Dong, Lily Q., PhD
The role of APPL2 in regulating insulin sensitivity in vivo
General Research Subject: Type 2 Diabetes
Focus: Insulin Action, Insulin Action\Insulin Resistance, Insulin Action\Metabolism, Signal Transduction (Non-Insulin Action), Signal Transduction (Non-Insulin Action)\Hormones
Type of Grant: Basic Science
Project Start Date: July 1, 2013
Project End Date: June 30, 2016
Diabetes Type: Type 2 diabetes
Insulin resistance has been well documented as an important factor leading to type 2 diabetes and metabolism disorders, but the reasons for causing this problem are largely unknown. We have recently identified a molecule called APPL2 in muscle cells that may initial this problem. The proposed study is to test if the mice can maintain healthy under over nutrition condition when we remove this trouble-making gene from the liver. Results from this study may lead to the development of new therapeutic drugs to prevent insulin resistance and type 2 diabetic disease.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
This project covers the areas of adiponectin signaling and its effects on glucose metabolism. Adiponectin, a hormone synthesized by and released from fat, has insulin-sensitizing and anti-diabetic effects. How adiponectin mediates its effects is largely unknown at this time. Recently, we discovered that APPL2, an intracellular signaling protein, binds to adiponectin receptors and blocks adiponectin signaling. This project focuses on characterizing the physiological role of APPL2 in mouse liver tissue. These results will be the first step to designing future human studies. Ultimately, determining how adiponectin mediates its effects on glucose metabolism and how it improves insulin sensitivity could aid in the development of new insulin-sensitizing drugs for the prevention and treatment of diabetes.
If a person with diabetes were to ask you how your project will help them in the future,
how would you respond?
This project will study how adiponectin mediates its effects in the body. Adiponectin is a hormone made by fat and released into the blood where it can have effects all over the body. Adiponectin has been shown to control sugar (glucose) metabolism, but how adiponectin increases metabolism is not known. Adiponectin levels have been shown to be low in obese and type 2 diabetic patients. These patients are also insulin resistant, meaning the insulin their body makes does not work as well as it should. Insulin resistance results in less glucose being taken up by muscle and fat after a meal is eaten; therefore, blood glucose levels remain higher for a longer period of time. Over time the elevated glucose levels can cause damage to the body such as blindness, decreased kidney function resulting in the need for dialysis, as well as decreased blood flow to the extremities leading to possible amputation. A number of studies suggest that adiponectin may improve the ability of insulin to work.
We are interested in discovering how adiponectin works on a cellular and aninal levels. At this point researchers have shown that there are two receptors on the outside of cells that adiponectin binds to. How adiponectin mediates its effects on metabolism inside the cell is not known. We have discovered a protein inside the cell which appears to be involved, called APPL2. We intend to gain a better understanding of how this protein and others are involved in adiponectin signaling. When we know better how the hormone works, we can determine if it is working normally in human patients with insulin resistance and diabetes. If it is not, then we can labor to develop potential treatments, such as sensitizing drugs, to prevent and/or correct the problem.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I choose to investigate Type 2 Diabetes as my career for the following reasons:
1) Type 2 Diabetes affects millions of Americans each year and is particularly serious in South Texas where I live. It is the leading cause of kidney failure, blindness and amputation in adults and is one of the major health problems that affect the quality of life in this country. As a scientist, I strongly feel that I should dedicate my life to understanding the cause of this serous disease.
2) I have been involved in diabetes research for more than 17 years. I have experience with the approaches used in diabetes research and I know the direction we should pursue to reach the goal. I feel confident of the career I choose.
The ADA Research Award will definitely help me build up my career in several ways:
1) The funding will assist us in testing the hypothesis proposed in the grant application.
2) The funding will also help me to start the future directions. For instance, we will search for downstream signaling molecule(s) of APPL2 to further help us understand how adiponectin sensitizes insulin signaling.
In what direction do you see the future of diabetes research going?
A large body of evidence suggests that insulin resistance, a situation in which the insulin target cells, (i.e. liver, muscle and fat) no longer respond adequately to physiological concentration of insulin, plays an important role in the pathogenesis of Type 2 diabetes. However, the molecular mechanism behind insulin resistance is still largely unknown. Fully understanding the insulin signaling pathway is the direction to elucidate the mechanism and it will still be our major focus in diabetes research. The other direction we should go is to find ways that could sensitize insulin signaling, such as adioponectin signaling, in the body in an effect to overcome insulin resistance.
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