Patients with Long QT Syndrome Due to Impaired hERG-encoded Kv11.1 Potassium Channel Have Exaggerated Endocrine Pancreatic and Incretin Function Associated with Reactive Hypoglycemia
Background—Loss-of-function mutations in hERG (encoding the Kv11.1 voltage-gated potassium channel) cause long QT syndrome (LQT2) due to prolonged cardiac repolarization. However, Kv11.1 is also present in pancreatic α and β cells and intestinal L and K cells, secreting glucagon, insulin, and the incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), respectively. These hormones are crucial for glucose regulation and LQTS may cause disturbed glucose regulation. We measured secretion of these hormones and cardiac repolarization in response to glucose ingestion in LQT2 patients with functional mutations in hERG and matched healthy participants, testing the hypothesis that LQT2 patients have increased incretin and β cell- and decreased α cell function and thus lower glucose levels.
Methods—Eleven patients with LQT2 and 22 gender, age- and BMI-matched control participants underwent a 6-hour 75g oral glucose tolerance test (OGTT) with electrocardiography (ECG) recording and blood sampling for measurements of glucose, insulin, C-peptide, glucagon, GLP-1 and GIP.
Results—Compared with matched control participants LQT2 patients had 56-78% increased serum insulin, serum C-peptide, plasma GLP-1 and plasma GIP responses (p=0.03-0.001) and decreased plasma glucose levels after glucose ingestion (p=0.02) with more symptoms of hypoglycemia (p=0.04). 63% LQT2 patients developed hypoglycemic plasma glucose levels (<70 mg/dl) vs. 36 % control participants (p=0.16) and 18% patients developed serious hypoglycemia (<50 mg/dl) vs. none controls. LQT2 patients had defective glucagon responses to low glucose, p=0.008. β cell function (ISSI-2) was two-fold higher in LQT2 patients compared with controls (4398[95% CI 2259; 8562] vs. 2156[1961; 3201], p=0.03). Pharmacological Kv11.1 blockade (dofetilide) in rats had similar effects and siRNA inhibition of hERG in β and L-cells increased insulin and GLP-1 secretion with up to 50%. Glucose ingestion caused cardiac repolarization disturbances with increased QTc interval in both patients and controls, but with a 122% greater increase in QTcF interval in LQT2 patients (p=0.004).
Conclusions—Besides a prolonged cardiac repolarization phase, LQT2 patients display increased GLP-1, GIP and insulin secretion and defective glucagon secretion causing decreased plasma glucose and thus increased risk of hypoglycemia. Furthermore, glucose ingestion increased QT interval and aggravated the cardiac repolarization disturbances in LQT2 patients.
Clinical Trial Registration—ClinicalTrials.gov Identifier: NCT02775513.
- voltage-gated potassium channels
- insulin secretion
- long QT syndrome
- HERG arrhythmia
- Received July 1, 2016.
- Revision received February 6, 2017.
- Accepted February 14, 2017.
Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDervis License (http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.