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Title: Insulin signaling in skeletal muscle and liver of neonatal pigs during endotoxemia

item ORELLANA, RENAN - Children'S Nutrition Research Center (CNRC)
item SURYAWAN, AGUS - Children'S Nutrition Research Center (CNRC)
item KIMBALL, SCOT - Pennsylvania State University
item WU, GUOYAO - Texas A&M University Health Science Center
item NGUYEN, HANH - Children'S Nutrition Research Center (CNRC)
item JEFFERSON, LEONARD - Pennsylvania State University
item DAVIS, TERESA - Children'S Nutrition Research Center (CNRC)

Submitted to: Pediatric Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/2/2008
Publication Date: 11/1/2008
Citation: Orellana, R.A., Suryawan, A., Kimball, S.R., Wu, G., Nguyen, H.V., Jefferson, L.S., Davis, T.A. 2008. Insulin signaling in skeletal muscle and liver of neonatal pigs during endotoxemia. Pediatric Research. 64(5):505-510.

Interpretive Summary: In the present study, we discovered that newly born animals are different from adults in that insulin is able to activate the signals in muscle that lead to muscle growth, in spite of substances that normally deactivate those signals when an infection occurs, which in adult animals translates into insulin resistance. This finding is important because it may lead to understand mechanisms that protect the muscle during illness that can be targeted by nutritional and drug therapies, and therefore be beneficial to prevent muscle loss during illness in humans at different ages.

Technical Abstract: 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.