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Type 2 diabetes is associated with altered NF-?B DNA binding activity, JNK phosphorylation, and AMPK phosphorylation in skeletal muscle after LPS.

ABSTRACT: 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)-?B p65 DNA binding activity measured by ELISA, tumor necrosis factor-? and interleukin-6 mRNA expression analysed by real time reverse transcription polymerase chain reaction, and abundance of inhibitor of NF-?B (I?B)?, 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-?B 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.

SUBMITTER: Andreasen AS

PROVIDER: S-EPMC3172218 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Type 2 diabetes is associated with altered NF-κB DNA binding activity, JNK phosphorylation, and AMPK phosphorylation in skeletal muscle after LPS.

Andreasen Anne Sofie AS Kelly Meghan M Berg Ronan Martin Griffin RM Møller Kirsten K Pedersen Bente Klarlund BK

PloS one 20110913 9

<h4>Unlabelled</h4>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 ...[more]

PMID: 21931634

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Project description:Aims/hypothesisInsulin-mediated signals and AMP-activated protein kinase (AMPK)-mediated signals are activated in response to physiological conditions that represent energy abundance and shortage, respectively. Focal adhesion kinase (FAK) is implicated in insulin signalling and cancer progression in various non-muscle cell types and plays a regulatory role during skeletal muscle differentiation. The role of FAK in skeletal muscle in relation to insulin stimulation or AMPK activation is unknown. We examined the effects of insulin or AMPK activation on FAK phosphorylation in human skeletal muscle and the direct role of FAK on glucose and lipid metabolism. We hypothesised that insulin treatment and AMPK activation would have opposing effects on FAK phosphorylation and that gene silencing of FAK would alter metabolism.MethodsHuman muscle was treated with insulin or the AMPK-activating compound 5-aminoimadazole-4-carboxamide ribonucleotide (AICAR) to determine FAK phosphorylation and glucose transport. Primary human skeletal muscle cells were used to study the effects of insulin or AICAR treatment on FAK signalling during serum starvation, as well as to determine the metabolic consequences of silencing the FAK gene, PTK2.ResultsAMPK activation reduced tyrosine phosphorylation of FAK in skeletal muscle. AICAR reduced p-FAKY397 in isolated human skeletal muscle and cultured myotubes. Insulin stimulation did not alter FAK phosphorylation. Serum starvation increased AMPK activation, as demonstrated by increased p-ACCS222, concomitant with reduced p-FAKY397. FAK signalling was reduced owing to serum starvation and AICAR treatment as demonstrated by reduced p-paxillinY118. Silencing PTK2 in primary human skeletal muscle cells increased palmitate oxidation and reduced glycogen synthesis.Conclusions/interpretationAMPK regulates FAK signalling in skeletal muscle. Moreover, siRNA-mediated FAK knockdown enhances lipid oxidation while impairing glycogen synthesis in skeletal muscle. Further exploration of the interaction between AMPK and FAK may lead to novel therapeutic strategies for diabetes and other chronic conditions associated with an altered metabolic homeostasis.

Dataset Information

Type 2 diabetes is associated with altered NF-?B DNA binding activity, JNK phosphorylation, and AMPK phosphorylation in skeletal muscle after LPS.

Publications

Type 2 diabetes is associated with altered NF-κB DNA binding activity, JNK phosphorylation, and AMPK phosphorylation in skeletal muscle after LPS.

Similar Datasets

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