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

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Standard

Age-dependent transition from islet insulin hypersecretion to hyposecretion in mice with the long QT-syndrome loss-of-function mutation Kcnq1-A340V. / Lubberding, Anniek F; Zhang, Jinyi; Lundh, Morten; Nielsen, Thomas Svava; Søndergaard, Mathilde S; Villadsen, Maria; Skovhøj, Emil Z.; Boer, Geke A; Hansen, Jakob B; Thomsen, Morten B; Treebak, Jonas T; Holst, Jens J; Kanters, Jørgen K; Mandrup-Poulsen, Thomas; Jespersen, Thomas; Emanuelli, Brice; Torekov, Signe S.

In: Scientific Reports, Vol. 11, No. 1, 12253, 2021.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Lubberding, AF, Zhang, J, Lundh, M, Nielsen, TS, Søndergaard, MS, Villadsen, M, Skovhøj, EZ, Boer, GA, Hansen, JB, Thomsen, MB, Treebak, JT, Holst, JJ, Kanters, JK, Mandrup-Poulsen, T, Jespersen, T, Emanuelli, B & Torekov, SS 2021, 'Age-dependent transition from islet insulin hypersecretion to hyposecretion in mice with the long QT-syndrome loss-of-function mutation Kcnq1-A340V', Scientific Reports, vol. 11, no. 1, 12253. https://doi.org/10.1038/s41598-021-90452-8

APA

Lubberding, A. F., Zhang, J., Lundh, M., Nielsen, T. S., Søndergaard, M. S., Villadsen, M., Skovhøj, E. Z., Boer, G. A., Hansen, J. B., Thomsen, M. B., Treebak, J. T., Holst, J. J., Kanters, J. K., Mandrup-Poulsen, T., Jespersen, T., Emanuelli, B., & Torekov, S. S. (2021). Age-dependent transition from islet insulin hypersecretion to hyposecretion in mice with the long QT-syndrome loss-of-function mutation Kcnq1-A340V. Scientific Reports, 11(1), [12253]. https://doi.org/10.1038/s41598-021-90452-8

Vancouver

Lubberding AF, Zhang J, Lundh M, Nielsen TS, Søndergaard MS, Villadsen M et al. Age-dependent transition from islet insulin hypersecretion to hyposecretion in mice with the long QT-syndrome loss-of-function mutation Kcnq1-A340V. Scientific Reports. 2021;11(1). 12253. https://doi.org/10.1038/s41598-021-90452-8

Author

Lubberding, Anniek F ; Zhang, Jinyi ; Lundh, Morten ; Nielsen, Thomas Svava ; Søndergaard, Mathilde S ; Villadsen, Maria ; Skovhøj, Emil Z. ; Boer, Geke A ; Hansen, Jakob B ; Thomsen, Morten B ; Treebak, Jonas T ; Holst, Jens J ; Kanters, Jørgen K ; Mandrup-Poulsen, Thomas ; Jespersen, Thomas ; Emanuelli, Brice ; Torekov, Signe S. / Age-dependent transition from islet insulin hypersecretion to hyposecretion in mice with the long QT-syndrome loss-of-function mutation Kcnq1-A340V. In: Scientific Reports. 2021 ; Vol. 11, No. 1.

Bibtex

@article{51f59b6697e647f6b669894d49285525,
title = "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 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.",
author = "Lubberding, {Anniek F} and Jinyi Zhang and Morten Lundh and Nielsen, {Thomas Svava} and S{\o}ndergaard, {Mathilde S} and Maria Villadsen and Skovh{\o}j, {Emil Z.} and Boer, {Geke A} and Hansen, {Jakob B} and Thomsen, {Morten B} and Treebak, {Jonas T} and Holst, {Jens J} and Kanters, {J{\o}rgen K} and Thomas Mandrup-Poulsen and Thomas Jespersen and Brice Emanuelli and Torekov, {Signe S}",
year = "2021",
doi = "10.1038/s41598-021-90452-8",
language = "English",
volume = "11",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "nature publishing group",
number = "1",

}

RIS

TY - JOUR

T1 - Age-dependent transition from islet insulin hypersecretion to hyposecretion in mice with the long QT-syndrome loss-of-function mutation Kcnq1-A340V

AU - Lubberding, Anniek F

AU - Zhang, Jinyi

AU - Lundh, Morten

AU - Nielsen, Thomas Svava

AU - Søndergaard, Mathilde S

AU - Villadsen, Maria

AU - Skovhøj, Emil Z.

AU - Boer, Geke A

AU - Hansen, Jakob B

AU - Thomsen, Morten B

AU - Treebak, Jonas T

AU - Holst, Jens J

AU - Kanters, Jørgen K

AU - Mandrup-Poulsen, Thomas

AU - Jespersen, Thomas

AU - Emanuelli, Brice

AU - Torekov, Signe S

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

U2 - 10.1038/s41598-021-90452-8

DO - 10.1038/s41598-021-90452-8

M3 - Journal article

C2 - 34112814

VL - 11

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 12253

ER -

ID: 272376222