Insulin resistance and hyperglycemia are characteristic metabolic responses to infections (sepsis) and injury such as surger, burns, trauma and hemorrhage. Recent data suggests that intensive insulin treatment of patients reduces both morbidity and mortality associated with critical illness. However, little is known concerning the role of insulin resistance in the liver and the importance of this resistance in the physiological responses to injury. The liver plays a central role in the development of hyperglycemia and insulin is a primary modulator of hepatic glucose output. Thus, it is important to understand what causes hepatic insulin resistance, and the role this resistance plays in mortality following injury. The few research studies performed to date have focused on changes in insulin signaling in skeletal muscle following different kinds of injury or hemorrhage. Insulin resistance can be explained by changes in the number of insulin receptors or their activity, or a post-receptor defect. Little is known about the cellular mechanisms by which the liver becomes resistant to insulin and the mechanisms and potential reversibility of trauma and hemorrhage-induced insulin resistance in the liver is the subject of this proposal. Preliminary studies suggest that hepatic insulin resistance develops rapidly following surgical trauma and hemorrhage. Proinflammatory cytokines may be involved in the development of this insulin resistance, and there is a defect in at least one insulin regulated signaling pathway.
The aims of this proposal are to characterize the effects of experimental trauma (surgery) and hemorrhage on the development of hepatic insulin resistance, to investigate the mechanisms and causative factors leading to the insulin resistance and to determine whether insulin sensitizing agents can reverse or prevent the development of hepatic insulin resistance following trauma and hemorrhage. These studies are important in understanding the role of insulin resistance in the morbidity and mortality following various types of infections, surgery, burns, trauma and hemorrhage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK062071-02
Application #
6896609
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Serrano, Jose
Project Start
2004-06-01
Project End
2009-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
2
Fiscal Year
2005
Total Cost
$319,000
Indirect Cost
Name
University of Alabama Birmingham
Department
Pathology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Akscyn, Robert M; Franklin, J Lee; Gavrikova, Tatyana A et al. (2017) Polytrauma-induced hepatic stress response and the development of liver insulin resistance. Biochim Biophys Acta Mol Basis Dis 1863:2672-2679
Franklin, J Lee; Bennett, William L; Messina, Joseph L (2017) Insulin attenuates TNF?-induced hemopexin mRNA: An anti-inflammatory action of insulin in rat H4IIE hepatoma cells. Biochem Biophys Rep 9:211-216
Franklin, J Lee; Amsler, Maggie O; Messina, Joseph L (2016) Prenylation differentially inhibits insulin-dependent immediate early gene mRNA expression. Biochem Biophys Res Commun 474:594-598
Akscyn, Robert M; Franklin, John L; Gavrikova, Tatyana A et al. (2016) Skeletal muscle atrogene expression and insulin resistance in a rat model of polytrauma. Physiol Rep 4:
Akscyn, Robert M; Franklin, J Lee; Gavrikova, Tatyana A et al. (2015) A rat model of concurrent combined injuries (polytrauma). Int J Clin Exp Med 8:20097-110
Li, Li; Li, Xiaohua; Zhou, Wenjun et al. (2013) Acute psychological stress results in the rapid development of insulin resistance. J Endocrinol 217:175-84
Corrick, Ryan M; Li, Li; Frank, Stuart J et al. (2013) Hepatic growth hormone resistance after acute injury. Endocrinology 154:1577-88
Williams, Vanessa L; Martin, Rachel E; Franklin, John L et al. (2012) Injury-induced insulin resistance in adipose tissue. Biochem Biophys Res Commun 421:442-8
Jiang, Shaoning; Gavrikova, Tatyana A; Sharifov, Oleg F et al. (2012) Role of tissue macrophages in the development of critical illness diabetes. Shock 37:70-6
Zhai, Lidong; Ballinger, Scott W; Messina, Joseph L (2011) Role of reactive oxygen species in injury-induced insulin resistance. Mol Endocrinol 25:492-502

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