Variations in tissue selectivity amongst insulin secretagogues: a systematic review

Diabetes Obes Metab. 2012 Feb;14(2):130-8. doi: 10.1111/j.1463-1326.2011.01496.x. Epub 2011 Nov 3.


Aim: Insulin secretagogues promote insulin release by binding to sulfonylurea receptors on pancreatic β-cells (SUR1). However, these drugs also bind to receptor isoforms on cardiac myocytes (SUR2A) and vascular smooth muscle (SUR2B). Binding to SUR2A/SUR2B may inhibit ischaemic preconditioning, an endogenous protective mechanism enabling cardiac tissue to survive periods of ischaemia. This study was designed to identify insulin secretagogues that selectively bind to SUR1 when given at therapeutic doses.

Methods: Using accepted systematic review methods, three electronic databases were searched from inception to 13 June 2011. Original studies measuring the half-maximal inhibitory concentration (IC(50)) for an insulin secretagogue on K(ATP) channels using standard electrophysiological techniques were included. Steady-state concentrations (C(SS)) were estimated from the usual oral dose and clearance values for each drug.

Results: Data were extracted from 27 studies meeting all inclusion criteria. IC(50) values for SUR1 were below those for SUR2A/SUR2B for all insulin secretagogues and addition of C(SS) values identified three distinct patterns. The C(SS) for gliclazide, glipizide, mitiglinide and nateglinide lie between IC(50) values for SUR1 and SUR2A/SUR2B, suggesting that these drugs bind selectively to pancreatic receptors. The C(SS) for glimepiride and glyburide (glibenclamide) was above IC(50) values for all three isoforms, suggesting these drugs are non-selective. Tolbutamide and repaglinide may have partial pancreatic receptor selectivity because IC(50) values for SUR1 and SUR2A/SUR2B overlapped somewhat, with the C(SS) in the midst of these values.

Conclusions: Insulin secretagogues display different tissue selectivity characteristics at therapeutic doses. This may translate into different levels of cardiovascular risk.

Publication types

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

MeSH terms

  • ATP-Binding Cassette Transporters / drug effects*
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Carbamates / adverse effects
  • Cardiovascular Diseases / chemically induced
  • Cardiovascular Diseases / metabolism*
  • Cardiovascular Diseases / physiopathology
  • Cricetinae
  • Cyclohexanes / adverse effects
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Gliclazide / adverse effects
  • Glipizide / adverse effects
  • Glyburide / adverse effects
  • Humans
  • Hypoglycemic Agents / adverse effects*
  • Hypoglycemic Agents / pharmacology
  • Ischemic Preconditioning, Myocardial
  • Isoindoles / adverse effects
  • Mice
  • Muscle, Smooth, Vascular / drug effects*
  • Muscle, Smooth, Vascular / metabolism
  • Muscle, Smooth, Vascular / physiopathology
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • Nateglinide
  • Phenylalanine / adverse effects
  • Phenylalanine / analogs & derivatives
  • Piperidines / adverse effects
  • Potassium Channels, Inwardly Rectifying / drug effects*
  • Potassium Channels, Inwardly Rectifying / metabolism
  • Rats
  • Receptors, Drug / drug effects*
  • Receptors, Drug / metabolism
  • Risk Factors
  • Sulfonylurea Compounds / adverse effects
  • Sulfonylurea Receptors
  • Tolbutamide / adverse effects


  • ABCC8 protein, human
  • ABCC9 protein, human
  • ATP-Binding Cassette Transporters
  • Abcc8 protein, mouse
  • Abcc8 protein, rat
  • Abcc9 protein, mouse
  • Carbamates
  • Cyclohexanes
  • Hypoglycemic Agents
  • Isoindoles
  • Piperidines
  • Potassium Channels, Inwardly Rectifying
  • Receptors, Drug
  • Sulfonylurea Compounds
  • Sulfonylurea Receptors
  • Nateglinide
  • Phenylalanine
  • repaglinide
  • glimepiride
  • Tolbutamide
  • mitiglinide
  • Gliclazide
  • Glyburide
  • Glipizide