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.

Celebrities in the heart, strangers in the pancreatic beta cell: Voltage‐gated potassium channels Kv7.1 and Kv11.1 bridge long QT syndrome with hyperinsulinaemia as well as type 2 diabetes

“…Islets carrying the LoF mutation on both alleles hypersecreted insulin in response to glucose ex vivo at a young age (12‐14 weeks). Yet when performing the same experiments 10 weeks later, at 24 weeks of age, islets heterozygous and homozygous for the mutation now secreted less insulin in response to glucose compared to their littermate controls 53 . This transition from hyper‐ to hyposecretion of insulin is reminiscent of the phenotype described in KCNH6 / Kcnh6 LoF in humans and mice 58 and may explain the combination of hyperinsulinaemia 4,5 and diabetes 6 in patients with LQTS.…”

“…During an OGTT patients with LQT1 showed hypersecretion of insulin which resulted in symptomatic hypoglycaemia ~3‐5 hours after the glucose load. Follow‐up studies in mice with a clinically relevant LoF mutation in Kcnq1 showed that the hypersecretory phenotype was also present ex vivo 53 . This suggests that the hypersecretion of insulin found in the setting of KCNQ1/Kcnq1 LoF is because of an effect in the beta cell itself and/or in the other endocrine cells of the pancreatic islet, but not from effects occurring outside of the pancreas.…”

“…This, along with the increased QT interval, may pose an increased risk of cardiac arrhythmia 157 . This is exemplified in mice with LoF in Kcnq1 where refeeding after overnight fasting induced premature ventricular contractions that were not seen in wild‐type littermate controls 53 …”

“…157 This is exemplified in mice with LoF in Kcnq1 where refeeding after overnight fasting induced premature ventricular contractions that were not seen in wild-type littermate controls. 53 The combination of increased QT and cardiac arrhythmia in the setting of hyperglycaemia has been reported in multiple settings. A case report described QT prolongation and subsequent torsade de pointes during hyperglycaemia in a patient being refed after severe malnourishment.…”

Correlation of PET-MRI, Pathology, LOH, and Surgical Success in a Case of CHI With Atypical Large Pancreatic Focus

“…The authors proposed a combined mechanism of islet overgrowth due to the proproliferative effect of the paternal imprint pattern of the 11p15 region together with a lack of expression of the KCNQ1 voltage-gated potassium channel that is expressed only from the maternal allele. KCNQ1 itself is assumed to be involved in the regulation of potassium flux in pancreatic β cells [ 15 ]. Pancreatic histology in patients with CHI and BWS due to UPD11p shows a marked diffuse increase in the volume of endocrine tissue, often with a gradient in the degree of islet expansion across the entire pancreas [ 14 ].…”