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

A central aspect of type 2 diabetes is decreased functional β-cell mass. The orphan nuclear receptor Nr4a1 is critical for fuel utilization, but little is known regarding its regulation and function in the β-cell. Nr4a1 expression is decreased in type 2 diabetes rodent β-cells and type 2 diabetes patient islets. We have shown that Nr4a1-deficient mice have reduced β-cell mass and that Nr4a1 knockdown impairs glucose-stimulated insulin secretion (GSIS) in INS-1 832/13 β-cells. Here, we demonstrate that glucose concentration directly regulates β-cell Nr4a1 expression. We show that 11 mM glucose increases Nr4a1 expression in INS-1 832/13 β-cells and primary mouse islets. We show that glucose functions through the cAMP/PKA/CREB pathway to regulate Nr4a1 mRNA and protein expression. Using