All ETDs from UAB

Advisory Committee Chair

Joseph L Messina

Advisory Committee Members

Jeonga Kim

John D Mountz

Alexander Pereboev

Selvarangan Ponnazhagan

Document Type

Dissertation

Date of Award

2010

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Insulin resistance commonly occurs following injuries or critical illness independent of previous diabetic status. The development of insulin resistance and hyperglycemia is associated with increased mortality and morbidity in critically ill patients. However, the molecular mechanisms underlying the acute insulin resistance following injuries remain poorly understood. With an animal model of trauma and hemorrhage, we have previously demonstrated the rapid development of insulin resistance in liver, and a critical role of TNFα in hemorrhage-induced defects in insulin signaling following resuscitation. However, hepat-ic insulin signaling is impaired prior to a significant increase in plasma TNFα, suggesting the initial development of hemorrhage-induced hepatic insulin resistance may be TNFα independent. By inhibiting the activity of TNFα or reactive oxygen species (ROS), our current studies further demonstrated that elevated ROS is responsible for the initial development of hepatic insulin resistance following hemorrhage, while TNFα has a dominant role later, following resuscitation. The mechanisms by which ROS induces the rapid development of hepatic insulin resistance were next investigated. Both Inhibitory-κB kinases (IKK) and c-Jun N-terminal kinase (JNK) can be activated by ROS and inhibit insulin signaling, potentially by increasing serine phosphorylation of insulin receptor (IR) or insulin receptor substrates (IRSs). Activation of hepatic IKK and JNK was observed as early as 15 minutes after trauma and hemorrhage, which was concomitant with the rapid impairment of hepatic insulin signaling. The important roles of IKK and JNK in the early development of hemorrhage-induced insulin resistance were further demonstrated by direct inhibition of the IKKs (IKKα and ß) and JNK1 with adenovirus-mediated expression of dominant negative mutants of IKKs and JNK1 in liver. Using two approaches of Kupffer cell-depletion, we further demonstrated that the early development of hemorrhage-induced hepatic insulin resistance and activation of IKK and JNK are Kupffer cell independent. Thus, acute activation of IKK and JNK likely occurs within hepatocytes where they directly interact with IR or IRS proteins and inhibit insulin signaling. In conclusion, our studies provide mechanistic insights into the acute onset of hepatic insulin resistance following injury. IKK and JNK are potential therapeutic targets for treating hyperglycemia in the Intensive Care Unit.

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