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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-EMNR-E (04))
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Laughlin, Maren R
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East Carolina University
Schools of Medicine
United States
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Torres, Maria J; Ryan, Terence E; Lin, Chien-Te et al. (2018) Impact of 17?-estradiol on complex I kinetics and H2O2 production in liver and skeletal muscle mitochondria. J Biol Chem 293:16889-16898
Torres, Maria J; Kew, Kim A; Ryan, Terence E et al. (2018) 17?-Estradiol Directly Lowers Mitochondrial Membrane Microviscosity and Improves Bioenergetic Function in Skeletal Muscle. Cell Metab 27:167-179.e7
Kosaraju, Rasagna; Guesdon, William; Crouch, Miranda J et al. (2017) B Cell Activity Is Impaired in Human and Mouse Obesity and Is Responsive to an Essential Fatty Acid upon Murine Influenza Infection. J Immunol 198:4738-4752
Teodoro, Bruno G; Sampaio, Igor H; Bomfim, Lucas H M et al. (2017) Long-chain acyl-CoA synthetase 6 regulates lipid synthesis and mitochondrial oxidative capacity in human and rat skeletal muscle. J Physiol 595:677-693
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
Alleman, Rick J; Tsang, Alvin M; Ryan, Terence E et al. (2016) Exercise-induced protection against reperfusion arrhythmia involves stabilization of mitochondrial energetics. Am J Physiol Heart Circ Physiol 310:H1360-70
Heden, Timothy D; Neufer, P Darrell; Funai, Katsuhiko (2016) Looking Beyond Structure: Membrane Phospholipids of Skeletal Muscle Mitochondria. Trends Endocrinol Metab 27:553-562
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
Lark, Daniel S; Torres, Maria J; Lin, Chien-Te et al. (2016) Direct real-time quantification of mitochondrial oxidative phosphorylation efficiency in permeabilized skeletal muscle myofibers. Am J Physiol Cell Physiol 311:C239-45
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

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