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

Iuliia Polina, Hailey J. Jansen, Tiesong Li, Motahareh Moghtadaei, Loryn J. Bohne, Yingjie Liu, Pooja Krishnaswamy, Emmanuel E. Egom, Darrell D. Belke, Sara A. Rafferty, Martin Ezeani, Anne M. Gillis, Robert A. Rose

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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 (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.

Original languageEnglish (US)
Pages (from-to)7990-8000
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number14
DOIs
StatePublished - Apr 7 2020
Externally publishedYes

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. This work was supported by Canadian Institutes of Health Research Operating Grants MOP 142486 and PJT 166105 (to R.A.R.). H.J.J. was the recipient of a Nova Scotia Graduate Scholarship and a Dalhousie Medical Research Foundation MacDonald Graduate Scholarship and holds a Killam Postdoctoral Fellowship. L.J.B. holds a Libin Cardiovascular Institute of Alberta Graduate Studentship. Y.L. holds a Canadian Institutes of Health Research Postdoctoral Fellowship. E.E.E. held a Heart and Stroke Foundation of Canada Fellowship. R.A.R. held a New Investigator Award from the Heart and Stroke Foundation of Canada.

Funding Information:
ACKNOWLEDGMENTS. This work was supported by Canadian Institutes of Health Research Operating Grants MOP 142486 and PJT 166105 (to R.A.R.). H.J.J. was the recipient of a Nova Scotia Graduate Scholarship and a Dal-housie Medical Research Foundation MacDonald Graduate Scholarship and holds a Killam Postdoctoral Fellowship. L.J.B. holds a Libin Cardiovascular Institute of Alberta Graduate Studentship. Y.L. holds a Canadian Institutes of Health Research Postdoctoral Fellowship. E.E.E. held a Heart and Stroke Foundation of Canada Fellowship. R.A.R. held a New Investigator Award from the Heart and Stroke Foundation of Canada.

Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.

Keywords

  • Action potential
  • Atrial fibrillation
  • Diabetes mellitus
  • Na current
  • Phosphoinositide 3-kinase

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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