Treating diabetes today: a matter of selectivity of sulphonylureas

Diabetes Obes Metab. 2012 Jan;14 Suppl 1:9-13. doi: 10.1111/j.1463-1326.2011.01507.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • ATP-Binding Cassette Transporters / drug effects*
  • ATP-Binding Cassette Transporters / metabolism
  • Cyclic AMP / metabolism
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Exocytosis
  • Guanine Nucleotide Exchange Factors / drug effects
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • KATP Channels / drug effects
  • KATP Channels / metabolism
  • Potassium Channels, Inwardly Rectifying / drug effects*
  • Potassium Channels, Inwardly Rectifying / metabolism
  • Receptors, Drug / drug effects*
  • Receptors, Drug / metabolism
  • Signal Transduction / drug effects
  • Sulfonylurea Compounds / therapeutic use*
  • Sulfonylurea Receptors
  • Telomere-Binding Proteins / drug effects
  • Telomere-Binding Proteins / metabolism


  • ABCC8 protein, human
  • ATP-Binding Cassette Transporters
  • Guanine Nucleotide Exchange Factors
  • Hypoglycemic Agents
  • Insulin
  • KATP Channels
  • Potassium Channels, Inwardly Rectifying
  • RAPGEF4 protein, human
  • Receptors, Drug
  • Sulfonylurea Compounds
  • Sulfonylurea Receptors
  • TERF2IP protein, human
  • Telomere-Binding Proteins
  • Cyclic AMP