All ETDs from UAB

Advisory Committee Chair

Timothy W Garvey

Advisory Committee Members

John C Chatham

Yuchang Fu

Andrew J Paterson

Qinglin Yang

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) School of Health Professions

Abstract

Insulin resistance in diabetics comprises of a reversible component treatable with intensive glycemic control and a non-reversible component present in pre-diabetes that may lead to the development of overt diabetes. The reversible component is induced and exacerbated by hyperglycemia in both uncontrolled type 1 and type 2 diabetes, a process known as glucose-induced insulin resistance (GIIR) or glucose toxicity. The tribbles homolog 3 (TRIB3) has been identified as a pseudokinase that inhibits Akt activity by physically blocking its phosphorylation site. Expression of TRIB3 has been associated with various signals such as endoplasmic reticulum (ER) stress and nutrient availability in pancreatic beta cells, liver, adipose tissue and skeletal muscle. As skeletal muscle is the major tissue for insulin-stimulated glucose disposal, our interest in TRIB3 was first initiated when we identified TRIB3 as an upregulated gene in skeletal muscle from T2DM patients using high-density cDNA microarrays. Increased muscle TRIB3 content was repeatedly confirmed in multiple diabetic rodent models. Furthermore, overexpression of TRIB3 decreased, whereas knockdown of TRIB3 increased insulin-stimulated glucose uptake in L6 muscle cells. These data led us to the hypothesis that TRIB3 may act as a glucose sensor and can contribute to glucose-induced insulin resistance (glucose toxicity) in diabetes. In the current investigation, we endeavored to explore both the physiological and pathophysiological roles of TRIB3 in regulating energy metabolism and in the development of glucose-induced insulin resistance (glucose toxicity). In the study of physiological functions of TRIB3, we found that TRIB3 physiologically functions as a nutrient sensor and physiological regulation of TRIB3 is essential for energy balance under varied nutrient conditions. In the study of pathological role of TRIB3 in insulin resistance, we have found that TRIB3 mediates glucose-induced insulin resistance (glucose toxicity) and the mechanisms involves hexosamine biosynthetic pathway. Overall, these studies lead to novel knowledge about the functions and molecular mechanisms of TRIB3 in regulating energy balance and insulin signaling transduction, as well as its role in mediating glucose-induced insulin resistance (glucose toxicity), pointing TRIB3 as a potential target for treating insulin resistance and IR-related complications in diabetes.

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