Loss of insulin signaling may contribute to atrial fibrillation and atrial electrical remodeling in type 1 diabetes

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 14; pp. 7990 - 8000
• Main Authors: Polina, Iuliia, Jansen, Hailey J., Li, Tiesong, Moghtadaei, Motahareh, Bohne, Loryn J., Liu, Yingjie, Krishnaswamy, Pooja, Egom, Emmanuel E., Belke, Darrell D., Rafferty, Sara A., Ezeani, Martin, Gillis, Anne M., Rose, Robert A.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 07.04.2020
• Subjects: Action potential; Biological Sciences; Cardiac arrhythmia; Conduction; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Electrophysiology; Fibrillation; Insulin; Ion channels; Kinetics; Mapping; Morphology; Myocytes; P waves; Phosphatidylinositol 3,4,5-triphosphate; Potassium; Potassium channels (voltage-gated); Reduction; Signaling; Sodium channels (voltage-gated); Streptozocin; Velocity; Western blotting; atrial fibrillation; diabetes mellitus; Na+ current; action potential; phosphoinositide 3-kinase
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1914853117

Atrial fibrillation (AF) is prevalent in diabetes mellitus (DM); however, the basis for this is unknown. This study investigated AF susceptibility and atrial electrophysiology in type 1 diabetic Akita mice using in vivo intracardiac electrophysiology, high-resolution optical mapping in atrial preparations, and patch clamping in isolated atrial myocytes. qPCR and western blotting were used to assess ion channel expression. Akita mice were highly susceptible to AF in association with increased P-wave duration and slowed atrial conduction velocity. In a second model of type 1 DM, mice treated with streptozotocin (STZ) showed a similar increase in susceptibility to AF. Chronic insulin treatment reduced susceptibility and duration of AF and shortened P-wave duration in Akita mice. Atrial action potential (AP) morphology was altered in Akita mice due to a reduction in upstroke velocity and increases in AP duration. In Akita mice, atrial Na⁺ current (INa) and repolarizing K⁺ current (IK) carried by voltage gated K⁺ (Kv1.5) channels were reduced. The reduction in INa occurred in association with reduced expression of SCN5a and voltage gated Na⁺ (NaV1.5) channels as well as a shift in INa activation kinetics. Insulin potently and selectively increased INa in Akita mice without affecting IK. Chronic insulin treatment increased INa in association with increased expression of NaV1.5. Acute insulin also increased INa, although to a smaller extent, due to enhanced insulin signaling via phosphatidylinositol 3,4,5-triphosphate (PIP₃). Our study reveals a critical, selective role for insulin in regulating atrial INa, which impacts susceptibility to AF in type 1 DM.