Age-dependent transition from islet insulin hypersecretion to hyposecretion in mice with the long QT-syndrome loss-of-function mutation Kcnq1-A340V

Abstract Loss-of-function (LoF) mutations in KCNQ1, encoding the voltage-gated K+ channel Kv7.1, lead to long QT syndrome 1 (LQT1). LQT1 patients also present with post-prandial hyperinsulinemia and hypoglycaemia. In contrast, KCNQ1 polymorphisms are associated with diabetes, and LQTS patients have...

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Autores principales: Anniek F. Lubberding, Jinyi Zhang, Morten Lundh, Thomas Svava Nielsen, Mathilde S. Søndergaard, Maria Villadsen, Emil Z. Skovhøj, Geke A. Boer, Jakob B. Hansen, Morten B. Thomsen, Jonas T. Treebak, Jens J. Holst, Jørgen K. Kanters, Thomas Mandrup-Poulsen, Thomas Jespersen, Brice Emanuelli, Signe S. Torekov
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Publicado: Nature Portfolio 2021
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spelling oai:doaj.org-article:bdb0c435470a478696e2cc00273a49252021-12-02T17:47:23ZAge-dependent transition from islet insulin hypersecretion to hyposecretion in mice with the long QT-syndrome loss-of-function mutation Kcnq1-A340V10.1038/s41598-021-90452-82045-2322https://doaj.org/article/bdb0c435470a478696e2cc00273a49252021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90452-8https://doaj.org/toc/2045-2322Abstract Loss-of-function (LoF) mutations in KCNQ1, encoding the voltage-gated K+ channel Kv7.1, lead to long QT syndrome 1 (LQT1). LQT1 patients also present with post-prandial hyperinsulinemia and hypoglycaemia. In contrast, KCNQ1 polymorphisms are associated with diabetes, and LQTS patients have a higher prevalence of diabetes. We developed a mouse model with a LoF Kcnq1 mutation using CRISPR-Cas9 and hypothesized that this mouse model would display QT prolongation, increased glucose-stimulated insulin secretion and allow for interrogation of Kv7.1 function in islets. Mice were characterized by electrocardiography and oral glucose tolerance tests. Ex vivo, islet glucose-induced insulin release was measured, and beta-cell area quantified by immunohistochemistry. Homozygous mice had QT prolongation. Ex vivo, glucose-stimulated insulin release was increased in islets from homozygous mice at 12–14 weeks, while beta-cell area was reduced. Non-fasting blood glucose levels were decreased at this age. In follow-up studies 8–10 weeks later, beta-cell area was similar in all groups, while glucose-stimulated insulin secretion was now reduced in islets from hetero- and homozygous mice. Non-fasting blood glucose levels had normalized. These data suggest that Kv7.1 dysfunction is involved in a transition from hyper- to hyposecretion of insulin, potentially explaining the association with both hypoglycemia and hyperglycemia in LQT1 patients.Anniek F. LubberdingJinyi ZhangMorten LundhThomas Svava NielsenMathilde S. SøndergaardMaria VilladsenEmil Z. SkovhøjGeke A. BoerJakob B. HansenMorten B. ThomsenJonas T. TreebakJens J. HolstJørgen K. KantersThomas Mandrup-PoulsenThomas JespersenBrice EmanuelliSigne S. TorekovNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Anniek F. Lubberding
Jinyi Zhang
Morten Lundh
Thomas Svava Nielsen
Mathilde S. Søndergaard
Maria Villadsen
Emil Z. Skovhøj
Geke A. Boer
Jakob B. Hansen
Morten B. Thomsen
Jonas T. Treebak
Jens J. Holst
Jørgen K. Kanters
Thomas Mandrup-Poulsen
Thomas Jespersen
Brice Emanuelli
Signe S. Torekov
Age-dependent transition from islet insulin hypersecretion to hyposecretion in mice with the long QT-syndrome loss-of-function mutation Kcnq1-A340V
description Abstract Loss-of-function (LoF) mutations in KCNQ1, encoding the voltage-gated K+ channel Kv7.1, lead to long QT syndrome 1 (LQT1). LQT1 patients also present with post-prandial hyperinsulinemia and hypoglycaemia. In contrast, KCNQ1 polymorphisms are associated with diabetes, and LQTS patients have a higher prevalence of diabetes. We developed a mouse model with a LoF Kcnq1 mutation using CRISPR-Cas9 and hypothesized that this mouse model would display QT prolongation, increased glucose-stimulated insulin secretion and allow for interrogation of Kv7.1 function in islets. Mice were characterized by electrocardiography and oral glucose tolerance tests. Ex vivo, islet glucose-induced insulin release was measured, and beta-cell area quantified by immunohistochemistry. Homozygous mice had QT prolongation. Ex vivo, glucose-stimulated insulin release was increased in islets from homozygous mice at 12–14 weeks, while beta-cell area was reduced. Non-fasting blood glucose levels were decreased at this age. In follow-up studies 8–10 weeks later, beta-cell area was similar in all groups, while glucose-stimulated insulin secretion was now reduced in islets from hetero- and homozygous mice. Non-fasting blood glucose levels had normalized. These data suggest that Kv7.1 dysfunction is involved in a transition from hyper- to hyposecretion of insulin, potentially explaining the association with both hypoglycemia and hyperglycemia in LQT1 patients.
format article
author Anniek F. Lubberding
Jinyi Zhang
Morten Lundh
Thomas Svava Nielsen
Mathilde S. Søndergaard
Maria Villadsen
Emil Z. Skovhøj
Geke A. Boer
Jakob B. Hansen
Morten B. Thomsen
Jonas T. Treebak
Jens J. Holst
Jørgen K. Kanters
Thomas Mandrup-Poulsen
Thomas Jespersen
Brice Emanuelli
Signe S. Torekov
author_facet Anniek F. Lubberding
Jinyi Zhang
Morten Lundh
Thomas Svava Nielsen
Mathilde S. Søndergaard
Maria Villadsen
Emil Z. Skovhøj
Geke A. Boer
Jakob B. Hansen
Morten B. Thomsen
Jonas T. Treebak
Jens J. Holst
Jørgen K. Kanters
Thomas Mandrup-Poulsen
Thomas Jespersen
Brice Emanuelli
Signe S. Torekov
author_sort Anniek F. Lubberding
title Age-dependent transition from islet insulin hypersecretion to hyposecretion in mice with the long QT-syndrome loss-of-function mutation Kcnq1-A340V
title_short Age-dependent transition from islet insulin hypersecretion to hyposecretion in mice with the long QT-syndrome loss-of-function mutation Kcnq1-A340V
title_full Age-dependent transition from islet insulin hypersecretion to hyposecretion in mice with the long QT-syndrome loss-of-function mutation Kcnq1-A340V
title_fullStr Age-dependent transition from islet insulin hypersecretion to hyposecretion in mice with the long QT-syndrome loss-of-function mutation Kcnq1-A340V
title_full_unstemmed Age-dependent transition from islet insulin hypersecretion to hyposecretion in mice with the long QT-syndrome loss-of-function mutation Kcnq1-A340V
title_sort age-dependent transition from islet insulin hypersecretion to hyposecretion in mice with the long qt-syndrome loss-of-function mutation kcnq1-a340v
publisher Nature Portfolio
publishDate 2021
url https://doaj.org/article/bdb0c435470a478696e2cc00273a4925
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