title: Hepatic glycogen supercompensation activates AMP-activated protein kinase, impairs insulin signaling, and reduces glycogen deposition in the liver.
abstract: OBJECTIVE
  The objective of this study was to determine how increasing the hepatic glycogen content would affect the liver's ability to take up and metabolize glucose.
  
  
  METHODS
  During the first 4 h of the study, liver glycogen deposition was stimulated by intraportal fructose infusion in the presence of hyperglycemic-normoinsulinemia. This was followed by a 2-h hyperglycemic-normoinsulinemic control period, during which the fructose infusion was stopped, and a 2-h experimental period in which net hepatic glucose uptake (NHGU) and disposition (glycogen, lactate, and CO(2)) were measured in the absence of fructose but in the presence of a hyperglycemic-hyperinsulinemic challenge including portal vein glucose infusion.
  
  
  RESULTS
  Fructose infusion increased net hepatic glycogen synthesis (0.7 ± 0.5 vs. 6.4 ± 0.4 mg/kg/min; P < 0.001), causing a large difference in hepatic glycogen content (62 ± 9 vs. 100 ± 3 mg/g; P < 0.001). Hepatic glycogen supercompensation (fructose infusion group) did not alter NHGU, but it reduced the percent of NHGU directed to glycogen (79 ± 4 vs. 55 ± 6; P < 0.01) and increased the percent directed to lactate (12 ± 3 vs. 29 ± 5; P = 0.01) and oxidation (9 ± 3 vs. 16 ± 3; P = NS). This change was associated with increased AMP-activated protein kinase phosphorylation, diminished insulin signaling, and a shift in glycogenic enzyme activity toward a state discouraging glycogen accumulation.
  
  
  CONCLUSIONS
  These data indicate that increases in hepatic glycogen can generate a state of hepatic insulin resistance, which is characterized by impaired glycogen synthesis despite preserved NHGU.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee, USA. jason.winnick@vanderbilt.edu
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Winnick
authors.forename: Zhibo
authors.initials: Z
authors.lastname: An
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ramnanan
authors.forename: Marta
authors.initials: M
authors.lastname: Smith
authors.forename: Jose M
authors.initials: JM
authors.lastname: Irimia
authors.forename: Doss W
authors.initials: DW
authors.lastname: Neal
authors.forename: Mary Courtney
authors.initials: MC
authors.lastname: Moore
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Roach
authors.forename: Alan D
authors.initials: AD
authors.lastname: Cherrington
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose; D015153:Blotting, Western; D004285:Dogs; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005632:Fructose / Q000378:metabolism / Q000494:pharmacology; D005934:Glucagon / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008112:Liver Glycogen / Q000378:metabolism*; D008297:Male; D011169:Portal Vein / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D008112:Liver Glycogen; D005632:Fructose; D005934:Glucagon; D055372:AMP-Activated Protein Kinases