Original Article

OPEN

Effects of Glucose Fluctuations on

Electrocardiogram Readings and the Development
of Ventricular Arrhythmia in Diabetic Rats
Downloaded from http://journals.lww.com/cd by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnY

Li-Da Wu1, Feng Li1, Chao Wang2, Shi-Peng Dang1, Feng Xiao1, Zhen-Ye Zhang1, Jie Zhang1, Yu-Min Zhang1,
Cun-Yu Lu1, Ying Liu1, Guo-Qiang Zhong2, Ling-Ling Qian1,*, Ru-Xing Wang1,*
Qp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 03/26/2024

Abstract
Objective: Many studies have shown that blood glucose fluctuations (GFs) are more harmful to patients with diabetes mellitus
(DM) than sustained hyperglycemia. However, the effect of GF on electrocardiogram (ECG) parameters and vulnerability to
ventricular tachycardia/fibrillation (VT/VF) remains poorly characterized. This study aimed to assess the effect of GF on ECG
parameters and induction of VT/VF in streptozotocin (STZ)-induced diabetic Sprague-Dawley rats.
Methods: Male Sprague-Dawley rats were injected with STZ and randomly divided into 3 treatment groups: controlled STZ-
induced diabetic rats (C-STZ) (n = 10); uncontrolled STZ-induced diabetic rats (U-STZ) (n = 10); and STZ-induced diabetic rats
with glucose fluctuations (GF-STZ) (n = 10). After 12 weeks, baseline ECG recordings were taken and a VT/VF test was performed
with the administration of caffeine and dobutamine. Hematoxylin & eosin and masson staining were used to evaluate pathological
cardiac changes after intervention.
Results: No significant difference in heart rate, RR interval, P wave (duration and height), PR segment, PR interval, QRS wave
duration, and T wave height was observed among the 3 groups (P > 0.05). Compared with the C-STZ group, the U-STZ and
GF-STZ groups both had a longer T wave duration ((62.41 ± 2.38) ms vs. (78.37 ± 4.64) ms and (96.06 ± 4.60) ms, P < 0.05),
QT interval ((83.66 ± 2.31) ms vs. (101.75 ± 4.56) ms and (119.14 ± 4.88) ms, P < 0.05), and QTc interval ((77.45 ± 1.36) ms vs.
(91.36 ± 3.49) ms and (104.55 ± 3.01) ms, P < 0.05), all of which were longest in the GF-STZ group (P < 0.05). Additionally, the
GF-STZ group had the highest VT/VF occurrence and duration and the highest arrhythmia score.
Conclusion: This study revealed GF can significantly prolong the QT interval, QTc interval, and T wave duration, as well as
increase vulnerability to VT/VF in rats, which may be an important electrophysiological mechanism of GF-related ventricular
arrhythmia.
Keywords: Blood glucose; Electrocardiogram; Ventricular tachycardia/fibrillation; QT interval

1. Introduction fluctuation (GF). GF is an unstable state reflecting changes in

blood glucose levels between peaks and troughs.[2] Recently, stud-
Diabetes mellitus (DM) is a metabolic disease characterized by ies have demonstrated that, compared with chronic persistent
hyperglycemia that causes severe cardiovascular complications,
such as ischemic heart disease, heart failure, arrhythmias, and
even sudden death.[1] Hyperglycemia in people with DM can
be divided into 2 kinds: chronic sustained hyperglycemia and
chronic fluctuating hyperglycemia, also referred to as glucose CLINICAL PERSPECTIVE
WHAT IS NEW?
Editors: Tianyu Xu and Xiaoxia Fu.
Li-Da Wu, Feng Li, and Chao Wang contributed equally to this work. • Glucose fluctuations (GF), an unstable state reflecting
changes in blood glucose levels between peaks and
1
Department of Cardiology, Wuxi People’s Hospital Affiliated to Nanjing Medical
troughs, can significantly prolong the QT interval, QTc
University, Wuxi, Jiangsu 214023, China; 2 Department of Cardiology, The First
Affiliated Hospital of Nanning Medical University, Nanning, Guangxi 530021, China.
interval and T wave duration.
Supplemental Digital Content is available for this article. Direct URL citations • GF could promote cardiac electrical remodeling and
appear in the printed text and are provided in the HTML and PDF versions of this cardiac structural remodeling, ultimately lead to ven-
article on the journal’s website, www.cardio-discovery.org. tricular arrhythmia.
* Corresponding authors: Ling-Ling Qian, E-mail: qll900@sina.com; Ru-Xing
Wang, E-mail: ruxingw@aliyun.com. WHAT ARE THE CLINICAL IMPLICATIONS?
Copyright © 2022 The Chinese Medical Association, published by Wolters Kluwer
Health, Inc. • With the increasing number of patients with diabetes
This is an open-access article distributed under the terms of the Creative mellitus (DM) worldwide, more attention should be
Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY- paid to controlling GF in patients with DM.
NC-ND), where it is permissible to download and share the work provided it is
properly cited. The work cannot be changed in any way or used commercially • Therapeutic strategy targeting GF could constitute an
without permission from the journal. innovative approach to decrease ventricular arrhyth-
Received: 5 July 2021; Accepted: 15 March 2022 mia in patients with DM.
http://dx.doi.org/10.1097/CD9.0000000000000055

9
 Cardiology Discovery (2023) 3 • 1
hyperglycemia, GF strongly promotes the occurrence and devel-
opment of cardiovascular complications in people with DM.[3,4]
Therefore, it is of great clinical significance to investigate the
GF-related cardiovascular complications in these individuals.
An electrocardiogram (ECG) indicates the electrical activity
of the heart and provides valuable information about the heart’s
function and structure, and is thus a useful tool in clinical prac-
tice.[5] An increasing number of studies have demonstrated that
Downloaded from http://journals.lww.com/cd by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnY
several ECG parameters, including heart rate, P wave, QRS
wave duration, T wave, PR segment, RP interval, QT interval,
and corrected QT (QTc) interval, credibly reflect the cardiac
electrophysiology of the heart.[6–8] Moreover, abnormal ECG
parameters in general represent abnormal cardiac electrophys-
Qp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 03/26/2024
iology.[9] For instance, a prolonged P wave interval represents
delayed atrial conduction velocity, indicating an increased risk
of atrial fibrillation,[10,11] and a prolonged QTc interval rep-
resents an increased dispersion of ventricular repolarization,
which may induce malignant arrhythmias including ventricu-
lar tachycardia/fibrillation (VT/VF) and sudden death.[12,13] In
the present study, we aimed to assess the effect of GF on ECG
parameters and induction of VT/VF.
2. Materials and methods
2.1. Instruments and reagents
A blood glucose meter (Roche, Basel, Switzerland), blood
glucose test strips (Roche), BL-420I multi-channel biological
function experimental system (Chengdu Taimeng company,
Chengdu, Sichuan, China), streptozotocin (STZ; Sigma-Aldrich,
Milwaukee, Wisconsin, USA), short-acting insulin (Novo Alle,
Copenhagen, Denmark), long-acting insulin (Sanofi-Aventis,
Paris, France), 2% isoflurane (Reward, Beijing, China), and
0.9% sodium chloride solution (Hengrui Pharmaceutical
Company, Lianyungang, Jiangsu, China) were the main instru-
ments and reagents used in this study.
2.2. Experimental animal models
Male Sprague-Dawley rats (200 ± 20 g) were purchased from
Changzhou Cavins Laboratory Animal Co., Ltd (Animal
Certificate Number: 201822084). Rats were intraperitoneally
injected with STZ (Sigma-Aldrich; 60 mg/kg) to induce a dia-
betic state, and were included in the study if their blood glu-
cose concentration was less than 16.7 mmol/L after 2 weeks.[14]
Thirty rats were divided into 3 groups as described previously[4]:
uncontrolled diabetic rats (U-STZ) (n = 10), controlled diabetic
rats (C-STZ) (n = 10), and diabetic rats with glucose fluctua-
tions (GF-STZ) (n = 10). The C-STZ group rats received a sub-
cutaneous injection of long-acting insulin (20 U/kg, Glargine,
Sanofi-Aventis, Paris, France) twice a day (8:00 and 20:00) to
control their blood glucose levels. In the GF-STZ group, GFs
were induced by a 24-hour starvation period followed by a
24-hour consumption period with an adequate food. After the
starvation period, short-acting insulin (0.5 U/kg, Aspart, Novo
Nordisk, Copenhagen, Denmark) was used to reduce glucose
levels greater than 5.5 mol/L. Plasma glucose concentrations
were measured daily at a fixed time. Rats were kept in a patho-
gen-free environment. The animal model used in our present
study has been widely used to study various complications
caused by GF, including arrhythmias.[4,15,16] All protocols involv-
ing the use of animal subjects were approved by the Institutional
Animal Care and Use Committee of Nanjing Medical University
(IACUC-1712028).
2.3. ECG recording and VT/VF induction
To avoid activation of the sympathetic nervous system, after 2
days of exposure to adequate food, ECG was measured using
10
www.cardio-discovery.org
a BL-420I multi-channel biological function experimental sys-
tem. The P wave (duration and height), PR segment, PR interval,
QRS wave duration, QT interval, T wave duration, heart rate,
and RR interval were measured in Sprague-Dawley rats after
anesthetization with 2% isoflurane gas. The QTc interval was
calculated based on Bazett’s formula (QTc = QT/(RR/f)1/2, RR =
RR interval, where f = 150 ms).[17–19]
To perform the VT/VF vulnerability test after measuring the
baseline ECG, rats received an intraperitoneal injection of caf-
feine (120 mg/kg body weight) followed by an intravenous injec-
tion of dobutamine (50 mg/kg body weight), and measurements
were continued for 20 min.[20–22] A ventricular arrhythmia score
was assigned to each rat that described the severity of arrhyth-
mia, where: 0 = no arrhythmic events; 1 = one premature VT; 2
= bigeminy and/or salvos; 3 = VT; 4 = VF; and 5 = spontaneously
induced VF.[20–22]
2.4. Echocardiography examination
Detailed echocardiography examination was performed on
8 rats from each group. Rats were anesthetized by inhala-
tion of 2% isoflurane gas. Echocardiography (ie33; Philip,
Eindhoven, Noord-Brabant, the Netherlands) was used
to evaluate heart function, including left ventricular ejec-
tion fraction (LVEF), left ventricular fractional shorten-
ing (LVFS), left ventricular end-systolic internal diameter
(LVIDs), left ventricular end-systolic posterior wall thick-
ness, end-systolic interventricular septum, left ventricular
end-diastolic posterior wall thickness, left ventricular pos-
terior wall thickness at end-diastole, and end-diastolic inter-
ventricular septum.
2.5. Hematoxylin and eosin staining
Heart tissue samples were sliced into several sections of 0.5 to
0.8 cm thickness. Pieces were then fixed with 4% paraformal-
dehyde (#P0099-500; Beyotime Biotechnology Co., Shanghai,
China), dehydrated with gradient ethanol, waxed, and embed-
ded with paraffin. Finally, they were cut into 5 μm-thick slices
and stained with hematoxylin and eosin (HE) solution (#C0105;
Beyotime Biotechnology Co.). Sections were examined with
optical microscope (CKX53; OLYMPUS, Tokyo, Japan) under
a 40× objective lens.
2.6. Masson staining
Sections of heart tissue (of 5 μm thickness) were stained with
Masson trichrome staining solution (#D026; Nanjing Jiancheng
Bioengineering Institute, Nanjing, China). The slices were exam-
ined with optical microscope (CKX53; OLYMPUS) under a 40×
objective lens.
2.7. Statistical analysis
Statistical analysis was performed using SPSS v22.0 (IBM,
Armonk, New York, USA) and GraphPad Prism 5 (GraphPad
Software, San Diego, California, USA). One-way analysis of
variance (ANOVA) was used to compare data between multi-
ple groups, and Chi-square tests were used to compare the VT
occurrence among the 3 groups. P < 0.05 was considered sta-
tistically significant. Data are presented as the mean ± standard
error of the mean (SEM).
3. Results
3.1. Blood glucose level and body weight of rats
Blood glucose levels in the U-STZ group were all above 22.2
mmol/L. The blood glucose levels in C-STZ rats were maintained
 Wu et al. • 3 • 1 • 2023
at approximately 5.5 mmol/L, and in the GF-STZ rats, the level
fluctuated between 5.5 and 22.2 mmol/L [Figure 1A]. Moreover,
the mean body weight in rats from the GF-STZ group was sig-
nificantly lower than in the C-STZ group and U-STZ group
(P < 0.05, n = 10) [Figure 1B].
3.2. ECG and echocardiogram parameters in diabetic rats
Downloaded from http://journals.lww.com/cd by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnY
ECG parameters in diabetic rats are presented in Table 1.
Representative ECGs are shown in Figure 2A–C. No signifi-
cant difference in heart rate, RR interval, P wave, PR segment,
PR interval, QRS wave duration, or T wave height was found
among the 3 groups. However, the U-STZ and GF-STZ groups
Qp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 03/26/2024
had a longer mean T wave duration ((62.41 ± 2.38) ms vs.
(78.37 ± 4.64) ms and (96.06 ± 4.60) ms, P < 0.05) [Figure 2D],
QT interval ((83.66 ± 2.31) ms vs. (101.75 ± 4.56) ms and
(119.14 ± 4.88) ms, P < 0.05) [Figure 2E], and QTc interval
((77.45 ± 1.36) ms vs. (91.36 ± 3.49) ms and (104.55 ± 3.01)
ms, P < 0.05) [Figure 2F] compared with the C-STZ group,
all of which were found to be longest in the GF-STZ group
(P < 0.05).
Echocardiography was used to evaluate heart function. As
can be seen in Supplementary Figure 1 (http://links.lww.com/
CD9/A26) and Supplementary Table 1 (http://links.lww.com/
CD9/A26), in comparison with the C-STZ and U-STZ groups,
the LVEF and LVFS were both significantly decreased and the
LVIDs was significantly increased in the GF-STZ group, and
there was also a significant statistical difference in these val-
ues between the U-STZ and GF-STZ rats, indicating that GF
Figure 1: The blood glucose levels and body weight in diabetic rats. (A) Blood glucose levels in C-STZ, U-STZ, and GF-STZ groups were 5.5, > 22.2, and
5.5–22.2 mmol/L, respectively (n = 10 per group); (B) Body weight in the 3 groups (n = 10 per group). C-STZ: Controlled diabetic rats; GF-STZ: Diabetic rats
with glucose fluctuations; U-STZ: Uncontrolled diabetic rats.
11
Cardiology Discovery (2023) 3 • 1
significantly aggravated cardiac systolic dysfunction in diabetic
rats.
HE and Masson staining were used to evaluate pathological
cardiac changes after intervention. HE staining revealed that
the morphological structure of myocardial tissue in the U-STZ
rats was significantly more disorganized than in the C-STZ
rats, and in the GF-STZ rats, it was even more pronounced
[Supplementary Figure 2, http://links.lww.com/CD9/A26].
However, none of the groups had cardiac function levels that fell
below the standard threshold for heart failure. Furthermore, we
also observed the deposition of collagen fibers in the myocardial
tissue by Masson staining [Supplementary Figure 2, http://links.
lww.com/CD9/A26]. Compared with C-STZ rats, rats in the
U-STZ and GF-STZ groups showed increased levels of cardiac
fibrosis.
3.3. Increased vulnerability of VT/VF induction
No ventricular arrhythmias were observed in the C-STZ group
in the VT/VF vulnerability test [Figure 3A]. However, U-STZ
and GF-STZ rats showed abnormal electrical activity following
challenge with dobutamine and caffeine, including VT accom-
panied by sinus rhythm in the U-STZ group [Figure 3B] and
VT in the GF-STZ group [Figure 3C]. The VT occurrence in
GF-STZ group was higher than in the C-STZ and U-STZ groups
(80% vs. 0, P < 0.05 and 80% vs. 40%, respectively; P < 0.05)
[Figure 3D]. Similarly, the VT duration was longer [Figure 3E]
and the ventricular arrhythmia score greater in the GF-STZ
group [Figure 3F].
 Cardiology Discovery (2023) 3 • 1 www.cardio-discovery.org

Table 1
ECG parameters for the C-STZ, U-STZ, and STZ-GF groups of rats (n = 10 in each group).

ECG parameters C-STZ U-STZ GF-STZ F P

Heart rate (beats/min) 361.9 ± 8.24 350.30 ± 14.55 318.00 ± 16.24 2.85 0.08
P wave duration (ms) 23.20 ± 1.06 25.92 ± 0.60 27.30 ± 1.92 2.52 0.10
P wave height (mv) 0.16 ± 0.01 0.13 ± 0.01 0.14 ± 0.01 2.36 0.11
PR interval (ms) 51.41 ± 2.25 51.36 ± 2.07 54.79 ± 1.69 0.95 0.40
Downloaded from http://journals.lww.com/cd by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnY

PR segment (ms) 28.21 ± 2.24 25.44 ± 2.39 27.49 ± 1.75 0.45 0.64
RR interval (ms) 174.62 ± 3.89 187.64 ± 10.40 195.92 ± 11.37 1.37 0.27
QT interval (ms) 83.66 ± 2.31 101.75 ± 4.56* 119.14 ± 4.88*,† 18.90 <0.01
QTc interval (ms) 77.45 ± 1.36 91.36 ± 3.49* 104.55 ± 3.01*,† 23.83 <0.01
QRS wave duration (ms) 21.25 ± 0.45 23.38 ± 0.91 23.08 ± 0.84 2.28 0.12
Qp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 03/26/2024

T wave duration (ms) 62.41 ± 2.38 78.37 ± 4.64* 96.06 ± 4.60*,† 17.58 <0.01
T wave height (mv) 0.18 ± 0.01 0.22 ± 0.02 0.23 ± 0.02 2.64 0.09
Data are presented as mean ± SEM.
*P < 0.05 vs. C-STZ.
†
P < 0.05 vs. U-STZ.
C-STZ: Controlled diabetic rats; ECG: Electrocardiogram; GF-STZ: Diabetic rats with glucose fluctuations; HR: Heart rate; SEM: Standard error of the mean; U-STZ: Uncontrolled diabetic rats.

Figure 2: Electrocardiogram parameters in diabetic rats. (A–C) Representative electrocardiograms for C-STZ, U-STZ, and GF-STZ groups. (D–F) QT interval,
QTc interval, and T wave duration in C-STZ, U-STZ, and GF-STZ groups. C-STZ: Controlled diabetic rats; GF-STZ: Diabetic rats with glucose fluctuations;
U-STZ: Uncontrolled diabetic rats.

4. Discussion arrhythmias compared with normal individuals.[23–25] Recent

studies have demonstrated that GF are more harmful to patients
Diabetic cardiovascular complication is a leading cause of death. with DM than sustained hyperglycemia. However, the relation-
Clinical trials have demonstrated that diabetic patients have ship between GF and lethal ventricular arrhythmias, such as VT
more ECG abnormalities and a higher incidence of ventricular or VF, remains elusive.

12
 Wu et al. • 3 • 1 • 2023 Cardiology Discovery (2023) 3 • 1
Downloaded from http://journals.lww.com/cd by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnY
Qp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 03/26/2024

Figure 3: The induction of ventricular tachycardia/fibrillation (VT/VF) with caffeine and dobutamine. (A) Representative ECGs in the C-STZ group before (i)
and after (ii) injection with caffeine and dobutamine. (i) and (ii) SR. (B) Representative ECGs in the U-STZ group before (i) and after (ii) injection with caffeine
and dobutamine. (i) SR and (ii) VT with SR. (C) Representative ECGs in the GF-STZ group before (i) and after (ii) injection with caffeine and dobutamine. (i) SR
and (ii) VT/VF. (D–F) VT/VF occurrence (%), VT/VF duration (min) and arrhythmia score were all increased in the GF-STZ group with caffeine and dobutamine
challenge. C-STZ: Controlled diabetic rats; ECG: Electrocardiogram;GF-STZ: Diabetic rats with glucose fluctuations; SR: Sinus rhythm; U-STZ: Uncontrolled
diabetic rats; VT/VF: Ventricular tachycardia/fibrillation.

In this study, we aim to assess the effect of GF on ECG param-
eters and vulnerability to lethal ventricular arrhythmias in STZ-
induced diabetic rats. The most important findings of this study
were: (1) the QT interval, QTc interval, and T wave durations
were prolonged in the U-STZ group, and even more prolonged
in the GF-STZ group, compared with the C-STZ group; (2)
the vulnerability to ventricular arrhythmias was significantly
increased in the GF-STZ group.
The ECG is an established, useful, non-invasive cardiovas-
cular examination, providing multiple cardiac electrophysi-
ology measures. In general, heart rate and RR interval reflect
the frequency of sinus node impulses, which are significantly
influenced by cardiac autonomic nerves.[26] The PR segment and
PR interval reflect the total conduction duration of the atrio-
ventricular node and the His bundle-Purkinje system. The P
wave and QRS wave reflect atrial and ventricular depolariza-
tion, respectively.[27,28] Of note, multiple studies have revealed
a relationship between the P wave and atrial fibrillation.[10,29,30]
The QT interval, QTc interval and T wave duration represent
ventricular repolarization, and are thus more closely related to
the occurrence of ventricular arrhythmias. Until now, the ECG
characteristics in healthy and diabetic rats, and diabetic rats with
blood GF, have not been reported. STZ is an organic compound
that selectively destroys islet beta cells, thus inducing DM. In
our study, STZ-induced diabetic rats were used to establish an
animal model of GF and explore the underlying mechanism of
diabetic cardiovascular complications, as described previously.[4]
Twelve weeks later, ECG recordings were taken in these rats.
In this study, detailed ECG parameters were measured in the
C-STZ, U-STZ, and GF-STZ groups, providing a reference for
further research on diabetic cardiovascular complications.
Accumulating studies demonstrate that prolonged QT inter-
val, QTc interval, and T wave duration are all significantly asso-
ciated with several chronic diseases, especially in people with
DM.[31–33] Previous clinical studies revealed the prevalence of pro-
longed QTc duration reached 21% to 31% in individuals with
type 2 DM.[34,35] Consistent with previously reported results, we
found significantly prolonged QT intervals, QTc intervals, and
T wave durations in STZ-induced diabetic rats with high blood
glucose and GF. GF is the most influential factor in increased QT
and QTc intervals and T wave duration. Increasing numbers of
studies have demonstrated multiple underlying mechanisms for
abnormal ventricular repolarization, including abnormalities in
ion channels,[36] neuromodulation of cardiac repolarization,[37]
and repolarization remodeling.[38] Importantly, abnormalities in
multiple ion channels underlying mechanism for cardiac repo-
larization is demonstrated to be associated with DM-induced
QT prolongation and arrythmias. Monnerat et al[21] demon-
strated that the NOD-like receptor protein 3 inflammasome and
toll-like receptor 2 in macrophages in the mouse heart increase
the level of interleukin (IL)-1β. IL-1β contributes to a K+ cur-
rent reduction and prolongation of the QTc interval and action
potential, eventually contributing to arrhythmia. Similarly,
Bohne et al[39] showed that atrial K+ currents, including transient
outward and ultrarapid delayed rectifier currents, were signifi-
cantly reduced in db/db mice (a type 2 diabetic animal model),
leading to action potential duration prolongation, increased
repolarization heterogeneity, and elevated susceptibility to atrial
fibrillation. Additionally, Jin et al[40] revealed that the increased
susceptibility to DM-induced arrythmia was associated with
an increased late sodium current, which could be reversed by
inhibiting the late sodium current. Enhanced inward L-type

13
 Cardiology Discovery (2023) 3 • 1
calcium channel currents (ICa-L) and sodium/calcium exchanger
currents were also shown to be involved in the prolongation
of action potential duration and increased vulnerability to ven-
tricular arrhythmias.[41] Therefore, the underlying mechanisms
of GF-induced prolongation of the QT interval, QTc interval,
and T wave duration may include abnormalities in ion channels,
neuromodulation of cardiac repolarization, and cardiac repo-
larization remodeling, which all need to be further investigated.
Downloaded from http://journals.lww.com/cd by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnY
Accumulating studies have demonstrated that prolonged QT
and QTc intervals and T wave durations are significantly asso-
ciated with ventricular tachycardia and sudden death.[42–44] The
underlying mechanism for prolonged cardiac repolarization and
increased lethal ventricular arrhythmias has been the subject of
Qp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 03/26/2024
significant amounts of research for a long time. Many studies
have revealed that prolonged cardiac repolarization may induce
various abnormalities in cardiac electrophysiology, including
increased frequency of afterdepolarization, abnormal triggered
activity, and phase 2 reentry, subsequently leading to malignant
arrhythmia, including torsades de pointes and ventricular fibril-
lation.[37,38,45] The VT/VF vulnerability test has been widely used
to evaluate vulnerability to and severity of ventricular arrhyth-
mias.[20–22] Our study showed the highest VT occurrence, VT
duration, and arrhythmia score in the GF-STZ group in response
to challenge with dobutamine and caffeine, further indicating a
high risk of prolonged cardiac repolarization. Collectively, the
data from our study indicate that prolonged QT interval, QTc
interval, and T wave duration play an important role in malig-
nant ventricular arrhythmias caused by GF.
In future work, we will explore the molecular mechanism of
GF leading to a prolonged QT interval and the occurrence of
ventricular arrhythmias.
5. Conclusion
GF significantly prolongs the QT interval, QTc interval, and
T wave duration, and increases the vulnerability to VT/VF in
diabetic rats, and may thus be an important mechanism of
GF-related malignant ventricular arrhythmias.
Funding
This work was supported by the Natural Science Foundation
of China (81770331) and the Wuxi Health Commission for the
Youth Research Foundation (Q202034).
Author contributions
Ru-Xing Wang designed the experiments. Li-Da Wu, Feng Li,
Ling-Ling Qian, and Chao Wang performed the experiments.
Shi-Peng Dang, Feng Xiao, Guo-Qiang Zhong, and Zhen-Ye
Zhang analyzed the data. Ru-Xing Wang and Li-Da Wu wrote
the manuscript. Yu-Min Zhang, Cun-Yu Lu, Ying Liu, Jie Zhang
edited the manuscript. All authors read and approved the final
manuscript.
Conflicts of interest
None.
References
[1] Ritchie RH, Abel ED. Basic mechanisms of diabetic heart disease. Circ Res
2020;126(11):1501–1525. doi:10.1161/CIRCRESAHA.120.315913.
[2] Zhou JJ, Schwenke DC, Bahn G, et al. Glycemic variation and car-
diovascular risk in the veterans affairs diabetes trial. Diabetes Care
2018;41(10):2187–2194. doi:10.2337/dc18-0548.
[3] Wakasugi S, Mita T, Katakami N, et al. Associations between continu-
ous glucose monitoring-derived metrics and arterial stiffness in Japanese
14
www.cardio-discovery.org
patients with type 2 diabetes. Cardiovasc Diabetol 2021;20(1):15.
doi:10.1186/s12933-020-01194-2.
[4] Zhang ZY, Qian LL, Wang N, et al. Glucose fluctuations promote vas-
cular BK channels dysfunction via PKCα/NF-κB/MuRF1 signaling. J
Mol Cell Cardiol 2020;145:14–24. doi:10.1016/j.yjmcc.2020.05.021.
[5] Sun JY, Qiu Y, Guo HC, et al. A method to screen left ventricular
dysfunction through ECG based on convolutional neural network.
J Cardiovasc Electrophysiol 2021;32(4):1095–1102. doi:10.1111/
jce.14936.
[6] Zheng J, Zhang J, Danioko S, et al. A 12-lead electrocardiogram data-
base for arrhythmia research covering more than 10,000 patients. Sci
Data 2020;7(1):48. doi:10.1038/s41597-020-0386-x.
[7] Jimenez-Perez G, Alcaine A, Camara O. Delineation of the electro-
cardiogram with a mixed-quality-annotations dataset using con-
volutional neural networks. Sci Rep 2021;11(1):863. doi:10.1038/
s41598-020-79512-7.
[8] Walsh R, Lahrouchi N, Tadros R, et al. Enhancing rare variant inter-
pretation in inherited arrhythmias through quantitative analysis of
consortium disease cohorts and population controls. Genet Med
2021;23(1):47–58. doi:10.1038/s41436-020-00946-5.
[9] Lombardi F, Vicenzi M, Hnatkova K, et al. The search for non-in-
vasive markers of cardiac diseases comes back to the 12-lead elec-
trocardiogram. Int J Cardiol 2020;298:55–56. doi:10.1016/j.
ijcard.2019.10.013.
[10] Unkell M, Marinov M, Wolff PS, et al. P wave duration in paroxysmal
and persistent atrial fibrillation. Adv Clin Exp Med 2020;29(11):1347–
1354. doi:10.17219/acem/127680.
[11] Karantoumanis I, Doundoulakis I, Zafeiropoulos S, et al. Atrial
conduction time associated predictors of recurrent atrial fibrilla-
tion. Int J Cardiovasc Imaging 2021;37(4):1267–1277. doi:10.1007/
s10554-020-02113-y.
[12] Anikumar A, Moore EJ, Gall AJ, et al. QTc interval in survivors of
out of hospital cardiac arrest. Int J Cardiol 2021;323:118–123.
doi:10.1016/j.ijcard.2020.08.090.
[13] Perez MM, Medar S, Quigley L, et al. QTc prolongation in pediatric
patients with diabetic ketoacidosis. J Pediatr 2021;228:235–239.e2.
doi:10.1016/j.jpeds.2020.08.085.
[14] Tang X, Qian LL, Wang RX, et al. Regulation of coronary arterial
large conductance Ca2+-activated K+ channel protein expression and
function by n-3 polyunsaturated fatty acids in diabetic rats. J Vasc Res
2017;54(6):329–343. doi:10.1159/000479870.
[15] Saito S, Teshima Y, Fukui A, et al. Glucose fluctuations increase
the incidence of atrial fibrillation in diabetic rats. Cardiovasc Res
2014;104(1):5–14. doi:10.1093/cvr/cvu176.
[16] Ying C, Zhou X, Chang Z, et al. Blood glucose fluctuation accelerates
renal injury involved to inhibit the AKT signaling pathway in diabetic
rats. Endocrine 2016;53(1):81–96. doi:10.1007/s12020-016-0867-z.
[17] Joukar S, Zarisfi Z, Sepehri G, et al. Efficacy of Melissa officinalis
in suppressing ventricular arrhythmias following ischemia-reperfu-
sion of the heart: a comparison with amiodarone. Med Princ Pract
2014;23(4):340–345. doi:10.1159/000363452.
[18] Joukar S, Ghasemipour-Afshar E, Sheibani M, et al. Protective effects of
saffron (Crocus sativus) against lethal ventricular arrhythmias induced
by heart reperfusion in rat: a potential anti-arrhythmic agent. Pharm
Biol 2013;51(7):836–843. doi:10.3109/13880209.2013.767362.
[19] Ramezani-Aliakbari F, Badavi M, Dianat M, et al. The effects of
trimetazidine on QT-interval prolongation and cardiac hypertrophy
in diabetic rats. Arq Bras Cardiol 2019;112(2):173–178. doi:10.5935/
abc.20180248.
[20] Erickson JR, Pereira L, Wang L, et al. Diabetic hyperglycaemia acti-
vates CaMKII and arrhythmias by O-linked glycosylation. Nature
2013;502(7471):372–376. doi:10.1038/nature12537.
[21] Monnerat G, Alarcón ML, Vasconcellos LR, et al. Macrophage-
dependent IL-1β production induces cardiac arrhythmias in diabetic
mice. Nat Commun 2016;7:13344. doi:10.1038/ncomms13344.
[22] Popescu I, Yin G, Velmurugan S, et al. Lower sarcoplasmic retic-
ulum Ca(2+) threshold for triggering afterdepolarizations in dia-
betic rat hearts. Heart Rhythm 2019;16(5):765–772. doi:10.1016/j.
hrthm.2018.11.001.
[23] Lee S, Jeevaratnam K, Liu T, et al. Risk stratification of cardiac arrhyth-
mias and sudden cardiac death in type 2 diabetes mellitus patients
receiving insulin therapy: a population-based cohort study. Clin
Cardiol 2021;44(11):1602–1612. doi:10.1002/clc.23728.
[24] Kahn JK, Sisson JC, Vinik AI. QT interval prolongation and sudden
cardiac death in diabetic autonomic neuropathy. J Clin Endocrinol
Metab 1987;64(4):751–754. doi:10.1210/jcem-64-4-751.
 Wu et al. • 3 • 1 • 2023
[25] Zhang J, Yang J, Liu L, et al. Significant abnormal glycemic vari-
ability increased the risk for arrhythmias in elderly type 2 dia-
betic patients. BMC Endocr Disord 2021;21(1):83. doi:10.1186/
s12902-021-00753-2.
[26] Spallone V, Valensi P. SGLT2 inhibitors and the autonomic nervous sys-
tem in diabetes: a promising challenge to better understand multiple tar-
get improvement. Diabetes Metab 2021;47(4):101224. doi:10.1016/j.
diabet.2021.101224.
[27] Fienieg B, Hassing GJ, van der Wall H, et al. The association between
Downloaded from http://journals.lww.com/cd by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnY
body temperature and electrocardiographic parameters in normother-
mic healthy volunteers. Pacing Clin Electrophysiol 2021;44(1):44–53.
doi:10.1111/pace.14120.
[28] Dohy Z, Vereckei A, Horvath V, et al. How are ECG parameters related
to cardiac magnetic resonance images? Electrocardiographic predictors
of left ventricular hypertrophy and myocardial fibrosis in hypertrophic
Qp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 03/26/2024
cardiomyopathy. Ann Noninvasive Electrocardiol 2020;25(5):e12763.
doi:10.1111/anec.12763.
[29] Hari KJ, Nguyen TP, Soliman EZ. Relationship between P-wave dura-
tion and the risk of atrial fibrillation. Expert Rev Cardiovasc Ther
2018;16(11):837–843. doi:10.1080/14779072.2018.1533814.
[30] Nakatani Y, Sakamoto T, Yamaguchi Y, et al. P-wave vector magni-
tude predicts recurrence of atrial fibrillation after catheter abla-
tion in patients with persistent atrial fibrillation. Ann Noninvasive
Electrocardiol 2019;24(5):e12646. doi:10.1111/anec.12646.
[31] Ali-Ahmed F, Dalgaard F, Al-Khatib SM. Sudden cardiac death in
patients with myocarditis: evaluation, risk stratification, and manage-
ment. Am Heart J 2020;220:29–40. doi:10.1016/j.ahj.2019.08.007.
[32] Choi Y, Lee JH, Seo JI. Change in T/QRS ratio can be a supplementary diag-
nostic tool in predicting coronary artery disease in patients with NSTEMI.
Am J Emerg Med 2021;39:48–54. doi:10.1016/j.ajem.2020.01.013.
[33] Harms PP, van der Heijden AA, Rutters F, et al. Prevalence of ECG
abnormalities in people with type 2 diabetes: the Hoorn Diabetes
Care System cohort. J Diabetes Complications 2021;35(2):107810.
doi:10.1016/j.jdiacomp.2020.107810.
[34] Sertbas Y, Ozdemir A, Sertbas M, et al. The effect of glucose variability
on QTc duration and dispersion in patients with type 2 diabetes melli-
tus. Pak J Med Sci 2017;33(1):22–26. doi:10.12669/pjms.331.11440.
[35] Perez MM, Medar S, Quigley L, et al. QTc Prolongation in pediatric
patients with diabetic ketoacidosis. J Pediatr 2021;228:235–239.e2.
doi:10.1016/j.jpeds.2020.08.085.
15
Cardiology Discovery (2023) 3 • 1
[36] Isaksen JL, Ghouse J, Graff C, et al. Electrocardiographic T-wave
morphology and risk of mortality. Int J Cardiol 2021;328:199–205.
doi:10.1016/j.ijcard.2020.12.016.
[37] Ishizue N, Niwano S, Fukaya H, et al. Day-to-day variation of early
repolarization pattern predicts life-threatening arrhythmias in patients
with brugada syndrome. Circ J 2021;85(3):300–308. doi:10.1253/circj.
CJ-20-0142.
[38] Zhang Z, Liu MB, Huang X, et al. Mechanisms of premature ventricu-
lar complexes caused by QT prolongation. Biophys J 2021;120(2):352–
369. doi:10.1016/j.bpj.2020.12.001.
[39] Bohne LJ, Jansen HJ, Daniel I, et al. Electrical and structural remodel-
ing contribute to atrial fibrillation in type 2 diabetic db/db mice. Heart
Rhythm 2021;18(1):118–129. doi:10.1016/j.hrthm.2020.08.019.
[40] Jin X, Jiang Y, Xue G, et al. Increase of late sodium current contributes
to enhanced susceptibility to atrial fibrillation in diabetic mice. Eur J
Pharmacol 2019;857:172444. doi:10.1016/j.ejphar.2019.172444.
[41] Němec J, Kim JJ, Salama G. The link between abnormal calcium
handling and electrical instability in acquired long QT syndrome--
Does calcium precipitate arrhythmic storms? Prog Biophys Mol Biol
2016;120(1-3):210–221. doi:10.1016/j.pbiomolbio.2015.11.003.
[42] Jankelson L, Karam G, Becker ML, et al. QT prolongation, tor-
sades de pointes, and sudden death with short courses of chloro-
quine or hydroxychloroquine as used in COVID-19: a systematic
review. Heart Rhythm 2020;17(9):1472–1479. doi:10.1016/j.
hrthm.2020.05.008.
[43] Simpson TF, Salazar JW, Vittinghoff E, et al. Association of
QT-prolonging medications with risk of autopsy-defined causes of
sudden death. JAMA Intern Med 2020;180(5):698–706. doi:10.1001/
jamainternmed.2020.0148.
[44] You T, Luo C, Zhang K, et al. Electrophysiological mechanisms under-
lying T-wave alternans and their role in a rrhythmogenesis. Front
Physiol 2021;12:614946. doi:10.3389/fphys.2021.614946.
[45] Antzelevitch C, Yan GX. J wave syndromes. Heart Rhythm
2010;7(4):549–558. doi:10.1016/j.hrthm.2009.12.006.
How to cite this article: Wu L-D, Li F, Wang C, et al. Effects of Glucose
Fluctuations on Electrocardiogram Readings and the Development of
Ventricular Arrhythmia in Diabetic Rats. Cardiol Discov 2023;3(1):9–15.
doi: 10.1097/CD9.0000000000000055