title: Trauma and hemorrhage-induced acute hepatic insulin resistance: dominant role of tumor necrosis factor-alpha.
abstract: It has long been known that injury, infections, and other critical illnesses are often associated with hyperglycemia and hyperinsulinemia. Mortality of critically ill patients is greatly reduced by intensive insulin therapy, suggesting the significance of reversing or compensating for the development of acute insulin resistance. However, the development of acute injury/infection-induced insulin resistance is poorly studied, much less than the chronic diseases associated with insulin resistance, such as type 2 diabetes and obesity. We previously found that insulin resistance develops acutely in the liver after trauma and hemorrhage. The present study was designed to begin to understand the first steps in the development of trauma and hemorrhage-induced acute hepatic insulin resistance in an animal model of injury and blood loss similar to traumatic or surgical injury and hemorrhage. We present novel data that indicate that hepatic insulin resistance increased dramatically with an increasing extent of hemorrhage. With increasing extent of blood loss, there were increases in serum TNF-alpha levels, phosphorylation of liver insulin receptor substrate-1 on serine 307, and liver c-Jun N-terminal kinase activation/phosphorylation. Exogenous TNF-alpha infusion increased c-Jun N-terminal kinase phosphorylation and insulin receptor substrate-1 serine 307 phosphorylation, and inhibited insulin-induced signaling in liver. Conversely, neutralizing TNF-alpha antibody treatment reversed many of the hemorrhage-induced changes in hepatic insulin signaling. Our data indicate that the acute development of insulin resistance after trauma and hemorrhage may have some similarities to the insulin resistance that occurs in chronic diseases. However, because so little is known about this acute insulin-resistant state, much more needs to be done before we can attain a level of understanding similar to that of chronic states of insulin resistance.
authors.affiliation: Department of Pathology, Division of Molecular and Cellular Pathology, The University of Alabama at Birmingham, Birmingham, Alabama 35294-0019, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.forename: Hyeong T
authors.initials: HT
authors.lastname: Kim
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Ma
authors.forename: Ling
authors.initials: L
authors.lastname: Zhao
authors.forename: Lidong
authors.initials: L
authors.lastname: Zhai
authors.forename: Natalia
authors.initials: N
authors.lastname: Kokorina
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Messina
mesh_terms: D000208:Acute Disease; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D006470:Hemorrhage / Q000150:complications* / Q000473:pathology; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000097:blood / Q000502:physiology*; D014947:Wounds and Injuries / Q000150:complications* / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D018970:Insulin-Like Growth Factor Binding Protein 1; C526296:Irs1 protein, rat; D014409:Tumor Necrosis Factor-alpha; D051058:Oncogene Protein v-akt; D048031:JNK Mitogen-Activated Protein Kinases