Samson, Susan , M.D.
Role of Wnt signaling and TCF7L2 for beta cell function and regeneration in mouse models of diabetes
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Islet Biology\Beta Cell Growth and Differentiation, Islet Biology\Beta Cell Transcription Regulation, Islet Biology\Signal Transduction
Type of Grant: Junior Faculty
Project Start Date: January 1, 2011
Project End Date: December 31, 2014
Insulin is produced by the beta cells in the pancreas and the two major types of diabetes result when the beta cells are destroyed (type 1 diabetes) or cannot cope with insulin requirements, such as in obesity (type 2 diabetes). Insulin is a life-sustaining treatment but it is not a cure. Ideally, the best treatment would be to increase the number of beta cells in the body and boost insulin secretion. The goal of this study is to understand the signals which cause regeneration of the beta cells. Activation of a cell signaling pathway (Wnt) has been shown to increase beta cell division. This pathway is activated by the molecule, Glucagon-like peptide 1 (GLP-1), which is the basis for an important diabetes medication.
Recently, geneticists have discovered a gene called TCF7L2 which predisposes humans to diabetes and the protein made by the gene functions at the end of the Wnt pathway. This study looks at the importance of the Wnt pathway in the beta cells of mice. First, the ability of beta cells to regenerate in response to GLP-1 signals will be examined in diabetic mice with and without the Wnt pathway. Second, we will use mice in which TCF7L2 gene is deleted to understand if they are more prone to diabetes. By examining the importance of the Wnt pathway and TCF7L2 in mice, we will come closer to understanding how to regenerate beta cells and also the reason that the TCF7L2 gene is associated with diabetes in humans.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Diabetes develops when the insulin-producing cells of the pancreas, called beta cells, fail to secrete enough insulin to maintain blood glucose in a narrow and normal range. This can occur because the beta cells are destroyed (e.g. type 1 autoimmune diabetes) or because the beta cells cannot keep up with the demand for insulin (e.g. type 2 diabetes). For type 2 diabetes, a common sequence of events is weight gain leading to obesity and insulin resistance. Over time, this resistance overwhelms the beta cells' ability to produce and secret insulin. However, although obesity increases the risk for type 2 diabetes, not all obese people become diabetic. This means that there are additional, individual factors which impact whether or not a person will develop diabetes.
Over the last few years, genetic analyses of people with diabetes or pre-diabetes have uncovered several genes which have variations which increase the risk for type 2 diabetes. What is interesting is that many of these genes do not affect weight gain or obesity, but instead, are relevant for beta cell function and insulin production. My project is focused on understanding the function of a gene regulator called TCF7L2 (Transcription factor 7-like 2) in the beta cells in mouse models of aging, obesity and beta cell regeneration. Human sequence variations in the gene for TCF7L2 are the single most important genetic determinant for the risk of diabetes in people from many ethnic backgrounds. By investigating TCF7L2 contributions in the beta cell, we will come closer to understanding how variations in this gene contribute to diabetes risk for humans, and then we can work on ways to intervene.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Because the gene for TCF7L2 has been shown to be of such importance for human diabetes, this project has the potential to help us to find ways to enhance the positive actions of TCF7L2 in the beta cell as a means of treating diabetes or even pre-diabetes. This has relevance to both type 1 and type 2 diabetes. Because TCF7L2 regulates the expression of genes involved in cell replication, it could be involved in coaxing the regeneration of beta cells in response to cellular signals. For type 1 diabetes, this gives hope that if autoimmunity can be circumvented, then regeneration may be possible in patients with residual beta cell mass. For type 2 diabetes, understanding TCF7L2 also is relevant because we may learn how to increase the number of beta cells or improve their function in order to avoid failure with insulin resistance from aging and/or obesity. In addition, we will begin to understand the signals which potentially could enhance the positive actions of TCF7L2 which could lead to new treatments for diabetes. For example, a peptide called GLP-1 (for glucagon-like peptide 1) is able to increase beta cell division, at least in rodents, and there is data to support that GLP-1 affects the activity of TCF7L2, which could be the key molecule controlling GLP-1 mediated regeneration. Analogues of GLP-1 are currently in clinical use for treatment of type 2 diabetes. Through our studies we hope to find additional signals and targets of TCF7L2 which could enhance beta cell numbers and function to prevent, treat and/or cure diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
My interest in understanding and treating diabetes dates back to Medical school. I have stayed focused on this path throughout my training, culminating in a subspecialty in Endocrinology, Diabetes and Metabolism. As a practicing physician in the ethnically diverse city of Houston, I care for patients from all walks of life and backgrounds that are affected by diabetes. Although I value my time in the clinic and the potential to impact diabetic patients on a one-on-one level, my greatest hope has been to have the opportunity to work in the research environment and to make a long term contribution to the prevention and treatment of diabetes. This award provides essential funding for the scientific aspects of this project as well as providing me with the time and protection to do research outside of the clinic.
In what direction do you see the future of diabetes research going?
I believe that an important focus of diabetes research is to gain insight into how we can make more beta cells or restore their function. There are a variety of pathways through which we can gain an understanding of this topic. These include: 1) investigating the developmental factors which initiate the formation of beta cells in the embryo in order to harness their power for creating new beta cells, 2) determining ways in which to use abundant non-beta cell types to transform them into beta cells, and 3) understanding the signals which turn on beta cell division as a means of encouraging regeneration.
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