Atypical KCNQ1/Kv7 channel function in a neonatal diabetes patient: Hypersecretion preceded the failure of pancreatic beta-cells.
Publication Year:
2024
PubMed ID:
39055936
Funding Grants:
Public Summary:
KCNQ1/Kv7 is a potassium channel that plays a key role in regulating heart rhythm and glucose levels. Mutations in KCNQ1 are linked to conditions like long-QT syndrome and type 2 diabetes. However, its role in human pancreatic cells is not well understood. In this study, they identified a specific mutation (R397W) in a person with permanent neonatal diabetes mellitus (PNDM) who did not have heart problems. To explore how this mutation affects pancreatic function, they introduced it into human stem cells and created islet-like organoids. The mutation did not affect the development of these cells, but it led to increased insulin secretion by affecting calcium flux and spike frequency. Over time, the mutant cells showed reduced insulin secretion and deteriorated, mimicking a diabetic state, which worsened under high glucose conditions. This was linked to changes in calcium channel expression and energy production. Findings provide new insights into how KCNQ1 mutations contribute to insulin regulation and the development of hereditary diabetes.
Scientific Abstract:
KCNQ1/Kv7, a low-voltage-gated K(+) channel, regulates cardiac rhythm and glucose homeostasis. While KCNQ1 mutations are associated with long-QT syndrome and type2 diabetes, its function in human pancreatic cells remains controversial. We identified a homozygous KCNQ1 mutation (R397W) in an individual with permanent neonatal diabetes melitus (PNDM) without cardiovascular symptoms. To decipher the potential mechanism(s), we introduced the mutation into human embryonic stem cells and generated islet-like organoids (SC-islets) using CRISPR-mediated homology-repair. The mutation did not affect pancreatic differentiation, but affected channel function by increasing spike frequency and Ca(2+) flux, leading to insulin hypersecretion. With prolonged culturing, the mutant islets decreased their secretion and gradually deteriorated, modeling a diabetic state, which accelerated by high glucose levels. The molecular basis was the downregulated expression of voltage-activated Ca(2+) channels and oxidative phosphorylation. Our study provides a better understanding of the role of KCNQ1 in regulating insulin secretion and beta-cell survival in hereditary diabetes pathology.
