Table 2 Characteristics of included studies in systematic review and meta-analysis

Male Sprague Dawley rats

22 ± 2 (months)

300–325 (g)

T2DM

T2DM (a high-fat diet (62% calories obtained from fat)/ diet + 35 mg/kg of STZ by intraperitoneal + Melatonin (10 mg/kg) + Sitagliptin (20 mg/kg, i.p.) for 4 weeks

N = 42

7 groups (6 rats each)

1—control group received only thoracotomy without LAD ligation;

2—IR groups;

3—IR + Melatonin group;

4—IR + Sitagliptin group;

5—IR + Melatonin + Sitagliptin group;

6—IR + CC group;

7—IR + CC + Melatonin + Sitagliptin group

2 weeks

10 weeks

Improving antioxidative and antiapoptotic responses

Up-regulation of AMPK/SIRT1 activity via melatonin

[100]

Male C57BL/6 J mice

8 weeks

–

T1DM

T1DM 50 mg/kg (STZ) by intraperitoneal for 5 consecutive days + intraperitoneal injections of 10 mg/kg/d melatonin for 10 weeks

4 groups

1—normal glucose;

2—high glucose;

3—Mannitol;

4—melatonin

2 weeks

12 weeks after the first injection of STZ

amelioration of high glucose-induced CMECs injury by melatonin

Treatment of apoptosis and increased AMPK/SIRT1 signaling axis activity by melatonin in CMEC

[101]

Adult male Wister rats

8 weeks

170–200 (g)

T2DM

T2DM nicotinamide (100 mg/kg, ip) 20 min before STZ (55 mg/kg) + melatonin (10 mg/kg) by stomach tube daily for 15 days between 10:0 and 11:00 am

N = 20

4 groups (5 rats each)

1—control group received standard diet

2—melatonin treated group

3—diabetic group

4—group receiving melatonin for 15 days after the induction of diabetes

3 days

15 days post diabetic induction of STZ

Protective effects of melatonin against hyperglycemia, anti-lipid, antioxidant, anti-inflammatory and anti-apoptotic

MLT improves serum glucose levels, HbA1-c, lipid profile, insulin levels and insulin resistance, glutathione and IL-10 and Bcl-2 levels and prevents the increase of pro-inflammatory cytokines and the expression of Bax, caspase-3 and P53

[9]

Female Wistar strain rats

–

150–180 g

T1DM

T1DM 60 mg/kg (STZ) by intraperitoneal for 5 consecutive days + injected daily with melatonin i.p (10 mg/kg)

N = 30

3 groups (10 rats each)

Group I; control non-diabetic rats; group II; STZ-induced, untreated diabetic rats; group III; STZ-induced, melatonin-treated diabetic rats

3 days

6 weeks post diabetic induction of STZ

The role of melatonin in controlling oxidative stress with its antioxidant properties

Bringing the levels of GSH, GSH-Px, and SOD closer to the control group in diabetic rats treated with melatonin

[23]

Male Wister rats

–

200–220

(g)

T1DM

T1DM 60 mg/kg (STZ) by intraperitoneal for 5 consecutive days + injected melatonin i.p (10 mg/kg) daily for 21 days at 11:00

N = 32

4 groups (8 rats each)

I; control daily received intragastric administration of normal saline/ethanol; II; melatonin; III; diabetic; IV; diabetic + melatonin

2 days

21 days post diabetic induction of STZ

The positive effect of melatonin on diabetic myocardial damage and apoptosis

Increasing Bcl-2 expression and blocking activation of CD95 and caspases 9, 8, and 3 by oral melatonin treatment in diabetic

[16]

Male Sprague–Dawley rats

8–10-weeks

180–200 (g)

T1DM + T2DM

T1DM 60 mg/kg (STZ) by intraperitoneal + T2DM 0.125 mg/kg (dexamethasone solution) by subcutaneous administration during 13 days + Intraperitoneal injection (10 mg/kg) of melatonin from 14 to 23 days of the experiment

N = 42

5 groups

I; control;

II; T1DM;

III; T2DM;

IV; T1DM + melatonin;

V; T2DM + melatonin

3 days

24 days

Melatonin as a positive regulator of the immune system

Reduction of TNF-α, IL-1β, and IL-6 mediated by melatonin

[1]

Mature male albino rats

–

0.18–0.20 kg

T1DM

Intraperitoneal injection of alloxan with 5% monohydrate solution at a dose of 170 mg/kg body weight + Intraperitoneal injection (10 mg/kg) of melatonin at 8 am for seven days after five days

N = 158

3 groups

I; rats under artificial equinox; II; rats under constant dark; III; rats under constant light/ each group 5 subgroups: 1) control; 2) DM; 3) alloxan diabetic with melatonin; 4) alloxan diabetic with impaired glucose tolerance; 5) alloxan diabetic with IGT with melatonin

5 days

12 days

The positive effect of melatonin on impaired glucose tolerance under constant light conditions

Improvement of BG level and normalization of PK and LDH activities and increase of G6PD activity with melatonin administration

[10]

Male Sprague Dawley rats

8-weeks

–

T2DM

T2DM (a high-fat diet (40% fat, 41% carbohydrate, and 18% protein for 4 weeks) + induced with an intraperitoneal injection of STZ (60 mg/kg/day) + Oral induction of melatonin a dose of 20 mg/kg/day

N = 50

3 groups

I; control (n = 15);

II; DM (n = 20);

III; DM + Mel (n = 20)

7 days

12 weeks

Amelioration of oxidative stress damage and apoptosis of diabetic aorta by melatonin

Activation of the Notch1/Hes1 signaling pathway by melatonin

[4]

Male Wistar rats

–

180–200 (g)

T1DM

DM (Intraperitoneal injection of 60 mg/kg of STZ) + receive daily 10 mg melatonin/kg/b.w. (i.p.)

N = 40

3 groups

I; control; Injection of physiological solution containing 5% ethanol; II; DM; III; DM + Mel

3 days

18 days

Beneficial effects of melatonin in controlling vascular complications of diabetes

Prevention of increase in nitric oxide level in aortic tissue during diabetes with melatonin administration

[30]

Wild‐type mice

8‐weeks

20–25 (g)

T1DM

DM (intraperitoneal injection of STZ (50 mg/kg for 5 consecutive days)) + Oral administration of melatonin at a dose of 20 mg/kg per day for 4 weeks

N = 254

10 groups

(a) wild type (n = 32); (b) melatonin (n = 32) (c) DM (n = 30); d) DM + melatonin (n = 30); (e) DM + Parkin (n = 24); (f) DM + Parkin + Mel (n = 25); (g) DM + Mst1 (n = 21); (h) DM + Mst1‐Tg (n = 20); (i) DM + Mst1 + Mel (n = 20); (j) DM + Mst1‐Tg + Mel (n = 20)

7 days

4 weeks

Melatonin rescues the impaired mitophagy activity of DCM

Melatonin enhances Mst1/Parkin-mediated mitophagy, thereby

increasing clearance of dysfunctional mitochondria in mice with

DCM

[102]

Sprague–Dawley rats

–

200–220 g

T2DM

HG treatment (500 g/L, 4 ml/kg/h, i.v.) + melatonin (10 mg/kg/d, i.p., 5 days before operation)

4 groups

(1) Sham

(2) MI/R + V (vehicle)

(3) MI/R + HG

(4) MI/R + HG + melatonin

–

–

protective effect of melatonin against myocardial ischemia–reperfusion (MI/R) injury in acute hyperglycemic state

Rescue of the thioredoxin system by melatonin through downregulation of Txnip expression by Notch1/Hes1/Akt signaling in a membrane receptor-dependent manner

[26]

Wild-type and SykCKO mice

8-weeks

-

T1DM

DM (intraperitoneally injected with STZ, 50 mg/kg for 5 consecutive days) + melatonin (20 mg/kg/d) for 12 weeks

8 groups

1; WT; 2; Syk; 3; Mel; 4; DM + WT; 5; DM + Syk; 6; DM + Mel; 7; DM + Ad; 8; DM + Mel + Ad

After the first 4 weeks

12 weeks

The role of melatonin in diabetic cardiomyopathy

Inactivation of Syk/COX-1/SERCA axis by melatonin treatment

[24]

Male Wistar rats

–

0.18–0.20 kg

T1DM

DM induced by injection of alloxan (170 mg/kg) by an i.p + Melatonin (10 mg/kg daily orally for 14 days from the fifth day)

2 groups

Group I; DM; group II; DM + Mel

4 days

14 days post diabetic induction of STZ

Possible activation of glycolysis to restore events in the Cori cycle with melatonin

Restoration of pyruvate kinase activity and glycogen content to normal levels by melatonin in diabetic

[103]

Male Sprague–Dawley (SD) rats

–

250–280 (g)

T2DM

high-fat diet (containing 45% kcal as fat, 35% kcal as carbohydrate, and 20% kcal as protein) for 4 weeks and

injection STZ (40 mg/kg, i.p) + receive melatonin at 10 mg/kg/d

(1) control; (2) diabetic; (3) diabetic with AAV9-NC and treated with or without melatonin; (4) diabetic with AAV9-SIRT6 shRNA and treated with melatonin; (5) diabetic subjected to sham surgery; (6) diabetic with negative control

virus and treated with or without melatonin and then subjected to MI/R surgery; (7) diabetic with AAV9-SIRT6 shRNA and treated with melatonin and then subjected to MI/R surgery; (8) diabetic with luzindole and melatonin and then subjected to MI/R surgery

–

16 weeks post diabetic induction of STZ

A promising strategy to reduce DCM and reduce myocardial vulnerability to ischemia–reperfusion injury with melatonin

The pivotal role of melatonin in reducing myocardial vulnerability to MI/R injury with the focus of SIRT6-AMPK-PGC-1α-AKT

[104]

Male C57BL/6 J mice

–

–

T1DM

DM (intraperitoneally injected with STZ, 50 mg/kg for 5 consecutive days) + melatonin (10 mg/kg/d) for 4 weeks + H9c2 cells exposed to high glucose (33 mmol/L)

5 groups

Group I; con; group II; DM; group III; DM + Mel; group IV; Sirt-1 + DM; group V; Sirt-1 + Mel + DM

2 weeks

12 weeks after the first injection of STZ

Prevention of mitochondrial fission to reduce diabetes-induced cardiac dysfunction with melatonin

Drp1-mediated attenuation of mitochondrial fission by melatonin in a SIRT1/PGC-1α-dependent manner

[28]

C57BL/6 wild-type mice

8–12 weeks

-

T1DM

T1DM (intraperitoneally injected with STZ, 50 mg/kg for 5 consecutive days) + melatonin (20 mg/kg/d) for 4 weeks

N = 80

4 groups

Group I; Control; group II; Con + Mel; group III; DM;

group IV; Mel + DM

5 days

3 months after the first injection of STZ

Regulating autophagy, limiting apoptosis, remodeling, and reducing cardiac dysfunction in DCM with melatonin

Mst1/Sirt3 signaling by melatonin

[77]

Male KM mice

–

20 ± 2 (g)

T1DM

T1DM (intraperitoneally injected with STZ, 60 mg/kg for 3 consecutive days) + melatonin (10 mg/kg/d)

N = 40

4 groups

I; non-diabetes; II; DM; III; DM + Mel;

IV; DM with 0.5% of ethanol solution treatment as a negative control

3 days

8 weeks after the first injection of STZ

Antifibrotic effect of melatonin for the treatment of DCM

Inhibition of lncRMALAT1/miR-141-mediated NLRP3 inflammasome activation and TGF-β1/Smads signaling by melatonin

[105]

Male Sprague–Dawley rats

–

180–200 (g)

T1DM

T1DM (intraperitoneally injected with STZ, 50 mg/kg for 3 consecutive days) + melatonin (10 mg/kg/d) for 5 days

N = 144; 4 groups

(1) Con (n = 12); (2) DM (n = 12); (3) DM + Sham (n = 24); (4) DM + MI/R + vehicle treatment (n = 24); (5) DM + MI/R + MLT (n = 24); (6)DM + MI/R + MLT + KT5823 (n = 24); (7) DM + KT5823 (n = 12); (8) DM + MLT (n = 12)

7 days

5 days post diabetic induction of STZ

Amelioration of diabetic MI/R damage and reduction of myocardial apoptosis and oxidative stress to maintain cardiac function with melatonin

Modulation of Nrf-2-HO-1 and MAPK signaling by melatonin in diabetic MI/R injury

[106]

Male Wistar albino rats

–

250–300 (g)

T1DM

DM (intraperitoneally injected with STZ, 60 mg/kg) + melatonin (10 mg/kg/d) for 8 weeks + control received 0.1 M citrate buffer + 6 U/kg/day NPH insulin

N = 48

6 groups

(1) Con (n = 8); (2) Mel (n = 8); (3) DM (n = 8); (4) DM + Mel (n = 8); (5) DM + insulin (n = 8); (6) DM + insulin + MLT (n = 8)

48 h

8 weeks after the first injection of STZ

The therapeutic role of melatonin and insulin in preventing the damage caused by diabetes

Improving contractile responses and restoring responses to acetylcholine and reducing oxidative stress with melatonin and insulin treatment

[25]

Male mice

–

25–30 (g)

T1DM

DM (intraperitoneally injected with STZ, 50 mg/kgW) + melatonin (3 mg/kg/d) twice a week for consequent four weeks

N = 40

4 groups (n = 10) Control group (C), Control group + melatonin (CM), Diabetic group (D), Diabetic + melatonin (DM) group

3 days

4 weeks post diabetic induction of STZ

Effects of melatonin on aging factors with age to reduce cardiac damage in hyperglycemic conditions

Reversal of increased β-galactosidase and suppression of SOX2, Klotho, and Telomerase genes in T1D mice by melatonin administration

[107]

Male mice

–

25–30 (g)

T1DM

DM (intraperitoneally injected with STZ, 50 mg/kgW) + melatonin (3 mg/kg/d) twice a week for consequent four weeks + Swimming exercises for four weeks

N = 50

5 groups (n = 10)

Control; Diabetic group; Diabetic + Melatonin group; Diabetic + Exercise group; and Diabetic + Exercise + Melatonin group

3 days

4 weeks post diabetic induction of STZ

Reducing the harmful effects of diabetes on heart tissue with exercise and melatonin

Increase of cardiac SOD, GPx with the decrease of MDA and increase of TAC and decrease of TNF-α, caspase-3, and suppression of expression of Connexin-43 and Sirtuin1 in the combination of exercise and melatonin

[17]

male Wistar rats

12 weeks

270–340 g

T1DM

T1DM 45 mg/kg of STZ by intraperitoneal + Exercise protocol (Motorized rodent treadmill with electric shock plate motivation for 8 weeks, 5 days per week/ In the first 4 weeks, increasing the duration and speed of training gradually from 30 to 60 min per day and from 18 m per minute to 24 m per minute with a constant slope of 10 degrees during the study and a 2-min rest at the end of the training and no change in the parameters Exercise until the end of the study/ Fixed placement of sedentary mice without exercise on the treadmill)

N = 48

4 groups

(12 rats each)

i) Sedentary control,

ii) sedentary diabetic,

iii) exercise control,

iv) exercise diabetic

3 days

8 weeks

Prevention of cardiac autonomic neuropathy by early initiation of systemic exercise training

favorable change in the balance between parasympathetic and sympathetic activity

[54]

Male Wistar rats

–

350–500 g

T1DM

T1DM 50 mg/kg of STZ by intraperitoneal + Treadmill exercise protocol once a day, five days a week, for nine weeks/ The first week of animal adaptation (8 min, 8 m per minute)/ In the second week, increasing the duration and speed of training gradually up to 18 min a day at a speed of 11 m per minute/ Start training in the first two weeks with low voltage electrical stimulation

N = 79

sedentary control

(C-Sed, n = 14); exercised control (C-Ex, n = 15); sedentary

diabetes (DM-Sed, n = 25); and exercised diabetes (DM-Ex,

n = 25)

7 days

8 weeks

Reduction of left atrial dilatation and myocardial oxidative stress and dysfunction with low-intensity exercise

Decreasing the diameter of the left atrium and improving the function of the papillary muscles and increasing the activity of Antioxidant enzymes

[55]

Wistar male rats

–

250–270 g

T1DM

T1DM 50 mg/kg of STZ by intraperitoneal + Voluntary exercise of mild/moderate intensity in cages equipped with vertical treadmills for 24 h a day

nine groups (n = 10): 1- Diabetic sham

castration + placebo group, 2-Diabetic + placebo group, 3-Diabetic + Testosterone group, 4-Diabetic + Exercise + placebo group, 5-Diabetic + Exercise + Testosterone group, 6-Diabetic + castrated + placebo group, 7-Diabetic + castrated + Testosterone group, 8-Diabetic + castrated + Exercise + placebo group,9-Diabetic + castrated + Testosterone + Exercise group

72 h

6 weeks

Preventing the progression of diabetic cardiomyopathy due to angiogenesis in the heart by exercise

Increased expression of miRNA-126 in heart tissue

[56]

Wistar male rats

Four months old

230—250 g

T1DM

T1DM 50 mg/kg of STZ by intraperitoneal + Voluntary exercise of mild/moderate intensity in cages equipped with vertical treadmills for 24 h a day

N = 63

1—Diabetes: 2—Diabetes—Testosterone 3—Diabetes– Exercise 4—Diabetes -Exercise—Testosterone 5—Diabetes—castrated 6—Diabetes—castrated—Testosterone 7—Diabetes—castrated -Exercise 8—Diabetes—castrated – Testosterone-Exercise

72 h

6 weeks

Heighten the body's antioxidant system with exercise

Increasing the activities of SOD, GPX, and CAT and decreasing the level of MDA

[36]

C57BL/6J mice

10-week

20–25 g

T2DM

The normal diet contained 17% kcal from fat and 3.1 kcal/g + Training with moderate intensity on the treadmill and gradually increasing the speed and duration of running for five days a week

four groups:

(1) normal diet, (2) ND mice exercise,

(3) HFD,

(4) HFD-exercise

2 weeks

20 weeks

Exercise modulating hydrogen sulfide and pyroptotic signaling in the heart

Increasing cardiac H2S concentration and expression of H2S biosynthesis enzymes and protecting the diabetic heart by reducing pyroptosis with exercise

[43]

Male Wistar rats

–

200–250 g

T1DM

T1DM 50 mg/kg of STZ by intraperitoneal + Volunteer training for 24 h a day for 6 weeks

N = 28

four groups (n = 7): control,

exercise, diabetes, and exercise + Diabetes

–

6 weeks

Voluntary exercise is a useful tool to reduce oxidative stress in diabetes

Decreased MDA levels and increased SOD, GPX, and CAT levels

[33]

Sprague–Dawley rats

16–8 weeks

–

T1DM

T1DM 120 mg/kg of Alloxan by intraperitoneal + Treadmill exercise in the control and diabetic groups at a speed of 18 m per minute, 40 min per day for 5 days per week

N = 40

four groups (n = 10):

sedentary control, exercised control, sedentary diabetic rats, and exercised diabetic rats

3 days

8 weeks

Improvement of cardiac VEGF expression due to diabetes with treadmill exercise training

Increased expression of VEGF

[64]

Male diabetic db/db mice

4-week

–

T2DM

Moderate intensity treadmill training 5 days a week for 8 weeks (Week 1 running for 10 min at 10 m/min, 20 min at 10 m/min for week 2, 30 min at 12 m/min for week 3 weeks 4 to 8, 30 min at 15 m/min)

1-sedentary (db/db-sedentary) 2-exercise-trained (db/db-exercise) group

2-week

8 weeks

Improvement of cardiac markers of angiogenesis and endothelial dysfunction

A higher percentage of total HB and HB1AC and a decrease in TNF-α protein expression of TNF-α and mRNA expression of IL-6 and IL-1β

[41]

Male Wistar rats

–

210–230 g

T1DM

T1DM 60 mg/kg of STZ by intraperitoneal + running wheels equipped with digital wheel distance counters for 60 days

N = 32

4 groups: Control Sedentary(n = 6), Diabetic Sedentary(n = 10), Control Running(n = 6) and

Diabetic Running(n = 10)

10 days

60 days

Reluctance to participate in voluntary exercises and no significant effect of exercise on diabetic heart function

Decreased glucose levels with exercise and less mileage in diabetic rats

[108]

Male Sprague Dawley rats

4–6 months

180–200 g

T2DM

T2DM (a high-fat diet for 28 days + injected intraperitoneally 35

mg /kg) of STZ) + Swimming exercises for 5 min in the first week and a gradual increase for 5 days a week for 4 weeks

N = 32

4 equal groups; a) normal control, b) DM, c) DM + Exercise, d) DM + stevia R extracts

48 h

4 weeks

Cardioprotective effects of exercise against DCM

The effect of exercise on the concentration of MDA and catalase enzyme and the concentration of glutathione

[38]

Male Sprague Dawley rats

6-week

400–600 g

T2DM

T2DM (a high-fat high-sugar diet for 7 weeks + injected STZ (30 mg/kg, i.p) + control group inject citrate buffer (0.25 ml/kg)) + Aerobic exercise protocol: A motor-driven treadmill (In the first three days, the speed of the treadmill is 5 min at a speed of 8 m per minute and then change to 10 min at a speed of 10 m per minute) + MOTS-c treatment protocol: injected (0.5 mg/kg/day, i.p.), for 7 days/week

N = 55

1-control (C, n = 10)

2-high-fat high-sugar diet plus STZ (n = 45), 2–1- diabetes, 2–2-diabetes exercise, 2–3-diabetes plus MOTS-c treatment

3 days

8 weeks

Exercise-induced cardio-protection in diabetes

Activation of NRG1-ErbB4 signaling

[109]

Male Wistar rats

–

250–300 g

T1DM

T1DM 60 mg/kg of STZ by intraperitoneal + running exercise on a treadmill (5 days/week, 60 min/day at 22 m/min, 0-degree slope), at 10:00 AM, for 8 weeks + IMODTM (20 mg/kg) injected intraperitoneally, once a day at 8:00 AM for 8 weeks

8 groups (n = 8): control, exercise, IMODTM, exercise + IMODTM, diabetes, diabetic + exercise, diabetic + IMODTM, diabetic + exercise + IMODTM

72 h

8 weeks

Positive effects of exercise on oxidative stress and markers of heart damage and increasing the activity of antioxidant enzymes

The positive effects of exercise on the reduction of MDA and LDH along with the increase of TAC, SOD, and glutathione peroxidase

[37]

Male Wistar rats

8 Weeks

200–250 g

T1DM

Intraperitoneal injection of nicotinamide solution with a dose of 120 mg/kg and after 15 min STZ with a dose of 65 mg/kg + Endurance training, 5 sessions per week for 20–30 min with a speed of 27 m/min and an intensity of 75% of VO2max in the first week and a gradual increase to 60 min with a speed of 27 m/min and an intensity of 75% of VO2max

N = 36

3 groups

1—Endurance training,

2-—Diabetic control group and

3—Healthy control group

1 week

10 weeks

The positive effect of endurance training on angiogenesis and improvement of diabetic heart

Increased VEGF and VEGFR2 gene expression

[62]

Female Wistar rats

–

249–253 g

T1DM

T1DM 50 mg/kg of STZ by intraperitoneal + Treadmill acclimatization (10 min/day; 0.3 km/h) for 1 week/motorized treadmill training at low intensity (50% to 70% of maximum running speed) for 1 h/day, 5 days/week for 8 weeks, with a gradual increase in speed from 0.3 to 1.2 km/h

N = 52

Sedentary control (n = 8), trained control (n = 8), sedentary diabetic (n = 20), and trained diabetic (n = 16)

72 h

11 weeks after STZ injection

Improved autoregulation induced by exercise training

Exercise improves baroreflex sensitivity and heart rate and increases vagal tone

[110]

Male

Wistar rats

–

200 ± 217 g

T1DM

T1DM 55 mg/kg of STZ by intraperitoneal + exercise program for 4 weeks (5 sessions per week) at a speed of 15 to 18 m/min for 25 to 44 min

N = 40

control, diabetes, control + exercise and exercise + Diabetes

2 weeks

4 weeks

Reduction of apoptotic complications in diabetic cardiomyocytes with exercise

Decreased NT-proBNP

[86]

Male Wistar rats

10–12 Weeks

200–250 g

T1DM

T1DM 30 mg/kg of STZ by intraperitoneal + Aerobic exercise program with the intensity of 50–60% VO2max, 5 days a week for 6 weeks

N = 19; 4 groups: training(n = 6), sham(n = 6), control(n = 4) and healthy(n = 3)

4 days

6 weeks

Improving inflammatory indices and diabetic heart damage with exercise

Significant decrease in TNF-α and CK and a significant increase in PGC-1α

[40]

Male Wistar rats

8–10 weeks

253–265 g

T1DM

T1DM 50 mg/kg of STZ by intraperitoneal + Empagliflozin 10 mg/kg daily by oral gavage for six weeks + Endurance training program on the treadmill with a zero-degree slope for 5 sessions per week and 10 min at a speed 10 m per minute in the first week and the sixth week for 30 min at a speed of 18 m per minute in each training session

N = 40

five groups: control, diabetic,

diabetic + empagliflozin, diabetic + training and diabetic + training + empagliflozin

2 weeks

6 weeks

Aerobic exercise improves the inflammatory status, structure, and function of diabetic heart tissue

Decreased TNF-α and TGF-β

[58]

Male Wistar rats

–

200–232 g

T1DM

T1DM 60 mg/kg of STZ by intraperitoneal + ET on a treadmill daily for 8 weeks + GSE (200 mg/kg) orally via gavage once a day

N = 45

five groups: sedentary control, sedentary diabetic, trained

diabetic, GSE-treated secondary diabetic, and GSE-treated trained diabetic

1 day

8 weeks

The effect of exercise on improving left ventricular dysfunction

Improvement of systolic pressure gradient related to diastolic pressure

[111]

Male Wistar rats

6–8 weeks

140 ± 10 g

T1DM

T1DM 50 mg/kg of STZ by intraperitoneal + Acute resistance training includes four training sessions (climbing a 1-m ladder with a 2-cm net ladder and weights attached to the rats' tails + first day, 10 climbs without weight bearing + second day, light weights of 0.2 to 0.5 weights body + third day, 4–6 repetitions with weights of 0.2 to 0.5 of own body weight + increasing the weights gradually (30 g) + fourth day doing 10 climbs with 70 to 75% of your maximum carrying capacity with a 1.5-min rest in between repetitions

N = 20

two groups: (1) acute resistance exercise (2) sedentary control

4 days

4 days

The effect of resistance exercise on oxidative stress

Decreases MDA

[112]

Male outbred Wistar rats

12-week

280–320 g

T1DM

T1DM 60 mg/kg of STZ by intraperitoneal + Treadmill exercise training with gradual increases in speed and time running up to 1.8 km/h, 1.5 h/d, 5 days a week for 8 weeks

N = 34

untrained (n = 15) and trained (n = 19) groups

2 weeks

8 weeks

Prevention of adverse effects of diabetes on antioxidant defense with aerobic exercise

Decreased GPX activity

[113]

male Wistar rats

–

300 ± 350 g

T1DM

T1DM 60 mg/kg of STZ by intraperitoneal + control groups intraperitoneal injection of an equal volume of citrate buffer + treadmill exercise 5 days a week for an hour with 22 (m/min) speeds

6 groups (n = 10):

sedentary control, control with 15-day exercise, control with 60-day exercise, sedentary diabetic, diabetic with 15-day exercise, and diabetic with 60-day exercise

48 h

5 days

Prevention of diabetic heart hypertrophy with exercise

A decrease in the average ratio of heart weight to body weight

[59]

male Wistar rats

10 Weeks

220 ± 20 g

T1DM

T1DM 60 mg/kg of STZ by intraperitoneal + control group same volume of citrate buffer + aerobic training for 12 weeks in 5 sessions per week with a gradual increase in speed (18–26 m/min) and 10 to 55 min in the form of running on the treadmill

N = 21

Three groups: diabetic aerobic training, diabetic and healthy control groups

72 h

12 weeks

Improving heart function and preventing diabetic heart diseases with exercise

Increase expression Akt1 and mTORc1 genes

[114]

Old male wild-type mice + homozygous (db/db,C57BLKS/J)

5 weeks

–

T2DM

treadmill running 5 days/week, 60 min/day at a final intensity equivalent to approximately 50% of VO2Max

Two groups

Diabetic + exercise or Diabetic + sedentary treatments

–

10 weeks

Improving endothelial function and reducing chronic inflammation with exercise training

Reduction of IL-6, TNF-α protein level and improvement of insulin sensitivity and up-regulate SOD and phosphorylated- eNOS protein expression

[78]

Male Sprague–Dawley rats

4 weeks

125–150 g

T2DM

a high-fat diet (40% fat, w/w) and a low-dose of streptozotocin (35 mg/kg/ body mass^)–1) by intravenous injection + voluntary wheel running

a sedentary group or an exercise-trained group

24 h

12-week

Prevention of diabetic cardiomyopathy and disruption of SR protein content regulation by exercise

Improvement of SERCA2a protein content and maximum SERCA2a activity (Vmax)

[115]

Male Wistar rats

–

200–220 g

T1DM

T1DM 55 mg/kg of STZ by intraperitoneal + diabetes groups receive 0.9 IU × 100 g − 1 insulin once a day for 6 weeks + Running at speed of 18 m/min with a slope of 5%, for 30 min, once a day on a treadmill

N = 24 (n = 6):

1. diabetic

2. Insulin diabetic

3. Exercise + diabetic

4.Insulin + exercise + diabetic

48 h

6 weeks

Protection of heart diseases due to diabetes by exercise

Better effect on NDNF and VEGF

[116]

Male C57BL/6 mice

8 week

–

T2DM

Intraperitoneal injection of glucose solution (1.5 g/Kg) + treadmill running once per day, five times a week for 4 weeks at 60% of their maximal aerobic velocity

1-control (n = 35) fed standard diet 2- group received a high fat/high sucrose diet, 2–1: sedentary (n = 45), 2–2: exercise (n = 35)

12 weeks

4 weeks

Cardioprotective effect of regular exercise on diabetic heart vulnerability

Decreased iNOS expression and nitro-oxidative stress

[117]

CD1 male mice

10–12 weeks

25–35 g

T2DM

STZ injections over a 5-days (Low Dose STZ protocol) + Swimming training consists of 2 sessions a day with a 4-h rest period starting with 10 min and gradually increasing by 10 min daily for 5 days a week for 6 weeks

3 groups, a sedentary non-diabetic group, a sedentary diabetic group, and a swim-trained diabetic group

1 week

6 weeks

Beneficial effects of exercise on improving diabetic heart function

Decrease intracellular protein O-GlcNAcylation

[118]

db/db mice

–

–

T2DM

The db/ + control and db/db group of mice were exercised on a treadmill with a controlled speed (7 m/min. for db/db mice and 10 m/min. for db/ + controls) for 300 m/day, 5 days/week

4 groups:

(i) db/ + control, (ii) db/ + control + exercise, (iii) db/db (iv) db/

db + exercise

–

8 weeks

Reduction of fibrosis and myocyte detachment in diabetic heart

Decreased MMP9 activity in the diabetic exercise group

[119]

Male Sprague–Dawley rats

12 weeks

250–300 g

T1DM

Intraperitoneal injection of STZ (40 mg/kg) + treadmill exercise protocol (30 min daily for 4 weeks at a speed of 10 m/min)

N = 24 (each group = 8)

3 groups: A (control), B (diabetic untreated), and C (diabetic treated with low-intensity exercise)

3 days before to STZ

4 weeks

Reducing oxidative stress and apoptosis and maintaining myocardial integrity with low-intensity exercise

Decrease in myofibril loss, vacuolation of cytoplasm, and irregularity of fibrils and decrease in MDA and increase in SOD, GSH-Px, and CAT

[35]

C57BL/6 male mice

6–8 Weeks

180–200 g

T1DM

Injected intraperitoneally STZ (50 mg/kg body weight per day for 5 consecutive days) + treadmill exercise regularly at a speed of 22 cm/sec for 60 min per day, 5 days a week

N = 20

(a) sedentary, (b) exercised, (c) diabetes, (d) diabetic + exercise

1 week

12 weeks

Exercise inhibits cardiac remodeling in DCM

Inhibited Mst1 and miR-486a5p release

[60]

Male Sprague–Dawley rats

–

8-week

T2DM

A high-fat diet of total energy 20 kJ/g + intraperitoneally injected STZ at 30 mg/kg BW + NC group (intraperitoneal injection of 0.01 mM citric acid buffer of equal volume) + 8 weeks of exercise at moderate intensity by the speed of 15.2 m/min, the slope of 3°, 60 min per day, and 5 days per week

1-control (n = 8)

2-T2DM (n = 16)

3- T2DM + aerobic treadmill exercise (n = 16)

72 h

8 weeks

Exercise as an alternative therapy for diabetic cardiomyopathy

Suppressing expression of MMP-2, CTGF, TGF-β1, p-Smad2 and p-Smad3, and increased expression of TIMP–1, Smad7

[57]

Male Wistar rats

200–250 g

T1DM

intraperitoneal injection of STZ 50 mg/kg + voluntary exercise + testosterone 2 mg/kg/day

9 groups (n = 7): 1, sham operation; 2, diabetic; 3, testosterone; 4, exercise; 5, testosterone + exercise; 6, castrated; 7, testosterone–castrated; 8, exercise–castrated; 9, testosterone and exercise–castrated

2 days

6 weeks

Improving angiogenesis by exercise in diabetic rats

Enhancement miR-132 levels

[120]

Male C57BL/6 mice

6 weeks

–

T2DM

Injected intraperitoneally low-dose STZ (120 mg/kg body weight) + a high-fat diet (45% of energy as fat) + exercise by training at 0.5/0.6/0.7/0.8/1.0 km/h for 1 h

1—non-diabetes Mellites sedentary control, 2—STZ/HF sedentary control, 3—STZ/HF treadmill running,

1 week

16 weeks

The effect of exercise in improving diabetic cardiomyopathy

Improving blood pressure and systolic dysfunction and increasing the level of oxidative phosphorylation, increasing the membrane potential and reducing the level of ROS and oxygen consumption

[57]

Male Sprague Dawley

6-week

–

T2DM

T2DM = 7 weeks by a high-fat diet combined with a low-dose injection of STZ (30 mg/kg) + Control rats with vehicle citrate buffer (0.25 ml/kg) + Aerobic Exercise Protocol- A motor-driven treadmill for aerobic exercise training (a speed of 21 m/min for 1 h, 50–60% of VO2 max (1 h per days for 5 days of 8 weeks)) + Resistance Exercise Protocol (A special animal ladder 1 m long, with 2 cm grid steps and an 85° gradient)

Six groups

(1) non-diabetic sedentary control, (2) non-diabetic aerobic exercise control, (3) non-diabetic resistance exercise control, (4) diabetic sedentary control, (5) diabetic aerobic exercise, (6) diabetic resistance exercise

3 days

8 weeks

Improving diabetic heart function with aerobic exercise

Increase the expression levels of titin and decrease collagen I, TGFβ1 expression level

[121]

Male Wistar rats

12–14 weeks

140–180 g

T1DM

Intraperitoneal injection of nicotinamide (110 mg/kg body weight) and STZ (50 mg/kg body weight) + training group in an 8-week exercise protocol on a treadmill with an intensity of 25 m per minute, a slope of 5% and 30 min per session

Two groups: diabetic control and diabetic training

48 h

8 weeks

Aerobic exercise as an activator of the angiogenic pathway of diabetic heart tissue

Increase expression mir-126, raf1, PI3K, VEGF and decrease blood glucose levels and insulin resistance

[122]

Male Sprague‐Dawley

–

200 ± 20 g

T1DM

T1DM = a high‐fat and high‐ Sugar diet for 4 weeks + intraperitoneal injections STZ twice (40 mg/kg) + Control (a regular chow and injection with the same citrate buffer) + Running for 60 min on 5 days a week on a treadmill with an incline of 10 degrees/treadmill speed in the LIT group (20 m/min) and the HIT group (34 m/min)

n = 40

1- diabetic cardiomyopathy, 2-DCM + low‐intensity training, 3-DCM + high‐intensity training, 4- control

5 weeks

12 weeks

Improvement of diabetic cardiomyopathy with exercise

Enhances cardiac IGFI-R/PI3K/Akt and Bcl-2 family-associated pro-survival pathways

[46]

Male Wistar rats

8-weeks

–

 + moderate aerobic exercise training on a treadmill 60 min/day, 5 days/week, for 10 weeks

N = 48

control, diabetes, DM + exercise

48 h

10 weeks

The effect of exercise training on cardiac survival pathways in diabetic rats

Enhances cardiac IGFI-R/PI3K/Akt and Bcl-2 family associated pro-survival pathways

[45]