Tumor necrosis factor alpha abolished the suppressive effect of insulin on hepatic glucose production and glycogenolysis stimulated by cAMP

Background: Tumor necrosis factor alpha (TNFα) is implicated in the development of insulin resistance in obesity, type 2 diabetes and cancer. However, its ability to modulate the action of insulin on glycogen catabolism in the liver is controversial. The aim of the present study was to investigate whether TNFα acutely affects the suppression by insulin of hepatic glucose production (HGP) and glycogenolysis stimulated by cyclic adenosine monophosphate (cAMP).

Methods: TNFα (10 μg/kg) was injected intravenously to rats and, 1 or 6h later, their livers were subjected to in situ perfusion with cAMP (3 μM), in the presence or absence of physiological (20 μU/mL) or supraphysiological (500 μU/mL) concentrations of insulin.

Results: The injection of TNFα, 1 or 6h before liver perfusion, had no direct effect on the action of cAMP in stimulating HGP and glycogenolysis. However, when TNFα was injected 1h, but not 6h, before liver perfusion it completely abolished (p<0.05) the suppressive effect of 20 μU/mL insulin on HGP and glycogenolysis stimulated by cAMP. Furthermore, the injection of TNFα 1h or 6h before liver perfusion did not influence the suppression of cAMP-stimulated HGP and glycogenolysis by 500 μU/mL insulin.

Conclusion: TNFα acutely abolished the suppressive effect of physiological, but not supraphysiological, levels of insulin on HGP and glycogenolysis stimulated by cAMP, suggesting an important role of this mechanism to the increased HGP in several pathological states.