Journal article
A loss-of-function mutation in KCNJ11 causing sulfonylurea-sensitive diabetes in early adult life
- Abstract:
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Aims/hypothesis
The ATP-sensitive potassium (KATP) channel couples beta cell electrical activity to glucose-stimulated insulin secretion. Loss-of-function mutations in either the pore-forming (inwardly rectifying potassium channel 6.2 [Kir6.2], encoded by KCNJ11) or regulatory (sulfonylurea receptor 1, encoded by ABCC8) subunits result in congenital hyperinsulinism, whereas gain-of-function mutations cause neonatal diabetes. Here, we report a novel loss-of-function mutation (Ser118Leu) in the pore helix of Kir6.2 paradoxically associated with sulfonylurea-sensitive diabetes that presents in early adult life.Methods
A 31-year-old woman was diagnosed with mild hyperglycaemia during an employee screen. After three pregnancies, during which she was diagnosed with gestational diabetes, the patient continued to show elevated blood glucose and was treated with glibenclamide (known as glyburide in the USA and Canada) and metformin. Genetic testing identified a heterozygous mutation (S118L) in the KCNJ11 gene. Neither parent was known to have diabetes. We investigated the functional properties and membrane trafficking of mutant and wild-type KATP channels in Xenopus oocytes and in HEK-293T cells, using patch-clamp, two-electrode voltage-clamp and surface expression assays.Results
Functional analysis showed no changes in the ATP sensitivity or metabolic regulation of the mutant channel. However, the Kir6.2-S118L mutation impaired surface expression of the KATP channel by 40%, categorising this as a loss-of-function mutation.Conclusions/interpretation
Our data support the increasing evidence that individuals with mild loss-of-function KATP channel mutations may develop insulin deficiency in early adulthood and even frank diabetes in middle age. In this case, the patient may have had hyperinsulinism that escaped detection in early life. Our results support the importance of functional analysis of KATP channel mutations in cases of atypical diabetes.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 1.5MB, Terms of use)
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- Publisher copy:
- 10.1007/s00125-024-06103-w
Authors
+ Medical Research Council
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- Funder identifier:
- https://ror.org/03x94j517
- Grant:
- MR/T002107/1
+ Biotechnology and Biological Sciences Research Council
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- Funder identifier:
- https://ror.org/00cwqg982
- Grant:
- BB/R002517/1
- BB/R017220/1
- Publisher:
- Springer
- Journal:
- Diabetologia More from this journal
- Volume:
- 67
- Issue:
- 5
- Pages:
- 940-951
- Place of publication:
- Germany
- Publication date:
- 2024-02-17
- Acceptance date:
- 2023-11-28
- DOI:
- EISSN:
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1432-0428
- ISSN:
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0012-186X
- Pmid:
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38366195
- Language:
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English
- Keywords:
- Pubs id:
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1620389
- Local pid:
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pubs:1620389
- Deposit date:
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2024-07-22
- ARK identifier:
Terms of use
- Copyright holder:
- Vedovato et al.
- Copyright date:
- 2024
- Rights statement:
- © The Author(s) 2024. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
- Licence:
- CC Attribution (CC BY)
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