Journal article
The KCNJ11-E23K gene variant hastens diabetes progression by impairing glucose-induced insulin secretion
- Abstract:
- The ATP-sensitive K+ (KATP) channel controls blood glucose levels by coupling glucose metabolism to insulin secretion in pancreatic β-cells. E23K, a common polymorphism in the pore-forming KATP channel subunit (KCNJ11) gene, has been linked to increased risk of type 2 diabetes. Understanding the risk-allele-specific pathogenesis has the potential to improve personalized diabetes treatment, but the underlying mechanism has remained elusive. Using a genetically engineered mouse model, we now show that the K23 variant impairs glucose-induced insulin secretion and increases diabetes risk when combined with a high-fat diet (HFD) and obesity. KATP-channels in β-cells with two K23 risk alleles (KK) showed decreased ATP inhibition, and the threshold for glucose-stimulated insulin secretion from KK islets was increased. Consequently, the insulin response to glucose and glycemic control was impaired in KK mice fed a standard diet. On an HFD, the effects of the KK genotype were exacerbated, accelerating diet-induced diabetes progression and causing β-cell failure. We conclude that the K23 variant increases diabetes risk by impairing insulin secretion at threshold glucose levels, thus accelerating loss of β-cell function in the early stages of diabetes progression.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
Actions
Authors
+ Medical Research Council
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- Funder identifier:
- https://ror.org/03x94j517
- Grant:
- MR/T002107/1
+ European Research Council
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- Funder identifier:
- https://ror.org/0472cxd90
- Grant:
- 322620
+ Biotechnology and Biological Sciences Research Council
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- Funder identifier:
- https://ror.org/00cwqg982
- Grant:
- BB/R017220/1
- BB/S008608/1
- Publisher:
- American Diabetes Association
- Journal:
- Diabetes More from this journal
- Volume:
- 70
- Issue:
- 5
- Pages:
- 1145-1156
- Place of publication:
- United States
- Publication date:
- 2021-02-10
- Acceptance date:
- 2021-02-05
- DOI:
- EISSN:
-
1939-327X
- ISSN:
-
0012-1797
- Pmid:
-
33568422
- Language:
-
English
- Pubs id:
-
1161434
- Local pid:
-
pubs:1161434
- Deposit date:
-
2024-09-05
Terms of use
- Copyright holder:
- American Diabetes Association
- Copyright date:
- 2021
- Rights statement:
- © 2021 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
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