Brown, Nathan; Herring, Jacob; Tessem, Jeffery (Brigham Young University)
Faculty Advisor: Tessem, Jeffery (Brigham young University; Nutrition, Dietetics, and Food Science)
Diabetes is a global epidemic affecting millions of people. The total estimated cost of diabetes in the U.S. during 2017 was 327 billion dollars. Diabetes is characterized by the loss of pancreatic β-cell function which is caused by an autoimmune disorder in Type 1 diabetes or insulin resistance and β-cell exhaustion in Type 2 (T2D) diabetes.
It is shown that β-cell mitochondrial respiration is dependent on the nuclear receptor Nr4a1. Respiration rates of cells lacking Nr4a1 in the presence of 16 mM glucose resulted in a significant decrease in glucose-stimulated insulin secretion by impeding the production of ATP. It was also found that knockdown of Nr4a1 results in decreased expression of mitochondrial dehydrogenase subunits Idh3g and Sdhb. Thus, the orphan nuclear receptor Nr4a1 is critical for β-cell mitochondrial function and insulin secretion.
In subsequent studies it was shown that dihydroergotamine (DHE) induces Nr4a1 expression via recruitment of the super elongation complex to enable elongation of Nr4a1 promoter paused RNA polymerase II. While these experiments have been shown in cancer cells, I hypothesize that DHE will up-regulate Nr4a1 and other downstream targets. To test this I will use an in-vitro model to culture INS-1 832/3 rat insulinoma cell lines as a useful model for insulin secretion regulation and pancreatic islet beta-cell function studies. This study will shed further light on the regulation of the Nr4a1 nuclear receptor in pancreatic β-cells.