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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Standard

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. / Hyltén-Cavallius, Louise; Iepsen, Eva W; Wewer Albrechtsen, Nicolai J; Svendstrup, Mathilde; Lubberding, Anniek F; Hartmann, Bolette; Jespersen, Thomas; Linneberg, Allan; Christiansen, Michael; Vestergaard, Henrik; Pedersen, Oluf; Holst, Jens J; Kanters, Jørgen K; Hansen, Torben; Torekov, Signe S.

I: Circulation, Bind 135, Nr. 18, 2017, s. 1705-1719.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Harvard

Hyltén-Cavallius, L, Iepsen, EW, Wewer Albrechtsen, NJ, Svendstrup, M, Lubberding, AF, Hartmann, B, Jespersen, T, Linneberg, A, Christiansen, M, Vestergaard, H, Pedersen, O, Holst, JJ, Kanters, JK, Hansen, T & Torekov, SS 2017, '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', Circulation, bind 135, nr. 18, s. 1705-1719. https://doi.org/10.1161/CIRCULATIONAHA.116.024279

APA

Hyltén-Cavallius, L., Iepsen, E. W., Wewer Albrechtsen, N. J., Svendstrup, M., Lubberding, A. F., Hartmann, B., ... Torekov, S. S. (2017). 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. Circulation, 135(18), 1705-1719. https://doi.org/10.1161/CIRCULATIONAHA.116.024279

Vancouver

Hyltén-Cavallius L, Iepsen EW, Wewer Albrechtsen NJ, Svendstrup M, Lubberding AF, Hartmann B o.a. 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. Circulation. 2017;135(18):1705-1719. https://doi.org/10.1161/CIRCULATIONAHA.116.024279

Author

Hyltén-Cavallius, Louise ; Iepsen, Eva W ; Wewer Albrechtsen, Nicolai J ; Svendstrup, Mathilde ; Lubberding, Anniek F ; Hartmann, Bolette ; Jespersen, Thomas ; Linneberg, Allan ; Christiansen, Michael ; Vestergaard, Henrik ; Pedersen, Oluf ; Holst, Jens J ; Kanters, Jørgen K ; Hansen, Torben ; Torekov, Signe S. / 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. I: Circulation. 2017 ; Bind 135, Nr. 18. s. 1705-1719.

Bibtex

@article{b34157004dc04294a7bcf0de156cbde2,
title = "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",
abstract = "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.",
author = "Louise Hylt{\'e}n-Cavallius and Iepsen, {Eva W} and {Wewer Albrechtsen}, {Nicolai J} and Mathilde Svendstrup and Lubberding, {Anniek F} and Bolette Hartmann and Thomas Jespersen and Allan Linneberg and Michael Christiansen and Henrik Vestergaard and Oluf Pedersen and Holst, {Jens J} and Kanters, {J{\o}rgen K} and Torben Hansen and Torekov, {Signe S.}",
year = "2017",
doi = "10.1161/CIRCULATIONAHA.116.024279",
language = "English",
volume = "135",
pages = "1705--1719",
journal = "Circulation",
issn = "0009-7322",
publisher = "AHA/ASA",
number = "18",

}

RIS

TY - JOUR

T1 - 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

AU - Hyltén-Cavallius, Louise

AU - Iepsen, Eva W

AU - Wewer Albrechtsen, Nicolai J

AU - Svendstrup, Mathilde

AU - Lubberding, Anniek F

AU - Hartmann, Bolette

AU - Jespersen, Thomas

AU - Linneberg, Allan

AU - Christiansen, Michael

AU - Vestergaard, Henrik

AU - Pedersen, Oluf

AU - Holst, Jens J

AU - Kanters, Jørgen K

AU - Hansen, Torben

AU - Torekov, Signe S.

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

U2 - 10.1161/CIRCULATIONAHA.116.024279

DO - 10.1161/CIRCULATIONAHA.116.024279

M3 - Journal article

C2 - 28235848

VL - 135

SP - 1705

EP - 1719

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 18

ER -

ID: 174598430