Reactome | Meglitinides bind ABCC8

Meglitinides bind ABCC8

Stable Identifier

R-HSA-9650858

Type

Reaction [binding]

Species

Homo sapiens

Compartment

plasma membrane, extracellular region

ReviewStatus

5/5

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The KATP channel is a hetero-octameric complex of two different types of protein subunits: an inwardly rectifying K+ channel (KIR, subunit 6.x) and a sulfonylurea receptor (SUR). More than one isoform exists for both proteins: Kir6.1, Kir6.2 and SUR1, SUR2A, SUR2B. The subunits that are predominantly expressed in pancreatic β-cells are Kir6.2 and SUR1. In the pancreatic β-cell, the meglitinide class of drugs block KATP channels to stimulate insulin secretion. This action is a treatment for type 2 diabetes.

The first meglitinide, repaglinide (trade name Prandin), was FDA-approved in 1997 and is an insulin secretagogue used for the management of type 2 (non-insulin-dependent) diabetes mellitus (NIDDM2) (Balfour & Faulds 1998, Culy & Jarvis 2001). Studies suggest repaglinide associates with the sulfonylurea receptor SUR1 (ABCC8) subunit and stimulates insulin secretion by blocking ATP-dependent potassium channels (KATP) (Hansen et al. 2002, 2005, Ding et al. 2019). Such inhibition results in membrane depolarization and calcium influx through voltage-gated calcium channels leading to an increase in intracellular calcium and subsequent exocytosis of insulin-containing granules. Since the action of repaglinide involves promoting insulin release from pancreatic β cells, a major concern is hypoglycemia (Leonard et al. 2018).

The second meglitinide to be introduced was nateglinide (trade name Starlix), approved by the FDA in 2000 and the EMA in 2001. Like repaglinide, nateglinide is also thought to bind competitively to SUR1, inhibiting KATP channels and stimulating insulin secretion from pancreatic β cells. Nateglinide binds rapidly to SUR1, and it dissociates from it extremely rapidly in a manner of seconds, giving nateglinide a unique "fast on-fast off" effect (Hu et al. 2000). This provides good control of postprandial hyperglycemia when taken immediately before meals (Norman & Rabasseda 2001). The fast on-off effect of nateglinide also reduces the risk of hypoglycemia.

The third meglitinide used to treat NIDDM2 is mitiglinide (trade name Glufast), a rapidly-acting insulin secretion stimulant (Phillippe & Wargo 2013). It is approved in Japan for the treatment of NIDDM2 but has yet to gain FDA approval in the US. As with other meglitinides, mitiglinide is thought to elicit its action by associating with the SUR1 subunit and blocking the activity of the KATP channel, leading to insulin release (Reimann et al. 2001, Sunaga et al. 2001).

Literature References

PubMed ID	Title	Journal	Year
10773014	Pancreatic beta-cell K(ATP) channel activity and membrane-binding studies with nateglinide: A comparison with sulfonylureas and repaglinide Fanelli, B, Boettcher, BR, Wang, S, Hu, S, Schmitz, R, Bell, PA, Dunning, BE, Geisse, S	J. Pharmacol. Exp. Ther.	2000
23992284	Mitiglinide for type 2 diabetes treatment Wargo, KA, Phillippe, HM	Expert Opin Pharmacother	2013
11264248	Effects of mitiglinide (S 21403) on Kir6.2/SUR1, Kir6.2/SUR2A and Kir6.2/SUR2B types of ATP-sensitive potassium channel Proks, P, Reimann, F, Ashcroft, FM	Br. J. Pharmacol.	2001
11577798	Repaglinide: a review of its therapeutic use in type 2 diabetes mellitus Culy, CR, Jarvis, B	Drugs	2001
29108130	Comparative risk of serious hypoglycemia with oral antidiabetic monotherapy: A retrospective cohort study Cardillo, S, Leonard, CE, Bilker, WB, Flory, JH, Brensinger, CM, Han, X, Hennessy, S	Pharmacoepidemiol Drug Saf	2018
11716850	The effects of mitiglinide (KAD-1229), a new anti-diabetic drug, on ATP-sensitive K+ channels and insulin secretion: comparison with the sulfonylureas and nateglinide Sunaga, Y, Shibasaki, T, Seino, S, Yano, H, Gonoi, T, Ichikawa, K, Kusama, H	Eur. J. Pharmacol.	2001
9739505	Repaglinide Balfour, JA, Faulds, D	Drugs Aging	1998
12196472	Differential interactions of nateglinide and repaglinide on the human beta-cell sulphonylurea receptor 1 Ashcroft, FM, Carr, RD, Hansen, JB, Wahl, P, Christensen, IT, Hansen, AM	Diabetes	2002
12764427	Nateglinide: A structurally novel, short-acting, hypoglycemic agent Rabasseda, X, Norman, P	Drugs Today	2001
15678092	Kir6.2-dependent high-affinity repaglinide binding to beta-cell K(ATP) channels Ashcroft, FM, Carr, RD, Hansen, JB, Wahl, P, Hansen, AM	Br. J. Pharmacol.	2005
31067468	The Structural Basis for the Binding of Repaglinide to the Pancreatic K_ATP Channel Chen, L, Ding, D, Kang, Y, Wu, JX, Wang, M	Cell Rep	2019