title: Role of inhibitory κB kinase and c-Jun NH2-terminal kinase in the development of hepatic insulin resistance in critical illness diabetes.
abstract: Hyperglycemia and insulin resistance induced by acute injuries or critical illness are associated with increased mortality and morbidity, as well as later development of type 2 diabetes. The molecular mechanisms underlying the acute onset of insulin resistance following critical illness remain poorly understood. In the present studies, the roles of serine kinases, inhibitory κB kinase (IKK) and c-Jun NH(2)-terminal kinase (JNK), in the acute development of hepatic insulin resistance were investigated. In our animal model of critical illness diabetes, activation of hepatic IKK and JNK was observed as early as 15 min, concomitant with the rapid impairment of hepatic insulin signaling and increased serine phosphorylation of insulin receptor substrate 1. Inhibition of IKKα or IKKβ, or both, by adenovirus vector-mediated expression of dominant-negative IKKα or IKKβ in liver partially restored insulin signaling. Similarly, inhibition of JNK1 kinase by expression of dominant-negative JNK1 also resulted in improved hepatic insulin signaling, indicating that IKK and JNK1 kinases contribute to critical illness-induced insulin resistance in liver.
authors.affiliation: Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019, USA.
authors.forename: Shaoning
authors.initials: S
authors.lastname: Jiang
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Messina
mesh_terms: D000818:Animals; D016638:Critical Illness; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004789:Enzyme Activation; D006470:Hemorrhage / Q000503:physiopathology; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000502:physiology*; D007328:Insulin / Q000502:physiology; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D008099:Liver / Q000293:injuries / Q000378:metabolism; D008297:Male; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases