Journal Article

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

Miki, Takashi, Katoh, Megumi, Seino, Susumu, Minami, Kohtaro, Takahashi, Harumi, Yokoi, Norihide, Shibasaki, Tadao, Sunaga, Yasuhiro, Iwasaki, Masahiro, Zhang, Chang-Liang

2009

Overview

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.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: 8-Bromo Cyclic Adenosine Monophosphate - pharmacology / adenosine / Animals / Biological and medical sciences / Biomedical technology / Blood glucose / Blood Glucose - analysis / Carrier Proteins - genetics / Carrier Proteins - metabolism / Cell Line / Cercopithecus aethiops / COS Cells / cyclic AMP / Cyclic AMP - metabolism / Diabetes / digestive system / Energy transfer / fluorescence / Fluorescence Resonance Energy Transfer / Glucose / Glucose - administration & dosage / Glyburide - metabolism / Glyburide - pharmacology / glycemic effect / guanine nucleotide exchange factors / Guanine Nucleotide Exchange Factors - genetics / Guanine Nucleotide Exchange Factors - metabolism / guanosinetriphosphatase / Hormones / Hormones. Endocrine system / Hypoglycemic agents / Hypoglycemic Agents - chemistry / Hypoglycemic Agents - metabolism / Hypoglycemic Agents - pharmacology / Insulin / Insulin - blood / Insulin - metabolism / Insulin Secretion / Islets of Langerhans - metabolism / Medical research / Medical sciences / Metabolism / Mice / Mice, Inbred C57BL / Pharmacology / Pharmacology. Drug treatments / Prescription drugs / rap1 GTP-Binding Proteins - metabolism / Rodents / Sensors / Sulfonylurea Compounds - chemistry / Sulfonylurea Compounds - metabolism / Sulfonylurea Compounds - pharmacology / tolbutamide / Tolbutamide - metabolism / Tolbutamide - pharmacology / Vehicles