Variations in tissue selectivity amongst insulin secretagogues: a systematic review

Area of Science:

• Pharmacology
• Cardiovascular Medicine
• Endocrinology

Background:

• Insulin secretagogues stimulate insulin release by targeting sulfonylurea receptors (SUR1) on pancreatic beta-cells.
• These drugs can also bind to SUR2A and SUR2B isoforms in cardiac myocytes and vascular smooth muscle, potentially inhibiting cardioprotective mechanisms like ischaemic preconditioning.
• Understanding the tissue selectivity of insulin secretagogues at therapeutic doses is crucial for assessing cardiovascular risk.

Purpose of the Study:

• To identify insulin secretagogues that exhibit selective binding to SUR1 over SUR2A/SUR2B at clinically relevant concentrations.
• To evaluate the potential cardiovascular implications of varying tissue selectivity among different insulin secretagogues.

Main Methods:

• A systematic review of electronic databases was conducted to identify studies measuring the half-maximal inhibitory concentration (IC50) of insulin secretagogues on K(ATP) channels.
• Electrophysiological techniques were used to determine IC50 values for SUR1, SUR2A, and SUR2B.
• Steady-state concentrations (C(SS)) were estimated based on standard oral doses and drug clearance values.

Main Results:

• All studied insulin secretagogues showed lower IC50 values for SUR1 compared to SUR2A/SUR2B.
• Gliclazide, glipizide, mitiglinide, and nateglinide demonstrated selectivity for SUR1 at therapeutic concentrations.
• Glimepiride and glyburide (glibenclamide) were non-selective, while tolbutamide and repaglinide showed partial selectivity.

Conclusions:

• Insulin secretagogues possess distinct tissue selectivity profiles at therapeutic doses.
• These differences in selectivity may correlate with varying levels of cardiovascular risk among these antidiabetic agents.