Hepatic glycogen supercompensation activates AMP-activated protein kinase, impairs insulin signaling, and reduces glycogen deposition in the liver.

Winnick JJ, An Z, Ramnanan CJ, Smith M, Irimia JM, Neal DW, Moore MC, Roach PJ, Cherrington AD
Diabetes. 2011 60 (2): 398-407

PMID: 21270252 · PMCID: PMC3028338 · DOI:10.2337/db10-0592

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.

RESEARCH DESIGN AND 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.

MeSH Terms (17)

AMP-Activated Protein Kinases Analysis of Variance Animals Blood Glucose Blotting, Western Dogs Fatty Acids, Nonesterified Female Fructose Glucagon Insulin Liver Liver Glycogen Male Portal Vein Reverse Transcriptase Polymerase Chain Reaction Signal Transduction

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