How do deficient insulin signaling pathways affect skeletal muscle growth, maintenance, and function in a rodent model of type 2 diabetes mellitus?
General Research Subject: Insulin Resistance Pre Diabetes
Focus: Insulin Action\Signal Transduction, Integrated Physiology\Muscle, Pediatrics\Type 2
Type of Grant: Clinical Scientist Training Award
Project Start Date: July 1, 2011
Project End Date: June 30, 2014
Type II diabetes mellitus is a disease in which the body is unable to maintain normal levels of sugar in the blood because the body does not respond well to the insulin hormone. The number of people with diabetes is rapidly increasing, not only in adults, but also adolescents and children. Previous researchers have shown that some people with diabetes have smaller and weaker muscles. Preliminary data show that a mouse model of type II diabetes mellitus (db/db model) has much smaller muscles than healthy mice and cannot run as fast, even when these mice are very young. This young age of onset of muscle problems in diabetic mice is important because it happens before the mice become fully diabetic. This means that insulin resistance in young people that are prediabetic may cause problems with growth and maintenance of their muscles. The authors hypothesize that signaling pathways activated by insulin are needed for normal muscle growth, and that when the muscle is resistant to insulin, the muscle cannot grow properly. The authors propose two main aims: 1.) to fully understand the maturity, growth, and function of muscle in young and old diabetic mice, and 2.) to prove using gene transfer the mechanism by which insulin resistance leads to problems with muscle growth. Results from these experiments will help provide a basis for the future prevention and treatment of skeletal muscle atrophy in type II diabetes mellitus in youth and adults.
Mentor: Periasamy, Muthu, PhD Postdoctoral Fellow: Ostler, Joseph Eldon
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Growing evidence suggests that diabetes compromises muscle growth resulting in muscle atrophy. The major goal of our research is to understand how resistance to insulin (as seen in Type 2 diabetes mellitus) in muscle impairs muscle growth and function (strength). We will be using a mouse model of Type 2 diabetes mellitus to understand 1.) the timing of onset (early prediabetes vs. advanced hyperglycemia) and characteristics of muscle dysfunction, 2.) key cell signaling pathways that cause this muscle dysfunction, and 3.) Growth-promoting treatments that best improve muscle function in Type 2 diabetes mellitus.
An important goal of this project is to develop strategies to improve diabetic muscle health, which is of particular relevance to older individuals with diabetes, as decreased muscle size and strength in diabetics are associated with an increased risk of falls and associated fractures, as well as prolonged recovery times from these incidents. This research will also suggest if muscle wasting occurs in individuals with prediabetes or just in chronic advanced diabetes. If muscle growth and function is impaired early in the development of diabetes, this may be an important factor to address clinically when a clinician prescribes exercise as an early intervention to prevent the progression of a prediabetic patient. Finally, in addition to reducing the risk for serious injury, improving muscle growth and strength is important to the overall treatment of diabetes because it has been shown to decrease blood glucose levels, and facilitates compliance with doctor-mandated exercise (which also helps to decrease blood glucose levels).
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Our research will help to understand why people with diabetes have poor tolerance to exercise especially why their muscle becomes small and week. Poor muscle growth in diabetic patens will limit physical activity , to perform exercise, even normal activities around the house, and to maintain balance as you age so you don't fall and become seriously injured. In humans and animal with diabetes, it is clear that muscle does not grow normally and actually decreases in strength and size. Our sincere hope is that this research will lead to an understanding of how diabetes is affecting the muscles in your body, and begin to explore possible treatments to improve muscle strength and growth. Because muscle is a large consumer of glucose, improved muscle health will also help to better regulate your blood glucose levels, and will make it easier to complete the regular exercise that your doctor recommends to treat your diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
It is important for me personally to become involved in diabetes research because it affects several people close to me, including myself. In addition, an enormous and growing number of people from my country of birth, India, as well as my country of citizenship, the United States of America are currently struggling with the many clinical complications of diabetes. For many years I have been researching the biochemistry and physiology of healthy and diseased muscle. This award will allow us the financial freedom to thoroughly apply our expertise in studying muscle to an area of much need - diabetes.
In what direction do you see the future of diabetes research going?
The future of diabetes research is very bright. Many excellent
scientific tools from a variety of fields are becoming widely available
to probe the intricate pathways controlling metabolism. Due to our
rapidly developing understanding of the connections between cell
signaling and metabolism, I foresee that an increasing number of
rationally designed and mechanistically-targeted pharmaceutical
interventions will be developed in the next two decades that will
greatly improve our control of insulin resistance and the progression of
diabetes. In addition to these pharmaceutical improvements, I believe
that research will also lead to a drastic improvement in support
programs and technologies for diabetics to facilitate consistent
long-term compliance with the interventions that have and will be
discovered to prevent and control diabetes.
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