mTOR signaling in the control of glucose homeostasis
General Research Subject: Insulin Resistance Pre Diabetes
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2011
Project End Date: June 30, 2015
Type 2 diabetes is largely thought to result from the body's desensitization to signals that convey nutrient and energy levels that in a modern lifestyle can be excessively high. The mTOR kinase functions in two distinct complexes called mTORC1 and mTORC2 that coordinate cell growth with the availability of nutrients and energy. Our preliminary results demonstrate that inhibition of mTOR with the drug rapamycin causes glucose intolerance similar to type 2 diabetes. The proposed research will examine the mechanisms through which rapamycin affects glucose homeostasis in mice. Furthermore, as calorie restriction improves glucose homeostasis and downregulates mTOR signaling, the proposed research will determine if decreased food intake improves glucose homeostasis via either mTORC1 or mTORC2.
Mentor: Sabatini, David, MD, PhD Postdoctoral Fellow: Cantor, Jason
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Our research project focuses on understanding the role of mTOR, an essential regulator of metabolism and responsive to nutrients, in the regulation of hepatic glucose production and sensitivity to insulin. Hepatic insulin resistance is one of the primary effects of the metabolic syndrome, and metformin, the first line treatment for type 2 diabetes, acts in part by suppressing hepatic glucose production. We have proposed to determine the involvement of mTOR signaling in the regulation of hepatic insulin resistance in response to rapamycin, an FDA approved drug that acts as a specific inhibitor of mTOR. Our preliminary results indicate that mTOR does regulate hepatic glucose production and insulin sensitivity, although we have yet to determine the exact mechanism. We are further seeking to determine if mTOR signaling is involved in the response to metformin and calorie restriction, interventions that promote hepatic insulin sensitivity. By better understanding the mechanism, we may be able to develop drugs that are more effective at the treatment or prevention of diabetes.
Why is it important for you, personally, to become involved in diabetes research?
I would say that our research has the goal of understanding the pathogenesis of diabetes. In the longer term, we think that the activation of mTORC2, which our preliminary results indicate regulate gluconeogenesis, may prove to be valuable in the treatment of diabetes. Indirectly regulating mTORC2 may be a mechanism by which metformin, the first line treatment for type 2 diabetes, functions, and we may be able to develop better compounds.
What role will this award play in your research efforts?
Diabetes is such an important medical problem in our society today - as
obesity continues to increase, the rate of type 2 diabetes has exploded.
Our work on mTOR signaling has led us to the understanding that mTOR
signaling is central to the normal regulation of blood glucose. As an
MD/PhD I was very excited at the chance of tackling such an important
medical problem, and potentially improving the lives of so many people
with this increasingly prevalent disease.
In what direction do you see the future of diabetes research going?
I think diabetes research is going to increasingly focus on the molecular mechanism by diabetes develops and understanding how anti-diabetic drugs works. My lab is interested in determining how mTOR regulates diabetes with the goal of finding new and better ways to treat it.
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