The cAMP Sensor Epac2 Is a Direct Target of Antidiabetic Sulfonylurea Drugs

Expanding Sulfonylurea Mechanisms Sulfonylureas are important drugs used for treatment of diabetes that act through adenosine triphosphate–sensitive potassium channels to promote secretion of insulin from the pancreas. Zhang et al. (p. 607) present another mechanism by which the beneficial effects of sulfonylureas may also be obtained. Sulfonylureas were identified in a screen for substances that modify the activity of Epac2, a guanine nucleotide exchange factor for the small guanosine triphosphatase Rap1. Mice lacking Epac2 were less responsive to sulfonylureas, which may suggest that Epac2 would be a useful target for development of drugs for treatment of diabetes. A drug used to enhance insulin secretion in diabetes has a previously unrecognized protein target. Epac2, a guanine nucleotide exchange factor for the small guanosine triphosphatase Rap1, is activated by adenosine 3′,5′-monophosphate. Fluorescence resonance energy transfer and binding experiments revealed that sulfonylureas, widely used antidiabetic drugs, interact directly with Epac2. Sulfonylureas activated Rap1 specifically through Epac2. Sulfonylurea-stimulated insulin secretion was reduced both in vitro and in vivo in mice lacking Epac2, and the glucose-lowering effect of the sulfonylurea tolbutamide was decreased in these mice. Epac2 thus contributes to the effect of sulfonylureas to promote insulin secretion. Because Epac2 is also required for the action of incretins, gut hormones crucial for potentiating insulin secretion, it may be a promising target for antidiabetic drug development.