, and attenuated the stimulation of forskolin on the expression of Pck1 and G6pc. In addition, the capacity of primary hepatocytes isolated from Pak1^-/- mice in GPatthebasallevel is significantlylowerthanthatofthecontrollittermates.Thesein vitroobservations imply that the direct effect of Paks in hepatocytes is the stimulation of gluconeogenesis and that the impairment in IPPTT in Pak1^-/- mice is due to the lack of Pak1 elsewhere. Consecutive ip injection of forskolin for 2 weeks increased gut proglucagon expression, associated with improved IPPTT in aged Pak1^-/-miceandwild-type controls. In addition, administration of the DPP-IV (dipeptidyl peptidase-4) inhibitor sitagliptin for 1 week reversed the defect in IPPTT in aged Pak1^-/- mice, associated with increased plasma GLP-1 levels. Our observations indicate a potential role of Pak1 in the gut/pancreas/ liver axis in controlling glucose disposal and affirmed the therapeutic application of GLP-1 and DPP-IV inhibitors in attenuating hepatic gluconeogenesis.