Patti, Mary Elizabeth, MD
Molecular Mechanisms of Diabetes Risk
General Research Subject: Type 2 Diabetes
Focus: Insulin Action, Insulin Action\Insulin Resistance, Insulin Action\Metabolism
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2012
Project End Date: June 30, 2016
The goal of research training in the Patti Lab is to assist fellows in developing careers in diabetes investigation. Goals include: (1) learning state-of-the-art techniques, (2) encouraging critical thinking, (3) gaining experience in the design of experiments, analysis of results, and preparation of manuscripts and grants. Achieving these goals is possible given the experience and dedication of the research mentor applicant, and access to faculty and core laboratories of Joslin Diabetes Center, collaborators, and academic environment of Harvard Medical School.
Our long-term goal is to identify molecular mechanisms promoting risk for type 2 diabetes, with a focus on how family history and altered nutrition during pregnancy can change metabolism and increase diabetes risk. Current projects available to fellows include:
(1) Analysis of STARS-SRF pathway: By studying muscle samples from humans, we identified STARS as a gene which is overactive in diabetes; blocking this pathway improves how insulin works, reduces glucose, and improves exercise capacity in mice. Our studies will determine how the STARS-SRF pathway regulates metabolism, and test whether its long-term blockade may be a useful approach to diabetes treatment.
(2) Developmental risk of diabetes: We have recently shown that changes in nutrition during pregnancy reduce the number of stem cells and their function in offspring mice, potentially contributing to decreased muscle and increased fat. We are now using both mouse and human stem cells and iPS cells derived from humans with severe insulin resistance to determine whether nutrition can affect metabolism of stem cells and affect development.
Mentor: Mary Elizabeth Patti, MD Postdoctoral Fellow: Bharti Balhara, MD
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
The overarching long-term goal of my laboratory is to identify molecular mechanisms promoting risk for type 2 diabetes, with a focus on how family history of diabetes and altered nutrition during pregnancy can change metabolism and increase diabetes risk. The postdoctoral fellowship award recipient, Asma Ejaz, PhD, will be working on studies of the STARS-SRF pathway. This project started when we studied muscle biopsy samples from individuals with type 2 diabetes or risk for diabetes. We found that one gene, called STARS, and the proteins it regulates, were markedly overactive in diabetes. Based on this, we began to study the function of this gene and pathway in animals and in muscle cells. Interestingly, we found that blocking this pathway improves how insulin works, reduces glucose, and improves exercise capacity in mice. Our studies will now determine precisely how the STARS-SRF pathway regulates metabolism, and allow us to test whether its long-term blockade may be a useful approach to diabetes treatment.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
I would tell them that studies aimed to understand why some individuals develop diabetes is really important if we are to develop new methods of treatment or prevention. Our planned studies of the STARS-SRF pathway are a great example of this. We need to understand how this pathway can control metabolism in muscle. If we can block this pathway successfully, and it improves blood glucose and metabolism (as our preliminary studies suggest that it can), we can then identify additional chemical compounds which could be tested in mice with obesity and diabetes and perhaps ultimately in patients.
These studies emphasize that we cannot simply jump from idea to clinical trials. Detailed analysis of how compounds work are critical to identify both effective and safe ways to treat diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I care for many patients with diabetes in my role as an endocrinologist, and am absolutely committed to identifying new strategies for prevention and treatment, so that we can reverse the epidemic of obesity and type 2 diabetes. This award has been absolutely crucial to funding my research studies, as grant funding is increasingly difficult to obtain.
In what direction do you see the future of diabetes research going?
Diabetes risk results from a complex interaction between genes and environment (nutrition, lifestyle, body weight). I believe diabetes research will move toward an understanding of how genes and environment interact very early in life, especially during development, to alter metabolism in our cells and organs. These early life changes are likely to set the stage for maladaptive responses to obesity and inactivity during adult life which then increase risk for diabetes.
A second major area of diabetes research which is likely to increase in the future is the renewed focus on metabolism. Type 2 diabetes is a classical metabolic disease, yet regulation of metabolism is not well understood. Recent studies have really provided new ideas about how metabolism can be regulated, and how changes in regulation can also be detected in blood samples, potentially to improve our identification of individuals at risk for diabetes and also to individualize and improve treatment approaches.
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