Skip to main content
Download PDF

Co-administration of exercise training and melatonin on the function of diabetic heart tissue: a systematic review and meta-analysis of rodent models

Diabetology & Metabolic Syndrome volume 15, Article number: 67 (2023) Cite this article

Abstract

Purpose

Diabetes mellitus (DM), a hyperglycemic condition, occurs due to the failure of insulin secretion and resistance. This study investigated the combined effects of exercise training and melatonin (Mel) on the function of heart tissue in diabetic rodent models.

Methods

A systematic search was conducted in Embase, ProQuest, Cochrane library, Clinicaltrial.gov, WHO, Google Scholar, PubMed, Ovid, Scopus, Web of Science, Ongoing Trials Registers, and Conference Proceedings in July 2022 with no limit of date or language. All trials associated with the effect of Mel and exercise in diabetic rodent models were included. Of the 962 relevant publications, 58 studies met our inclusion criteria as follows; Mel and type 1 DM (16 studies), Mel and type 2 DM (6 studies), exercise and type 1 DM (24 studies), and exercise and type 2 DM (12 studies). Meta-analysis of the data was done using the Mantel Haenszel method.

Results

In most of these studies, antioxidant status and oxidative stress, inflammatory response, apoptosis rate, lipid profiles, and glucose levels were monitored in diabetic heart tissue. According to our findings, both Mel and exercise can improve antioxidant capacity by activating antioxidant enzymes compared to the control diabetic groups (p < 0.05). The levels of pro-inflammatory cytokines, especially TNF-α were reduced in diabetic rodents after being treated with Mel and exercise. Apoptotic changes were diminished in diabetic rodents subjected to the Mel regime and exercise in which p53 levels and the activity of Caspases reached near normal levels (p < 0.05). Based on the data, both Mel and exercise can change the lipid profile in diabetic rodents, especially rats, and close it to near-to-control levels.

Conclusion

These data showed that exercise and Mel can reduce the harmful effects of diabetic conditions on the heart through the regulation of lipid profile, antioxidant capacity, apoptosis, and inflammation.

Introduction

Diabetes Mellitus (DM) is a common global health problem with different socioeconomic complications [1, 2]. According to American Diabetes Association statistics, the number of diabetic patients is expected to increase to more than 600 million people in 2035. Of note, more than 10% of the adult population suffer from DM in Iran and it is estimated that about half of this population is unaware of their diabetic conditions [3]. Predisposing factors such as lifestyle changes, obesity, genetic predisposition, urbanization, physical inactivity, and aging have led to the prevalence of DM [4]. From biochemical aspects, DM coincides with abnormal insulin secretion and insensitivity, leading to dysregulation of carbohydrate, protein, and lipid metabolism. With the progression of the diabetic condition, several pathologies such as retinopathy, nephropathy, neuropathy, and cardiovascular diseases are possible [5, 6]. Clinical studies have revealed two main types of DM. Type 1 DM (T1DM) is induced following the progressive destruction of pancreatic insulin-producing beta cells via the activity of auto-reactive T lymphocytes [7]. In contrast to T1DM, type 2 DM (T2DM) is diagnosed with abnormal insulin activity and insulin resistance (IR) in the target cells, leading to hyperglycemic conditions. About 90% of DM is associated with T2DM and a potential risk (2- to threefold) of cardiovascular diseases [8]. It has been shown that DM increases heart tissue problems by two and five times in males and females, respectively compared to non-diabetic counterparts [9]. Prolonged hyperglycemia leads to the promotion of oxidative stress which per se triggers free radical formation and lipid peroxidation. These features cause a prominent inflammatory response, apoptotic changes, and pathological conditions in cardiac tissue [2, 10, 11]. Considering the high metabolic activity in cardiomyocytes, it is logical to think that these cells are prone to injury following the production of free radicals and oxidative stress. In line with this claim, several studies have confirmed the accumulation of reactive oxygen species (ROS) in cardiac tissue under diabetic conditions [12].

Melatonin (Mel) is a lipophilic hormone produced mainly in the brain parenchyma from tryptophan [13, 14]. Regarding the existence of physical and chemical activities, Mel with specific properties can be used in the management of DM [15, 16]. The modulation of inflammation and inhibition of apoptosis is the underlying mechanisms by which Mel protects cardiomyocytes against diabetic conditions [17]. Direct diffusion and internalization via cell-membrane bound receptors help Mel to actively neutralize cellular free radicals [18, 19].

Under resting conditions, normal cardiomyocytes possess high oxidative metabolism with relatively lower antioxidant capacity. Following physical activities, intracellular levels of ROS are increased and it is thought that exercise is an important stimulus for the regulation of various antioxidants [6]. It has been indicated that regular exercise can internalize glucose and glycogen into the cytosol, and maintains the glucose at the normal range by regulating the function of insulin [20]. These features contribute to the reduction of inflammatory response in pancreatic insulin-producing cells. Data confirmed that beta cell insulin sensitivity is improved with regular exercise [21]. In the current systematic review article, we investigated the effects of exercise training and Mel on cardiac tissue function in the diabetic rodent model.

Materials and methods

Search strategy

A systematic search was conducted in Embase, ProQuest, Cochrane library, Clinicaltrial.gov, WHO, Google Scholar, PubMed, Ovid, Scopus, Web of Science, Ongoing Trials Registers, and Conference Proceedings in July 2022 with no limit of date or language. The list of included review articles, experiments, and contacted authors of included trials was screened for subsequent analyses. We also monitored the abstracts from the international congresses. Unpublished or incomplete experiments were scoped via researchers known to participate in similar studies.

Inclusion and exclusion criteria

All experiments related to the application of exercise and Mel on diabetic heart tissue either mice or rats were included in this study. We excluded all studies that reported the effects of exercise or Mel on rodent non-cardiac tissues or human subjects or studies without access to the full text. The inclusion and exclusion criteria are summarized in Table 1. The title and abstract screening process was done independently by two researchers. Each author separately evaluated the full text of the selected articles. Any disagreement in different parts of the study was resolved by discussion between the reviewers until a consensus was reached.

Table 1 Inclusion and exclusion criteria used in this study for round-I selection
Full size table

Data extraction

Two authors independently recorded the information using a data extraction form as follows: author, year of publication and type, animal characteristics (including strain, species, and sex) and age and weight, and diabetic disease model with details of induction protocols and Mel, characteristics of exercise training (including type, path, time, dose, and frequency of exercise), study groups, duration of intervention, study results and mechanisms (see the following sections). We collected data for the nature of the reported outcome, animal number per group, and mean ± SD or mean ± SEM. In a single publication where different experiments were shown, data were treated as independent experiments. The disagreement was resolved by consulting a third party. For data presented graphically, we monitored the values of the graphs using Universal Desktop Ruler (version 2.9) or contacted the authors of the article for details.

Methodological quality

For this purpose, two reviewers assessed the methodological quality of the selected trials. The risk of bias was assessed through a 6-criterion appraisal checklist containing sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other biases. The internal validity of the enrolled studies (e.g., selection, performance, detection, and attrition bias) and other study quality measures (e.g., reporting quality, power) was assessed using a modified version of the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES) quality checklist [22].

Statistical analysis

Outcomes of interest in the current analysis were improvement of oxidative status, inflammatory and apoptotic responses, glucose levels, and positive effects on lipid profiles and myocardial damage in diabetic rodents. Meta-analysis of the data was done by using the Mantel Haenszel method with Comprehensive Meta-Analysis software (ver. 2.2; Biostat, Englewood, NJ, USA). All variables were continuous data. Mean ± SD was used to calculate the standardized mean difference and 95% confidence interval (CI). Statistical heterogeneity was analyzed using the I2 value and the result of the chi-square test. p < 0.05 and I2 > 50% were considered suggestive of statistical heterogeneity. A fixed-effect model was used when there was no statistically significant difference in the heterogeneity (P < 0.05); otherwise, a random-effect model was applied. To examine any potential publication bias in the studies, the results of the comprehensive meta-analysis are shown as Funnel plots.

Results

Description of studies

We found 962 relevant publications during the search of electronic databases. Among them, 596 were excluded after an intensive and preliminary screening of the titles and abstracts, duplicate publications, or human subjects. The full text of 109 articles was evaluated and finally, 58 studies met our inclusion criteria related to the effects of Mel and exercise on diabetic cardiac tissue (Table 2). Among the included studies, 40 articles were conducted on T1DM, and 18 on T2DM. Mice and rats have been used in most of the publications. Heart tissue has been studied as one of the most important body tissues in diabetes. The common pathways for these changes included oxidative stress, antioxidant enzyme activity, angiogenesis, autophagy, apoptosis, and inflammatory indicators, of which 36 studies met all inclusion criteria. A flow chart for data selection is represented in Fig. 1.

Table 2 Characteristics of included studies in systematic review and meta-analysis
Full size table
Fig. 1
figure 1

Preferred reporting items for systematic reviews and meta-analyses (PRISMA) diagram of included studies in qualitative and quantitative stages

Full size image

Risk of bias in the included studies

In the current study, a modified CAMARADES quality checklist was used to assess the internal and external validity of the selected studies. The checklist contains details notably randomized allocation (model/sham groups), blinded induction of the model and assessment of outcomes, calculation of the sample size, compliance with the existing animal welfare act, the disclosure of all relevant conflicts of interest, reporting of animal exclusions, and publication in peer-reviewed journals. All articles had been issued in peer-reviewed journals.

Results

Mel-treated diabetic rodents

Oxidative status

According to our analysis, administration of Mel on diabetic rodents can significantly improve antioxidant capacity [superoxide dismutase (SOD), glutathione, and glutathione peroxidase (GPx)] compared to the matched control groups. Based on the data, 4 experiments (n = 198; 41 Mel + DM and 41 DM) were associated with the impact of Mel on SOD under diabetic conditions. These studies indicated that Mel can significantly induce the activity of SOD in diabetic rats (Standardized mean difference (SMD): 3.229 CI 95%, 0.164 to 6.294; p = 0.039; I2 = 95.29%) (Fig. 2A) [4, 17, 23, 24]. Two experiments (n = 78; 18 Mel-treated DM and 18 DM) studied the effect of Mel on glutathione under diabetic conditions. Heterogeneity analysis indicated p < 0.001 and Higgins’ I2 reached 97.44%. Results showed that in the random model, SMD for GSH was 7.922 (CI 95%, − 13.125 to 28.969; p = 0.461) (Fig. 2B) [23, 25]. Along with these studies, 3 experiments (n = 106; 21 Mel + DM and 21 DM) investigated the therapeutic effects of Mel on GPx activity under diabetic conditions. Heterogeneity analysis and Higgins’ I2 were p < 0.001 and 93.12%, respectively. The analysis results showed SMD of GPx was 4.834 (CI 95%, mean difference: 0.105 to 9.563; p = 0.045; Fig. 2C) [9, 17, 24]. Other 4 experiments (n = 226; 59 Mel + DM and 59 DM) released data associated with the impact of Mel on malondialdehyde (MDA) under diabetic conditions. Heterogeneity analysis for these experiments yielded a p-value of < 0.001 and Higgins’ I2 reached 97.51%. Therefore, the random model was applied and the results showed that SMD of MDA reached − 0.487 (CI 95%, mean difference: − 3.810 to 2.836; p < 0.774) (Fig. 2D and Table 3) [4, 17, 23, 26].

Fig. 2
figure 2

Improvement of oxidative status in diabetic rodents with Mel administration. CI: confidence interval. A Superoxide dismutase, B glutathione, C glutathione peroxidase, D malondialdehyde

Full size image
Table 3 Forest plot results of the effect of Mel on diabetic heart tissue
Full size table

Inflammatory status

According to our data, 3 experiments (n = 110; 25 Mel + DM and 25 DM) investigated the effect of Mel on interleukin-6 (IL-6) levels in diabetic rats. Heterogeneity analysis revealed a significant difference (p = 0.001) between control and diabetic rats with Higgins’ I2 values of 96.73%. The results showed that in the random-effect model, the SMD of IL-6 was -5.466 (CI 95%, mean difference: − 14.022 to 3.091; p = 0.211) (Fig. 3A) [1, 9, 27]. Besides, 2 experiments (n = 35; 10 Mel + DM diabetic and 10 DM) monitored the changes in the levels of IL-1β in diabetic rats after administration of Mel. Based on data, heterogeneity, and Higgins’ I2 were p < 0.001 and 94.26%, respectively. The SMD of IL-1β was − 55.600 (CI 95%, mean difference: -156.323 to 45.122; p = 0.279) (Fig. 3B) [1, 9]. There are 3 experiments (n = 110; 25 Mel + DM and 25 DM) related to the effect of Mel on TNF-α in diabetic rats. Heterogeneity analysis revealed a p-value of < 0.001 and Higgins’ I2 score was 93.65%. Using the random-effect model, the SMD of TNF-α was − 11.575 (CI 95%, mean difference: − 21.922 to − 1.228; p = 0.028; Fig. 3C and Table 3) [1, 9, 27].

Fig. 3
figure 3

Modulation of inflammatory status in diabetic rodents received Mel. CI: confidence interval. A IL-6, B IL-1β, C TNF-α

Full size image

Apoptotic indices

Six experiments (n = 288; 70 Mel + DM and 70 DM) were associated with the effect of Mel on Caspase-3 activity under diabetic conditions. Heterogeneity analysis indicated p < 0.001 and Higgins’ I2 was 97.36%. When using the random-effect model, the SMD of Caspase-3 was − 3.730 (CI 95%, − 7.845 to 0.386; p = 0.076; Fig. 4A) [4, 9, 16, 17, 26, 28]. We also found that four experiments (n = 198; 52 Mel-treated DM and 52 DM) released data on the status of Bcl-2 in diabetic conditions after administration of Mel. Heterogeneity analysis showed a p-value of < 0.001 and Higgins’ I2 was 97.24%. SMD of Bcl-2 was 3.648 (CI 95%, − 0.707 to 8.003; p = 0.101) in the random model (Fig. 4B) [4, 9, 16, 26]. Three experiments (n = 166; 44 Mel-treated diabetics and 44 diabetics) were found related to the analysis of Bax levels under diabetic conditions and Mel administration. Heterogeneity analysis indicated that the p-value and Higgins’ I2 were < 0.001 and 98.39%, respectively. The SMD of Bax was -2.206 (CI 95%, − 9.195 to 4.783; p = 0.536; Fig. 4C) [4, 9, 26] in the analysis according to the random-effect model. Four experiments (n = 162; 51 Mel-treated diabetics and 51 diabetics) were conducted to evaluate the apoptosis index under diabetic conditions with Mel administration. According to heterogeneity analysis, the p-value and Higgins’ I2 were < 0.001 and 86.10%, respectively. The apoptosis index was reduced after intervention according to the random model analysis (SMD: − 8.614 (CI 95%, − 11.948 to − 5.280; p < 0.001; Fig. 4D) [4, 16, 28, 29]. Two experiments (n = 52; 13 Mel-treated diabetics and 13 diabetics) investigated the levels of p53 in diabetics subjected to Mel administration. Heterogeneity analysis indicated p = 0.210 and Higgins’ I2 value of 36.36%. Based on the low heterogeneity analysis, the SMD of p53 was − 10.326 (CI 95%, − 13.280 to − 7.371; p < 0.001) in the fixed-effect model, and this value reached -10.397 (CI 95%, − 14.113 to − 6.681; p < 0.001) in the random model (Fig. 4E and Table 3) [9, 16].

Fig. 4
figure 4

Status of Caspase-3 in diabetic rodents received Mel. CI: confidence interval. A Caspase-3, B Bcl-2. C Bax, D Apoptosis Index, E P53

Full size image

Lipid and Glucose profiles

Six experiments (n = 218; 53 Mel + DM and 53 DM) were associated with the effect of Mel on lipid and glucose profiles under diabetic conditions. Heterogeneity analysis revealed that the p-value and Higgins’ I2 were 0.001 and 94.38%, respectively. The results showed that the SMD of glucose level was − 4.454 (CI 95%, − 7.051 to − 1.858; p < 0.001; Fig. 5A) [10, 16, 25, 30, 31]. Four experiments (n = 156; 35 Mel + DM and 35 DM) were done concerning total cholesterol (TC) analysis in DM with the administration of Mel. Heterogeneity analysis indicated P = 0.001 and Higgins’ I2 was 86.53%. TC was reduced after treatment (SMD: − 5.449; CI 95%, − 8.195 to − 2.703; p < 0.001; Fig. 5B) [9, 27, 32]. Four experiments (n = 156; 35 Mel + DM and 35 DM) released data on triglyceride in DM and Mel. Heterogeneity analysis indicated p < 0.001 and Higgins’ I2 was 94.74%. Similar to TC, the amount of TG was decreased (SMD:-6.605; CI 95%, − 11.057 to − 2.153; p = 0.004; Fig. 5C) [9, 27, 32]. Four experiments (n = 156; 35 Mel + DM and 35 DM) released data on HDL in diabetic rodents that received Mel. Heterogeneity analysis indicated p = 0.001 and Higgins’ I2 was 96.11%. The HDL value was increased in treated rats with Mel using the random model analysis (SMD: 5.975; CI 95%, 0.708 to 11.242; p = 0.026; Fig. 5D) [9, 27, 32]. Four experiments (n = 156; 35 Mel + DM and 35 DM) released data on VLDL in DM and Mel. Heterogeneity analysis indicated p < 0.001 and Higgins’ I2 was 94.77%. Data showed that the amount of VLDL was decreased in the random model (SMD: 5.975; CI 95%, − 13.620 to − 2.298; p = 0.006; Fig. 5E and Table 3) [9, 27, 32].

Fig. 5
figure 5

Glucose levels in in diabetic rodents received Mel. CI: confidence interval. A Level Glucose, B total cholesterol, C triglyceride, D HDL, E vLDL

Full size image

Exercise-treated diabetic

Oxidative status

Five experiments (n = 162; 45 Exc + DM and 45 DM) released data on SOD under diabetic conditions exposed to Exc. Heterogeneity analysis indicated p = 0.001 with Higgins’ I2 value of 86.42%. SMD of SOD was 3.327 (CI 95%, 1.616 to 5.038; p < 0.001; Fig. 6A) [17, 20, 33,34,35] using a random effect model. Five experiments (n = 156; 43 Exc + DM and 43 DM) released data on GPx in DM and Exc. Heterogeneity analysis indicated p < 0.001 and Higgins’ I2 was 96.10%. SMD of GPx in the random model was 4.505 (CI 95%, 0.303 to 8.707; p = 0.036; Fig. 6B) [17, 33, 34, 36, 37]. Eight experiments (n = 204; 64 Exc + DM and 64 DM) released data on MDA in DM and Exc. Heterogeneity analysis indicated p = 0.001 and Higgins’ I2 was 96.04%. The SMD of MDA was − 4.766 (CI 95%, − 8.686 to − 0.846; p = 0.017; Fig. 6C and Table 4) [17, 33, 34, 36,37,38,39,40] in the random effect model.

Fig. 6
figure 6

Oxidative stress status in diabetic rodents with regular exercise. CI: confidence interval. A Superoxide dismutase (SOD), B glutathione peroxidase (GPx), C malondialdehyde (MDA)

Full size image
Table 4 Forest plot results of the effect of exercise on diabetic heart tissue
Full size table

Inflammatory status

Two experiments (n = 72; 17 Exc + DM and 14 DM) released data on IL-6 in DM and Exc. Heterogeneity analysis indicated p < 0.001 and Higgins’ I2 was 97.29%. Analysis results showed that in the random model, the SMD was − 1.260 (CI 95%, − 8.630 to 6.110; p = 0.738; Fig. 7A) [41, 42]. Two experiments (n = 56; 16 Exc + DM and 16 DM) released data on IL-1β in DM and Exc. Heterogeneity analysis indicated p < 0.001 and Higgins’ I2 was 94.92%. The analysis results showed a decrease in IL-1β in the random model (SMD: − 5.201 (CI 95%, − 13.122 to 2.721; p = 0.198; Fig. 7B) [41, 43]. Two experiments (n = 39; 14 Exc + DM and 14 DM) released data on TNF-α in DM and Exc. Heterogeneity analysis indicated p = 0.994 and Higgins’ I2 was 00.00%. Analysis results showed that in the fixed-effect model, SMD of TNF-α was − 11.862 (CI 95%, − 15.056 to − 8.668; p < 0.001), and in the random model this value reached − 11.862 (CI 95%, − 15.056 to − 8.668; p < 0.001; Fig. 7C and Table 4) [41, 44].

Fig. 7
figure 7

Inflammatory response status in diabetic rodents with regular exercise. CI: confidence interval. A IL-6, B IL-1β, C TNF-α

Full size image

Apoptotic indices

Five experiments (n = 140; 47 Exc + DM and 47 DM) released data on Caspase-3 in DM and Exc. Heterogeneity analysis indicated p < 0.001 and Higgins’ I2 was 96.03%. In the random model, Caspase-3 was decreased (SMD: − 11.459; CI 95%, − 16.582 to − 6.336; p < 0.001; Fig. 8A) [45,46,47,48,49]. Five experiments (n = 110; 42 Exc + DM and 42 DM) released data on Bcl-2 in DM and Exc. Heterogeneity analysis indicated p < 0.001 and Higgins’ I2 was 94.83%. The SMD of Bcl-2 was 2.920 (CI 95%, − 0.935 to 6.776; p = 0.138; Fig. 8B) [45, 48, 50,51,52] in random effect analysis. Five experiments (n = 110; 42 Exc + DM and 42 DM) released data on Bax in DM and Exc. Heterogeneity analysis indicated p < 0.001 and Higgins’ I2 was 96.59%. The value of Bax was decreased in the intervention group compared to the non-treated control (SMD: -1.627; CI 95%, 6.924 to 3.531; p = 0.536; Fig. 8C) [45, 48, 50,51,52]. Three experiments (n = 68; 21 Exc + DM and 21 DM) released data on the apoptosis index in DM and Exc. Heterogeneity analysis indicated p < 0.001 and Higgins’ I2 was 90.76%. SMD of apoptosis index was reduced in the experiment group in the random model (SMD: − 6.530; CI 95%, − 11.641 to − 1.419; p = 0.012; Fig. 8D) [35, 45, 49]. Four experiments (n = 100; 32 Exc + DM and 32 DM) released data on p53 in DM and Exc. Heterogeneity analysis indicated p < 0.001 and Higgins’ I2 was 96.81%. Analysis results showed that the SMD of p53 in the random model was -6.347 (CI 95%, -13.743 to -1.048; p = 0.093; Fig. 8E and Table 4) [47, 48, 50, 53].

Fig. 8
figure 8

Apoptotic indices in diabetic rodents with regular exercise. CI: confidence interval. A Caspase-3, B Bcl-2, C Bax, D Apoptosis Index, E P53

Full size image

Lipid and Glucose profiles

Twelve experiments (n = 362; 113 Exc + DM and 114 DM) released data on the level of glucose in DM and Exc. Heterogeneity analysis indicated p < 0.001 and Higgins’ I2 was 86.18%. Analysis results showed that SMD of glucose levels in the random model was -2.779 (CI 95%, -3.770 to -1.789; p < 0.001; Fig. 9A) [37,38,39, 41, 43, 52, 54,55,56,57,58,59]. Two experiments (n = 84; 23 Exc + DM and 23 DM) released data on TC in DM and Exc. Heterogeneity analysis indicated p = 0.848 and Higgins’ I2 was 00.00%. Results showed that in the fixed-effect model, the SMD of TC was − 7.566 (CI 95%, − 9.217 to − 5.915; p < 0.001), and in the random model this value reached − 7.566 (CI 95%, − 9.217 to − 5.915; p < 0.001; Fig. 9B) [57, 60]. Two experiments (n = 84; 23 Exc + DM and 23 DM) released data on triglyceride levels in DM and Exc. Heterogeneity analysis indicated p = 0.054 and Higgins’ I2 was 73.06%. Analysis results showed that in the fixed-effect model, the SMD of triglycerides was − 3.410 (CI 95%, − 4.334 to − 4.466; p < 0.001) and in the random model this value reached − 3.409 (CI 95%, − 5.190 to − 1.628; p < 0.001; Fig. 9C) [57, 60]. Two experiments (n = 84; 23 Exc + DM and 23 DM) released data on HDL in DM and Exc. Heterogeneity analysis indicated p < 0.001 and Higgins’ I2 was 96.13%. Results showed that HDL was increased in the random model (SMD: 9.299; CI 95%, − 1.350 to 19.927; p < 0.087; Fig. 9D) [57, 60]. Two experiments (n = 84; 23 Exc + DM and 23 DM) released data on VLDL in DM and Exc. Heterogeneity analysis indicated p = 0.045 and Higgins’ I2 was 75.05%. Analysis results showed that in the fixed-effect model, SMD of VLDL was − 6.835 (CI 95%, − 8.381 to − 5.290; p < 0.001), and in the random model, this value reached − 6.929 (CI 95%, − 10.033 to − 3.825; p < 0.001; Fig. 9E and Table 4) [57, 60].

Fig. 9
figure 9

Improvement of lipid and glucose profiles in diabetic rodents with regular exercise. CI: confidence interval. A Level glucose, B total cholesterol, C triglyceride, D HDL, E vLDL

Full size image

VEGF

Five experiments (n = 162; 48 Exc + DM and 48 DM) released data on VEGF in DM and Exc. Heterogeneity analysis indicated p = 0.210 and Higgins’ I2 was 36.36%. Subgroup analysis results showed that in the fixed-effect model, SMD of VEGF was 2.524 (CI 95%, 1.934 to 3.114; p < 0.001), and in the random model this value was 3.694 (CI 95%, 1.834 to 5.554; p < 0.001; Fig. 10 and Table 4) [41, 61,62,63,64].

Fig. 10
figure 10

Changes in VEGF levels in diabetic rodents with regular exercise. CI: confidence interval

Full size image

Discussion

Biological similarity to humans is one of the most important characteristics of laboratory animals such as mice and rats. Therefore, these animals are preferred in most experimental studies related to DM. The prevalence of metabolic diseases, mainly DM, has become one of the main concerns related to cardiovascular complications in recent decades. Here, the combined effect of Mel and Exc was investigated on oxidative status, inflammation, apoptosis, and lipid and glucose profile of heart tissue in diabetic rodents [65, 66]. We found that Mel along with Exc increases the level of cardiac SOD, GSH, and GPx enzymes in a mouse model of DM, showing an increase in antioxidant defenses under diabetic conditions. Studies have shown that Exc can lead to an increase in antioxidant enzyme activity in diabetic rats. In addition, Mel can increase the activity of these antioxidant enzymes in STZ-induced diabetic rats. Reduction of free radicals and regulation of antioxidant balance is one of the features of Exc which can eliminate free radicals such as ROS. One of the effective functions of Mel in diabetic conditions is the stabilization of microsomal membranes against oxidative stress [67]. It should be noted that with the activity of Mel, ROS and active nitrogen species (RNS) can be oxidized to N1-acetyl-N2-formyl-5-methoxykynuramine [68]. Mel activates nuclear Nrf2 (NF-E2-related factor 2), which in turn initiates antioxidant mechanisms [68]. In addition, the antioxidant enzyme's key role in redox homeostasis is coherent as the γ-glutamyl tripeptides may serve as a substrate for the GPx/Glutathione reductase (GR)/NADPH system which is directly linked with energy metabolism through the pentose phosphate pathway [69]. As a free radical-producing system, lipid peroxidation is directly related to tissue damage caused by diabetic conditions. Of note, MDA is a suitable factor for the evaluation of lipid peroxidation rate. Studies have reported increased levels of MDA with the progression of diabetic changes. Glutathione provides major protection against oxidative damage by participating in the cellular defense system against oxidative damage. It has been reported that tissue damage caused by various stimuli is associated with glutathione depletion [25, 70].

We also showed that DM increases the expression of inflammatory cytokines such as IL-6, IL-1β, and TNF-α. The use of Mel and Exc reduces these factors and closes them to almost normal levels, indicating the reduction of inflammation changes inside the heart tissue. Studies have shown that TNF-α participates in insulin resistance and ROS production through the regulation of glucolipotoxicity pathways [71, 72]. By neutralizing ROS and RNS, Mel can prevent tissue damage, block transcription factors of pro-inflammatory cytokines, and reduce free radical damage to biomolecules [9]. Myocardial inflammation is also involved in the pathophysiology of diabetic cardiomyopathy [9, 73]. It was suggested that inflammation is the main pathogenic feature and is associated with hyperlipidemia and hyperglycemia [9]. Within the cardiac tissue, inflammatory signaling is usually initiated in response to myocardial injury, because of the overproduction of mitochondrial ROS [9]. Nuclear factor-κB (NF-κB) is a key regulator of inflammatory responses, regulating the expression of pro-inflammatory cytokines in the heart [74]. Pro-inflammatory cytokines are directly responsible for the complications of diabetes and heart disease [74]. Studies have shown that treatment of diabetic mice with Mel led to a significant decrease in the levels of TNF-a, IL-1β, and IL-6 [74,75,76,77]. Under diabetic conditions, endothelial function is impaired due to the elevation of TNF-α or IL-6, suggesting that these cytokines can also promote endothelial dysfunction in coronary arteries [78]. Exc can significantly reduce TNF-α and IL-6 levels in diabetic rats [78]. Since Exc significantly affects cellular homeostasis, the levels of cytokines decrease after adaptation to regular exercise [44].

A significant increase of pro-apoptotic proteins such as Bax, Caspase-3, and p53 with a decrease of anti-apoptotic protein Bcl-2 has been observed in the heart tissue of diabetic rats [79]. Data indicated that treatment of diabetic mice with Mel can restore the balance between apoptosis regulatory proteins [79]. Hyperglycemia leads to excessive production and accumulation of ROS in mitochondria, which triggers intrinsic apoptotic signals [80]. It seems that these conditions promote mitochondrial dysfunction in endothelial cells in an AMPK-dependent manner [81]. Accumulation of systemic glucose and byproducts as well as ROS contribute to mitochondrial apoptotic death through the cytochrome C leakage into the cytosol and activation of Caspase-3 [82]. Mel has the potential to reduce mitochondrial dysfunction by the regulation of the AMPK signaling cascade [63]. The reduction of cardiomyocyte damage is associated with the reduction of mitochondrial oxidant stress and apoptosis [63]. The reduction of Caspase-3 by Mel and Exc blunts the deleterious effects of hyperglycemic conditions on cardiac tissue [17].

Exc increases the activity of antioxidant enzymes and cell resistance to oxidative stress [83]. As a correlate, Exc can neutralize oxidative damage, improve insulin sensitivity, and increase glucose metabolism [84]. Also, Exc before ischemia leads to the reduction of pro-apoptotic/anti-apoptotic proteins and inactivation of the Caspase pathway, especially Caspase-3 [85]. One of the important effects of Exc is related to the expression of protein kinase B. These mechanisms can protect the host cells against apoptosis by the phosphorylation of the Bcl-2 family and regulation of pro-apoptotic proteins such as Bax [86, 87].

Mel treatment significantly can reduce hyperglycemia and block hemoglobin glycosylation in diabetic rats [88,89,90]. Due to insulinogenic and antioxidant activities, Mel can stimulate insulin secretion, regenerate β-cells, or even protects remaining β-cells [91]. One of the therapeutic effects of Mel in diabetic conditions is associated with the reduction of oxidative stress induced by homocysteine [92]. It has been indicated that the elevation of homocysteine accelerates insulin-receptor cleavage and diminishes insulin-resistant conditions [72].

There is a positive correlation between diabetic hyperlipidemia and the occurrence of cardiovascular diseases [93]. Mel has been shown to exert anti-dyslipidemic effects under diabetic conditions [93, 94]. A significant increase in serum triglyceride, TC, LDL-C, and VLDL-C levels along with a decrease in HDL-C levels occurs in DM [95,96,97]. The underlying mechanism of the Mel cholesterol-lowering effect may be through decreasing cholesterol absorption from the gut or increasing endogenous cholesterol clearance [98]. Mel effectively prevents hyperlipidemia by increasing insulin secretion and lipid storage in fat cells [9]. The accumulation of excess fat in fat cells causes insulin resistance. Under such conditions, the secretion of insulin and adipose cytokines leads to the death of pancreatic beta cells because of free fatty acids [99]. It was suggested that exercise training reduces fat accumulation. Besides, Exc changes the amount of some adipokines and reduces the accumulation of fatty acids, and increases insulin sensitivity [99].

Conclusions

The occurrence of diabetic conditions is associated with cardiovascular pathologies, especially in cardiomyocytes with the promotion of apoptotic changes, inflammatory responses, oxidative status, etc. These features can affect the normal physiology of the heart, leading to micro- and macro-vascular injuries. Here, systematic review and meta-analysis indicated that co-administration of Mel and Exc can blunt the detrimental effect of DM via the regulation of anti-oxidant capacity, lipid metabolism, inflammatory response, and apoptotic changes, leading to the reduction of cardiomyopathy in diabetic patients.

Availability of data and materials

All data generated or analyzed during this study and supporting our findings are included and can be found in the manuscript. The raw data can be provided by the corresponding author upon reasonable request.

Abbreviations

AMPK:

AMP-activated protein kinase

CI:

Confidence interval

COX-2:

Cyclooxygenase-2

DM:

Diabetes mellitus

Exc:

Exercise

GPx:

Glutathione peroxidase

LDL:

Low-density lipoprotein

Mel:

Melatonin

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

SMD:

Standardized mean difference

SOD:

Superoxide dismutase

T2DM:

T1DM, type 2 DM

T1DM:

Type 1 DM

VLDL:

Very-low-density lipoprotein

References

  1. Ivankiv YI, Oleshchuk OM. Immunomodulatory effect of melatonin supplementation in experimental diabetes. Pharmacia. 2020;67:223.

    Article  CAS  Google Scholar 

  2. Xue F, et al. Cardiomyocyte-specific knockout of ADAM17 ameliorates left ventricular remodeling and function in diabetic cardiomyopathy of mice. Signal Transduct Target Ther. 2022;7(1):259.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. American Diabetes Association. Standards of medical care in diabetes—2013. Diabetes Care. 2013;36(Supplement_1):S11–66.

    Article  Google Scholar 

  4. Ren B-C, et al. Melatonin attenuates aortic oxidative stress injury and apoptosis in STZ-diabetes rats by Notch1/Hes1 pathway. J Steroid Biochem Mol Biol. 2021;212: 105948.

    Article  CAS  PubMed  Google Scholar 

  5. Azimi-Nezhad M, et al. Prevalence of type 2 diabetes mellitus in Iran and its relationship with gender, urbanisation, education, marital status and occupation. Singapore Med J. 2008;49(7):571.

    CAS  PubMed  Google Scholar 

  6. Ghalavand, A., et al., Effects of aerobic training on cardiorespiratory factors in men with type 2 diabetes. 2014.

  7. Burrack AL, Martinov T, Fife BT. T cell-mediated beta cell destruction: autoimmunity and alloimmunity in the context of type 1 diabetes. Front Endocrinol. 2017;8:343.

    Article  Google Scholar 

  8. Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 2011;11(2):98–107.

    Article  CAS  PubMed  Google Scholar 

  9. Abdulwahab DA, et al. Melatonin protects the heart and pancreas by improving glucose homeostasis, oxidative stress, inflammation and apoptosis in T2DM-induced rats. Heliyon. 2021;7(3): e06474.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kushnir OY, Yaremii I. Effect of melatonin on the carbohydrate metabolism in the heart of rats with alloxan diabetes. Pharmacologyonline. 2019;3:211–9.

    Google Scholar 

  11. Hao P, et al. Serum metal ion-induced cross-linking of photoelectrochemical peptides and circulating proteins for evaluating cardiac ischemia/reperfusion. ACS sensors. 2022;7(3):775–83.

    Article  CAS  PubMed  Google Scholar 

  12. Ansley DM, Wang B. Oxidative stress and myocardial injury in the diabetic heart. J Pathol. 2013;229(2):232–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Rodriguez C, et al. Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res. 2004;36(1):1–9.

    Article  CAS  PubMed  Google Scholar 

  14. Peschke E. Melatonin, endocrine pancreas and diabetes. J Pineal Res. 2008;44(1):26–40.

    CAS  PubMed  Google Scholar 

  15. Stebelová K, Herichová I, Zeman M. Diabetes induces changes in melatonin concentrations in peripheral tissues of rat. Neuroendocrinol Lett. 2007;28(2):159–65.

    PubMed  Google Scholar 

  16. Amin AH, El-Missiry MA, Othman AI. Melatonin ameliorates metabolic risk factors, modulates apoptotic proteins, and protects the rat heart against diabetes-induced apoptosis. Eur J Pharmacol. 2015;747:166–73.

    Article  CAS  PubMed  Google Scholar 

  17. Rahbarghazi A, et al. Melatonin and prolonged physical activity attenuated the detrimental effects of diabetic condition on murine cardiac tissue. Tissue Cell. 2021;69: 101486.

    Article  CAS  PubMed  Google Scholar 

  18. López-Burillo S, et al. Melatonin, xanthurenic acid, resveratrol, EGCG, vitamin C and α-lipoic acid differentially reduce oxidative DNA damage induced by Fenton reagents: a study of their individual and synergistic actions. J Pineal Res. 2003;34(4):269–77.

    Article  PubMed  Google Scholar 

  19. Martínez-Alfaro M, et al. Effect of melatonin administration on DNA damage and repair responses in lymphocytes of rats subchronically exposed to lead. Mutation Research/Genetic Toxicology and Environmental Mutagenesis. 2012;742(1–2):37–42.

    Article  Google Scholar 

  20. Farhangi N, Nazem F, Zehsaz F. Effect of endurance exercise on antioxidant enzyme activities and lipid peroxidation in the heart of the streptozotocin-induced diabetic rats. SSU J. 2017;24(10):798–809.

    Google Scholar 

  21. Earnest CP. Exercise interval training: an improved stimulus for improving the physiology of pre-diabetes. Med Hypotheses. 2008;71(5):752–61.

    Article  CAS  PubMed  Google Scholar 

  22. Sadigh-Eteghad S, et al. D-galactose-induced brain ageing model: a systematic review and meta-analysis on cognitive outcomes and oxidative stress indices. PLoS ONE. 2017;12(8): e0184122.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Aksoy N, et al. Effects of melatonin on oxidative–antioxidative status of tissues in streptozotocin-induced diabetic rats. Cell Biochem Funct. 2003;21(2):121–5.

    Article  CAS  PubMed  Google Scholar 

  24. Zhou H, et al. Melatonin therapy for diabetic cardiomyopathy: a mechanism involving Syk-mitochondrial complex I-SERCA pathway. Cell Signal. 2018;47:88–100.

    Article  CAS  PubMed  Google Scholar 

  25. Paskaloglu K, Șener G, Ayanğolu-Dülger G. Melatonin treatment protects against diabetes-induced functional and biochemical changes in rat aorta and corpus cavernosum. Eur J Pharmacol. 2004;499(3):345–54.

    Article  CAS  PubMed  Google Scholar 

  26. Yu L, et al. Melatonin rescues cardiac thioredoxin system during ischemia-reperfusion injury in acute hyperglycemic state by restoring N otch1/H es1/A kt signaling in a membrane receptor-dependent manner. J Pineal Res. 2017;62(1): e12375.

    Article  Google Scholar 

  27. Rahman MM, et al. Melatonin supplementation plus exercise behavior ameliorate insulin resistance, hypertension and fatigue in a rat model of type 2 diabetes mellitus. Biomed Pharmacother. 2017;92:606–14.

    Article  CAS  PubMed  Google Scholar 

  28. Ding M, et al. Melatonin prevents D rp1-mediated mitochondrial fission in diabetic hearts through SIRT 1-PGC 1α pathway. J Pineal Res. 2018;65(2): e12491.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Zhang M, et al. Melatonin protects against diabetic cardiomyopathy through Mst1/Sirt3 signaling. J Pineal Res. 2017;63(2): e12418.

    Article  Google Scholar 

  30. Sudnikovich EJ, et al. Melatonin attenuates metabolic disorders due to streptozotocin-induced diabetes in rats. Eur J Pharmacol. 2007;569(3):180–7.

    Article  CAS  PubMed  Google Scholar 

  31. Al-Rashedi A, et al. Oxidative effects in streptozotocin-induced male and female mice: the effect of garlic oil and melatonin. J Pharm Res Int. 2021. https://doi.org/10.9734/jpri/2021/v33i58A34124.

    Article  Google Scholar 

  32. Salmanoglu DS, et al. Melatonin and L-carnitin improves endothelial disfunction and oxidative stress in Type 2 diabetic rats. Redox Biol. 2016;8:199–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Naderi R, et al. Voluntary exercise protects heart from oxidative stress in diabetic rats. Adv Pharm Bull. 2015;5(2):231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Salehi I, Mohammadi M, Asadi Fakhr A. The effect of treadmill exercise on antioxidant status in the hearts of the diabetic rats. Avicenna J Clin Med. 2009;16(2):20–7.

    Google Scholar 

  35. Kanter M, et al. Effects of low intensity exercise against apoptosis and oxidative stress in Streptozotocin-induced diabetic rat heart. Exp Clin Endocrinol Diabetes. 2017;125(09):583–91.

    Article  CAS  PubMed  Google Scholar 

  36. Chodari L, et al. Oxidative stress is markedly reduced by combined voluntary exercise and testosterone in the heart of diabetic rats. Acta Endocrinol. 2019;15(2):173.

    CAS  Google Scholar 

  37. Ali-Aghdam A, et al. Immunomodulator drug (IMODTM) and exercise improve cardiac oxidative stress and antioxidant balance in diabetic rats. Jundishapur J Nat Pharm Prod. 2020. https://doi.org/10.5812/jjnpp.62898.

    Article  Google Scholar 

  38. Hussein AM, et al. Exercise and Stevia rebaudiana (R) extracts attenuate diabetic cardiomyopathy in type 2 diabetic rats: possible underlying mechanisms. Endocr Metab Immune Disord Drug Targets. 2020;20:1117–32.

    Article  CAS  PubMed  Google Scholar 

  39. Riahi S, et al. Chronic aerobic exercise decreases lectin-like low density lipoprotein (lox-1) receptor expression in heart of diabetic rat. Iran Biomed J. 2016;20(1):26.

    PubMed  PubMed Central  Google Scholar 

  40. Rahimi M, et al. The effect of resistance exercise on oxidative stress in cardiac and skeletal muscles of streptozotocin-induced diabetic rats. J Basic Clin Pathophysiol. 2014;2(1).

  41. Broderick TL, et al. Anti-inflammatory and angiogenic effects of exercise training in cardiac muscle of diabetic mice. Diabetes Metab Syndr Obes. 2019;12:565.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Boudia D, et al. Beneficial effects of exercise training in heart failure are lost in male diabetic rats. J Appl Physiol. 2017;123(6):1579–91.

    Article  CAS  PubMed  Google Scholar 

  43. Kar S, et al. Exercise training promotes cardiac hydrogen sulfide biosynthesis and mitigates pyroptosis to prevent high-fat diet-induced diabetic cardiomyopathy. Antioxidants. 2019;8(12):638.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Soleymani AA, et al. The Effect of six weeks of aerobic exercise on inflammation and damage indicators of heart tissue in type 1 diabetic male rats. Iran J Diabetes Metab. 2022;21(6):356–65.

    Google Scholar 

  45. Cheng S-M, et al. Exercise training enhances cardiac IGFI-R/PI3K/Akt and Bcl-2 family associated pro-survival pathways in streptozotocin-induced diabetic rats. Int J Cardiol. 2013;167(2):478–85.

    Article  PubMed  Google Scholar 

  46. Chengji W, Xianjin F. Exercise protects against diabetic cardiomyopathy by the inhibition of the endoplasmic reticulum stress pathway in rats. J Cell Physiol. 2019;234(2):1682–8.

    Article  PubMed  Google Scholar 

  47. Jokar M, SherafatiMoghadam M. Effect of 4 weeks of high-intensity interval training on P53 and caspase-3 proteins content in the heart muscle tissue of rats with type 1 diabetes. SSU Journals. 2022;29(11):4255–67.

    Google Scholar 

  48. Jafari A, Nikookheslat S, Karimi P. The effect of caffeine supplementation combined with high-intensity interval training on the levels of the cardiac tissue apoptosis-related proteins in diabetic rats. Razi J Med Sci. 2021;28(4):1–12.

    Google Scholar 

  49. Sun D, et al. Exercise alleviates cardiac remodelling in diabetic cardiomyopathy via the miR-486a-5p-Mst1 pathway. Iran J Basic Med Sci. 2021;24(2):150.

    PubMed  PubMed Central  Google Scholar 

  50. Alimanesh Z, et al. The effect of continued training with crocin on apoptosis markers in liver tissue of high fat diet induced diabetic rats. Mol Cell Biomech. 2020;17(4):155.

    Article  Google Scholar 

  51. Delfan M, Afrasiabian N. The effect of four-week endurance training with probiotic supplementation on the expression of Bax and Bcl-2 in cardiomyocytes of diabetic rats. Daneshvar Med. 2021;29(3):17–28.

    Google Scholar 

  52. Montazery Taleghani H, et al. The effect of 8 weeks resistance exercise on cardaic apoptosis biomarkers in diabetic rats. Metab Exerc. 2019;9(2):149–61.

    Google Scholar 

  53. Zarrinkalam E, et al. Effect of aerobic exercise training on left ventricular apoptotic and antioxidant indices in high fat diet and streptozotocin-induced type 2 diabetic rat model. Iran J Endocrinol Metab. 2021;23(5):319–28.

    Google Scholar 

  54. Nakos I, et al. Exercise training attenuates the development of cardiac autonomic dysfunction in diabetic rats. In Vivo. 2018;32(6):1433–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Gimenes C, et al. Low intensity physical exercise attenuates cardiac remodeling and myocardial oxidative stress and dysfunction in diabetic rats. J Diabetes Res. 2015;2015:1–10.

    Article  Google Scholar 

  56. Chodari L, et al. The effect of testosterone and voluntary exercise, alone or together, on miRNA-126 expression changes in heart of diabetic rats. Acta Endocrinol. 2017;13(3):266.

    CAS  Google Scholar 

  57. Wang SY, et al. Exercise enhances cardiac function by improving mitochondrial dysfunction and maintaining energy homoeostasis in the development of diabetic cardiomyopathy. J Mol Med. 2020;98(2):245–61.

    Article  CAS  PubMed  Google Scholar 

  58. Mohammadi E, et al. Effect of a six-week endurance exercise and empagliflozin consumption on some structural and functional indices of the heart in male diabetic rats. Iran J Diabetes Metab. 2022;22(1):14–24.

    Google Scholar 

  59. Sheikhzadeh F, et al. The effect of regular moderate exercise, on cardiac hypertrophy and blood glucose level in diabetic adult male rats. Int Res J Appl Basic Sci. 2013;6(4):499–503.

    Google Scholar 

  60. Sharma G, et al. Temporal dynamics of pre and post myocardial infarcted tissue with concomitant preconditioning of aerobic exercise in chronic diabetic rats. Life Sci. 2019;225:79–87.

    Article  CAS  PubMed  Google Scholar 

  61. Bakhtiari F, Matin Homaee H, Ghazalian F. The effects of 4 weeks aerobic training on oxidative and angiogenesis markers of cardiac tissue in type 2 diabetic male wistar rats. Armaghane Danesh. 2019;24(5):892–905.

    Google Scholar 

  62. Vali Zadeh S, et al. The effects of endurance training on gene expression of VEGF and VEGFR2 of cardiac tissue in Type 2 diabetic male wistar. J Arak Univ Med Sci. 2018;21(6):107–18.

    Google Scholar 

  63. Erekat NS, Al-Jarrah MD, Al Khatib AJ. Treadmill exercise training improves vascular endothelial growth factor expression in the cardiac muscle of type I diabetic rats. Cardiol Res. 2014;5(1):23.

    PubMed  PubMed Central  Google Scholar 

  64. Lew JK-S, et al. Exercise regulates microRNAs to preserve coronary and cardiac function in the diabetic heart. Circ Res. 2020;127(11):1384–400.

    Article  CAS  PubMed  Google Scholar 

  65. Bugos O, Bhide M, Zilka N. Beyond the rat models of human neurodegenerative disorders. Cell Mol Neurobiol. 2009;29(6):859–69.

    Article  PubMed  Google Scholar 

  66. Yang B, et al. Motion prediction for beating heart surgery with GRU. Biomed Signal Process Control. 2023;83: 104641.

    Article  Google Scholar 

  67. Alghamdi B. The neuroprotective role of melatonin in neurological disorders. J Neurosci Res. 2018;96(7):1136–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Fu Z, et al. Cardioprotective role of melatonin in acute myocardial infarction. Front Physiol. 2020;11:366.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Ishihara R, et al. Melatonin improves the antioxidant capacity in cardiac tissue of Wistar rats after exhaustive exercise. Free Radical Res. 2021;55(7):677–92.

    Article  Google Scholar 

  70. Cuzzocrea S, et al. Antioxidant therapy: a new pharmacological approach in shock, inflammation, and ischemia/reperfusion injury. Pharmacol Rev. 2001;53(1):135–59.

    CAS  PubMed  Google Scholar 

  71. Akash MSH, Rehman K, Liaqat A. Tumor necrosis factor-alpha: role in development of insulin resistance and pathogenesis of type 2 diabetes mellitus. J Cell Biochem. 2018;119(1):105–10.

    Article  CAS  PubMed  Google Scholar 

  72. Zhang X, et al. Homocysteine inhibits pro-insulin receptor cleavage and causes insulin resistance via protein cysteine-homocysteinylation. Cell Rep. 2021;37(2): 109821.

    Article  CAS  PubMed  Google Scholar 

  73. Zhou L, et al. Usefulness of enzyme-free and enzyme-resistant detection of complement component 5 to evaluate acute myocardial infarction. Sens Actuators, B Chem. 2022;369: 132315.

    Article  CAS  Google Scholar 

  74. Nishida K, Otsu K. Inflammation and metabolic cardiomyopathy. Cardiovasc Res. 2017;113(4):389–98.

    Article  CAS  PubMed  Google Scholar 

  75. Mann DL. Innate immunity and the failing heart: the cytokine hypothesis revisited. Circ Res. 2015;116(7):1254–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Fuentes-Antrás J, et al. Activation of toll-like receptors and inflammasome complexes in the diabetic cardiomyopathy-associated inflammation. Int J Endocrinol. 2014;2014:1–10.

    Article  Google Scholar 

  77. Zhang B, et al. Myricitrin alleviates oxidative stress-induced inflammation and apoptosis and protects mice against diabetic cardiomyopathy. Sci Rep. 2017;7(1):1–16.

    Google Scholar 

  78. Lee S, Park Y, Zhang C. Exercise training prevents coronary endothelial dysfunction in type 2 diabetic mice. Am J Biomed Sci. 2011;3(4):241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Pourhanifeh MH, et al. Melatonin: new insights on its therapeutic properties in diabetic complications. Diabetol Metab Syndr. 2020;12(1):1–20.

    Article  Google Scholar 

  80. Li J, et al. Resveratrol prevents ROS-induced apoptosis in high glucose-treated retinal capillary endothelial cells via the activation of AMPK/Sirt1/PGC-1α pathway. Oxidat Med Cell Longev. 2017;2017:1–10.

    CAS  Google Scholar 

  81. Zhang Y, et al. Melatonin attenuates myocardial ischemia-reperfusion injury via improving mitochondrial fusion/mitophagy and activating the AMPK-OPA1 signaling pathways. J Pineal Res. 2019;66(2): e12542.

    Article  PubMed  Google Scholar 

  82. Glassberg MK, et al. 17β-estradiol replacement reverses age-related lung disease in estrogen-deficient C57BL/6J mice. Endocrinology. 2014;155(2):441–8.

    Article  CAS  PubMed  Google Scholar 

  83. Mazzola PN, et al. Regular exercise prevents oxidative stress in the brain of hyperphenylalaninemic rats. Metab Brain Dis. 2011;26(4):291–7.

    Article  CAS  PubMed  Google Scholar 

  84. Derouich M, Boutayeb A. The effect of physical exercise on the dynamics of glucose and insulin. J Biomech. 2002;35(7):911–7.

    Article  CAS  PubMed  Google Scholar 

  85. Hong J-H, et al. Effects of vitamin E on oxidative stress and membrane fluidity in brain of streptozotocin-induced diabetic rats. Clin Chim Acta. 2004;340(1–2):107–15.

    Article  CAS  PubMed  Google Scholar 

  86. Tanoorsaz S, Behpoor N, Tadibi V. Changes in cardiac levels of caspase-8, Bcl-2 and NT-proB-NP following 4 weeks of aerobic exercise in diabetic rats. Int J Basic Sci Med. 2017;2(4):172–7.

    Article  Google Scholar 

  87. Kim DY, et al. Treadmill exercise ameliorates apoptotic cell death in the retinas of diabetic rats. Mol Med Rep. 2013;7(6):1745–50.

    Article  CAS  PubMed  Google Scholar 

  88. Gurel-Gokmen B, et al. Melatonin improves hyperglycemia induced damages in rat brain. Diabetes Metab Res Rev. 2018;34(8): e3060.

    Article  PubMed  Google Scholar 

  89. Hajam YA, et al. Combined administration of exogenous melatonin and insulin ameliorates streptozotocin induced toxic alteration on hematological parameters in diabetic male Wistar rats. Toxicol Rep. 2020;7:353–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Klepac N, Rudeš Z, Klepac R. Effects of melatonin on plasma oxidative stress in rats with streptozotocin induced diabetes. Biomed Pharmacother. 2006;60(1):32–5.

    Article  CAS  PubMed  Google Scholar 

  91. Mayo JC, et al. Melatonin uptake by cells: an answer to its relationship with glucose? Molecules. 2018;23(8):1999.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Karolczak K, Watala C. Melatonin as a reducer of neuro-and Vasculotoxic oxidative stress induced by homocysteine. Antioxidants. 2021;10(8):1178.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Bhakkiyalakshmi E, et al. Anti-hyperlipidemic and anti-peroxidative role of pterostilbene via Nrf2 signaling in experimental diabetes. Eur J Pharmacol. 2016;777:9–16.

    Article  CAS  PubMed  Google Scholar 

  94. Feingold, K.R. and C. Grunfeld, Diabetes and dyslipidemia. Endotext, 2000: p. 2000–2015.

  95. Anwar MM, Meki A-RM. Oxidative stress in streptozotocin-induced diabetic rats: effects of garlic oil and melatonin. Comp Biochem Physiol A: Mol Integr Physiol. 2003;135(4):539–47.

    Article  PubMed  Google Scholar 

  96. Bibak B, et al. Effects of melatonin on biochemical factors and food and water consumption in diabetic rats. Adv Biomed Res. 2014;3:173.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Hadjzadeh M, et al. The effect of melatonin against gastric oxidative stress and dyslipidemia in streptozotocin-induced diabetic rats. Acta Endocrinol. 2018;14(4):453.

    CAS  Google Scholar 

  98. Tengattini S, et al. Cardiovascular diseases: protective effects of melatonin. J Pineal Res. 2008;44(1):16–25.

    CAS  PubMed  Google Scholar 

  99. Malekshahi Nia H, et al. The effect of 6 weeks of continuous aerobic exercise on insulin resistance, nitric oxide and some lipid profiles of diabetic male rats. Jundishapur Sci Med J. 2018;17(4):401–13.

    Google Scholar 

  100. Song R, et al. Melatonin postconditioning combined with sitagliptin exerts full cardioprotection in diabetic hearts of aged rats through an AMPK-dependent mechanism. Arch Biol Sci. 2021;73(1):83–92.

    Article  Google Scholar 

  101. Wang B, et al. Melatonin attenuates diabetic myocardial microvascular injury through activating the AMPK/SIRT1 signaling pathway. Oxidat Med Cell Longev. 2021;2021:8882130.

    Article  Google Scholar 

  102. Wang S, et al. Melatonin activates Parkin translocation and rescues the impaired mitophagy activity of diabetic cardiomyopathy through Mst1 inhibition. J Cell Mol Med. 2018;22(10):5132–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Kushnir OY, et al. Influence of melatonin on the activity of main enzymes of cori cycle in skeletal muscles, heart, liver and kidneys of alloxan-induced diabetic rats. Arch Balkan Medical Union. 2019;54(2):260–6.

    Article  CAS  Google Scholar 

  104. Yaremii I, et al. Effect of melatonin injections on the glutathione system in heart tissue of rats under experimental diabetes. Georgian Med News. 2020;302:136–40.

    Google Scholar 

  105. Che H, et al. Melatonin alleviates cardiac fibrosis via inhibiting lncRNA MALAT1/miR-141-mediated NLRP3 inflammasome and TGF-β1/Smads signaling in diabetic cardiomyopathy. FASEB J. 2020;34(4):5282–98.

    Article  CAS  PubMed  Google Scholar 

  106. Yu L-M, et al. Melatonin protects diabetic heart against ischemia-reperfusion injury, role of membrane receptor-dependent cGMP-PKG activation. Biochem Biophys Acta. 2018;1864(2):563–78.

    CAS  Google Scholar 

  107. Rahbarghazi R, et al. Putative effect of melatonin on cardiomyocyte senescence in mice with type 1 diabetes mellitus. J Diabetes Metab Disord. 2022;21(1):353–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. FC H, et al., Effects of voluntary exercise on heart function in streptozotocin [STZ]-induced diabetic rat. 2007.

  109. Li S, et al. MOTS-c and exercise restore cardiac function by activating of NRG1-ErbB signaling in diabetic rats. Front Endocrinol. 2022. https://doi.org/10.3389/fendo.2022.812032.

    Article  Google Scholar 

  110. Souza SB, et al. Role of exercise training in cardiovascular autonomic dysfunction and mortality in diabetic ovariectomized rats. Hypertension. 2007;50(4):786–91.

    Article  CAS  PubMed  Google Scholar 

  111. Badavi M, et al. Combination of grape seed extract and exercise training improves left ventricular dysfunction in STZ-induced diabetic rats. Int Cardiovasc Res J. 2017;9(1).

  112. Samadi A, et al. The effect of resistance exercise on oxidative stress in cardiac and skeletal muscle tissues of streptozotocin-induced diabetic rats. J Basic Clin Pathophysiol. 2013;2(1):28–33.

    Google Scholar 

  113. Gül M, Atalay M, Hänninen O. Endurance training and glutathione-dependent antioxidant defense mechanism in heart of the diabetic rats. J Sports Sci Med. 2003;2(2):52.

    PubMed  PubMed Central  Google Scholar 

  114. Mirsepasi M, et al. The effect of 12 weeks aerobic training on expression of AKT1 and mTORc1 genes in the left ventricle of type 2 diabetic rats. Iran J Diabetes Obes. 2018;10(3):137–43.

    Google Scholar 

  115. Epp RA, et al. Exercise training prevents the development of cardiac dysfunction in the low-dose streptozotocin diabetic rats fed a high-fat diet. Can J Physiol Pharmacol. 2013;91(1):80–9.

    Article  CAS  PubMed  Google Scholar 

  116. Arabzadeh E, et al. Alteration of follistatin-like 1, neuron-derived neurotrophic factor, and vascular endothelial growth factor in diabetic cardiac muscle after moderate-intensity aerobic exercise with insulin. Sport sciences for health. 2020;16(3):491–9.

    Article  Google Scholar 

  117. Kleindienst A, et al. Exercise does not activate the β3 adrenergic receptor–eNOS pathway, but reduces inducible NOS expression to protect the heart of obese diabetic mice. Basic Res Cardiol. 2016;111(4):1–12.

    Article  CAS  Google Scholar 

  118. Bennett CE, et al. Exercise training mitigates aberrant cardiac protein O-GlcNAcylation in streptozotocin-induced diabetic mice. Life Sci. 2013;92(11):657–63.

    Article  CAS  PubMed  Google Scholar 

  119. Chaturvedi P, et al. Cardiosome mediated regulation of MMP 9 in diabetic heart: Role of mir29b and mir455 in exercise. J Cell Mol Med. 2015;19(9):2153–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Chodari L, Dariushnejad H, Ghorbanzadeh V. Voluntary wheel running and testosterone replacement increases heart angiogenesis through miR-132 in castrated diabetic rats. Physiol Int. 2019;106(1):48–58.

    Article  CAS  PubMed  Google Scholar 

  121. Li S, et al. Changes in titin and collagen modulate effects of aerobic and resistance exercise on diabetic cardiac function. J Cardiovasc Transl Res. 2019;12(5):404–14.

    Article  PubMed  Google Scholar 

  122. Dastah S, Tofighi A, Bonab SB. The effect of aerobic exercise on the expression of mir-126 and related target genes in the endothelial tissue of the cardiac muscle of diabetic rats. Microvasc Res. 2021;138: 104212.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Authors wish to appreciate the personnel of Applied Cell Sciences for their help and guidance.

Funding

This study was supported by a grant from Tabriz University of Medical Sciences (IR.TBZMED.VCR.REC.1398.035).

Author information

Author notes

  1. Afshin Rahbarghazi, Reza Rahbarghazi and Hanieh Salehi-Pourmehr contributed equally to this work

Authors and Affiliations

  1. Department of Physical Education and Sports Sciences, Faculty of Educational Science and Psychology, University of Mohaghegh Ardabil, Daneshgah Street, Ardabil, 56199-11367, Iran

    Afshin Rahbarghazi

  2. Stem Cell Research Center, Tabriz University of Medical Sciences, Imam Reza St., Golgasht St, Tabriz, Iran

    Afshin Rahbarghazi & Reza Rahbarghazi

  3. Department of Sport Sciences, Azarbaijan Shahid Madani University, Tabriz, Iran

    Karim Azali Alamdari

  4. Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Reza Rahbarghazi

  5. Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

    Reza Rahbarghazi

  6. Research Center for Evidence-Based Medicine, Iranian EBM Centre: A Joanna Briggs Institute (JBI) Center of Excellence, Tabriz University of Medical Sciences, Tabriz, Iran

    Hanieh Salehi-Pourmehr

Authors
  1. Afshin Rahbarghazi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karim Azali Alamdari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Reza Rahbarghazi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hanieh Salehi-Pourmehr
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AR and KAA performed systematic research, collected data, and prepared a draft. HSP performed the statistical analysis. RR (CA) supervised the study. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Afshin Rahbarghazi, Reza Rahbarghazi or Hanieh Salehi-Pourmehr.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors have declared their consent for this publication.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise 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 view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rahbarghazi, A., Alamdari, K.A., Rahbarghazi, R. et al. Co-administration of exercise training and melatonin on the function of diabetic heart tissue: a systematic review and meta-analysis of rodent models. Diabetol Metab Syndr 15, 67 (2023). https://doi.org/10.1186/s13098-023-01045-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13098-023-01045-6

Keywords

Diabetology & Metabolic Syndrome

ISSN: 1758-5996

Contact us