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

Authors :
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
Source :
Scientific reports [Sci Rep] 2021 Jun 10; Vol. 11 (1), pp. 12253. Date of Electronic Publication: 2021 Jun 10.
Publication Year :
2021

Abstract

Loss-of-function (LoF) mutations in KCNQ1, encoding the voltage-gated K <superscript>+</superscript> channel K <subscript>v</subscript> 7.1, 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 K <subscript>v</subscript> 7.1 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 K <subscript>v</subscript> 7.1 dysfunction is involved in a transition from hyper- to hyposecretion of insulin, potentially explaining the association with both hypoglycemia and hyperglycemia in LQT1 patients.

Details

Language :
English
ISSN :
2045-2322
Volume :
11
Issue :
1
Database :
MEDLINE
Journal :
Scientific reports
Publication Type :
Academic Journal
Accession number :
34112814
Full Text :
https://doi.org/10.1038/s41598-021-90452-8