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 INaoccurred in association with reduced expression ofSCN5aand voltage gated Na+(NaV1.5) channels as well as a shift in INaactivation kinetics. Insulin potently and selectively increased INain Akita mice without affecting IK. Chronic insulin treatment increased INain 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.

Atrial remodeling and atrial fibrillation in acquired forms of cardiovascular disease

“…32,33 Recently, it has been shown that Akita and STZ models of T1DM are characterized by substantial increases in AF susceptibility and duration in association with electrical remodeling of the atria. 34,35 P-wave durations were prolonged in both models, and atrial conduction velocity was reduced in Akita mice. Detailed electrophysiological and molecular studies demonstrated that atrial AP upstroke velocity (V max ) was reduced, and APD was prolonged in Akita mice.…”

“…39 In contrast, Akita atrial myocytes showed no changes in mRNA expression of Cx40. 34 Cx43 is also expressed in the atria but was unchanged in the atria in Akita mice. 34 More research is needed in this area to understand the role connexins play in T1DM.…”

“…36 Importantly, it has been shown that insulin has important and selective effects on atrial I Na in Akita mice. 34 Specifically, chronic insulin treatment increased Na V 1.5 protein levels, atrial I Na density, and AP upstroke velocity. Insulin also could increase atrial I Na and AP upstroke velocity more rapidly (and to a smaller extent compared to chronic insulin) via the rapid activation of PIP 3 signaling.…”

Sex, age, type of diabetes and incidence of atrial fibrillation in patients with diabetes mellitus: a nationwide analysis

“…By contrast, our analysis had sufficient statistical power to demonstrate that (1) type 1 diabetes was also associated with a significantly higher incidence of AF than in non-diabetics patients, indicating that insulin resistance would not be the only promoter of AF in patients with diabetes (2) this association was seen both in men and in women, (3) the adjusted hazard ratios for the risk of AF were actually even higher than for type 2 diabetes, particularly for women and (4) the higher relative risk of AF in women was seen across all ages, the women-to-men ratio being around 1.8 at age 45 and progressively decreasing with increasing age, which was somewhat different than what was seen for type 2. Recent pre-clinical studies suggested that loss of insulin signalling may contribute to atrial electrical remodelling and atrial fibrillation in murine models of type 1 diabetes [ 27 ].…”

Mechanisms of Chronic Metabolic Stress in Arrhythmias

“…One group showed that decreased phosphoinositide 3-kinase (PI3K) activity, which is downstream of the insulin receptor, contributes to increased action potential duration in both type 1 and type 2 diabetics’ cardiomyocytes, and this was mediated by increased late sodium current [ 113 ]. Another group has shown that type 1 diabetic atrial myocytes have decreased sodium flux, which is corrected by insulin treatment [ 114 ]. Although the pathophysiology of type 1 diabetes is different in several important ways from type 2 diabetes, which is much more common in obese adults, the results may have some relevance to DIO and HFD arrhythmogenesis.…”