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

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          Significance

          Atrial fibrillation (AF) is prevalent in diabetic patients, yet the basis for AF in diabetes is poorly understood. We have used type 1 diabetic Akita mice to study the effects of insulin on atrial electrophysiology in diabetes. We demonstrate that Akita mice are highly susceptible to AF due to impaired electrical conduction and that insulin treatment can reduce the occurrence of this arrhythmia. Atrial action potential morphology was altered in Akita mice in association with reductions in atrial Na + current (I Na) and repolarizing potassium current. Insulin treatment potently increased atrial I Na via distinct chronic and acute effects. These experiments identify antiarrhythmic effects of insulin in type 1 diabetes via potent effects on atrial I Na.

          Abstract

          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 (I Na) and repolarizing K + current (I K) carried by voltage gated K + (K v1.5) channels were reduced. The reduction in I Na occurred in association with reduced expression of SCN5a and voltage gated Na + (Na V1.5) channels as well as a shift in I Na activation kinetics. Insulin potently and selectively increased I Na in Akita mice without affecting I K. Chronic insulin treatment increased I Na in association with increased expression of Na V1.5. Acute insulin also increased I Na, although to a smaller extent, due to enhanced insulin signaling via phosphatidylinositol 3,4,5-triphosphate (PIP 3). Our study reveals a critical, selective role for insulin in regulating atrial I Na, which impacts susceptibility to AF in type 1 DM.

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          Author and article information

          Journal
          Proc Natl Acad Sci U S A
          Proc. Natl. Acad. Sci. U.S.A
          pnas
          pnas
          PNAS
          Proceedings of the National Academy of Sciences of the United States of America
          National Academy of Sciences
          0027-8424
          1091-6490
          7 April 2020
          20 March 2020
          : 117
          : 14
          : 7990-8000
          Affiliations
          [1] aDepartment of Physiology and Biophysics, Faculty of Medicine, Dalhousie University , Halifax, NS, Canada, B3H 4R2;
          [2] bLibin Cardiovascular Institute of Alberta, Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary , Calgary, AB, Canada, T2N 4Z6;
          [3] cLibin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary , Calgary, AB, Canada, T2N 4Z6
          Author notes
          2To whom correspondence may be addressed. Email: robert.rose@ 123456ucalgary.ca .

          Edited by Christine E. Seidman, Howard Hughes Medical Institute, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, and approved February 20, 2020 (received for review August 29, 2019)

          Author contributions: I.P., H.J.J., and R.A.R. designed research; I.P., H.J.J., T.L., M.M., L.J.B., Y.L., P.K., E.E.E., D.D.B., S.A.R., M.E., and R.A.R. performed research; I.P., H.J.J., T.L., M.M., L.J.B., Y.L., D.D.B., A.M.G., and R.A.R. analyzed data; and I.P., H.J.J., A.M.G., and R.A.R. wrote the paper.

          1I.P and H.J.J. contributed equally to this work.

          Article
          PMC7148583 PMC7148583 7148583 201914853
          10.1073/pnas.1914853117
          7148583
          32198206
          7ea03041-2888-40f5-bd41-696df1986926
          Copyright @ 2020

          Published under the PNAS license.

          History
          Page count
          Pages: 11
          Funding
          Funded by: Gouvernement du Canada | Canadian Institutes of Health Research (CIHR) 501100000024
          Award ID: MOP 142486
          Award Recipient : Robert A Rose
          Funded by: Gouvernement du Canada | Canadian Institutes of Health Research (CIHR) 501100000024
          Award ID: MOP 93718
          Award Recipient : Robert A Rose
          Categories
          Biological Sciences
          Medical Sciences

          Na+ current,action potential,diabetes mellitus,atrial fibrillation,phosphoinositide 3-kinase

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