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. 2011 Feb;60(2):398-407.
doi: 10.2337/db10-0592.

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

Jason J Winnick  1 , Zhibo An, Christopher J Ramnanan, Marta Smith, Jose M Irimia, Doss W Neal, Mary Courtney Moore, Peter J Roach, Alan D Cherrington
Affiliations

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

Jason J Winnick et al. Diabetes. 2011 Feb.

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.

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.

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Figures

FIG. 1.
FIG. 1.
Schematic representation of the study. Portal fructose infusion rates of 0, 0.4, and 1.0 mg/kg/min represent the MOD, HIGH, and SC groups, respectively.
FIG. 2.
FIG. 2.
Arterial blood glucose (A), hepatic sinusoidal insulin (B), hepatic sinusoidal glucagon (C), NHGU (D), net hepatic glycogen synthesis (E), and NHLO (in glucose equivalents) (F) during the final 20 min of the 4-h glycogen loading period. *P < 0.05 compared with MOD; #P < 0.05 compared with HIGH.
FIG. 3.
FIG. 3.
Arterial blood glucose (A), glucose load to the liver (B), hepatic sinusoidal insulin (C), and hepatic sinusoidal glucagon (D) before and during the 120-min experimental period. No differences were detected among groups at any time point (P > 0.05).
FIG. 4.
FIG. 4.
NHGU (A), net hepatic glycogen synthesis (B), NHLO (in glucose equivalents) (C), and hepatic glucose oxidation (D) during the experimental period. AUC during the final hour of the experimental period for hepatic glucose oxidation (P = 0.01) and NHLO (P = 0.02) was lower in MOD compared with SC, whereas hepatic glycogen synthesis was higher (P = 0.05).
FIG. 5.
FIG. 5.
The disposition of glucose taken up by the liver during the final hour of the experimental period into carbon dioxide (CO2; bricked area), lactate (hatched area), and glycogen (dotted area). *P < 0.05 for net hepatic glycogen synthesis and NHLO in SC compared with both HIGH and MOD.
FIG. 6.
FIG. 6.
Hepatic glycogen content (A), Akt (B), GSK3-β (C), and AMPK (D) phosphorylation and GS (E) and GP (F) activity ratios from liver biopsies taken at the conclusion of the experimental period. *P < 0.05 compared with MOD; #P < 0.05 compared with HIGH.
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