title: NF-κB-dependent airway inflammation triggers systemic insulin resistance.
abstract: Inflammatory lung diseases (e.g., pneumonia and acute respiratory distress syndrome) are associated with hyperglycemia, even in patients without a prior diagnosis of Type 2 diabetes. It is unknown whether the lung inflammation itself or the accompanying comorbidities contribute to the increased risk of hyperglycemia and insulin resistance. To investigate whether inflammatory signaling by airway epithelial cells can induce systemic insulin resistance, we used a line of doxycycline-inducible transgenic mice that express a constitutive activator of the NF-κB in airway epithelial cells. Airway inflammation with accompanying neutrophilic infiltration was induced with doxycycline over 5 days. Then, hyperinsulinemic-euglycemic clamps were performed in chronically catheterized, conscious mice to assess insulin action. Lung inflammation decreased the whole body glucose requirements and was associated with secondary activation of inflammation in multiple tissues. Metabolic changes occurred in the absence of hypoxemia. Lung inflammation markedly attenuated insulin-induced suppression of hepatic glucose production and moderately impaired insulin action in peripheral tissues. The hepatic Akt signaling pathway was intact, while hepatic markers of inflammation and plasma lactate were increased. As insulin signaling was intact, the inability of insulin to suppress glucose production in the liver could have been driven by the increase in lactate, which is a substrate for gluconeogenesis, or due to an inflammation-driven signal that is independent of Akt. Thus, localized airway inflammation that is observed during inflammatory lung diseases can contribute to systemic inflammation and insulin resistance.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee;
authors.forename: Travis J
authors.initials: TJ
authors.lastname: Cyphert
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee; Biomedical Sciences, Missouri State University, Springfield, Missouri; and.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Morris
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee; College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee;
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: House
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee;
authors.forename: Tammy M
authors.initials: TM
authors.lastname: Barnes
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee;
authors.forename: Yolanda F
authors.initials: YF
authors.lastname: Otero
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Whitney J
authors.initials: WJ
authors.lastname: Barham
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Raphael P
authors.initials: RP
authors.lastname: Hunt
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Rinat
authors.initials: R
authors.lastname: Zaynagetdinov
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Yull
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee; Owen.McGuinness@vanderbilt.edu.
authors.forename: Owen P
authors.initials: OP
authors.lastname: McGuinness
mesh_terms: D000818:Animals; D001249:Asthma; D001786:Blood Glucose / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance; D008168:Lung / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D011014:Pneumonia / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D016207:Cytokines; D007328:Insulin; D016328:NF-kappa B
keywords: glucose production; interleukin-5; tumor necrosis factor