Insulin signaling in skeletal muscle and liver of neonatal pigs during endotoxemia.
Sepsis has been associated with tumor necrosis factor alpha (TNF-alpha) and nitric oxide (NO) overproduction, insulin resistance, and a profound suppression of muscle protein synthesis. However, lesser suppression of muscle protein synthesis in neonatal pigs occurs in response to endotoxin (LPS) when glucose and amino acids are provided. We hypothesize that the LPS-induced TNF-alpha and NO overproduction down-regulates insulin signaling pathway activation in neonatal pigs in the presence of fed levels of insulin, glucose, and amino acids. In skeletal muscle, inducible NOS activity was increased in response to LPS infusion, but phosphorylation of the insulin receptor, insulin receptor substrate-1 (IRS-1), p42/p44 mitogen-activated protein kinase (MAPK), and protein kinase B, the association of IRS-1 with phosphatidylinositol 3-kinase (PI 3-kinase), and constitutive NOS activity were not altered. In liver, activation of the insulin receptor, IRS-1, and PI 3-kinase were not affected by LPS, but p42 MAPK phosphorylation was increased. The absence of a down-regulation in the insulin signaling cascade in muscle despite the LPS-induced increase in TNF-alpha and muscle iNOS, may contribute to the near-maintenance of muscle protein synthesis rates in the presence of glucose and amino acids in LPS-infused neonatal pigs.
Orellana
Renán A
RA
Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA. orellana@bcm.edu
Suryawan
Agus
A
Kimball
Scot R
SR
Wu
Guoyao
G
Nguyen
Hanh V
HV
Jefferson
Leonard S
LS
Davis
Teresa A
TA
D000596:Amino Acids / Q000008:administration & dosage; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000139:chemically induced / Q000378:metabolism*; D005947:Glucose / Q000008:administration & dosage; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D008070:Lipopolysaccharides; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000596:Amino Acids; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C440499:lipopolysaccharide, Escherichia coli O111 B4; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D005947:Glucose