Trauma and Hemorrhage-Induced Acute Hepatic Insulin Resistance: Dominant Role of Tumor Necrosis Factor-α
- 10 January 2008
- journal article
- research article
- Published by The Endocrine Society in Endocrinology
- Vol. 149 (5), 2369-2382
- https://doi.org/10.1210/en.2007-0922
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-α levels, phosphorylation of liver insulin receptor substrate-1 on serine 307, and liver c-Jun N-terminal kinase activation/phosphorylation. Exogenous TNF-α 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-α 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.Keywords
This publication has 58 references indexed in Scilit:
- Insulin regulation of growth hormone receptor gene expressionMolecular and Cellular Endocrinology, 2007
- Anti-rat soluble IL-6 receptor antibody down-regulates cardiac IL-6 and improves cardiac function following trauma–hemorrhageJournal of Molecular and Cellular Cardiology, 2007
- Mechanism of IL-6-mediated cardiac dysfunction following trauma-hemorrhageJournal of Molecular and Cellular Cardiology, 2006
- Insights into the role of interleukin-6 in the induction of hepatic injury after trauma-hemorrhagic shockJournal of Applied Physiology, 2004
- Akt protects mouse hepatocytes from TNF-α- and Fas-mediated apoptosis through NK-κB activationAmerican Journal of Physiology-Gastrointestinal and Liver Physiology, 2001
- Signalling through the insulin receptorCurrent Opinion in Cell Biology, 2000
- The role of TNFα and TNF receptors in obesity and insulin resistanceJournal of Internal Medicine, 1999
- The mechanism of insulin action.1999
- The JNK Pathway Regulates the In Vivo Deletion of Immature CD4+CD8+ ThymocytesThe Journal of Experimental Medicine, 1998
- Tumor Necrosis Factor Signaling to Stress-activated Protein Kinase (SAPK)/Jun NH2-terminal Kinase (JNK) and p38Journal of Biological Chemistry, 1998