Disassociation of muscle insulin signaling and insulin-stimulated glucose uptake during endotoxemia.

Mulligan KX, Morris RT, Otero YF, Wasserman DH, McGuinness OP
PLoS One. 2012 7 (1): e30160

PMID: 22276152 · PMCID: PMC3262801 · DOI:10.1371/journal.pone.0030160

Lipopolysaccharide (LPS) elicits a strong immune response, which leads to the release of inflammatory cytokines. Increased cytokine production has been shown to impair insulin-mediated glucose disposal. LPS can alter other factors, such as muscle blood flow and insulin signaling in the myocyte, that can influence glucose disposal. We hypothesize that LPS induced impairments in cardiovascular function contribute to the associated impairments in insulin action in vivo. Male wild-type C57BL/6J mice had a catheter implanted in the jugular vein for infusions and the carotid artery for sampling 5 days prior to the hyperinsulinemic-euglycemic clamp. Mice were treated with vehicle, low- (1 ug/gBW) or high-dose (10 ug/gBW) LPS 4 hours prior to the clamp. Muscle glucose uptake (MGU) was assessed using [2-(14)C] deoxyglucose. While both low- and high-dose LPS inhibited insulin-stimulated MGU compared to vehicle-treated mice, the impairment was more significant with the high-dose treatment (∼25% in soleus and ∼70% in both gastrocnemius and vastus lateralis). Interestingly, insulin signaling through the PI3-kinase pathway in the muscle was not affected by this treatment suggesting that the decrease in MGU is not directly due to impairments in muscle insulin action. Echocardiography demonstrated that high-dose LPS treatment significantly decreased stroke volume (∼30%), heart rate (∼35%), and cardiac output (∼50%). These observations were not seen with vehicle or low-dose LPS treatment. High-dose LPS treatment also significantly decreased muscle blood flow (∼70%) and whole body oxygen consumption (∼50%). Thus, in vivo acute endotoxemia does not impair insulin signaling through the PI3-kinase pathway in skeletal muscle and decreased tissue blood flow likely plays a central role in the impairment of glucose uptake in the muscle.

MeSH Terms (19)

Animals Biological Transport Blood Pressure Blotting, Western Echocardiography Endotoxemia Glucose Insulin Interleukin-1beta Interleukin-6 Interleukin-10 Lipopolysaccharides Male Mice Mice, Inbred C57BL Radioimmunoassay Rats Real-Time Polymerase Chain Reaction Tumor Necrosis Factor-alpha

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