title: Interaction between the central and peripheral effects of insulin in controlling hepatic glucose metabolism in the conscious dog.
abstract: The importance of hypothalamic insulin action to the regulation of hepatic glucose metabolism in the presence of a normal liver/brain insulin ratio (3:1) is unknown. Thus, we assessed the role of central insulin action in the response of the liver to normal physiologic hyperinsulinemia over 4 h. Using a pancreatic clamp, hepatic portal vein insulin delivery was increased three- or eightfold in the conscious dog. Insulin action was studied in the presence or absence of intracerebroventricularly mediated blockade of hypothalamic insulin action. Euglycemia was maintained, and glucagon was clamped at basal. Both the molecular and metabolic aspects of insulin action were assessed. Blockade of hypothalamic insulin signaling did not alter the insulin-mediated suppression of hepatic gluconeogenic gene transcription but blunted the induction of glucokinase gene transcription and completely blocked the inhibition of glycogen synthase kinase-3β gene transcription. Thus, central and peripheral insulin action combined to control some, but not other, hepatic enzyme programs. Nevertheless, inhibition of hypothalamic insulin action did not alter the effects of the hormone on hepatic glucose flux (production or uptake). These data indicate that brain insulin action is not a determinant of the rapid (<4 h) inhibition of hepatic glucose metabolism caused by normal physiologic hyperinsulinemia in this large animal model.
authors.affiliation: Vanderbilt University School of Medicine, Department of Molecular Physiology and Biophysics, Nashville, Tennessee, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ramnanan
authors.forename: Guillaume
authors.initials: G
authors.lastname: Kraft
authors.forename: Marta S
authors.initials: MS
authors.lastname: Smith
authors.forename: Ben
authors.initials: B
authors.lastname: Farmer
authors.forename: Doss
authors.initials: D
authors.lastname: Neal
authors.forename: Phillip E
authors.initials: PE
authors.lastname: Williams
authors.forename: Margaret
authors.initials: M
authors.lastname: Lautz
authors.forename: Tiffany
authors.initials: T
authors.lastname: Farmer
authors.forename: E Patrick
authors.initials: EP
authors.lastname: Donahue
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 / Q000502:physiology*; D004285:Dogs; D005260:Female; D005941:Glucokinase / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D050261:Glycogenolysis; D007031:Hypothalamus / Q000502:physiology; D007328:Insulin / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D007328:Insulin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D005941:Glucokinase; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D005947:Glucose