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

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

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
Fig. 1
figure 1

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

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

Table 3 Forest plot results of the effect of Mel on diabetic heart tissue

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

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

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

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)

Table 4 Forest plot results of the effect of exercise on diabetic heart tissue

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

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

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

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

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

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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).

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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.

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

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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

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