Type 2 Diabetes Is Associated with Altered NF-κB DNA Binding Activity, JNK Phosphorylation, and AMPK Phosphorylation in Skeletal Muscle after LPS

• Published in: PloS one Vol. 6; no. 9; p. e23999
• Main Authors: Andreasen, Anne Sofie, Kelly, Meghan, Berg, Ronan Martin Griffin, Møller, Kirsten, Pedersen, Bente Klarlund
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13.09.2011; Public Library of Science (PLoS)
• Subjects: Acetyl-CoA carboxylase; Acetyl-CoA Carboxylase - metabolism; Adult; Age; Aged; AMP; AMP-activated protein kinase; AMP-Activated Protein Kinases - metabolism; Binding; Biology; Biopsy; c-Jun protein; Clinical Trial; Cytokines; Deoxyribonucleic acid; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Diabetes Mellitus, Type 2 - physiopathology; DNA; DNA - metabolism; Drug delivery systems; E coli; Enzyme-linked immunosorbent assay; Ethical standards; Ethics; Family medical history; Fatty acids; Gene expression; Gene Expression Regulation - drug effects; Glucose; Glucose metabolism; Glucose tolerance; Humans; Hyperglycemia; Infectious diseases; Inflammation; Informed consent; Insulin Resistance; Intensive care; Interleukin 6; Intermediates; Intravenous administration; JNK Mitogen-Activated Protein Kinases - metabolism; JNK protein; Kinases; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Male; Medicine; Metabolism; Middle Aged; Muscle, Skeletal - drug effects; Muscle, Skeletal - enzymology; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Musculoskeletal system; NF-κB protein; Oxidation; Patients; Phosphorylation; Phosphorylation - drug effects; Plasma; Polymerase chain reaction; Protein Binding - drug effects; Protein expression; Proteins; Reverse transcription; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sepsis; Signal transduction; Skeletal muscle; TNF inhibitors; Transcription Factor RelA - genetics; Transcription Factor RelA - metabolism; Transcription factors; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Western blotting; Denmark
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0023999

Systemic inflammation is often associated with impaired glucose metabolism. We therefore studied the activation of inflammatory pathway intermediates that interfere with glucose uptake during systemic inflammation by applying a standardised inflammatory stimulus in vivo. After ethical approval, informed consent and a thorough physical examination, 10 patients with type 2 diabetes and 10 participants with normal glucose tolerance (NGT) were given an intravenous bolus of E. coli lipopolysaccharide (LPS) of 0.3 ng/kg. Skeletal muscle biopsies and plasma were obtained at baseline and two, four and six hours after LPS. Nuclear factor (NF)-κB p65 DNA binding activity measured by ELISA, tumor necrosis factor-α and interleukin-6 mRNA expression analysed by real time reverse transcription polymerase chain reaction, and abundance of inhibitor of NF-κB (IκB)α, phosphorylated c-Jun-N-terminal kinase (JNK), AMP-activated protein kinase (AMPK), and acetyl-CoA carboxylase measured by Western blotting were detected in muscle biopsy samples. Relative to subjects with NGT, patients with type 2 diabetes exhibited a more pronounced increase in NF-κB binding activity and JNK phosphorylation after LPS, whereas skeletal muscle cytokine mRNA expression did not differ significantly between groups. AMPK phosphorylation increased in volunteers with NGT, but not in those with diabetes. The present findings indicate that pathways regulating glucose uptake in skeletal muscle may be involved in the development of inflammation-associated hyperglycemia. Patients with type 2 diabetes exhibit changes in these pathways, which may ultimately render such patients more prone to develop dysregulated glucose disposal in the context of systemic inflammation. ClinicalTrials.gov NCT00412906.