Sulfonylureas are widely used oral drugs in the treatment of
diabetes mellitus. They function by the inhibition of
ATP-sensitive K+ channels in pancreatic β-cells, which are thus considered the 'classical'
sulfonylurea receptor. Next to the
ATP-sensitive K+ channels, additional sulfonylurea-interacting
proteins were identified, which might contribute to the physiological effects of this
drug family. Most recently, Epac2 (exchange
protein directly activated by cAMP 2) was added to the list of
sulfonylurea receptors. However, this finding caused controversy in the literature. The critical discussion of the present paper comes to the conclusion that sulfonylureas are not able to activate Epac2 directly and are unlikely to bind to Epac2. Increased
blood glucose levels after food intake result in the secretion of
insulin from pancreatic β-cells.
Glucose levels are detected 'indirectly' by β-cells: owing to increased glycolysis rates, the ratio of cellular
ATP/
ADP increases and causes the closure of
ATP-sensitive K+ channels. In consequence, cells depolarize and voltage-dependent Ca2+ channels open to cause an increase in the cellular Ca2+ concentration. Finally, Ca2+ induces the fusion of
insulin-containing granules with the plasma membrane. Sulfonylureas, such as
tolbutamide,
glibenclamide or
acetohexamide, form a class of orally applicable drugs used in the treatment of
non-insulin-dependent diabetes mellitus.