Harris, Thurl E.
Lipid-mediated regulation of mTOR activity
General Research Subject: Insulin Resistance Pre Diabetes
Focus: Insulin Action\Insulin Resistance, Insulin Action\Metabolism, Insulin Action\Signal Transduction
Type of Grant: Junior Faculty
Project Start Date: July 1, 2011
Project End Date: June 30, 2014
Lipids are essential building blocks for cell growth and proliferation, yet can also inhibit the ability of insulin to promote glucose disposal. This study proposes that cellular lipid status is an unrecognized and important metabolic input that is coordinated by the protein mTOR to control cell growth and metabolism. The cellular mechanisms underlying lipid-mediated control of mTOR will be investigated. These studies may lead to the development of a new class of compounds capable of inhibiting mTOR by the novel mechanism of complex dissociation, leading to mew treatments to improve glucose uptake.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
How obesity impairs insulin sensitivity is a critical question in diabetes research. The mTOR complex plays an essential role integrating cellular metabolites such as glucose and amino acids with growth factor status to control cell growth and metabolism. Our findings have led to us to hypothesize that cellular lipid status can also regulate mTOR activity. There is increasing evidence that mTOR is activated in obesity, resulting in negative feedback towards the insulin signaling pathway. Precisely why mTOR is activated in obese individuals is not clear, although several mechanisms have been proposed. This project will examine how lipids can regulate mTOR during obesity, and the functional consequences thereof. Determining how mTOR is controlled may uncover therapeutic approaches for ameliorating obesity-induced insulin resistance.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Obesity-induced diseases include hypertension, cardiovascular disease, insulin resistance, and hyperlipidemia. In the year 2010, it was estimated that 68% of the U.S. population could be defined as overweight or obese, with a body mass index (BMI) >25.0, with fully one third being morbidly obese (BMI>30). My studies have focused on mTOR signaling in insulin responsive tissues such as skeletal muscle and fat in order to understand the molecular basis of insulin resistance. As a central integrator of metabolic status, the proper control of mTOR activity in the metabolite-replete state of obesity is crucial for whole body glucose disposal. By defining the molecular mechanisms controlling mTOR activity we believe that we will uncover how mTOR becomes dysregulated in obesity. Our long term goal is to identify how to improve insulin signaling in insulin resistant individuals.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Among all racial and ethnic groups in the U.S., it is American Indians that have the highest prevalence of type II diabetes. As a member of the Chickasaw nation, I have seen first-hand the terrible toll that diabetes can take. By understanding how mTOR functions under conditions of obesity improved methods for preventing, or even reversing, obesity-induced insulin resistance can be realized. My training in insulin signaling, animal physiology and lipid metabolism has prepared me for these investigations into mTOR signaling. Importantly, the results from this proposal will greatly aid me to become competitive for funding from the NIH to continue my studies into obesity-induced insulin resistance.
In what direction do you see the future of diabetes research going?
The increasing incidence of diabetes in the USA is largely driven by the rise in obesity and decreasing physical activity. Understanding how obesity induces insulin resistance will be of the utmost importance in diabetes research. Ultimately, a complete understanding of obesity-driven insulin resistance will require integrating our knowledge of cellular mechanisms with animal and human physiology. Only when candidate pathways are examined in the context of the whole organism will we be able to identify those that can be targeted to reduce the pathologies that arise from obesity-induced insulin resistance. In addition, human genetic studies will be important for identifying potential molecular targets.
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