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

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Reaction [binding]
Homo sapiens
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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).

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 sulphonylureas 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 ().

1st generation SUs have increased risk of mortality due to cardiovascular events and have been superseded by 2nd generation SUs.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.

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).

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).

Literature References
PubMed ID Title Journal Year
6435940 Glyburide and glipizide, second-generation oral sulfonylurea hypoglycemic agents

Prendergast, BD

Clin Pharm 1984
3517644 Effects of tolazamide and exogenous insulin on insulin action in patients with non-insulin-dependent diabetes mellitus

Rizza, RA, Bell, PM, Firth, RG

N. Engl. J. Med. 1986
10342826 Identification of the high-affinity tolbutamide site on the SUR1 subunit of the K(ATP) channel

Gribble, FM, Ashfield, R, Ashcroft, FM, Ashcroft, SJ

Diabetes 1999
6019353 Clinical experience with the oral antidiabetic compound, tolazamide

Gfeller, KF, McKendry, JB

Can Med Assoc J 1967
8675920 Individual sulfonylureas and serious hypoglycemia in older people

Griffin, MR, Ray, WA, Shorr, RI, Daugherty, JR

J Am Geriatr Soc 1996
26517901 Molecular action of sulphonylureas on KATP channels: a real partnership between drugs and nucleotides

de Wet, H, Proks, P

Biochem. Soc. Trans. 2015
10526167 The tolbutamide site of SUR1 and a mechanism for its functional coupling to K(ATP) channel closure

Bryan, J, Gonzalez, G, Babenko, AP

FEBS Lett. 1999
9726229 Tissue specificity of sulfonylureas: studies on cloned cardiac and beta-cell K(ATP) channels

Gribble, FM, Tucker, SJ, Seino, S, Ashcroft, FM

Diabetes 1998
9350615 The interaction of nucleotides with the tolbutamide block of cloned ATP-sensitive K+ channel currents expressed in Xenopus oocytes: a reinterpretation

Gribble, FM, Tucker, SJ, Ashcroft, FM

J. Physiol. (Lond.) 1997
3923453 Glyburide: a second-generation sulfonylurea hypoglycemic agent. History, chemistry, metabolism, pharmacokinetics, clinical use and adverse effects

Feldman, JM

Pharmacotherapy 1985
12475777 Sulfonylurea stimulation of insulin secretion

Green, N, Ashcroft, F, Proks, P, Gribble, F, Reimann, F

Diabetes 2002
11078469 Gliclazide modified release: from once-daily administration to 24-hour blood glucose control

Harrower, A

Metab. Clin. Exp. 2000
15305887 GUIDE study: double-blind comparison of once-daily gliclazide MR and glimepiride in type 2 diabetic patients

Novials, A, Rottiers, R, Kempler, P, Rutten, GE, Drzewoski, J, Shaw, KM, Di Mario, U, Grimaldi, A, Schernthaner, G, Kvapil, M

Eur. J. Clin. Invest. 2004
17259518 A systematic review and meta-analysis of hypoglycemia and cardiovascular events: a comparison of glyburide with other secretagogues and with insulin

Gangji, AS, Cukierman, T, Goldsmith, CH, Gerstein, HC, Clase, CM

Diabetes Care 2007
6424440 Clinical pharmacology of glipizide

Wåhlin-Boll, E, Melander, A

Am. J. Med. 1983
13459201 Studies on the mechanism of tolbutamide hypoglycemia in animal and human subjects


Ann. N. Y. Acad. Sci. 1957
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