Frizzell, Norma , Ph.D.
The role of succination of protein in the development of endoplasmic reticulum stress in diabetes
General Research Subject: Type 2 Diabetes
Focus: Adipocytes, Integrated Physiology\Regulation of Glucose Kinetics, Obesity\Animal Models
Type of Grant: Junior Faculty
Project Start Date: January 1, 2011
Project End Date: December 31, 2013
Diabetes Type: Type 2 diabetes
Increased obesity is associated with the development of type 2 diabetes. When the body takes in an excessive fuel supply in the form of sugars and fats it tries to store them inside the fat cells (adipocytes). However, a continuously elevated supply of sugar (glucose) can cause stress inside the adipocyte as it provides the cell with more energy than it requires. Excess energy production by the mitochondria (energy producing organelle) sends inhibitory signals to certain metabolic pathways to pause glucose metabolism. This results in the accumulation of other intermediates and one of these, fumarate, can react with proteins and irreversibly modify them. The addition of fumarate to protein forms a stable product called 2SC. The preliminary data in this proposal suggests that 2SC may cause damage inside the adipocyte as it can modify many proteins involved in normal metabolic functions. 2SC may cause problems with the normal folding of proteins or the way they interact with other. The adipocyte is very sensitive to this internal damage and has an emergency response called 'ER stress' which attempts to refold proteins. This research plan will test the hypothesis that 2SC modifies many important proteins, including specific members of the ER stress response, and this prevents the adipocyte from taking control of intracellular damage and accelerates the development of Type 2 diabetes. This proposal will investigate the reduction of 2SC by known ER stress inhibitory drugs and expects to uncover new information on how they work and their therapeutic potential for diabetes treatment.
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 primarily focuses on what happens in the adipocytes (fat cells) during Type 2 diabetes, however as I learn more about how the adipocyte is affected I may find that what I learn is also applicable to other tissues e.g. pancreas and perhaps therefore also Type 1 diabetes.
In the case of Type 2 diabetes many patients are overweight/obese long before their diabetes develops. I believe that the expanding fat cell is going through many stressful changes as it continues to get bigger and try to store the excess energy (sugars and fats) provided to the body. I believe that for many Type 2 diabetics that the trigger for their diabetes lies in the changes happening in the fat cell.
My research specifically examines how excessive intake of glucose causes a 'mitochondrial stress' which then causes further stress in other organelles inside the cell. This project will specifically focus on the endoplasmic reticulum; it is the protein folding center for the cell. If the endoplasmic reticulum is 'stressed' and can no longer fold proteins properly then the adipocyte cannot function properly to store fats and produce hormones. This may trigger cell death and inflammation inside the adipose tissue and initiate the development of diabetes. By understanding what happens at the early stages of damage to the adipocyte I hope this project will help prevent diabetes. If nutrient excess continues to be a problem I hope this project will be useful in also treating diabetes (especially in the early stages) as the drugs I will examine help to reduce the damage caused by high metabolism in the mitochondria.
My project will specifically examine what happens when the fat cell takes in too much glucose. We have recently discovered a new protein modification (named 2SC) which increases when fuel supply to the adipocyte is high. This new protein modification accumulates on many proteins and they cannot function properly any longer. By understanding how this modification causes damage and looking at drugs which can lower the levels of the modification I hope we can keep the adipocytes in a much 'healthier' state and either prevent or treat the early development of diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
I would inform them that my project is aiming to look at a very early event that is beginning inside the cells probably before they have even been diagnosed with diabetes. Until now the adipocyte has not been studies as much as other tissues related to diabetes. Everyone believed it was just a large fat storage center. However, the adipocyte makes many important hormones to control all these other organs so damage and inflammation in the adipocyte could be a very bad thing. My project will help us understand how the changes that that occur in the adipocyte at the protein level and my project is rather different as the problem I have identified is not specific to one protein alone. Many proteins are affected and so I may be looking at 'the big picture' of how total damage begins.
As I uncover the how nutrient excess causes this damage I will also look at compounds which prevent and reverse it. I am excited as one of the compounds I believe has potential is already on the market to treat other diseases and we may have found a new way in which it works to help preserve the mitochondria in over-nourished adipocytes.
Also by opening up a new area of research to other investigators I hope we can have more people work on this with new ideas and other therapeutic compounds in mind.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
As a biochemist I am interested in understanding how the food we eat affects our bodies and what is actually occurring inside our cells as we process our fuels. I enjoy understanding how proteins and metabolites are processed in a healthy versus unhealthy situation and by knowing more about it we can help educate the public on their food and lifestyle choices. Diabetes affects so many people that I feel my work could have a very important and wide impact if we can elucidate a very early event that triggers the development of diet & obesity related diabetes.
I also have an immediate family member diagnosed with Type 2 diabetes several years ago and I have a very strong interest in understanding exactly what is occurring inside the body and how best to care of the body and prevent the development of diabetes and its downstream complications.
This award will be critical in helping me to develop and expand my own laboratory which will allow me to directly address the research questions I have. I have lots of very exciting preliminary data on how protein modifications can have an effect on protein function in the adipocyte and now I can pursue this further and identify exactly how very specific proteins are targeted. When we understand this we can look at how exercise and drugs could prevent this.
In what direction do you see the future of diabetes research going?
The adipocyte (fat cell) was largely unexplored until ~10 years ago when people realized that it did not just store fat. As people now learn that the adipocyte is very important in secreting the hormones that control many other organs they have made a larger effort to understand how. Some of the most effective drugs on the market (e.g. TZDs) have direct actions on aspects. This is an exciting time for adipocyte research and as we learn more about the precise molecular events that contribute to the demise of a 'healthy' fat-storing adipocyte we will simultaneously identify which areas new drugs and therapies should target. But new drug targets will only become apparent when we fully understand what is going on inside the adipocyte.
I also believe that 'personalized medicine' will receive a lot more interest in the future. The ability to take a sample of our blood/urine and screen for not just one thing but a whole metabolomic profile of what happens when we eat a meal or exercise. This may be truly useful for people whose diabetes is the result of an unidentified genetic component, by seeing where in the pathway he problem lies we may be able to see how a diet/medicine/exercise may help.
I truly hope that obesity-related diabetes research emphasizes the importance of exercise in the future. I believe that people who consume a calorie rich diet are not aware of the real effects of their diet but if we can demonstrate scientifically that even a little exercise can affect their metabolism in a positive way, then perhaps we can help our future generations by encouraging more exercise in schools.
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