Author(s): Michael Avondet
Mentor(s):
Institution BYU
Diabetes mellitus affects over 537 million adults globally, a number projected to rise to 783 million by 2045. Both type 1 and type 2 diabetes involve the loss of functional pancreatic β-cell mass, which encompasses both proliferation and survival rates of β-cells and their efficiency in insulin secretion. Nr4a1 is a promising nuclear receptor that plays essential roles in sustaining functional β-cell mass, notably in regulating cell proliferation and glucose-stimulated insulin secretion (GSIS). In diabetic conditions, Nr4a1 downregulation has been linked to β-cell dysfunction, suggesting its potential as a therapeutic target. Recent research in acute myeloid leukemia (AML) demonstrates that treatment with dihydroergotamine (DHE), an FDA approved drug, reactivates impaired Nr4a1 expression and activity in human cancerous blood cells. Although similar impairment and inactivity of Nr4a1 receptors is noted in diabetic β-cells from pancreatic islets, the impact of DHE on expression remains unexplored. We hypothesized that DHE treatment would increase the expression of Nr4a1 receptors, resulting in heightened expression of Nr4a1 targets and bolstered β-cell proliferation and GSIS. This study showcases data describing the impact of DHE on Nr4a1 nuclear receptor and target gene expression in INS-1 β-cells under varying metabolic conditions. In addition, we present the effect of DHE on functional measures of β-cell proliferation and GSIS. Results from this research may provide insights into novel therapeutic pathways for improving functional β-cell mass and combating diabetes.