Aggravation by prostaglandin E2 of interleukin-6-dependent insulin resistance in hepatocytes

Authors

  • Janin Henkel,

    1. From Universität Potsdam, Institut für Ernährungswissenschaft, Biochemie der Ernährung, Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany
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  • Frank Neuschäfer-Rube,

    1. From Universität Potsdam, Institut für Ernährungswissenschaft, Biochemie der Ernährung, Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany
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  • Andrea Pathe-Neuschäfer-Rube,

    1. From Universität Potsdam, Institut für Ernährungswissenschaft, Biochemie der Ernährung, Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany
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  • Gerhard P. Püschel

    Corresponding author
    1. From Universität Potsdam, Institut für Ernährungswissenschaft, Biochemie der Ernährung, Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany
    • Universität Potsdam, Institut für Ernährungswissenschaft, Abt. Biochemie der Ernährung, Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany
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    • fax: (49) 33200-88-541


  • Potential conflict of interest: Nothing to report.

Abstract

Hepatic insulin resistance is a major contributor to fasting hyperglycemia in patients with metabolic syndrome and type 2 diabetes. Circumstantial evidence suggests that cyclooxygenase products in addition to cytokines might contribute to insulin resistance. However, direct evidence for a role of prostaglandins in the development of hepatic insulin resistance is lacking. Therefore, the impact of prostaglandin E2 (PGE2) alone and in combination with interleukin-6 (IL-6) on insulin signaling was studied in primary hepatocyte cultures. Rat hepatocytes were incubated with IL-6 and/or PGE2 and subsequently with insulin. Glycogen synthesis was monitored by radiochemical analysis; the activation state of proteins of the insulin receptor signal chain was analyzed by western blot with phosphospecific antibodies. In hepatocytes, insulin-stimulated glycogen synthesis and insulin-dependent phosphorylation of Akt-kinase were attenuated synergistically by prior incubation with IL-6 and/or PGE2 while insulin receptor autophosphorylation was barely affected. IL-6 but not PGE2 induced suppressors of cytokine signaling (SOCS3). PGE2 but not IL-6 activated extracellular signal-regulated kinase 1/2 (ERK1/2) persistently. Inhibition of ERK1/2 activation by PD98059 abolished the PGE2-dependent but not the IL-6-dependent attenuation of insulin signaling. In HepG2 cells expressing a recombinant EP3-receptor, PGE2 pre-incubation activated ERK1/2, caused a serine phosphorylation of insulin receptor substrate 1 (IRS1), and reduced the insulin-dependent Akt-phosphorylation. Conclusion: PGE2 might contribute to hepatic insulin resistance via an EP3-receptor-dependent ERK1/2 activation resulting in a serine phosphorylation of insulin receptor substrate, thereby preventing an insulin-dependent activation of Akt and glycogen synthesis. Since different molecular mechanisms appear to be employed, PGE2 may synergize with IL-6, which interrupted the insulin receptor signal chain, principally by an induction of SOCS, namely SOCS3. (HEPATOLOGY 2009.)

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