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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.

ABSTRACT: Loss-of-function (LoF) mutations in KCNQ1, encoding the voltage-gated K⁺ channel K_v7.1, 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_v7.1 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_v7.1 dysfunction is involved in a transition from hyper- to hyposecretion of insulin, potentially explaining the association with both hypoglycemia and hyperglycemia in LQT1 patients.

SUBMITTER: Lubberding AF

PROVIDER: S-EPMC8192901 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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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.

Lubberding Anniek F AF Zhang Jinyi J Lundh Morten M Nielsen Thomas Svava TS Søndergaard Mathilde S MS Villadsen Maria M Skovhøj Emil Z EZ Boer Geke A GA Hansen Jakob B JB Thomsen Morten B MB Treebak Jonas T JT Holst Jens J JJ Kanters Jørgen K JK Mandrup-Poulsen Thomas T Jespersen Thomas T Emanuelli Brice B Torekov Signe S SS

Scientific reports 20210610 1

Loss-of-function (LoF) mutations in KCNQ1, encoding the voltage-gated K<sup>+</sup> channel K<sub>v</sub>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 glu ...[more]

PMID: 34112814

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Project description:Insulin receptor (Insr) protein can be found at higher levels in pancreatic b-cells than in most other cell types, but the consequences of b-cell insulin resistance remain enigmatic. Ins1cre allele was used to delete Insr specifically in b-cells of both female and male mice which were compared to Ins1cre-containing littermate controls at multiple ages and on multiple diets. RNA-seq of recombined b-cells revealed significant differences in multiple pathways previously implicated in insulin secretion and cellular fate, including rewired Ras and NFkB signaling. Male, but not female, bInsrKO mice had reduced oxygen consumption rate, while action potential and calcium oscillation frequencies were increased in Insr knockout b-cells from female, but not male mice. Female bInsrKO and bInsrHET mice exhibited elevated insulin release in perifusion experiments, during hyperglycemic clamps, and following i.p. glucose challenge. Deletion of Insr did not reduce b-cell mass up to 9 months of age, nor did it impair hyperglycemia-induced proliferation. Based on our data, we adapted a mathematical model to include b-cell insulin resistance, which predicted that b-cell Insr knockout would improve glucose tolerance depending on the degree of whole-body insulin resistance. Indeed, glucose tolerance was significantly improved in female bInsrKO and bInsrHET mice when compared to controls at 9, 21 and 39 weeks. We did not observe improved glucose tolerance in adult male mice or in high fat diet-fed mice, corroborating the prediction that global insulin resistance obscures the effects of b-cell specific insulin resistance. We further validated our in vivo findings using the Ins1-CreERT transgenic line and found improved glucose tolerance 4 weeks after tamoxifen-mediated Insr deletion. Collectively, our data show that loss of b-cell Insr alone is sufficient to drive glucose-induced hyperinsulinemia, thereby improving glucose homeostasis in otherwise insulin sensitive dietary and age contexts.

Dataset Information

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

Publications

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

Similar Datasets

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