Large-Scale Association Studies of Variants in Genes Encoding the Pancreatic β-Cell KATP Channel Subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) Confirm That the KCNJ11 E23K Variant Is Associated With Type 2 Diabetes
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The genes ABCC8 and KCNJ11, which encode the subunits sulfonylurea receptor 1 (SUR1) and inwardly rectifying potassium channel (Kir6.2) of the β-cell ATP-sensitive potassium (KATP) channel, control insulin secretion. Common polymorphisms in these genes (ABCC8 exon 16–3t/c, exon 18 T/C, KCNJ11 E23K) have been variably associated with type 2 diabetes, but no large (∼2,000 subjects) case-control studies have been performed. We evaluated the role of these three variants by studying 2,486 U.K. subjects: 854 with type 2 diabetes, 1,182 population control subjects, and 150 parent-offspring type 2 diabetic trios. The E23K allele was associated with diabetes in the case-control study (odds ratio [OR] 1.18 [95% CI 1.04–1.34], P = 0.01) but did not show familial association with diabetes. Neither the exon 16 nor the exon 18 ABCC8 variants were associated with diabetes (1.04 [0.91–1.18], P = 0.57; 0.93 [0.71–1.23], P = 0.63, respectively). Meta-analysis of all case-control data showed that the E23K allele was associated with type 2 diabetes (K allele OR 1.23 [1.12–1.36], P = 0.000015; KK genotype 1.65 [1.34–2.02], P = 0.000002); but the ABCC8 variants were not associated. Our results confirm that E23K increases risk of type 2 diabetes and show that large-scale association studies are important for the identification of diabetes susceptibility alleles.
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Tissue-specific expression of KATP-channel isoforms: SUR1 and Kir6.2 in pancreas and brain; Kir6.2 and SUR2A in heart and skeletal muscle; SUR2B in brain and smooth muscle; Kir6.1 and SUR2B in vascular smooth muscle.
“Moreover, different isoforms of the two subunits are expressed, depending on the tissue-specific expression of the KATP-channels: SUR1 and Kir6.2 are expressed in the pancreas and brain,296 Kir6.2 and SUR2A are expressed in the heart and skeletal muscle,297 while SUR2B is expressed in the brain and smooth muscle,298 and Kir6.1 and SUR2B are expressed in vascular smooth muscle.299”
From Pancreatic regulation of glucose homeostasis. (2016) · cites this paper as [296]
Citation 296 is attached to the pancreas-and-brain clause, not the later tissue-specific pairings. The paper’s introductory passage (indexed as Abstract; page unavailable) identifies SUR1 and Kir6.2 as subunits of the pancreatic β-cell KATP channel, but our copy does not state that both are expressed in the brain. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDefects in ion channels underlie many major human disorders, including neuronal disorders, diabetes and heart failure.
“Defects in ion channels underlie many major disorders in humans, also known as channelopathies, including neuronal disorders76, diabetes77 and heart failure78.”
From Unexplored therapeutic opportunities in the human genome (2018) · cites this paper as [77]
A common variant in Kir6.2 (E23K) is associated with a slightly increased risk of T2DM, but its effects on KATP channel activity and insulin secretion are very small and controversial.
“Finally, a common variant in Kir6.2 (E23K) is associated with a slightly increased risk of T2DM (216, 586). While its effects on KATP channel activity (604, 605) and insulin secretion (696) are very small (585) and controversial (552), it is important to note that even a tiny increase in channel activity can lead to ND (705).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [216]
Before this study, unequivocal replications of T2D susceptibility variants were limited to PPARG, KCNJ11 and TCF7L2.
“unequivocal replications are so far limited to variants in just three genes: PPARG, KCNJ11 and TCF7L2 (2-4).”
From Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes (2007) · cites this paper as [3]
Other known T2D susceptibility variants in the WTCCC scan had effect sizes consistent with earlier reports.
“The other known T2D susceptibility variants were detected with effect sizes consistent with previous reports (2, 3).”
From Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes (2007) · cites this paper as [3]
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- Authors
- Gloyn, A. L., Weedon, M. N., Owen, K. R., Turner, M. J., Knight, B. A., Hitman, G., Walker, M., Levy, J. C., Sampson, M., Halford, S., McCarthy, M. I., Hattersley, A. T., & Frayling, T. M.
- Affiliations
- Centre for Molecular Genetics, Peninsula Medical School, Exeter, U.K.
- University of London (GB)
- Newcastle University (GB)
- The Diabetes Research Laboratories, Radcliffe Infirmary, University of Oxford, Oxford, U.K.
- Norfolk and Norwich University Hospital (GB)
- Imperial College London (GB)
- Centre for Human Genetics (GB)
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2003-02-01
- Volume
- 52
- Issue
- 2
- Pages
- 568-572
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2169174186
- Cited by
- 754
- References
- 27
- Citations by year
- 2026: 5 · 2025: 15 · 2024: 8 · 2023: 16 · 2022: 10 · 2021: 14 · 2020: 15 · 2019: 20 · 2018: 25 · 2017: 27 · 2016: 33 · 2015: 30 · 2014: 40 · 2013: 42 · 2012: 46
- FWCI
- 38.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- Funders
- Medical Research Council
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- type 2 diabetes, KCNJ11, ABCC8, Kir6.2, SUR1, ATP-sensitive potassium channels, genetic susceptibility, insulin secretion, pancreatic beta cells, parent-offspring trios, familial association
- MeSH terms
- Adult, Alleles, Diabetes Mellitus, Type 2, Exons, Female, Genotype, Humans, Islets of Langerhans, Male, Middle Aged, Receptors, Drug, Genetic Variation, Potassium Channels, Cohort Studies, ATP-Binding Cassette Transporters, Amino Acid Substitution, Potassium Channels, Inwardly Rectifying, Sulfonylurea Receptors
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