Research Description
Beta-cell insulin secretion is essential for regulating blood glucose. Type 2 diabetes (T2D) occurs when demand for insulin exceeds beta-cells’ capacity to secrete enough insulin to maintain proper glucose levels. The capacity of beta-cells to secrete insulin is largely set by genetics. One challenge in interpreting animal islet genetic studies and relating the findings to human disease is unraveling the links between changes in specific genes and islet function. This involves changes in many proteins when the gene is a transcription factor (a protein which regulates expression of other genes). Transcription factors and the genes they regulate make up a gene regulatory network (GRN¬). The Attie lab recently identified one transcription factor in mice, Zfp148, as a regulator of insulin secretion responses. Mutations in the human counterpart, ZNF148, confer risk for T2D. Mice lacking Zfp148 only in beta cells resist diabetogenic effects of high-fat diets and secrete more insulin. Consequently, understanding how Zfp148 affects insulin release may identify new features of beta cell biology and lead to new therapies for diabetes. Beta cells which lack Zfp148 have over 600 genes changed. Some have roles in how beta cells handle calcium or other components of the insulin secretion machinery. The proposed studies will define the Zfp148 GRN to determine which of the changed genes are targets (direct or indirect) of Zfp148 and, of these, which genes affect two mechanisms in beta cells for regulating insulin secretion altered by Zfp148 loss: production of the energy source ATP and levels of cell calcium.Research Profile
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?My project explores previously understudied factors affecting diabetes severity. Type 2 diabetes risk is strongly influenced by genetics. My project concerns one gene, Zfp148, which affects the cells in the body that normally secrete insulin and fail in diabetes. Loss of this gene in our animal model preserves function of these cells when the mice are fed a high-fat, high-sucrose diet similar to diets which, in humans, are associated with obesity and diabetes. Because of its role in regulating other genes in insulin-producing cells, this work, in addition to helping define methods for preserving these insulin-producing cells, will also help scientists to understand other genes that are important in the function and failure of these cells. This will therefore allow researchers to develop newer therapies for diabetes and ways of predicting those patients who might best benefit from specific existing therapies. Further, the analysis methods I’m developing as part of this project can be applied beyond insulin-producing cells to other tissues affected by diabetes progression, allowing clinicians and researchers to more completely understand how these tissues work in healthy individuals, how they become dysfunctional in diabetes, and how they may be treated to restore function.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?Diabetes is not a single disease; it is many diseases with a common set of symptoms. Each person has their own set of risk factors. Some are genetic, and inherited. Others are environmental, like diet and exercise. The current understanding of how diabetes develops is is unable to connect these factors, which would let researchers and clinicians do three things more effectively by: 1) identifying those at risk of developing diabetes, thereby helping these people to avoid diabetes; 2) developing newer, more effective therapies for diabetes; and 3) identifying those people with diabetes most likely to benefit from existing therapies. As part of the effort to better understand how diabetes develops, and how it may be prevented, my project focuses on one of the genes that may play a significant role in the function of insulin-producing cells, loss of which causes diabetes. Understanding this gene, and how it influences diabetes risk and progression, will help investigators better understand how insulin-producing cells fail, how that failure may be prevented, and identify new targets for therapies to prevent loss of these cells and thereby avert or reverse diabetes.
Why important for you, personally, to become involved in diabetes research? What role will this award play?I have a long-standing interest in studying metabolism, which is connected to many diseases including diabetes. Diabetes, and its risk factors are linked to many other diseases and provides a natural start to learn about common causes of these disorders. Current diabetes research focuses on highly complex biology, requiring the analysis of large amounts of data of different types. The gene I will study in this project regulates other genes. Understanding how that works, and how it is linked to survival of the insulin-producing cells that, when lost, cause diabetes, will require me to develop novel techniques for integrating these data and new skills essential to my future work beyond this project. On a personal level, my family has a strong history of metabolic diseases, including diabetes. Knowing that I can help them by increasing knowledge of how these diseases develop, how they progress, and how they may be prevented is very personally moving.
In what direction do you see the future of diabetes research going?I think there will be a greater emphasis on understand the complexity of diabetes, in terms of its underlying risk factors, progression and therapies. This will require integration of many different kinds of large data. Cutting-edge techniques in current research produce far more data than can be efficiently used to understand diabetes risk and progression, develop therapies, and aid in developing personalized medicine. Highly integrative projects, like this one, are necessary steps to provide the tools and integrated data necessary for these future experiments.