Type 2 diabetes is a disease that affects more than 25 million Americans (or over 8% of the population). As rates of obesity increase, we see concomitant increases in rates of type 2 diabetes. The prevalence of diabetes is significantly higher in Veterans than in the general population and also continues to rise. It is increasingly recognized that a key defect in type 2 diabetes is failure of the pancreatic beta cells to produce enough insulin to keep up with the demands of insulin resistance. Gaining an understanding of the normal physiologic mechanisms that control beta cell proliferation can allow us to develop targeted therapeutics that can help maintain and expand functional beta cell mass. We have used a mouse model of obesity to identify genes that are involved in regulating the adaptive proliferative response of the beta cell Looking at the natural adaptive responses to increased insulin demand provides a useful tool to identify mechanisms of beta cell replication. Using this model, we have identified a novel transcription factor, tcf19, which is highly correlated with the proliferative response in mouse islets. Tcf19 is largely uncharacterized, but is known to be a cell cycle regulated gene. Our preliminary results indicate that tcf19 is expressed in the beta cell and is required for beta cell growth and survival. We hypothesize that tcf19 is a key transcriptional regulator of beta cell replication and is also important in the regulation of ER stress response genes to prevent apoptosis. In this proposal, we will examine the transcriptional activity of tcf19 in the beta cell using chromatin immunoprecipitation to identify direct transcriptional targets of tcf19. Specifically, we will look for regulation of key cell cycle and ER chaperone genes to understand the mechanism for the effects of tcf19 on ?-cell growth. We will next use an adenoviral expression system to determine if tcf19 is sufficient to promote ?-cell proliferation and protect from ?-cell apoptosis in mouse and human islets. We will also further examine the effects of tcf19 on transcription in human islets. Finally, we will generate and characterize a ?-cell specifi knockout of tcf19 to confirm that it is necessary for ?-cell expansion and survival in vivo. Upon completion of the proposed studies, we will have a clear understanding of the role of this novel regulator of ?-cell mass. Ultimately, our goal is to clearly elucidate the pathways that regulate ? cell proliferation and survival as a means to increase ?-cell mass. If we are able to increase ?-cell mass in the face of insulin resistance, we will be able to prevent the onset of type 2 diabete in those at high risk and improve treatment for individuals already suffering from diabetes.

Public Health Relevance

As obesity rates continue to increase, type 2 diabetes is becoming increasingly prevalent in the population. Over 15% of the Veterans seeking care in VA Hospitals have diabetes, and it remains the main cause of blindness, kidney disease requiring dialysis, and amputation. We now understand that one of the key problems in Veterans with type 2 diabetes is a failure of the pancreatic beta cells to produce enough insulin to keep up with demand. This project will examine how specific genes regulate the ability of the pancreatic beta cells to grow and survive in the face of toxic conditions from high blood sugars and high blood cholesterol in type 2 diabetes. Ultimately, we hope to identify pathways that can be targeted in the development of new treatments for diabetes that specifically increase beta cell numbers and insulin production.

Agency
National Institute of Health (NIH)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001880-02
Application #
8668718
Study Section
Endocriniology A (ENDA)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Wm S. Middleton Memorial Veterans Hosp
Department
Type
DUNS #
City
Madison
State
WI
Country
United States
Zip Code
53705