All ETDs from UAB

Advisory Committee Chair

Joseph L Messina

Advisory Committee Members

Scott W Ballinger

Xu Feng

W Timothy Garvey

C Roger White

Document Type

Dissertation

Date of Award

2009

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Hyperglycemia develops in the intensive care unit in many patients following injury, infection and critical illness. However, little is known about the mechanism of acute development of insulin resistance that causes this hyperglycemia, even though reducing or normalizing the elevated glucose levels has become a major therapeutic target in many ICUs. Using rodent models of injury, acute hepatic insulin resistance occurs within minutes and continues for at least several hours even following fluid resuscitation. We have previously reported that TNF-alpha; is necessary for the hepatic insulin resistance in the rat following resuscitation. However, whether TNF-alpha; plays a role in the acute onset of hepatic insulin resistance is unclear. We found that insulin's ability to induce phosphorylation of insulin signaling molecules were rescued in the TNFR1/2KO mice following resuscitation, but not at early times of development of hepatic insulin resistance, during hemorrhage. This suggests that TNF-alpha; does not play a role in the early development of hepatic insulin resistance following trauma and hemorrhage, but has a key role in the continued insulin resistant state following resuscitation. Reactive oxygen species (ROS) are thought to play a role in the chronic development of insulin resistance and are also increased following injury. Therefore, we investigated the possible association between increased ROS and the acute development of hepatic insulin resistance. In wild type mice, ROS levels were significantly increased during hemorrhage. We then asked whether mice overexpressing SOD2, which endogenously decreases ROS levels, were protected from the development of hepatic insulin resistance following hemorrhage. Insulin's ability to activate insulin signaling in the liver following hemorrhage was maintained by overexpression of SOD2. Furthermore, pretreatment with NAC and MnTBAP decreased ROS levels, and maintained hepatic insulin signaling following hemorrhage. Our data indicate that ROS may play an important role in the early development of hepatic insulin resistance following hemorrhage, whereas TNF-alpha; plays a critical role after the initial development of insulin resistance.

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