John Hancock; Benjamin Bickman; Kyle Kener; Kevin Garland; Claudia M Tellez Freitas; Scott Weber; Chad Hancock, Brigham Young University
The prevalence of diabetes, a disease that affects all ages, continues to increase at a rapid rate. Type 1 diabetes results from the autoimmune destruction of pancreatic β-cells while type 2 diabetes results from insulin resistance, which leads to eventual β-cell apoptosis. In both diseases, preventing the death of insulin producing β-cells, or regenerating functional β-cell mass, would be an essential step for finding a cure. The orphan nuclear receptor Nr4a1 has been shown to play an important role in β-cell growth. In vitro, overexpression of Nr4a1 leads to increased β-cell proliferation, and lentiviral knockdown of Nr4a1 leads to decreased β-cell proliferation. Lentiviral knockdown of Nr4a1 also reduces glucose induced mitochondrial respiration, insulin secretion, and the expression of some genes associated with glucose metabolism. To better understand the role Nr4a1 plays in the progression of diabetes, we examined a full-body knockout mouse model under conditions of a normal or high fat diet. We measured blood glucose weekly, weight monthly, and glucose tolerance monthly until 20 weeks of age. When harvested at 20 weeks, we measured mitochondrial respiration of various tissues and the levels of B-cells, T-cells, and neutrophils in the blood. Our data demonstrate systemic effects of Nr4a1 in terms of fuel utilization and diabetic progression.