Loss of glucose-stimulated Beta-cell Nr4a1 expression impairs insulin secretion and glucose homeostasis.

A central aspect of type 2 diabetes (T2D) is decreased functional Beta-cell mass. The orphan nuclear receptor Nr4a1 is critical for fuel utilization, but little is known regarding its function and regulation in the Beta-cell. Nr4a1 expression is decreased in T2D rodent Beta-cells and T2D patient islets. We have shown that Nr4a1 deficient mice have reduced Beta-cell mass and that Nr4a1 knock-down impairs glucose-stimulated insulin secretion (GSIS) in INS-1 832/13 Beta-cells. Here, we demonstrate that glucose concentration directly regulates Beta-cell Nr4a1 expression. We show that 11 mM glucose increases Nr4a1 expression in INS-1 832/13 Beta-cells and primary mouse islets. We show that glucose functions through the cAMP/PKA/CREB pathway to regulate Nr4a1 mRNA and protein expression. Using Nr4a1-/- animals, we show that Nr4a1 is necessary for GSIS and systemic glucose handling. Using RNA-seq, we define Nr4a1-regulated pathways in response to glucose in the mouse islet, including Glut2 expression. Our data suggests that Nr4a1 plays a critical role in the Beta-cells response to the fed state.