TY - JOUR

T1 - Celebrities in the heart, strangers in the pancreatic beta cell

T2 - Voltage-gated potassium channels Kv7.1 and Kv11.1 bridge long QT syndrome with hyperinsulinaemia as well as type 2 diabetes

AU - Lubberding, Anniek F.

AU - Juhl, Christian R.

AU - Skovhoj, Emil Z.

AU - Kanters, Jorgen K.

AU - Mandrup-Poulsen, Thomas

AU - Torekov, Signe S.

PY - 2022

Y1 - 2022

N2 - Voltage-gated potassium (K-v) channels play an important role in the repolarization of a variety of excitable tissues, including in the cardiomyocyte and the pancreatic beta cell. Recently, individuals carrying loss-of-function (LoF) mutations in KCNQ1, encoding K(v)7.1, and KCNH2 (hERG), encoding K(v)11.1, were found to exhibit post-prandial hyperinsulinaemia and episodes of hypoglycaemia. These LoF mutations also cause the cardiac disorder long QT syndrome (LQTS), which can be aggravated by hypoglycaemia. Interestingly, patients with LQTS also have a higher burden of diabetes compared to the background population, an apparent paradox in relation to the hyperinsulinaemic phenotype, and KCNQ1 has been identified as a type 2 diabetes risk gene. This review article summarizes the involvement of delayed rectifier K+ channels in pancreatic beta cell function, with emphasis on K(v)7.1 and K(v)11.1, using the cardiomyocyte for context. The functional and clinical consequences of LoF mutations and polymorphisms in these channels on blood glucose homeostasis are explored using evidence from pre-clinical, clinical and genome-wide association studies, thereby evaluating the link between LQTS, hyperinsulinaemia and type 2 diabetes.

AB - Voltage-gated potassium (K-v) channels play an important role in the repolarization of a variety of excitable tissues, including in the cardiomyocyte and the pancreatic beta cell. Recently, individuals carrying loss-of-function (LoF) mutations in KCNQ1, encoding K(v)7.1, and KCNH2 (hERG), encoding K(v)11.1, were found to exhibit post-prandial hyperinsulinaemia and episodes of hypoglycaemia. These LoF mutations also cause the cardiac disorder long QT syndrome (LQTS), which can be aggravated by hypoglycaemia. Interestingly, patients with LQTS also have a higher burden of diabetes compared to the background population, an apparent paradox in relation to the hyperinsulinaemic phenotype, and KCNQ1 has been identified as a type 2 diabetes risk gene. This review article summarizes the involvement of delayed rectifier K+ channels in pancreatic beta cell function, with emphasis on K(v)7.1 and K(v)11.1, using the cardiomyocyte for context. The functional and clinical consequences of LoF mutations and polymorphisms in these channels on blood glucose homeostasis are explored using evidence from pre-clinical, clinical and genome-wide association studies, thereby evaluating the link between LQTS, hyperinsulinaemia and type 2 diabetes.

KW - cardiac

KW - delayed rectifier

KW - glucose homeostasis

KW - insulin

KW - KCNH2

KW - KCNQ1

KW - K-v

KW - pancreatic islet

KW - GENOME-WIDE ASSOCIATION

KW - BECKWITH-WIEDEMANN SYNDROME

KW - DEPENDENT K+ CHANNELS

KW - INSULIN-SECRETION

KW - I-KS

KW - ELECTRICAL-ACTIVITY

KW - ACTION-POTENTIALS

KW - MOLECULAR PHYSIOLOGY

KW - GENETIC ARCHITECTURE

KW - SUSCEPTIBILITY LOCI

U2 - 10.1111/apha.13781

DO - 10.1111/apha.13781

M3 - Review

C2 - 34990074

VL - 234

JO - Acta Physiologica

JF - Acta Physiologica

SN - 1748-1708

IS - 3

M1 - 13781

ER -