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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.
- Source :
-
Scientific reports [Sci Rep] 2021 Jun 10; Vol. 11 (1), pp. 12253. Date of Electronic Publication: 2021 Jun 10. - Publication Year :
- 2021
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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.
- Subjects :
- Alleles
Amino Acid Substitution
Animals
Disease Models, Animal
Disease Susceptibility
Glucose metabolism
Long QT Syndrome etiology
Mice
Insulin biosynthesis
Insulin Secretion
Islets of Langerhans metabolism
KCNQ1 Potassium Channel genetics
Long QT Syndrome metabolism
Long QT Syndrome physiopathology
Loss of Function Mutation
Subjects
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