Patti, Mary Elizabeth, MD
STARS and SRF: molecular mediators of diabetes risk and novel therapeutic targets
General Research Subject: Type 2 Diabetes
Focus: Insulin Action, Insulin Action\Insulin Resistance, Insulin Action\Metabolism, Integrated Physiology, Integrated Physiology\Insulin Resistance
Type of Grant: Basic Science
Project Start Date: July 1, 2012
Project End Date: June 30, 2015
Despite improvements in prevention and treatment of type 2 diabetes, it remains unknown why some individuals become resistant to the effects of insulin (insulin resistance) or develop diabetes. To find new genes and proteins which contribute to diabetes development, we have examined how genes are turned on and off in leg muscle samples from volunteers with either a family history of diabetes, or individuals with existing type 2 diabetes.
From those studies, we identified a set of proteins, called STARS and SRF, which are present in higher quantities in insulin resistance and type 2 diabetes. Follow-up studies in cells and animals show that if the activity of these proteins is blocked, the amount of glucose taken up into cells is increased, and blood glucose levels are reduced in mice. In addition, reducing the amount of STARS protein causes less weight gain when mice are fed a high-fat diet, a finding which is probably due to increased metabolism and exercise capacity in these mice. These findings indicate that this group of proteins is a potential drug target for diabetes prevention and treatment. Thus, the overall goal of this grant is to determine how this set of proteins regulates energy metabolism. To accomplish this, detailed testing of metabolism in cells with either increased or reduced activity of these proteins will be performed, and effects of blocking this pathway on metabolism and insulin resistance will be tested in both cells and mice.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Our focus on the STARS-SRF pathway 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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