Simmons, Rebecca Anne, MD
Epigenetic regulation of ß-cell dysfunction
General Research Subject: Type 2 Diabetes
Focus: Islet Biology\Beta Cell Transcription Regulation
Type of Grant: Basic Science
Project Start Date: January 1, 2011
Project End Date: December 31, 2013
Diabetes Type: Type 2 diabetes
Poor fetal growth, known as intrauterine growth retardation (IUGR), has been linked to later development of type 2 diabetes in adulthood. The mechanisms underlying this phenomena are unknown. We believe that a process called epigenetics, inherited changes in phenotype (appearance) or gene expression caused by mechanisms other than changes in the underlying DNA sequence, contribute to the abnormal function of the insulin-producing cells which eventually leads to the development of type-2 diabetes. The studies outlined in this proposal will determine whether epigenetics contributes to the development of abnormal ß-cell function that occurs in the growth retarded fetus.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
The developing embryo and fetus are highly sensitive to their environments. In general, the fetus has three types of responses to an adverse environment: it can accelerate its maturation, conserve nutrients (by reducing growth and activity), or terminate the pregnancy altogether by spontaneous miscarriage or premature delivery. If the fetus adapts to a poor intrauterine environment by slowing its growth, this metabolic adaptation while increasing chances of surviving, can have adverse consequences after birth particularly in the face of a surfeit of nutrients. Such conditions are proposed to conflict with the earlier programming, and diseases such as type 2 diabetes and obesity are the consequences. Many studies have demonstrated a strong link between poor fetal growth and the subsequent development of diseases in later life. For example, infants who are born at term, but whose weight is below average, are at risk for developing obesity and type II diabetes as children and as adults. It is not known what causes the development of diabetes in these individuals who were growth retarded at birth. To understand these mechanisms, we have developed an animal model of intrauterine growth retardation. Newborn growth retarded rats are insulin resistant, and ß-cells of the pancreas dwindle and cannot compensate for higher blood levels of glucose as the rats develop diabetes. The focus of our research is to elucidate mechanisms that lead to the failure of ß-cell compensation and loss of ß-cell mass in growth retarded animals. This project is focused on the molecular mechanisms (epigenetics) by which an abnormal intrauterine environment causes life-long changes in ß-cell function in the offspring. Epigenetics is the study of inherited changes in phenotype (appearance) or gene expression caused by mechanisms other than changes in the underlying DNA sequence. These changes may remain through cell divisions for the remainder of the cell's life and may also last for multiple generations. However, there is no change in the underlying DNA sequence of the organism; instead, non-genetic factors (abnormal intrauterine environment) cause the organism's genes to behave (or 'express themselves') differently. Once we determine what epigenetic changes occur and which are causal prior to the onset of diabetes, we can then design specific therapies to prevent these changes and thus prevent the onset of diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Currently, there are many therapies being used to treat cancer patients that are targeted to epigenetic changes in tumor cells. We believe that such therapies may also be used to prevent loss of ß-cells.
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 clinician, I have witnessed first hand the dramatic increase in incidence of type 1 and particularly type 2 diabetes in children. The emotional and financial toll that this places on individuals and society makes it imperative that we focus our research endeavors on preventing this disease. I believe that interrupting this process very early in life is the most promising area of research and thus I have focused my efforts in this area.
This award will allow me to elucidate novel mechanisms that underlie the development of diabetes such that new therapies can be designed to prevent the onset of the disease.
In what direction do you see the future of diabetes research going?
This is an exciting time for diabetes research as new technologies such as high-throughput sequencing allows us to interrogate the genome as well as the epigenome. This new area of research will undoubtedly reveal new mechanisms underlying diabetes which in turn will allow for the design of novel therapies as well as approaches to prevent the onset of disease.
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