ArticleDiabetes2013
Increased persistent sodium current due to decreased PI3K signaling contributes to QT prolongation in the diabetic heart.
Article in Diabetes, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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Who cites it
54 citing papers in PubMed, 83 citations in OpenAlex.
- Ranolazine After Incomplete Percutaneous Coronary Revascularization in Patients With Versus Without Diabetes Mellitus: RIVER-PCI Trial.Journal of the American College of Cardiology · 2017Trial
- Very early administration of glucose-insulin-potassium by emergency medical service for acute coronary syndromes: Biological mechanisms for benefit in the IMMEDIATE Trial.American heart journal · 2016Trial
- Cardiac remodelling in type 2 diabetes: Pathophysiological mechanisms and opportunities for multiscale computational modelling and simulation.The Journal of physiology · 2026Review
- Insights and perspectives into the etiology of TKI-induced cardiotoxicity.ASPET discovery · 2026Article
- Calcium Signaling and Cardiac Adaptation to Stress: Focus on Pregnancy and Diabetes.Biomolecules · 2025Review
- Atrial APD prolongation caused by the upregulation of RAGE and subsequentActa biochimica et biophysica Sinica · 2025Article
- Empagliflozin inhibits increased Na influx in atrial cardiomyocytes of patients with HFpEF.Cardiovascular research · 2024Article
- Increased GIRK channel activity prevents arrhythmia in mice with heart failure by enhancing ventricular repolarization.Scientific reports · 2023Article
- The association of QTc prolongation with cardiovascular events in cancer patients taking tyrosine kinase inhibitors (TKIs).Cardio-oncology (London, England) · 2023Article
- Caveolin-3 and Caveolae regulate ventricular repolarization.Journal of molecular and cellular cardiology · 2023Article
- Transcriptional Dysregulation Underlies Both Monogenic Arrhythmia Syndrome and Common Modifiers of Cardiac Repolarization.Circulation · 2023Article
- Inhibition of late sodium current via PI3K/Akt signaling prevents cellular remodeling in tachypacing-induced HL-1 atrial myocytes.Pflugers Archiv : European journal of physiology · 2023Article
- Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways.Nature communications · 2022Article
- Cardioprotective Effects of 1-(3,6-Dibromo-carbazol-9-yl)-3-Phenylamino-Propan-2-Ol in Diabetic Hearts via Nicotinamide Phosphoribosyltransferase Activation.The Journal of pharmacology and experimental therapeutics · 2022Article
- The Molecular Mechanisms of Cardiotoxicity Induced by HER2, VEGF, and Tyrosine Kinase Inhibitors: an Updated Review.Cardiovascular drugs and therapy · 2022Review
- Effects of high glucose and insulin on the electrophysiological properties of cardiomyocytes derived from human-induced pluripotent stem cells.Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2022Article
- Knockout of interleukin-17A diminishes ventricular arrhythmia susceptibility in diabetic mice via inhibiting NF-κB-mediated electrical remodeling.Acta pharmacologica Sinica · 2022Article
- Common Ancestry-Specific Ion Channel Variants Predispose to Drug-Induced Arrhythmias.Circulation · 2022Article
- Declining Levels and Bioavailability of IGF-I in Cardiovascular Aging Associate With QT Prolongation-Results From the 1946 British Birth Cohort.Frontiers in cardiovascular medicine · 2022Article
- Two-hit mechanism of cardiac arrhythmias in diabetic hyperglycaemia: reduced repolarization reserve, neurohormonal stimulation, and heart failure exacerbate susceptibility.Cardiovascular research · 2021Article
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Diabetes is an independent risk factor for sudden cardiac death and ventricular arrhythmia complications of acute coronary syndrome. Prolongation of the QT interval on the electrocardiogram is also a risk factor for arrhythmias and sudden death, and the increased prevalence of QT prolongation is an independent risk factor for cardiovascular death in diabetic patients. The pathophysiological mechanisms responsible for this lethal complication are poorly understood. Diabetes is associated with a reduction in phosphoinositide 3-kinase (PI3K) signaling, which regulates the action potential duration (APD) of individual myocytes and thus the QT interval by altering multiple ion currents, including the persistent sodium current INaP. Here, we report a mechanism for diabetes-induced QT prolongation that involves an increase in INaP caused by defective PI3K signaling. Cardiac myocytes of mice with type 1 or type 2 diabetes exhibited an increase in APD that was reversed by expression of constitutively active PI3K or intracellular infusion of phosphatidylinositol 3,4,5-trisphosphate (PIP3), the second messenger produced by PI3K. The diabetic myocytes also showed an increase in INaP that was reversed by activated PI3K or PIP3. The increases in APD and INaP in myocytes translated into QT interval prolongation for both types of diabetic mice. The long QT interval of type 1 diabetic hearts was shortened by insulin treatment ex vivo, and this effect was blocked by a PI3K inhibitor. Treatment of both types of diabetic mouse hearts with an INaP blocker also shortened the QT interval. These results indicate that downregulation of cardiac PI3K signaling in diabetes prolongs the QT interval at least in part by causing an increase in INaP. This mechanism may explain why the diabetic population has an increased risk of life-threatening arrhythmias.
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