UNLABELLED: 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 E(2) (PGE(2)) 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 PGE(2) 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 PGE(2) while insulin receptor autophosphorylation was barely affected. IL-6 but not PGE(2) induced suppressors of cytokine signaling (SOCS3). PGE(2) but not IL-6 activated extracellular signal-regulated kinase 1/2 (ERK1/2) persistently. Inhibition of ERK1/2 activation by PD98059 abolished the PGE(2)-dependent but not the IL-6-dependent attenuation of insulin signaling. In HepG2 cells expressing a recombinant EP3-receptor, PGE(2) pre-incubation activated ERK1/2, caused a serine phosphorylation of insulin receptor substrate 1 (IRS1), and reduced the insulin-dependent Akt-phosphorylation. CONCLUSION: PGE(2) 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, PGE(2) may synergize with IL-6, which interrupted the insulin receptor signal chain, principally by an induction of SOCS, namely SOCS3.
UNLABELLED: 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 E(2) (PGE(2)) 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 PGE(2) 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 PGE(2) while insulin receptor autophosphorylation was barely affected. IL-6 but not PGE(2) induced suppressors of cytokine signaling (SOCS3). PGE(2) but not IL-6 activated extracellular signal-regulated kinase 1/2 (ERK1/2) persistently. Inhibition of ERK1/2 activation by PD98059 abolished the PGE(2)-dependent but not the IL-6-dependent attenuation of insulin signaling. In HepG2 cells expressing a recombinant EP3-receptor, PGE(2) pre-incubation activated ERK1/2, caused a serine phosphorylation of insulin receptor substrate 1 (IRS1), and reduced the insulin-dependent Akt-phosphorylation. CONCLUSION:PGE(2) 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, PGE(2) may synergize with IL-6, which interrupted the insulin receptor signal chain, principally by an induction of SOCS, namely SOCS3.
Authors: Christian von Loeffelholz; Stefanie Lieske; Frank Neuschäfer-Rube; Diana M Willmes; Nathanael Raschzok; Igor M Sauer; Jörg König; Martin F Fromm; Paul Horn; Antonios Chatzigeorgiou; Andrea Pathe-Neuschäfer-Rube; Jens Jordan; Andreas F H Pfeiffer; Geltrude Mingrone; Stefan R Bornstein; Peter Stroehle; Christoph Harms; F Thomas Wunderlich; Stephen L Helfand; Michel Bernier; Rafael de Cabo; Gerald I Shulman; Triantafyllos Chavakis; Gerhard P Püschel; Andreas L Birkenfeld Journal: Hepatology Date: 2017-06-26 Impact factor: 17.425
Authors: Janin Henkel; Charles Dominic Coleman; Anne Schraplau; Korinna Jӧhrens; Daniela Weber; José Pedro Castro; Martin Hugo; Tim Julius Schulz; Stephanie Krämer; Annette Schürmann; Gerhard Paul Püschel Journal: Mol Med Date: 2017-03-21 Impact factor: 6.354
Authors: Dong Luo; Abul Fajol; Anja T Umbach; Angelika A Noegel; Stefan Laufer; Florian Lang; Michael Föller Journal: Pflugers Arch Date: 2014-06-07 Impact factor: 3.657
Authors: V B Matthews; T L Allen; S Risis; M H S Chan; D C Henstridge; N Watson; L A Zaffino; J R Babb; J Boon; P J Meikle; J B Jowett; M J Watt; J-O Jansson; C R Bruce; M A Febbraio Journal: Diabetologia Date: 2010-08-11 Impact factor: 10.122