Sulphonylurea action revisited: the post-cloning era
Open accessAbstract
Hypoglycaemic agents such as sulphonylureas and the newer group of "glinides" stimulate insulin secretion by closing ATP-sensitive potassium (K(ATP)) channels in pancreatic beta cells, but have varying cross-reactivity with related channels in extrapancreatic tissues such as heart, vascular smooth and skeletal muscle. Experiments on the structure-function relationships of recombinant K(ATP) channels and the phenotypes of mice deficient in different K(ATP) channel subunits have provided important insights into the mechanisms underlying sulphonylurea selectivity, and the potential consequences of K(ATP) channel blockade outside the pancreatic beta cell. The different pharmacological properties of K(ATP) channels from beta cells compared with those from cardiac, smooth and skeletal muscle, are accounted for by the expression of alternative types of sulphonylurea receptor, with non-identical drug binding sites. The sulphonylureas and glinides are found to fall into two groups: one exhibiting selectivity for beta cell sulphonylurea receptors (SUR1), and the other blocking cardiovascular and skeletal muscle sulphonylurea receptors (SUR2) with potencies similar to their action on SUR1. In seeking potential side effects of K(ATP) channel inhibitors in humans, it is essential to take these drug differences into account, along with the probability (suggested by the studies on K(ATP) channel knockout mice) that the effects of extrapancreatic K(ATP) channel inhibition might be either subtle or rare. Further studies are still required before a final decision can be made on whether non-selective agents are appropriate for the therapy of Type 2 diabetes.
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KATP channels are blocked by sulfonylureas, glinides and benzamido derivatives, and are activated by K+ channel openers like diazoxide.
“KATP channels are blocked by sulfonylureas (such as gliclazide, glibenclamide and tolbutamide), by glinides (like repaglinide and nateglinide) and by benzamido derivatives (e.g. meglitinide), and they are activated by K+ channel openers like diazoxide (230).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [230]
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Association and Stoichiometry of KATP Channel Subunits
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“It has also been found that exocytosis is directly modulated by the ATP/ADP ratio [140], which could theoretically be detected by the granule SUR subunits.”
Sulfonylurea and K+-Channel Opener Sensitivity of KATP Channels
Koster, J. C., Sha, Q., & Nichols, C. G. (1999) · The Journal of General Physiology · doi:10.1085/jgp.114.2.203 · Cited by 97 · cited 1× · see citing works
“2 might be involved in coupling to SUR [104, 105, 106].”
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Glucagon-like peptide 1 (GLP-1)
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Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men
Rorsman, P., & Ashcroft, F. M. (2018) · Physiological Reviews · doi:10.1152/physrev.00008.2017 · Cited by 793 · see citing works
Reversible changes in pancreatic islet structure and function produced by elevated blood glucose
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- Authors
- Gribble, F. M., & Reimann, F.
- Affiliations
- Addenbrooke's Hospital (GB)
- Corresponding author
- Gribble, F. M.
- Venue
- Diabetologia
- Published
- 2003-07-01
- Volume
- 46
- Issue
- 7
- Pages
- 875-891
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2008677894
- Cited by
- 284
- References
- 8
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 9 · 2023: 9 · 2022: 5 · 2021: 11 · 2020: 11 · 2019: 9 · 2018: 12 · 2017: 14 · 2016: 8 · 2015: 15 · 2014: 13 · 2013: 14 · 2012: 13
- FWCI
- 1.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Diabetes UK
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- sulfonylureas, glinides, ATP-sensitive potassium channels, insulin secretion, pancreatic beta cells, type 2 diabetes, drug selectivity, antidiabetic drugs
- MeSH terms
- Animals, Diabetes Mellitus, Type 2, Humans, Hypoglycemic Agents, Membrane Proteins, Research, Sulfonylurea Compounds, Potassium Channels
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