(2024) 22:362
Zheng et al. BMC Medicine
https://doi.org/10.1186/s12916-024-03595-6

BMC Medicine

RESEARCH ARTICLE

Open Access

Time‑restricted eating with or withouta low‑carbohydrate diet improved myocardial
status and thyroid function in individuals
with metabolic syndrome: secondary analysis
of a randomized clinical trial
Yixuan Zheng1, Jingya Wang2, Mengmeng Liu1, Xingchen Zhou1, Xiaoying Lin1, Qian Liang1, Jing Yang1,3,
Meng Zhang1, Ziyi Chen1, Meng Li1, Yue Wang1, Jing Sui4, Wei Qiang1, Hui Guo1, Bingyin Shi1* andMingqian He1,3*

Abstract
Background Obesity and metabolic syndrome (MetS) have become urgent worldwide health problems, predisposing patients to unfavorable myocardial status and thyroid dysfunction. Low-carbohydrate diet (LCD) and timerestricted eating (TRE) have been confirmed to be effective methods for weight management and improving MetS,
but their effects on the myocardium and thyroid are unclear.
Methods We conducted a secondary analysis in a randomized clinical diet-induced weight-loss trial. Participants(N = 169) diagnosed with MetS were randomized to the LCD group, the 8 h TRE group, or the combination of the LCD
and TRE group for 3 months. Myocardial enzymes and thyroid function were tested before and after the intervention.
Pearson’s or Spearman’s correlation was assessed between functions of the myocardium and thyroid and cardiometabolic parameters at baseline.
Results A total of 162 participants who began the trial were included in the intention-to-treat (ITT) analysis, and 57
participants who adhered to their assigned protocol were involved in the per-protocol (PP) analysis. Relative to baseline, lactate dehydrogenase, creatine kinase MB, hydroxybutyrate dehydrogenase, and free triiodothyronine (FT3)
declined, and free thyroxine (FT4) increased after all 3 interventions (both analyses). Creatine kinase (CK) decreased
only in the TRE (− 18 [44] U/L, P < 0.001) and combination (− 22 [64] U/L, P = 0.003) groups (PP analysis). Thyrotropin(− 0.24 [0.83] μIU/mL, P = 0.011) and T3 (− 0.10 ± 0.04 ng/mL, P = 0.011) decreased in the combination group (ITT
analysis). T4 (0.82 ± 0.39 μg/dL, P = 0.046), thyroglobulin antibodies (TgAb, 2 [1] %, P = 0.021), and thyroid microsomal
antibodies (TMAb, 2 [2] %, P < 0.001) increased, while the T3/T4 ratio (− 0.01 ± 0.01, P = 0.020) decreased only in the TRE
group (PP analysis). However, no significant difference between groups was observed in either analysis. At baseline, CK was positively correlated with the visceral fat area. FT3 was positively associated with triglycerides and total*Correspondence:
Bingyin Shi
shibingy@126.com
Mingqian He
mingqian_he@xjtufh.edu.cn
Full list of author information is available at the end of the article© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0
International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as longas you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if
you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article orparts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicatedotherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To
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Zheng et al. BMC Medicine(2024) 22:362

Page 2 of 11cholesterol. FT4 was negatively related to insulin and C-peptide levels. TgAb and TMAb were negatively correlatedwith the waist-to-hip ratio.
Conclusions TRE with or without LCD confers remarkable metabolic benefits on myocardial status and thyroid function in subjects with MetS.
Trial registration ClinicalTrials.gov, NCT04475822.
Keywords Metabolic syndrome, Low-carbohydrate diet, Time-restricted eating, Myocardial enzymes, Thyroid
function

Background
Metabolic syndrome (MetS) is a cluster of concomitantconditions, including abdominal obesity, elevated bloodpressure, insulin resistance (IR), and hyperglycemia, thatpredispose individuals to cardiovascular disease (CVD),
type 2 diabetes mellitus (T2DM), and mortality. Alongwith elevated prevalence rates of obesity [1], MetS affects
more than 30% of the population worldwide [2–4]. As
critical methods of lifestyle modification, multifarious
dietary interventions [5], such as a low-carbohydrate
diet (LCD) and time-restricted eating (TRE), are emerging and are well established to cause 5% to 7% weight loss
on average. However, no dietary strategy is consistently
superior to others for the MetS population.
Compared with individuals without MetS, individuals with MetS are more than twofold more likely to havemyocardial infarction (MI) [6, 7], and a dose–response
relationship was found between cumulative exposure to
MetS components and MI [8]. As indicators of myocardial injury, myocardial enzymes are closely correlatedwith the risk of obesity and MetS [9, 10], and higher levels of myocardial enzymes have been observed in obese
patients and MetS patients [11, 12]. Additionally, MetS is
closely related to thyroid dysfunction. Thyroid hormones(THs) play vital roles in maintaining the basal metabolic
rate; controlling protein, carbohydrate, and lipid metabolism; and modulating heart rate, body temperature, cardiovascular functions, and weight [13, 14]. An increasing
number of studies have shown that subclinical or clinicalhypothyroidism in individuals with obesity and MetS is
characterized by increased thyrotropin (TSH) and triiodothyronine (T3) levels and decreased thyroxine (T4)levels [15–18], with increasing risks of metabolic disorders, such as dyslipidemia, IR, and nonalcoholic fatty
liver disease [19–21]. THs levels and autoantibody titers
are associated with MetS components even in euthyroid
individuals [22–24].
Despite considerable evidence on the benefits of LCD
and TRE for improving MetS [25, 26], whether theseinterventions also ameliorate myocardial status and thyroid dysfunction in individuals with MetS and whichis the superior method are still unclear. Controversial
results have been reported regarding THs after LCD or

TRE in participants with obesity and MetS. Some studies have shown that THs are altered to varying degrees[27, 28], but some studies have failed to find any changes[29, 30]. In addition, studies on the effects of diet-induced
weight loss on thyroid autoantibodies and myocardial enzymes in individuals with MetS are scarce. Furthermore, no study to date has directly compared theeffects of LCD, TRE, or their combination on myocardial
enzymes and thyroid function in the MetS population.
Therefore, we aimed to evaluate the effects of LCD,
TRE, and their combination on the myocardium and thyroid and to determine which is the superior method. We
hypothesized that all three interventions could improvethyroid function and myocardial status and that TRE
with or without LCD may result in prominent improvements due to additional benefits for weight and cardiometabolic risk factors [31].

Methods
Study design

The detailed protocol is reported elsewhere [31]. Briefly,
we conducted a single-center, 3-month, open-label, clinical trial to investigate the effects of LCD, TRE, and their
combination on body weight and cardiometabolic risk
factors in patients with MetS. We conducted this secondary analysis to explore the effects of LCD, TRE, andtheir combination on myocardial status and thyroid function. This trial was ethically approved by the Institutional
Review Board of the First Affiliated Hospital of Xi’an
Jiaotong University, and all participants provided written
informed consent. The original study [31] and this secondary analysis followed the Consolidated Standards ofReporting Trials (CONSORT) reporting guideline.
ParticipantsParticipants were recruited by fliers, posters, and advertisements. Free-living men and women with MetS who
met at least 3 out of 5 criteria [32] and were aged 18 to
65 years were eligible for screening. The exclusion criteria included pregnancy or lactation, night shift work, history of major diseases or related diseases, participationin other weight loss trials, consumption of a prescribed
diet for special diseases or any drugs that affect appetite,Zheng et al. BMC Medicine(2024) 22:362

and history of bariatric surgery. The present trial was
screened from July 2020 to September 2020 and wascompleted in January 2021.
ProtocolThe detailed methods and procedures have been published previously [31]. In brief, the protocol included a
run-in period before the intervention, during which participants were instructed to maintain their habitual dietand physical activity level for 2 weeks to stabilize weight.
Participants in the LCD group were required to follow
a reduced-carbohydrate diet (carbohydrates < 130 g/
day or < 26% total energy) without time limitations. Participants in the TRE group were restrained from eating
ad libitum (AL) within 8 h per day and fasted for 16 h.
Participants in the combination group were instructed torestrict both carbohydrate intake and the eating window.
Participants in the latter two groups voluntarily choseeither early TRE (eTRE, eat from 8 AM to 4 PM and fastfrom 4 PM to 8 AM the next day) or late TRE (lTRE, eatfrom 12 to 8 PM and fast from 8 to 12 PM the next day)according to their eating habits. All participants were notallowed to change their physical activity habits or dose of
medication during the trial.
Dietary guidance was carried out online through aunique and novel application called Zhihui Hao Yiyuan,
which was established as a medical assistance platform.
All participants were encouraged but not compulsory
to write a daily dietary log. Nutrient intake was assessed
every other week through an online Food Frequency
Questionnaire (FFQ) which also included a 2-week recallof mealtime and days of adherence.
Outcome measurement

Specific processes and approaches to obtaining anthropometric metrics have been described elsewhere [31]. In
the original study, the primary outcomes were changes
in weight and body fat after 3-month interventions, andthe secondary outcomes included changes in blood pressure, blood glucose, blood lipid, and uric acid. This secondary analysis reported additional outcomes includingchanges in myocardial enzymes and thyroid function
after 3-month interventions.
Blood samples were obtained at the First AffiliatedHospital of Xi’an Jiaotong University after a whole-night
fast (from 8 PM on) before and after intervention following a standard procedure of blood sample collection
and stored at – 80 °C until assessment. The staff whocollected and analyzed the outcomes were blinded tothe participant assignments. Myocardial enzymes were
tested by velocity assays using a LABOSPECT 008AS

Page 3 of 11

automatic biochemical analyzer. The laboratory reference
ranges of lactate dehydrogenase (LDH), creatine kinase(CK), creatine kinase MB (CKMB), and hydroxybutyrate
dehydrogenase (HBDH) were 120–250 U/L, 50–210 U/L,
0–24 U/L, and 72–182 U/L, respectively, using standard
reagents to the nearest 1 U/L, 1 U/L, 1 U/L, and 1 U/L,
respectively. THs were measured by radioimmunoassay
using GC-2016 16th automatic sampling change equipment. The laboratory reference ranges of free triiodothyronine (FT3), free thyroxine (FT4), TSH, T3, and T4 were2.91–9.08 pmol/L, 9.05–25.50 pmol/L, 0.25–5.00 μIU/
mL, 0.78–2.20 ng/mL, and 4.20–13.50 μg/dL, respectively, using standard reagents to the nearest 0.01 pmol/L,
0.01 pmol/L, 0.01 μIU/mL, 0.01 ng/mL, and 0.01 μg/dL,
respectively. Thyroid autoantibodies were tested byradioimmunoassay using an FM-2000 gamma immune
counter, the laboratory reference ranges of thyroglobulin antibodies (TgAb) and thyroid microsomal antibodies(TMAb) were < 30% and < 20% with standard reagents tothe nearest 1% and 1%, respectively.
Statistical analysis

Data from participants who started the 3-month intervention were included in this intention-to-treat (ITT)
analysis. Missing data were handled by multiple imputations with the use of the Markov chain Monte Carlo
method. The per-protocol (PP) analysis included participants who adhered to their assigned protocol. The
data are presented as the means ± standard errors of themeans (SEMs) for normally distributed variables, medians (interquartile ranges) for abnormally distributed variables, or numbers (percentages) for categorical variables.
Comparisons among groups at baseline were assessedusing one-way ANOVA for normally distributed variables,
the Kruskal–Wallis H test for abnormally distributed
variables, or the chi-square test or Fisher’s exact test
for categorical variables. Within-group comparisons ofoutcome variables were performed by paired t tests fornormally distributed variables or paired Wilcoxon tests
for abnormally distributed variables, and between-groupcomparisons of changes were performed by independent samples t tests for normally distributed variablesor Mann–Whitney U tests for abnormally distributed
variables. Statistical significance was considered when
two-tailed P < 0.05. Pearson’s correlation for normally
distributed variables or Spearman’s correlation for abnormally distributed variables was performed to investigate
the correlation between functions of the myocardium
and thyroid and cardiometabolic parameters at baseline. All the statistical analyses were performed using
R version 4.1.3

Zheng et al. BMC Medicine(2024) 22:362

Page 4 of 11

Fig. 1 Participant flow. eTRE, early time-restricted eating; lTRE, late time-restricted eating

Results
Participant characteristics

As Fig. 1 shows, 290 individuals were screened at the
beginning of the study, 121 individuals were excluded
because they failed to meet the study criteria (n = 77),
had scheduling conflicts (n = 20), or declined to participate (n = 24), and 169 individuals were randomly
assigned at a 1:1:1 ratio to the LCD group (n = 56), TRE
group (n = 57), or combination group (n = 56). Seven
participants dropped out before commencing the study,
4 of whom had scheduling conflicts and 3 of whom had
adherence concerns. In total, 162 participants started
the interventions (55 in the LCD group, 55 in the TRE
group, and 52 in the combination group), and 135
completed the interventions (47 in the LCD group, 44
in the TRE group, and 44 in the combination group).
Fifty-seven participants (15 in the LCD group, 28 in
the TRE group, and 14 in the combination group) who
adhered to their assigned protocol were included in the
PP analysis (LCD: daily carbohydrate intake < 150 g/day
on ≥ 5 days/week for 3 months; TRE: daily eating window ≤ 8 h on ≥ 5 days/week for 3 months; combination
treatment: combined criteria of LCD and TRE.)
The baseline data are outlined in Table 1. The
mean ± SEM average body mass index (BMI) was above

28.0 kg/m2 in each group. The majority of participants
had normal myocardial and thyroid functions; 33/162(20.4%) had elevated myocardial enzymes, and 26/162(16.0%) had thyroid dysfunction. Overall, the baselinecharacteristics were significantly equal among the threeintervention arms and between those who completed
the study and those who withdrew (Additional file 1:
Table S1).
Only 3 participants (2 in the LCD group and 1 in the
TRE group) had been diagnosed with hypothyroidism
and were taking levothyroxine sodium tablets before theintervention; no other medication in addition to cardiovascular medication was taken by any of the participants.
All participants maintained their medication dosage anddid not change their level of physical activity during the
3-month intervention. The intake of aquatic products
was decreased in the TRE group and the intake of phytocomycetes was increased in the combination group(Additional file 1: Table S3).
LCD, TRE, and their combination reduced LDH, CK, CKMB,
and HBDH

All three groups exhibited equivalent reductions in LDH,
CK, CKMB, and HBDH after the 3-month intervention(P < 0.01). Moreover, there was no significant differenceZheng et al. BMC Medicine(2024) 22:362

Page 5 of 11

Table 1 Baseline characteristics of participants
LCD

TRE

Both

(N = 55)(N = 55)(N = 52)

P value

Male, no. (%)

27 (49.1)

31 (56.4)

31 (59.6)

0.320

Age (years)

41.8 ± 1.4

42.6 ± 1.5

39.3 ± 1.3

0.252
0.953

Weight (kg)84.5 ± 2.4

84.6 ± 2.3

85.4 ± 2.0

Body mass index (kg/m2)

29.1 ± 0.5

29.3 ± 0.5

29.0 ± 0.50.924High school education, no. (%)

52 (94.5)

49 (89.1)

46 (88.5)

0.470

2 (3.6)2 (3.6)0 (0.0)

Income of household, no. (%)  < ¥30,000

0.171¥30,000–¥100,000

11 (20.0)

12 (21.8)

18 (34.6)¥100,000–¥200,000

24 (43.6)

22 (40.0)

15 (28.8)¥200,000–¥500,000  > ¥500,000

18 (32.7)

15 (27.3)

18 (34.6)

0 (0.0)4 (7.3)

1 (1.9)Current smoker, no. (%)

14 (25.5)

16 (29.1)

18 (34.6)

0.602

Current drinker, no. (%)

14 (25.5)

17 (30.9)

12 (23.1)

0.662

Myocardial enzymes
Lactate dehydrogenase (U/L)

200 ± 6

195 ± 4187 ± 4

0.228

Creatine kinase (CK, U/L)

93 (86)98 (68)96 (68)

0.858

CKMB (U/L)

13 (4)

12 (5)

13 (4)

0.795

HBDH (U/L)

166 ± 4162 ± 3155 ± 30.319

Thyroid function
Free T3 (FT3, pmol/L)

7.00 ± 0.10

7.02 ± 0.11

6.86 ± 0.11

0.507

Free T4 (FT4, pmol/L)

16.68 ± 0.29

16.65 ± 0.32

16.74 ± 0.33

0.977

Thyrotropin (μIU/mL)

1.37 (1.35)

1.40 (1.21)

1.54 (1.44)

0.462

Triiodothyronine (T3, ng/mL)

1.46 ± 0.03

1.48 ± 0.04

1.48 ± 0.04

0.906

Thyroxine (T4, μg/dL)

9.82 ± 0.19

9.24 ± 0.26

9.47 ± 0.22

0.179

T3/T4 ratio

0.15 ± 0.00

0.16 ± 0.00

0.16 ± 0.00

0.124

Thyroglobulin antibodies (%)

5 (2)

4 (1)

5 (1)

0.526

Thyroid microsomal antibodies (%)

4 (2)

4 (1)

4 (1)

0.223

LCD, low-carbohydrate diet; TRE, time-restricted eating; Both, combination treatment; CKMB, creatine kinase MB; HBDH, hydroxybutyrate dehydrogenase. Unlessotherwise indicated, the data are presented as the mean ± standard error of the mean for normally distributed variables or the median (interquartile range) for
abnormally distributed variables. Differences among treatment arms (LCD, TRE, and Both) were tested by one-way ANOVA for normally distributed variables, theKruskal–Wallis H test for abnormally distributed variables, or chi-square tests for categorical variablesin the reductions in myocardial enzymes among the threegroups (Fig. 2A–D and Table 2). Differently, PP analysis
revealed that CK levels decreased only in the TRE (− 18[44] U/L, P < 0.001) and combination (− 22 [64] U/L,
P = 0.003) groups, without significant changes in the LCD(− 11 [10] U/L, P = 0.075) group (Fig. 3B and Additional
file 1: Table S4); moreover, changes in the other three
myocardial enzymes were similar to those observed in
the ITT analysis (Fig. 3A, C, and D and Additional file 1:
Table S4). No significant difference between the eTRE
and lTRE groups was observed for either the TRE or
combination group (Additional file 1: Table S6).
LCD, TRE, and their combination altered FT3 and FT4,
while only combination treatment reduced TSH

After 3 months, FT3 levels decreased and FT4 levels
increased in all three groups (Fig. 2E and F and Table 2).

Reductions in TSH (− 0.24 [0.83] μIU/mL, P = 0.011) andT3 (− 0.10 ± 0.04 ng/mL, P = 0.011) were observed in the
combination group (Fig. 2G and H and Table 2). Only theTRE group exhibited an increase in T4 (0.70 ± 0.28 μg/dL,
P = 0.013; Fig. 2I and Table 2). The T3/T4 ratio
decreased in both the TRE (− 0.01 ± 0.01, P = 0.003) andcombination (− 0.01 ± 0.00, P = 0.012) groups (Fig. 2J andTable 2). No significant difference in changes in THs wasobserved among the three groups. The results from the
PP analysis differed moderately from those from the primary analysis. Relative to those at baseline, TSH and T3
levels remained unchanged in all three groups (Fig. 3G
and H), and the T3/T4 ratio decreased only in the TRE(− 0.01 ± 0.01, P = 0.020) group (Fig. 3J and Additional
file 1: Table S4). The eTRE and lTRE subgroups in boththe TRE and combination groups showed comparable
improvements in THs (Additional file 1: Table S6).

Zheng et al. BMC Medicine(2024) 22:362

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Fig. 2 Changes in myocardial enzymes and thyroid function among participants. A–D Changes in myocardial enzymes among the three groups
after the low-carbohydrate diet (LCD), 8-h time-restricted eating (TRE), or combination treatment (Both). A Lactate dehydrogenase (LDH), B creatine
kinase (CK), C creatine kinase MB (CKMB), and D hydroxybutyrate dehydrogenase (HBDH). E–J Changes in thyroid hormone levels among the threegroups after intervention. E Free triiodothyronine (FT3), F free thyroxine (FT4), G thyrotropin (TSH), H triiodothyronine (T3), I thyroxine (T4), and J
the T3/T4 ratio. K, L Changes in K thyroglobulin antibodies (TgAb) and L thyroid microsomal antibodies (TMAb) among the three interventions
after 3 months. Changes from baseline are presented as the mean ± standard error of the mean for normally distributed variables or the median(interquartile range) for abnormally distributed variables. Analysis was conducted on 162 participants who began interventions (55 in the LCD
group, 55 in the TRE group, and 52 in the Both group). *P < 0.05, **P < 0.01, ***P < 0.001: significant differences shown on the x-axis comparedwith baseline (paired t test for normally distributed variables or paired Wilcoxon test for abnormally distributed variables)

LCD, TRE, and their combination increased TgAb and TMAb

Compared to baseline, the TgAb and TMAb levels
increased in all three groups (Fig. 2K and L and Table 2).
The changes in thyroid autoantibodies were not significantly different among the groups (Table 2). PP analysis
revealed that TgAb (2 (1) %, P = 0.021) and TMAb (2 (2)%, P < 0.001) increased only in the TRE group (Fig. 3K
and L and Additional file 1: Table S4). No significant difference was observed in TgAb or TMAb between the two
subgroups (eTRE vs. lTRE) (Additional file 1: Table S6).
Correlation analysis

Pearson’s or Spearman’s correlation was assessed between
functions of the myocardium and thyroid and cardiometabolic parameters at baseline (Additional file 1: Fig.
S1). CK was positively correlated with visceral fat area
(VFA, r = 0.213, P = 0.013). FT3 was positively associated with triglyceride (r = 0.237, P = 0.006) and total cholesterol (r = 0.223, P = 0.009). FT4 was negatively related
to fasting insulin (r =  − 0.244, P = 0.004) and C-peptide(r =  − 0.238, P = 0.005). TgAb and TMAb were negatively
correlated with the waist-to-hip ratio (WHR, r =  − 0.237,
P = 0.006; r =  − 0.245, P = 0.004, respectively).

Discussion
In this study, we observed that all three distinct interventions improved myocardial status and thyroid function, while TRE with or without LCD had apparent
beneficial effects on CK, TSH, T3, T4, and the T3/T4
ratio. In the preliminary analysis, eTRE and lTRE had

comparable effects on the myocardium and thyroid. Correlations between the functions of the myocardium andthyroid and cardiometabolic risk factors were observed
at baseline. In addition, the results of the PP analysis
seemed more precise in that only adherent participants
were included, which could reflect the real effects of thediverse diet without bias from higher compliance in the
TRE group [31]. However, whether the changes in theintake of aquatic products and phytocomycetes indicatedthat the exact iodine intake changed accordingly was
unclear. To our knowledge, the present study is the firstto directly compare the effects of LCD and TRE on myocardial status and thyroid function, especially on thyroid
autoimmunity, in subjects with MetS.
Although the majority of the patients were within thereference range at baseline, myocardial enzymes, including LDH, CK, CKMB, and HBDH, markedly decreased
after all three interventions, without differences among
the groups. Our findings are consistent with other studies
that showed decreased LDH, CK, and HBDH after weightloss induced by bariatric surgery [33] and reduced LDH
after a low-calorie diet [34]. However, the results of existing trials on changes in myocardial enzymes via LCD and
TRE are sparse, and further studies are needed to investigate the effects of LCD and TRE on myocardial enzymes
in individuals with MetS to verify our findings. Notably,in the PP analysis, CK decreased only in the TRE andcombination groups, partially because of decreased VFA
in the TRE and combination treatments but not in the
LCD group [31], given that CK was positively correlated

Zheng et al. BMC Medicine(2024) 22:362

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Table 2 Changes in myocardial enzymes and thyroid function after 3 months among participants
LCD (group A)
N = 55

TRE (group B)
P value

N = 55

P value

Both (group C)

P value between-groupcomparison

N = 52

P value

A vs. B

A vs. CB vs. C< 0.001

0.838

0.665

0.989

0.001

0.713

0.711

0.989

< 0.001

0.526

0.601

0.974

< 0.001

0.925

0.839

0.700

< 0.001

0.811

0.472

0.558

< 0.001

0.656

0.798

0.969

0.011

0.693

0.149

0.233

0.011

0.457

0.220

0.451

0.121

0.583

0.729

0.437

0.012

0.238

0.300

0.802

0.001

0.852

0.373

0.472

< 0.001

0.371

0.084

0.298

Myocardial enzymes
LDH (U/L)

3m

176 ± 4△− 24 ± 6

Creatine kinase (CK, U/L)

3m

77 (65)△− 13 (40)CKMB (U/L)

3m

12 (3)△− 1 (4)

HBDH (U/L)

3m

152 ± 3△

− 13 ± 43m5.95 ± 0.09△

− 1.04 ± 0.15

Free T4 (pmol/L)

3m

20.21 ± 1.34△

3.53 ± 1.33

Thyrotropin (μIU/mL)

3m

1.42 (1.11)△− 0.01 (0.65)

Triiodothyronine (T3, ng/mL)

3m

1.43 ± 0.04△

− 0.03 ± 0.04

3m

10.29 ± 0.28△

0.46 ± 0.27

T3/T4 ratio

3m

0.14 ± 0.01△

− 0.01 ± 0.00

TgAb (%)

3m

7 (2)

△

2 (2)

TMAb (%)

3m

6 (2)

△

2 (2)

171 ± 3
< 0.001− 24 ± 4

166 ± 2
< 0.00180 (45)0.002− 14 (32)< 0.00111 (3)
0.003− 2 (3)− 12 ± 3− 18 (47)
11 (3)< 0.001

150 ± 30.001

− 21 ± 3
83 (48)− 2 (4)145 ± 20.001

− 10 ± 3

Thyroid function
Free T3 (pmol/L)

Thyroxine (T4, μg/dL)

6.11 ± 0.18
< 0.001− 0.91 ± 0.20

5.93 ± 0.09
< 0.00118.70 ± 0.36
< 0.001

2.05 ± 0.46

< 0.001

1.34 (1.08)
0.528− 0.13 (1.02)− 0.01 ± 0.08

0.435

0.70 ± 0.28

0.076

− 0.01 ± 0.01
2 (2)

0.003

2 (2)

− 0.01 ± 0.00
7 (2)

0.001

6 (1)
0.003

0.34 ± 0.22
0.15 ± 0.01

7 (1)
0.011

− 0.10 ± 0.04
9.81 ± 0.27

0.013

0.15 ± 0.01
0.189

− 0.24 (0.83)
1.38 ± 0.04

9.94 ± 0.27
0.087

2.03 ± 0.35
1.31 (0.99)

1.47 ± 0.07
0.511

− 0.93 ± 0.12
18.77 ± 0.33

2 (2)
6 (2)

< 0.0012 (2)LCD low-carbohydrate diet, TRE time-restricted eating, Both combination treatment, LDH lactate dehydrogenase, CKMB creatine kinase MB, HBDH hydroxybutyrate
dehydrogenase, TgAb thyroglobulin antibodies, TMAb thyroid microsomal antibodies. All the data are presented as the mean ± standard error of the mean for normally
distributed variables or the median (interquartile range) for abnormally distributed variables. The outcome variables tested at postintervention are represented
by “3 m,” and the variations from baseline to 3 months are represented by “△” in the table. Within-group comparisons of outcome variables between baseline andfollow-up were performed by paired t tests for normally distributed variables or paired Wilcoxon tests for abnormally distributed variables, and between-groupcomparisons (e.g., LCD vs. TRE, LCD vs. Both, and TRE vs. Both) of changes were tested by independent sample t tests for normally distributed variables or Mann–
Whitney U tests for abnormally distributed variables. Significant P values are italicizedwith VFA (Additional file 1: Fig. S1A). As an ATP-regenerating enzyme, CK regulates energy metabolism, affects
cardiovascular hemodynamics [35], and is abundant intype II skeletal muscle fibers, which particularly contribute to IR and obesity. Accordingly, higher levels of
serum CK are found in patients with obesity [11, 12]. CK
is correlated with multiple MetS components, such as
BMI, waist circumference, and blood pressure [9, 10, 36].
Therefore, TRE with or without LCD markedly reduced
CK levels and could ameliorate unfavorable myocardial
status and cardiovascular risk.
Studies on the effects of LCD and TRE on THs haveyielded inconsistent results. As the most sensitive andsignificant serum biomarker of thyroid function, TSH

decreased only in the combination group according to
the ITT analysis and showed a decreasing trend but was
insignificant in the combination group according to the
PP analysis, which is consistent with the findings of several trials that failed to detect any significant changes in
TSH after LCD or TRE intervention [26–28]. Nevertheless, studies on the effects of LCD combined with TRE
on TSH are scarce, and further larger-scale trials areneeded to investigate whether TRE combined with LCD
could induce a reduction in TSH levels. Notably, TRE
with or without LCD led to a significant reduction in the
T3/T4 ratio (an index of deiodinase activity), indicatingthat the reduction in (F)T3 and increase in (F)T4 may besignals of decreased deiodinase activity and peripheral

Zheng et al. BMC Medicine(2024) 22:362

Page 8 of 11

Fig. 3 Changes in myocardial enzymes and thyroid function according to the PP analysis. A–D Changes in myocardial enzymes among the threegroups in the per-protocol (PP) analysis after the low-carbohydrate diet (LCD), 8-h time-restricted eating (TRE), or combination treatment (Both)interventions. A Lactate dehydrogenase (LDH), B creatine kinase (CK), C creatine kinase MB (CKMB), and D hydroxybutyrate dehydrogenase (HBDH).
E–J Changes in thyroid hormone levels among the three groups according to the PP analysis after intervention. E Free triiodothyronine (FT3), F
free thyroxine (FT4), G thyrotropin (TSH), H triiodothyronine (T3), I thyroxine (T4), and J the T3/T4 ratio. K, L Changes in K thyroglobulin antibodies(TgAb) and L thyroid microsomal antibodies (TMAb) in the PP analysis among the three interventions after 3 months. Changes from baseline arepresented as the mean ± standard error of the mean for normally distributed variables or the median (interquartile range) for abnormally distributed
variables. Analysis was conducted on 57 adherent participants (15 in the LCD group, 28 in the TRE group, and 14 in the Both group). *P < 0.05,**P < 0.01, ***P < 0.001: significant differences shown on the x-axis compared with baseline (paired t test for normally distributed variables or paired
Wilcoxon test for abnormally distributed variables)

conversion from T4 to T3. Another explanation for theobserved trends toward (F)T3 and (F)T4 is decreased
ATP-dependent uptake of T4 into T3-producing tissues, including the liver [37]. (F)T3 activates thermogenesis and induces an increase in energy expenditureand oxygen consumption. Therefore, a reduction in (F)T3 may represent strong self-protection to save energy
and decrease resting energy expenditure in response toenergy deficits induced by carb restriction or fasting. Ourfindings of changes in FT3 and FT4 were consistent withthe findings of other trials after LCD (15% carbohydrate)[27] or gastric banding [38]. However, our findings wereat odds with several trials that showed no significant
changes in FT3 or FT4 after LCD [29] or TRE [30]. These
differences might be partially attributed to differences inthe scales and durations of the study, thyroid function atbaseline, or extent of weight loss. Overall, in this study,
we found that all three interventions improved FT3 andFT4 levels, while only TRE with or without LCD significantly improved T3, T4, and the T3/T4 ratio.
Consistent with previous findings [39, 40], we also
observed that THs were closely associated with the lipid
profile and insulin sensitivity (Additional file 1: Fig. S1B
and S1C), which are not only MetS components but
also risk factors for multiple chronic diseases, revealing
the mechanism of correlation between thyroid dysfunction and chronic endocrine disorders. Recently, several
TH analogs or thyromimetics have been developed tomodulate lipid and glucose levels based on the possibility

that THs control multiple signaling pathways involved inrelated metabolism [41–43].
Our results showed that TgAb and TMAb levels
increased after all three interventions in the ITT analysis but increased only in the TRE group after the PP
analysis. For participants with negative baseline thyroid
autoantibodies, TgAb and TMAb levels increased after
all three interventions in both the ITT and PP analyses(Additional file 1: Fig. S2). Elevated thyroid autoantibodies are common not only in patients with autoimmune thyroid disease but also in individuals without
evident thyroid dysfunction. The percentage of patientswith a positive serum TgAb concentration is estimatedto be 12.6% in the Chinese general population [44].
Negative correlations have been observed between
TgAb levels and BMI [45], prevalence of impaired
fasting glucose, hypertriglyceridemia, and metabolic
dysfunction-associated fatty liver disease [23, 46]. We
found that TgAb and TMAb levels were negatively
correlated with the WHR (Additional file 1: Fig. S1D),
which was recently identified as a stronger adiposity surrogate associated with mortality than BMI [47].
However, several studies have reported a correlation
between positivity or higher titers of TgAb and MetS
components [48–50]. These inconsistencies might be
partly due to altered thyroid function and differences inthe specificity and sensitivity of the antibody detection
methods. To date, no study has investigated the effects
of LCD or TRE on thyroid autoimmunity, and whether

Zheng et al. BMC Medicine(2024) 22:362

increased thyroid autoantibody levels, even within
the normal range, adversely impair thyroid function is
unclear. Further studies are warranted to elucidate theeffects of LCD and TRE on thyroid autoimmunity andexplore the underlying mechanism involved.
Following circadian rhythms, eTRE was previously
suggested to be superior to lTRE [51]. We observed thateTRE and lTRE improved myocardial enzymes and thyroid function comparably, which indicated that people
could choose freely following preferences. Indeed, studies comparing the effects of eTRE and lTRE on the myocardium and thyroid are scarce. Zhang et al. reported
that TSH levels were significantly lower in the eTRE
group than in the lTRE group after 4 but not 8 weeks[52]. Although our early or late TRE method involves
self-selection but not randomization, the outcomes could
still be used to tentatively explore the effects of eTRE
and lTRE on the myocardium and thyroid. Further randomized controlled trials with longer durations and larger
scales are needed to verify our findings.
This analysis has several limitations. First, the lack ofan AL control group limits the exploration of the effectsof TRE alone and LCD alone, although we conducted acomparison between pre- and postintervention data.
Second, in line with the findings of other TRE trials [51,53, 54], participants in the TRE group spontaneously
reduced their daily carbohydrate intake by approximately
4.6%, and the exact daily iodine intake of all participants was obscure. Third, to enhance adherence, eTRE
and lTRE were not randomized but rather self-selected,
which impaired the reliability of the analytical results tosome extent. Further randomized trials are warranted tocompare the effects of eTRE and lTRE on the thyroid andmyocardium. Moreover, a limited number of participantsin the LCD and combination groups were included in the
PP analysis, and further larger-scale and strict follow-up
trials are warranted to verify our findings. Finally, thyroid antibodies are influenced by multiple factors, andthe results vary depending on the testing methods used;additional trials are needed to verify our results.

Conclusions
Taken together, LCD, TRE, and their combination all
improved functions of the myocardium and thyroid eventhough the majority were within the reference range atbaseline, and TRE with or without LCD conferred substantial benefits regarding CK, TSH, T3, T4, and the T3/
T4 ratio, suggesting that TRE with or without LCD canserve as effective dietary strategy for ameliorating the
myocardial status and thyroid function in patients with
MetS.

Page 9 of 11

Abbreviations
MetS	Metabolic syndrome
LCD	Low-carbohydrate diet
TRE	Time-restricted eating
LDH	Lactate dehydrogenase
CK	Creatine kinase
CKMB	Creatine kinase MB
HBDH	Hydroxybutyrate dehydrogenaseTHs	Thyroid hormones
FT3	Free triiodothyronine
FT4	Free thyroxine
TSH	Thyrotropin
TgAb	Thyroglobulin antibodies
TMAb	Thyroid microsomal antibodies

Supplementary Information
The online version contains supplementary material available at https://​doi.​
org/​10.​1186/​s12916-​024-​03595-6.
Additional file 1: Fig. S1. Correlations between myocardial and thyroid
functions and cardiometabolic risk factors at baseline. Fig. S2. Changes
in TgAb and TMAb after 3 months in participants with negative baseline
thyroid autoimmunity. Table S1. Baseline characteristics of all, completed,and dropout participants. Table S2. Baseline characteristics of adherent participants. Table S3. Intake of food containing high iodine among
completed participants. Table S4. Changes in myocardial enzymes andthyroid function after 3-month intervention among adherent participants.
Table S5. Baseline characteristics of the early TRE and late TRE subgroups.
Table S6. Changes in myocardial enzymes and thyroid function after
3-month intervention between early TRE and late TRE subgroups.
Acknowledgements
We sincerely thank the patients who participated in the research. We thankMrs. Alice Chung for helping with dietary instruction.
Authors’ contributions
YZ and MH conducted the clinical trial, analyzed the data, and wrote themanuscript. BS designed the research and revised the manuscript. ML1, XZ,
and XL assisted with the data analysis. JW, QL, JY, MZ, ZC, ML2, YW, JS, WQ,
and HG assisted with the conduction of the clinical trial. All authors read andapproved the final manuscript.
Funding
This study was supported by the Natural Science Foundation Programof Shaanxi (No. 2024JC-YBQN-0828), the Key Research and Development
Program of Shaanxi (No. 2023-ZDLSF-40), and Natural Science Foundation
Program of Shaanxi (No. 2023-JC-QN-0927).
Availability of data and materials
All data generated or analyzed during this study are included in this publishedarticle and its supplementary information files. All data reported in this paper
and any additional information required to reanalyze the data reported in thispaper will be shared by the lead contact upon reasonable request.

Declarations
Ethics approval and consent to participate
The study was conducted in accordance with the Declaration of Helsinki, andthe protocol was approved by the Institutional Review Board of the First Affiliated Hospital of Xi’an Jiaotong University (XJTU1AF2020LSK-003). Participants
provided written informed consent and received no compensation.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.

Zheng et al. BMC Medicine(2024) 22:362

Author details
1
Department of Endocrinology, the First Affiliated Hospital of Xi’an JiaoTong
University, 277 West Yanta Road, Xi’an, Shaanxi 710061, People’s Republicof China. 2 Department of Gastroenterology, Xi’an Children’s Hospital, Shaanxi
Research Institute for Pediatric Diseases, The Affiliated Children’s Hospitalof Xi’an JiaoTong University and National Regional Medical Center for Children(Northwest), No 69, Xiju Yuan Lane, Xi’an, Shaanxi 710003, People’s Republicof China. 3 Med-X Institute, Center for Immunological and Metabolic Diseases,
The First Affiliated Hospital of Xi’an JiaoTong University, 277 West Yanta Road,
Xi’an, Shaanxi 710061, People’s Republic of China. 4 Department of Endocrinology and International Medical Center, the First Affiliated Hospital of Xi’an
JiaoTong University, 277 West Yanta Road, Xi’an, Shaanxi 710061, People’s
Republic of China.
Received: 2 January 2024 Accepted: 28 August 2024

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