Sulfonylurea Stimulation of Insulin Secretion
Open accessAbstract
Sulfonylureas are widely used to treat type 2 diabetes because they stimulate insulin secretion from pancreatic β-cells. They primarily act by binding to the SUR subunit of the ATP-sensitive potassium (KATP) channel 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 sulfonylurea inhibition is not complete, even at saturating drug concentrations. KATP channels are also found in cardiac, skeletal, and smooth muscle, but in these tissues are composed of different SUR subunits that confer different drug sensitivities. Thus tolbutamide and gliclazide block channels containing SUR1 (β-cell type), but not SUR2 (cardiac, smooth muscle types), whereas glibenclamide, glimepiride, repaglinide, and meglitinide block both types of channels. This difference has been exploited to determine residues contributing to the sulfonylurea-binding site. Sulfonylurea block is decreased by mutations or agents (e.g., phosphatidylinositol bisphosphate) that increase KATP channel open probability. We now propose a kinetic model that explains this effect in terms of changes in the channel open probability and in the transduction between the drug-binding site and the channel gate. We also clarify the mechanism by which MgADP produces an apparent increase of sulfonylurea efficacy on channels containing SUR1 (but not SUR2).
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Binding of one ATP molecule is sufficient to completely close the channel, while inhibition by SUs is incomplete as channel might still open when SUs are bound to SUR1.
“Moreover, while the binding of only one ATP molecule is sufficient to completely close the channel,306 inhibition by SUs is incomplete as the channel might still open even when SUs are bound to SUR1.299”
From Pancreatic regulation of glucose homeostasis. (2016) · cites this paper as [299]
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- Authors
- Proks, P., Reimann, F., Green, N., Gribble, F., & Ashcroft, F.
- Affiliations
- University of Oxford (GB)
- University of Cambridge (GB)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2002-12-01
- Volume
- 51
- Issue
- suppl_3
- Pages
- S368-S376
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2009480581
- Cited by
- 510
- References
- 54
- Citations by year
- 2026: 21 · 2025: 20 · 2024: 28 · 2023: 33 · 2022: 27 · 2021: 39 · 2020: 26 · 2019: 21 · 2018: 26 · 2017: 26 · 2016: 29 · 2015: 32 · 2014: 26 · 2013: 14 · 2012: 13
- FWCI
- 1.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- GlaxoSmithKline
- Wellcome Trust
- Royal Society
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Keywords
- sulfonylureas, insulin secretion, pancreatic beta cells, ATP-sensitive potassium channels, SUR1, SUR2, open probability, kinetic model, MgADP, phosphatidylinositol bisphosphate, type 2 diabetes, glibenclamide, gliclazide, tolbutamide, meglitinides, repaglinide, glimepiride
- MeSH terms
- Insulin Secretion, Adenosine Triphosphate, Animals, Binding Sites, Insulin, Receptors, Drug, Sulfonylurea Compounds, Potassium Channels, ATP-Binding Cassette Transporters, Potassium Channels, Inwardly Rectifying, Potassium Channel Blockers, Sulfonylurea Receptors
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