SU drugs bind ABCC8 (in KCNJ11 tetramer:ABCC8:Mg2+:ADP tetramer)

Sulfonylurea (SU) drugs represent a group of anti-hyperglycemic agents used mainly in the treatment of type 2 diabetes mellitus (T2DM) for over 60 years. They can be utilized as adjuvant therapy with any other class of oral diabetic medications besides meglitinides or can be considered in patients intolerant or have a contraindication to metformin. They are commonly divided into first and second generations. Examples of first-generation SUs include chlorpropamide, tolazamide, and tolbutamide, while second-generation SUs include glipizide, gliclazide, and glyburide. Glimepiride is sometimes also referred to as a third-generation medication. Chlorpropamide, glyburide, and glimepiride have a prolonged duration of action when compared to short-acting medications such as gliclazide and tolbutamide. Due to their low cost, wide availability and effectiveness, SUs have remained a frequently prescribed medication, despite potential hypoglycemic risks (Mizuno et al. 2008, Lorenzati et al. 2010, Carbone et al. 2018).<br><br>SUs stimulate insulin secretion from pancreatic β-cells primarily by closing ATP-sensitive K+ channels (KATP) in the β-cell plasma membrane. They are primarily thought to act by binding to the SUR subunit of KATP and inducing channel closure. However, the channel is still able to open to a limited extent when the drug is bound, so that high-affinity SU inhibition is not complete, even at saturating drug concentrations. Tolbutamide and gliclazide block channels containing SUR1 (aka ABCC8) (found in pancreatic beta-cells) (Gribble et al. 1998, de Wet & Proks 2015), but not SUR2 (found in cardiac and smooth muscle cells), whereas glibenclamide, glimepiride, repaglinide, and meglitinide can block both types of channels. Animal experiments revealed KATP channels possess both high-affinity- and low-affinity-binding sites for SUs and meglitinides (Gribble et al. 1997, Ashfield et al. 1999, Proks et al. 2002). Binding of the SU tolbutamide to the high affinity site on SUR1 abolishes the stimulatory action of MgADP on the KATP channel and is thought to be the primary mechanism by which tolbutamide inhibits the KATP channel ().<br><br>1st generation SUs have increased risk of mortality due to cardiovascular events and have been superseded by 2nd generation SUs. The first generation SU tolbutamide (trade name Orinase) is an oral SU hypoglycaemic agent used to treat T2DM (Recant & Fischer 1957). Its proposed mechanism of action is thought to occur through interaction with the SUR1 subunit of KATP channels (Babenko et al. 1999). Chlorpropamide (trade name Diabinese) is a long-acting first-generation SU used to treat T2DM. Its longer-acting nature increases the risk of hypoglycemia so is not recommended for the elderly and patients with mild to moderate hepatic and renal impairment (Shorr et al. 1996). Tolazamide (trade name Tolinase) was FDA-approved in 1986 and is used to treat T2DM (McKendry & Gfeller 1967, Firth et al. 1986). Although its exact mechanism of action is unknown, it likely binds to SUR1 of KATP channels, blocking channel activity.<br><br>2nd generation SUs are widely employed worldwide as the mainstay of anti-diabetic therapy. Glipizide (trade name Glucotrol) is a 2nd-gen SU used to treat T2DM (Prendergast 1984). Approved in the US since 1984. Glipizide displays rapid absorption and onset of action with the shortest half-life and duration of action, reducing the risk for long-lasting hypoglycemia that is often observed with other anti-diabetic agents (Melander & Wåhlin-Boll 1983). Gliclazide (trade name Diamicron) was FDA-approved in 1972 is an anti-diabetic medication used to treat T2DM. Gliclazide is considered a second-generation SU which presents a higher potency and a shorter half-life than other SUs (Harrower 2000). While it was shown to have the same efficacy as glimepiride, a European GUIDE study showed that it has approximately 50% less hypoglycaemic confirmed episodes in comparison with glimepiride (Schernthaner et al. 2004).<br><br>Glyburide (aka glibenclamide, trade name Diabeta, Flycron) is a second-generation SU drug which was FDA-approved in 1984 and id 200 times more potent than tolbutamide. Glyburide has a therapeutic effectiveness comparable to that of the first-generation sulfonylurea chlorpropamide but with a lower frequency of adverse effects. Glyburide should not be prescribed to diabetic patients with liver disease, significant renal disease or elderly patients (Prendergast 1984, Feldman 1985). This medication is a major cause of medication-induced hypoglycemia and the risk is greater than with other SUs (Gangji et al. 2007). Glimepiride, introduced in 1995, is a second-generation sulfonylurea (SU) drug used for the management of T2DM (Massi-Benedetti 2003). Compared to glipizide, another second-generation SU drug, glimepiride has a longer duration of action. It is sometimes classified as a third-generation SU because it has larger substitutions than other second-generation SUs (Basit et al. 2012).

磺酰脲类（SU）药物是一类主要应用于2型糖尿病（T2DM）治疗超过60年的抗高血糖药物。它们可作为除美格列奈之外的任何口服降糖药物辅助治疗，或考虑用于对二甲双胍不耐受或有禁忌症的患者。它们通常分为第一代和第二代。第一代磺酰脲类药物的例子包括氯磺丙脲、托拉扎米和甲苯磺丁脲，而第二代磺酰脲类药物包括格列吡嗪、格列齐特和格列本脲。格列吡嗪有时也被称为第三代药物。与格列齐特和甲苯磺丁脲等短效药物相比，氯磺丙脲、格列本脲和格列吡嗪具有更长的作用持续时间。由于其低成本、广泛可用性和有效性，尽管存在潜在的低血糖风险（Mizuno等，2008年，Lorenzati等，2010年，Carbone等，2018年），磺酰脲类药物仍然是一种常用的处方药物。

磺酰脲类药物主要通过关闭β细胞质膜上的ATP敏感钾通道（KATP）来刺激胰岛素从胰腺β细胞分泌。它们主要通过结合KATP的SUR亚单位并诱导通道关闭而发挥作用。然而，当药物结合时，通道仍然能有限地打开，因此高亲和力磺酰脲的抑制并不完全，即使在饱和药物浓度下也是如此。甲苯磺丁脲和格列齐特阻断含有SUR1（又称ABCC8）的通道（存在于胰腺β细胞中）（Gribble等，1998年，de Wet & Proks，2015年），但不是SUR2（存在于心脏和平滑肌细胞中），而格列本脲、格列吡嗪、瑞格列奈和美格列奈可以阻断这两种类型的通道。动物实验表明，KATP通道具有磺酰脲类和美格列奈的高亲和力和低亲和力结合位点（Gribble等，1997年，Ashfield等，1999年，Proks等，2002年）。磺酰脲类药物甲苯磺丁脲与SUR1的高亲和力位点结合，消除了MgADP对KATP通道的刺激性作用，并被认为是通过抑制KATP通道的主要机制（）。

第一代磺酰脲类药物因心血管事件增加死亡风险而被第二代磺酰脲类药物取代。第一代磺酰脲类药物甲苯磺丁脲（商品名Orinase）是一种口服磺酰脲类降糖药，用于治疗T2DM（Recant & Fischer，1957年）。其拟议的作用机制被认为是通过与KATP通道的SUR1亚单位相互作用（Babenko等，1999年）。氯磺丙脲（商品名Diabinese）是一种长效第一代磺酰脲类药物，用于治疗T2DM。由于其长效特性增加了低血糖的风险，因此不推荐用于老年人以及肝肾功能轻度到中度损害的患者（Shorr等，1996年）。托拉扎米（商品名Tolinase）于1986年获得FDA批准，用于治疗T2DM（McKendry & Gfeller，1967年，Firth等，1986年）。尽管其确切的作用机制尚不清楚，但它很可能与KATP通道的SUR1结合，阻断通道活性。

第二代磺酰脲类药物作为全球抗糖尿病治疗的主要手段得到广泛应用。格列吡嗪（商品名Glucotrol）是一种第二代磺酰脲类药物，用于治疗T2DM（Prendergast，1984年）。自1984年以来在美国获得批准。格列吡嗪显示快速吸收和作用起效，具有最短的半衰期和作用持续时间，从而降低了与其他抗糖尿病药物相比常见的不良的低血糖风险（Melander & Wåhlin-Boll，1983年）。格列齐特（商品名Diamicron）于1972年获得FDA批准，是一种用于治疗T2DM的抗糖尿病药物。格列齐特被认为是一种第二代磺酰脲类药物，其效力高于其他磺酰脲类药物，且半衰期更短。虽然它已被证明与格列吡嗪具有相同的疗效，但欧洲GUIDE研究显示，与格列吡嗪相比，其低血糖确认事件减少约50%（Schernthaner等，2004年）。

格列本脲（又称格列本脲，商品名Diabeta，Flycron）是一种第二代磺酰脲类药物，于1984年获得FDA批准，其效力是甲苯磺丁脲的200倍。格列本脲的疗效与第一代磺酰脲类药物氯磺丙脲相当，但不良反应发生率较低。格列本脲不应用于患有肝病、严重肾病或老年人的糖尿病患者（Prendergast，1984年，Feldman，1985年）。该药物是药物诱导的低血糖的主要原因之一，其风险高于其他磺酰脲类药物（Gangji等，2007年）。格列吡嗪于1995年推出，是一种用于管理T2DM的第二代磺酰脲类药物（Massi-Benedetti，2003年）。与另一种第二代磺酰脲类药物格列吡嗪相比，格列吡嗪具有更长的作用持续时间。有时它被归类为第三代磺酰脲类药物，因为它比其他第二代磺酰脲类药物具有更大的取代基（Basit等，2012年）。