title: Reduced Insulin Resistance Contributes to the Beneficial Effect of Protein Tyrosine Phosphatase-1B Deletion in a Mouse Model of Sepsis.
abstract: Hyperglycemia is a common feature of septic patients and has been associated with poor outcome and high mortality. In contrast, insulin has been shown to decrease mortality and to prevent the incidence of multiorgan failure but is often associated with deleterious hypoglycemia. Protein Tyrosine Phosphatase 1B (PTP1B) is a negative regulator of both insulin signaling and NO production, and has been shown to be an aggravating factor in septic shock. To evaluate the potential therapeutic effect of PTP1B blockade on glucose metabolism and insulin resistance in an experimental model of sepsis, we assessed the effect of PTP1B gene deletion in a cecal ligation and puncture (CLP) model of sepsis. PTP1B gene deletion significantly limited CLP-induced insulin resistance, improved AMP-activated protein kinase signaling pathway and Glucose Transporter 4 translocation, and decreased inflammation. These effects were associated with a reduction of sepsis-induced endothelial dysfunction/impaired NO production and especially of insulin-mediated dilatation. This modulation of insulin resistance may contribute to the beneficial effect of PTP1B blockade in septic shock, especially in terms of inflammation and cardiac metabolism.
authors.affiliation: *Normandie Univ, UNIROUEN, Inserm (Institut National de la Santé et de la Recherche Médicale) U1096, Rouen, France †Lille University, LIRIC INSERM U995/Team "Glycation: From Inflammation to Aging," Lille, France ‡Inserm (Institut National de la Santé et de la Recherche Médicale) U1060, Lyon, France §Rouen University Hospital Department of Intensive Care, Rouen, France.
authors.forename: Eugénie
authors.initials: E
authors.lastname: Delile
authors.forename: Rémi
authors.initials: R
authors.lastname: Nevière
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Thiébaut
authors.forename: Julie
authors.initials: J
authors.lastname: Maupoint
authors.forename: Paul
authors.initials: P
authors.lastname: Mulder
authors.forename: David
authors.initials: D
authors.lastname: Coquerel
authors.forename: Sylvanie
authors.initials: S
authors.lastname: Renet
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rieusset
authors.forename: Vincent
authors.initials: V
authors.lastname: Richard
authors.forename: Fabienne
authors.initials: F
authors.lastname: Tamion
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D017353:Gene Deletion; D007333:Insulin Resistance; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000172:deficiency*; D018805:Sepsis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction; D014664:Vasodilation
chemical_list: D009569:Nitric Oxide; D055372:AMP-Activated Protein Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse