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

doi:10.1073/pnas.1914853117

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 journal › Article › peer-review

35 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 (I_Na) and repolarizing K⁺ current (I_K) carried by voltage gated K⁺ (Kv1.5) 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 (PIP₃). Our study reveals a critical, selective role for insulin in regulating atrial I_Na, which impacts susceptibility to AF in type 1 DM.

Original language	English (US)
Pages (from-to)	7990-8000
Number of pages	11
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	117
Issue number	14
DOIs	https://doi.org/10.1073/pnas.1914853117
State	Published - Apr 7 2020
Externally published	Yes

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access

10.1073/pnas.1914853117

OpenUrl availability

Full text

Cite this

Polina, I., Jansen, H. J., Li, T., Moghtadaei, M., Bohne, L. J., Liu, Y., Krishnaswamy, P., Egom, E. E., Belke, D. D., Rafferty, S. A., Ezeani, M., Gillis, A. M., & Rose, R. A. (2020). Loss of insulin signaling may contribute to atrial fibrillation and atrial electrical remodeling in type 1 diabetes. Proceedings of the National Academy of Sciences of the United States of America, 117(14), 7990-8000. https://doi.org/10.1073/pnas.1914853117

Polina, I, Jansen, HJ, Li, T, Moghtadaei, M, Bohne, LJ, Liu, Y, Krishnaswamy, P, Egom, EE, Belke, DD, Rafferty, SA, Ezeani, M, Gillis, AM & Rose, RA 2020, 'Loss of insulin signaling may contribute to atrial fibrillation and atrial electrical remodeling in type 1 diabetes', Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 14, pp. 7990-8000. https://doi.org/10.1073/pnas.1914853117

@article{9001aaff348d416998d27d888eaca171,

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

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.",

keywords = "Action potential, Atrial fibrillation, Diabetes mellitus, Na current, Phosphoinositide 3-kinase",

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

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: {\textcopyright} 2020 National Academy of Sciences. All rights reserved.",

year = "2020",

month = apr,

day = "7",

doi = "10.1073/pnas.1914853117",

language = "English (US)",

volume = "117",

pages = "7990--8000",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "14",

}

TY - JOUR

T1 - Loss of insulin signaling may contribute to atrial fibrillation and atrial electrical remodeling in type 1 diabetes

AU - Polina, Iuliia

AU - Jansen, Hailey J.

AU - Li, Tiesong

AU - Moghtadaei, Motahareh

AU - Bohne, Loryn J.

AU - Liu, Yingjie

AU - Krishnaswamy, Pooja

AU - Egom, Emmanuel E.

AU - Belke, Darrell D.

AU - Rafferty, Sara A.

AU - Ezeani, Martin

AU - Gillis, Anne M.

AU - Rose, Robert A.

N1 - 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.

PY - 2020/4/7

Y1 - 2020/4/7

N2 - 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.

AB - 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.

KW - Action potential

KW - Atrial fibrillation

KW - Diabetes mellitus

KW - Na current

KW - Phosphoinositide 3-kinase

UR - http://www.scopus.com/inward/record.url?scp=85083114577&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85083114577&partnerID=8YFLogxK

U2 - 10.1073/pnas.1914853117

DO - 10.1073/pnas.1914853117

M3 - Article

C2 - 32198206

AN - SCOPUS:85083114577

SN - 0027-8424

VL - 117

SP - 7990

EP - 8000

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 14

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

Access

OpenUrl availability

Other files and links

Fingerprint

Cite this