title: Brain insulin action augments hepatic glycogen synthesis without suppressing glucose production or gluconeogenesis in dogs.
abstract: In rodents, acute brain insulin action reduces blood glucose levels by suppressing the expression of enzymes in the hepatic gluconeogenic pathway, thereby reducing gluconeogenesis and endogenous glucose production (EGP). Whether a similar mechanism is functional in large animals, including humans, is unknown. Here, we demonstrated that in canines, physiologic brain hyperinsulinemia brought about by infusion of insulin into the head arteries (during a pancreatic clamp to maintain basal hepatic insulin and glucagon levels) activated hypothalamic Akt, altered STAT3 signaling in the liver, and suppressed hepatic gluconeogenic gene expression without altering EGP or gluconeogenesis. Rather, brain hyperinsulinemia slowly caused a modest reduction in net hepatic glucose output (NHGO) that was attributable to increased net hepatic glucose uptake and glycogen synthesis. This was associated with decreased levels of glycogen synthase kinase 3β (GSK3β) protein and mRNA and with decreased glycogen synthase phosphorylation, changes that were blocked by hypothalamic PI3K inhibition. Therefore, we conclude that the canine brain senses physiologic elevations in plasma insulin, and that this in turn regulates genetic events in the liver. In the context of basal insulin and glucagon levels at the liver, this input augments hepatic glucose uptake and glycogen synthesis, reducing NHGO without altering EGP.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615, USA. chris.ramnanan@vanderbilt.edu
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ramnanan
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Saraswathi
authors.forename: Marta S
authors.initials: MS
authors.lastname: Smith
authors.forename: E Patrick
authors.initials: EP
authors.lastname: Donahue
authors.forename: Ben
authors.initials: B
authors.lastname: Farmer
authors.forename: Tiffany D
authors.initials: TD
authors.lastname: Farmer
authors.forename: Doss
authors.initials: D
authors.lastname: Neal
authors.forename: Philip E
authors.initials: PE
authors.lastname: Williams
authors.forename: Margaret
authors.initials: M
authors.lastname: Lautz
authors.forename: Andrea
authors.initials: A
authors.lastname: Mari
authors.forename: Alan D
authors.initials: AD
authors.lastname: Cherrington
authors.forename: Dale S
authors.initials: DS
authors.lastname: Edgerton
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D004285:Dogs; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005934:Glucagon / Q000097:blood; D005943:Gluconeogenesis / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D006003:Glycogen / Q000096:biosynthesis*; D006801:Humans; D006946:Hyperinsulinism / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*
chemical_list: D005230:Fatty Acids, Nonesterified; D007328:Insulin; D006003:Glycogen; D005934:Glucagon; D005947:Glucose