Insulin resistance, which is characterized by the inability of peripheral tissue to respond to insulin, is linked to obesity and hyperlipidemia. Chronic exposure to fatty acids contributes to the development and progression of this disease;however, the exact mechanisms underlying the onset of this condition are unknown. A prominent theory asserts that diminished mitochondrial fat oxidation causes glucose intolerance due do an accumulation of intramuscular lipids. Growing evidence, including data from our lab, dispute this theory. We have shown that the onset of insulin resistance is accompanied by increased, rather than decreased, rates of fat oxidation. These data call into question the development of anti-diabetic drugs aimed at increasing mitochondrial mass and oxidative capacity. Recently, there has been a growing interest in the field of redox signaling. Multiple lines of research demonstrate a negative association between insulin sensitivity and reactive oxygen species (ROS) production. This proposal seeks to explore the link between mitochondrial fat oxidation, redox stress and insulin signaling in skeletal muscle. We hypothesize that mitochondrial lipid overload induces a shift toward an oxidative environment that serves to trigger redoxsensitive pathways involved in the insulin signaling. To this end, we will examine how pharmacological modulation of fatty acid delivery to the mitochondria affects cellular redox status as well as use molecular biology techniques to determine the involvement of redox-sensitive proteins known to affect insulin signaling. These experiments could potentially provide a mechanism by which changes in mitochondrial lipid metabolism are relayed to the rest of the cell. Additionally, we will examine how alterations in fatty acid delivery to the mitochondria in the skeletal muscle affect redox balance and glucose homeostasis in an in vivo mouse model. Completion of these studies will not only provide insights into the role of fatty acid flux through the mitochondria in the development of insulin resistance but also offer important mechanistic information relating mitochondrial stress and insulin signaling.

Public Health Relevance

Obesity and chronic exposure to a high fat diet disrupt glucose disposal into skeletal muscle, which in turn increases risk of metabolic diseases such as type 2 diabetes. By examining obesity-related perturbations in fat and glucose oxidation, this project will aid efforts to understand, treat and prevent insulin resistance and glucose intolerance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DK094573-02
Application #
8368085
Study Section
Special Emphasis Panel (ZDK1-GRB-9 (O1))
Program Officer
Castle, Arthur
Project Start
2011-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$52,190
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705