All ETDs from UAB

Advisory Committee Chair

W Timothy Garvey

Advisory Committee Members

Marcas M Bamman

John C Chatham

Stuart J Frank

Joseph Messina

Joanne Murphy-Ullrich

Document Type

Dissertation

Date of Award

2011

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

THE ROLE OF TRIB3 IN INSULIN RESISTANCE: ITS ACTION AS NUTRIENT SENSOR AND REGULATOR OF INSULIN ACTION JIARONG LIU LAMIQUIZ PATHOLOGY ABSTRACT Insulin resistance is a hallmark of Type 2 diabetes (T2DM). A reduced capacity for insulin to stimulate increases in glucose uptake and glucose oxidation in insulin sensitive tissues, such as skeletal muscle and adipose tissue, are common defects in patients with insulin resistance, T2DM, and other related diseases. Tribbles homolog 3 (TRIB3) has been demonstrated to play a role in insulin resistance by serving as a negative regulator of Akt in mouse liver, fat, and pancreas. In a previous microarray study, we have discovered that TRIB3 gene is upregulated in skeletal muscle in diabetic patients compared with insulin sensitive subjects. Therefore, the goal of this research is to explore whether TRIB3 can modulate glucose uptake and oxidation, and play a role in insulin resistance in another insulin target tissue - skeletal muscle. In this dissertation, we report two main functions of TRIB3 in skeletal muscle. Regarding a pathophysiological role for TRIB3, we found that hyperglycemia can induce increments in TRIB3 expression in part through glucose metabolism via the hexosamine biosynthesis pathway. TRIB3 expression is increased in the skeletal muscle of overt diabetic patients and various diabetic rodent models when compared with their normoglycemic controls. Over-expression of TIRB3 in L6-GLUT4 cells leads to decreased insulin-stimulated glucose uptake and cell surface translocation of GULT4 transporter through diminished phosphorylation of IRS-1 and Akt. At the same time, down-regulation elicits increases in both basal and insulin-stimulated glucose uptake by increasing phosphorylation of IRS-1 and Akt. These data for the first time indicate that TRIB3 can contribute to glucose-induced insulin resistance (i.e., "glucose toxicity"). Regarding a physiological role for TRIB3, we found that TRIB3 can also function as a nutrient sensor during short-term nutrient excess and deprivation. Under these conditions, TRIB3 is regulated oppositely (i.e., up- versus down-regulation) in skeletal muscle and adipose tissue, which helps modulate nutrient metabolism in these energy-using and energy-storing tissues, respectively. Muscle TRIB3 is increased while adipose TRIB3 is suppressed after 7 days of western diet feeding in rats. On the other hand, during a short-term fast, muscle TRIB3 is decreased and adipose TRIB3 is upregulated. These changes alternatively alter insulin-sensitive glucose transport depending on the need for nutrient uptake (muscle) or storage (adipose).We also found that TRIB3 can modulate intracellular glucose metabolism. In L6 myotubes, TRIB3 over-expression acutely upregulates mitochondrial glucose oxidation, while suppression of TRIB3 decreases mitochondrial glucose oxidation. We propose that increased TRIB3 expression during nutrient excess limits glucose uptake into muscle and promotes oxidation of intracellular fuel (e.g., glycogen) in skeletal muscle, at the same time the suppression of TRIB3 in adipose increases glucose uptake and allows excess fuel to be stored in fat. In fasting, suppressed muscle TRIB3 increases glucose uptake and restrains glucose oxidation in order to prime the cells for glycogen repletion at the next available meal (nutrient influx), while elevated adipose TRIB3 reduces glucose uptake and fat storage allowing lipolysis to proceed in order to shunt fatty acids to muscle and other tissues. Overall, this work reveals novel roles and molecular mechanisms for TRIB3 in the regulation of insulin signaling transduction, glucose transport, glucose oxidation, and insulin resistance. Moreover, this study provides solid rationale for TRIB3 as a therapeutic target in insulin resistance, T2DM, and related diseases.

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