The underlying mechanism responsible for the development of diet-induced insulin resistance in skeletal muscle remains unresolved. Decreased insulin sensitivity is a key factor in the etiology of type 2 diabetes and, as such, identifying the underlying mechanism of insulin resistance is critical to devising appropriate prevention and treatment strategies. Recent evidence indicates high dietary fat intake increases mitochondrial hydrogen peroxide production and emission in muscle, shifting the intracellular redox environment to a more oxidized state. Blocking the hydrogen peroxide emission through the use of mitochondrial targeted antioxidants prevents the shift in cellular redox environment and preserves insulin sensitivity, providing evidence the mitochondrial respiratory system senses and initiates a counterbalance response to cellular nutritional overload. The long-term objectives of this project are to define the underlying bioenergetics mechanisms regulating mitochondrial hydrogen peroxide production/emission, to determine the impact on and integration with cellular redox systems, and to decipher the mechanism by which redox signaling networks link to the control of insulin sensitivity. The specific goals of this project ae to determine if flux through ?-oxidation is a primary factor governing mitochondrial hydrogen peroxide emission, cellular redox state, and insulin sensitivity;to determine the mechanism(s) regulating hydrogen peroxide production/emission by the pyruvate dehydrogenase complex;and to determine the potential role of hydrogen peroxide induced redox regulation of phosphatase activity as a potential mediator of diet-induced insulin resistance. State-of-the-art mitochondrial function analyses as well as gain- and loss-of-function mouse models will be employed to address these goals. It is anticipated these studies will reveal new insights regarding the underlying mechanism by which metabolic imbalance leads to insulin resistance in skeletal muscle, providing the framework for devising appropriately targeted prevention and/or treatment strategies.

Public Health Relevance

This project seeks to define the underlying mechanism for the decrease in insulin sensitivity that occurs in skeletal muscle in response to nutritional overload, the primary event in the etiology of type 2 diabetes. This is highly significant as understanding the fundamental cause of insulin resistance is essential to devising appropriate preventive and/or treatment measures to reduce the health and financial impact of the obesity and diabetes epidemics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK096907-02
Application #
8511626
Study Section
Special Emphasis Panel (ZRG1-EMNR-E (04))
Program Officer
Laughlin, Maren R
Project Start
2012-07-17
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$339,606
Indirect Cost
$105,593
Name
East Carolina University
Department
Physiology
Type
Schools of Medicine
DUNS #
607579018
City
Greenville
State
NC
Country
United States
Zip Code
27858
Ryan, Terence E; Schmidt, Cameron A; Green, Thomas D et al. (2016) Targeted Expression of Catalase to Mitochondria Protects Against Ischemic Myopathy in High-Fat Diet-Fed Mice. Diabetes 65:2553-68
Heden, Timothy D; Neufer, P Darrell; Funai, Katsuhiko (2016) Looking Beyond Structure: Membrane Phospholipids of Skeletal Muscle Mitochondria. Trends Endocrinol Metab 27:553-62
Murashov, Alexander K; Pak, Elena S; Koury, Michael et al. (2016) Paternal long-term exercise programs offspring for low energy expenditure and increased risk for obesity in mice. FASEB J 30:775-84
Ryan, Terence E; Schmidt, Cameron A; Alleman, Rick J et al. (2016) Mitochondrial therapy improves limb perfusion and myopathy following hindlimb ischemia. J Mol Cell Cardiol 97:191-6
Fisher-Wellman, Kelsey H; Lin, Chien-Te; Ryan, Terence E et al. (2015) Pyruvate dehydrogenase complex and nicotinamide nucleotide transhydrogenase constitute an energy-consuming redox circuit. Biochem J 467:271-80
Nopparat, J; Zhang, J; Lu, J-P et al. (2015) δ-Catenin, a Wnt/β-catenin modulator, reveals inducible mutagenesis promoting cancer cell survival adaptation and metabolic reprogramming. Oncogene 34:1542-52
Ludzki, Alison; Paglialunga, Sabina; Smith, Brennan K et al. (2015) Rapid Repression of ADP Transport by Palmitoyl-CoA Is Attenuated by Exercise Training in Humans: A Potential Mechanism to Decrease Oxidative Stress and Improve Skeletal Muscle Insulin Signaling. Diabetes 64:2769-79
Brown, David A; Hale, Sharon L; Baines, Christopher P et al. (2014) Reduction of early reperfusion injury with the mitochondria-targeting peptide bendavia. J Cardiovasc Pharmacol Ther 19:121-32
Rogers, Carlyle; Davis, Barbara; Neufer, P Darrell et al. (2014) A transient increase in lipid peroxidation primes preadipocytes for delayed mitochondrial inner membrane permeabilization and ATP depletion during prolonged exposure to fatty acids. Free Radic Biol Med 67:330-41
Ryan, Terence E; Brophy, Patricia; Lin, Chien-Te et al. (2014) Assessment of in vivo skeletal muscle mitochondrial respiratory capacity in humans by near-infrared spectroscopy: a comparison with in situ measurements. J Physiol 592:3231-41

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