title: Treating diabetes today: a matter of selectivity of sulphonylureas.
abstract: It is well known that sulphonylureas (SUs), commonly used in the treatment of type 2 diabetes mellitus, stimulate insulin secretion by closing ATP-sensitive K(+)  (K(ATP) ) channels in pancreatic β-cells by binding to the SU receptor SUR1. SUs are now known also to activate cAMP sensor Epac2 (cAMP-GEFII) to Rap1 signalling, which promotes insulin granule exocytosis. For SUs to exert their full effects in insulin secretion, they are required to activate Epac2 as well as to inhibit the β-cell K(ATP)  channels. As Epac2 is also necessary for potentiation of glucose-induced insulin secretion by cAMP-increasing agents, such as incretin, Epac2 is a target of both cAMP and SUs. The distinct effects of various SUs appear to be because of their different actions on Epac2/Rap1 signalling as well as K(ATP)  channels. Differently from other SUs, gliclazide is unique in that it is specific for β-cell K(ATP)  channel and does not activate Epac2.
authors: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan. seino@med.kobe-u.ac.jp
authors: S
authors: S
authors: Seino
authors: H
authors: H
authors: Takahashi
authors: T
authors: T
authors: Takahashi
authors: T
authors: T
authors: Shibasaki
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000187:drug effects* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D005089:Exocytosis; D020662:Guanine Nucleotide Exchange Factors / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D054086:KATP Channels / Q000187:drug effects / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects* / Q000378:metabolism; D011955:Receptors, Drug / Q000187:drug effects* / Q000378:metabolism; D000089804:Shelterin Complex; D015398:Signal Transduction / Q000187:drug effects; D013453:Sulfonylurea Compounds / Q000627:therapeutic use*; D064233:Sulfonylurea Receptors; D034501:Telomere-Binding Proteins / Q000187:drug effects / Q000378:metabolism
chemical_list: C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; D020662:Guanine Nucleotide Exchange Factors; D007004:Hypoglycemic Agents; D007328:Insulin; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; C442864:RAPGEF4 protein, human; D011955:Receptors, Drug; D000089804:Shelterin Complex; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors; C440809:TERF2IP protein, human; D034501:Telomere-Binding Proteins; D000242:Cyclic AMP