Faculty of Pharmacy & Pharmaceutical Sciences, 3126 Dentistry/Pharmacy Centre, University of Alberta, Edmonton, Alberta, Canada.
Diabetes Obes Metab. 2012 Feb;14(2):130-8. doi: 10.1111/j.1463-1326.2011.01496.x. Epub 2011 Nov 3.
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.
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.
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.
Insulin secretagogues display different tissue selectivity characteristics at therapeutic doses. This may translate into different levels of cardiovascular risk.
胰岛素促分泌剂通过与胰腺β细胞上的磺酰脲受体（SUR1）结合来促进胰岛素释放。然而，这些药物也与心肌细胞（SUR2A）和血管平滑肌（SUR2B）上的受体亚型结合。与 SUR2A/SUR2B 结合可能会抑制缺血预适应，这是一种使心脏组织能够在缺血期间存活的内源性保护机制。本研究旨在鉴定在治疗剂量下选择性结合 SUR1 的胰岛素促分泌剂。
使用公认的系统评价方法，从创建到 2011 年 6 月 13 日，在三个电子数据库中进行了搜索。纳入的原始研究使用标准电生理学技术测量胰岛素促分泌剂对 K（ATP）通道的半最大抑制浓度（IC（50））。稳态浓度（C（SS））根据每种药物的常用口服剂量和清除值进行估算。
符合所有纳入标准的 27 项研究的数据被提取出来。所有胰岛素促分泌剂的 SUR1 的 IC（50）值均低于 SUR2A/SUR2B，而添加 C（SS）值则确定了三种不同的模式。格列齐特、格列吡嗪、米格列奈和那格列奈的 C（SS）值位于 SUR1 和 SUR2A/SUR2B 的 IC（50）值之间，表明这些药物选择性地结合胰腺受体。格列美脲和格列本脲（glibenclamide）的 C（SS）值高于所有三种亚型的 IC（50）值，表明这些药物是非选择性的。甲苯磺丁脲和瑞格列奈可能具有部分胰腺受体选择性，因为 SUR1 和 SUR2A/SUR2B 的 IC（50）值有些重叠，而 C（SS）值则处于这些值之间。
在治疗剂量下，胰岛素促分泌剂表现出不同的组织选择性特征。这可能转化为不同水平的心血管风险。
