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Administration of coenzyme Q10 to a diabetic rat model: changes in biochemical, antioxidant, and histopathological indicators

  • Jerine S. Peter
  • Shalini M
  • Giridharan R
  • Kadar S. Basha
  • Udhaya B. Lavinya
  • Sabina Evan PrinceEmail author
Original Article
  • 7 Downloads

Abstract

Background

Diabetes mellitus is a metabolic disorder caused by impaired glucose metabolism. Coenzyme Q10 is an endogenous vitamin with significant antioxidant properties.

Aims and objective

The aim of our study is to investigate the protective effect of coenzyme Q10 against streptozotocin-induced diabetic rats.

Materials and methods

Five groups of rats were used as follows: normal control (given normal saline), diabetic control (STZ 50 mg/kg b.w., i.p.), coenzyme Q10-treated diabetic rats (10 mg/kg b.w.), glibenclamide-treated diabetic rats (0.6 mg/kg b.w.) as standard group, and drug alone-treated group (coenzyme Q10 10 mg/kg b.w.). The rats were sacrificed after the study duration of 30 days. Biochemical and antioxidant parameters and histopathological evaluation were carried out in experimental rats.

Results and discussion

The diabetic control group showed significant alterations in biochemical and histological parameters. Coenzyme Q10 was able to bring back the altered parameters to normal levels which were similar to that of the glibenclamide-treated group.

Conclusion

Coenzyme Q10 could, therefore, be used as an adjunct in the management of diabetes.

Antidiabetic activity of conenzyme Q10

Keywords

Streptozotocin Coenzyme Q10 Diabetes mellitus Antioxidant Glibenclamide 

Introduction

Streptozotocin (STZ) is a common agent for diabetes. It is derived from Streptomyces achromogenes. It induces type 1 diabetes, oxidative stress, and hyperglycemia. β Cell of the pancreas is destroyed by STZ. These induce DNA strand break and methylation in pancreatic islet cell. Several herbal drugs have been recognized to have clinical properties such as antibacterial, antiinflammatory, antiallergic, and antiviral activity [1]. There is no effective therapy in modern medicine for diabetes mellitus (DM), which results due to multiple factors that may be environmental, hereditary, and/or abnormal insulin secretion. This may affect various metabolisms like carbohydrates, protein, fat, and also damaging the β cells of the pancreas, kidney, and liver [2]. Diabetic nephropathy is the major cause of death in type 1 DM [3, 4], whereas liver disease is the major cause of death in type 2 DM [5]. Type 2 DM is a common disorder in developed countries which has affected 190 million people globally [6]. DM is due to high blood glucose level and abnormal metabolism in carbohydrate, protein, and fat which cause damages to many organs [7]. Long-term complications of DM can be grouped into vascular and non-vascular complications [8]. The vascular complications involve microvascular retinopathy, neuropathy, nephropathy, and macrovascular complications like coronary disease, cerebrovascular disease, and peripheral vascular disease [9]. Non-vascular complications involve sexual dysfunction, gastroparesis, and skin changes [8]. DM is a chronic disease associated with a reactive oxygen species (ROS) [10, 11, 12]. World Health Organization (WHO) has estimated that DM patients would double in number in 2025; it would rise from 150 million to 300 million [13]. Coenzyme Q10 is a vitamin-like substance which is found in every cell of the body. Coenzyme Q10 is endogenously synthesized antioxidant. It is a component of oxidative phosphorylation in mitochondria which produces ATP from the energy of carbohydrate and fatty acids. Coenzyme Q10 is rich in antioxidant activity which is a potential lipophilic compound with long polyisoprene tail that is known to regenerate and recycle other antioxidants like tocopherol and ascorbate. It is known to degrade the free radical by suppressing the lipid peroxidation; preventing the injuries to DNA; and blocking oxidative injuries to protein, lipids, and all other compound essential for antioxidant. It is a cofactor that has the potential role in ATP production and mitochondrial respiratory chain [14]. It is also known as ubiquinone 50 that is known to have a crucial role in the functioning of heart muscles and muscle tissues. It is mainly produced in the body which decreases due to aging, cancer, and drugs [15].The aim of the research is to study the effectiveness of coenzyme Q10 in STZ-induced diabetes in rats. In this present scenario, scientist and pharmaceutical industries are focusing of herbal plants to discover a curative drug for DM.

General experimental procedures

Chemicals

Synthetic coenzyme Q10 and streptozotocin were purchased from Sigma-Aldrich, India, and the standard hepatoprotective drug silymarin from Quality Pharmaceuticals Ltd., India. Streptozotocin was dissolved in citrate buffer while silymarin was dissolved in sterile distilled water. Coenzyme Q10 was dissolved in 0.2 mL corn oil. All the other chemicals and reagents used in the current study were of analytical grade procured from SD Fine Chemicals Pvt. Ltd., Mumbai, India.

Animals and treatment

Healthy female Wistar albino rats were purchased from Animal house, VIT University, Vellore, Tamil Nadu, India. The mean body weight of the rats ranged between 200 and 250 g. The rats were freely provided with water and lab rodent diet feed which was obtained from Hindustan Lever Ltd. (Mumbai, India). They were grown in a controlled temperature of 12 h light/dark cycle. The experiment was carried out under the guidelines of CPCSEA, and the ethical clearance number is VIT/IAEC/11th/October 10th/No. 26.

Experimental design

DM was induced to the rat by intraperitoneal injection of STZ after overnight fasting. The presence of diabetes was confirmed by measuring blood glucose after 24 h. Diabetes was induced to the rat by STZ (50 mg/kg b.w.). Glibenclamide (0.6 mg/kg b.w.) is used as the standard for this study [16]. The drug coenzyme Q10 (10 mg/kg b.w.) is used for studying its protective activities [17]. The rats were divided into five groups of six rats each. Group 1 includes normal control (given normal saline), group 2 includes diabetic control (STZ 50 mg/kg b.w., i.p.), group 3 includes coenzyme Q10 (10 mg/kg b.w.)–treated diabetic rats, group 4 includes glibenclamide (0.6 mg/kg b.w.)-treated diabetic rats as standard group, and group 5 includes drug alone–treated group (coenzyme Q10 10 mg/kg b.w.). This treatment was followed for a period of 28 days.

Assessment of body weight and blood glucose levels

The body weight and blood glucose levels were measured at regular intervals of 7 days. Blood glucose was measured using one-touch glucometer.

Serum sample preparation and tissue collections

At the end of the study, rats were killed by anesthesia (ketamine 60 mg/kg, xylazine 8 mg/kg, i.p.). Blood was collected from the trunk. The kidney, liver, and pancreas were dissected from the rat and washed free from blood in phosphate buffered saline solution. Later, they were stored in 10% formalin solution. The blood is collected in a centrifuge tube, and then, the serum is separated from the blood. The serum is used for analyzing various biochemical assays.

Renal enzyme markers and serum assays

The collected serum was used in analyzing the renal function markers like urea, creatinine, and uric acid and also to determine total cholesterol, high-density lipoprotein (HDL), triglyceride, HbA1C, and total protein levels [18]. Commercially available kits were used to analyze these parameters.

Histological and antioxidant analysis

Histological analysis of the liver, kidney, and pancreas in the study animals was carried out by routine histological methods. Portions of liver and kidney were homogenized in PBS, and the antioxidant parameters such as thiobarbituric acid reactive substances (TBARS) [19], activities of superoxide dismutase (SOD) [20], and catalase [21] were assayed and recorded.

Statistical analysis

The data obtained from each group were combined and its difference determined. They are statically expressed by mean ± SD. ANOVA was done. This was followed by Student Newman–Keul’s test. p < 0.05 implied significance.

Results and discussion

Effect of CoQ10 on body weight of STZ-induced rats

The average body weight of the normal group was 200 g. The STZ-induced diabetic rats are observed to possess significant (p < 0.05) decrease in its body weight, which is gradually descending on each week (Fig. 1). CoQ10- and glibenclamide-treated diabetic rats are able to possess increase in the body weight. The CoQ10 alone group possessed the normal body weight.
Fig. 1

Effect of CoQ10 on body weight of STZ-induced rats. Each value represents the mean ± SD of six rats. Comparisons were made as follows: a—group 1 vs groups 2, 3, 4, 5; b—group 2 vs groups 3, 4, 5; c—group 3 vs groups 4, 5; d—group 4 vs group 5. The symbols represent statistical significance at *p < 0.05. Statistical analysis was calculated by one-way ANOVA followed by the Student Newman–Keul’s test

Effect of CoQ10 on glucose level of STZ-induced rats

STZ-induced rats is observed to show a significant (p < 0.05) elevation in the level of glucose, which ranges from 350 to 450 mg/dL in the respective days (Fig. 2). The glucose level of group 1 ranges from 80 to 120 mg/dL. CoQ10 is observed to possess significant (p < 0.05) decrease in the glucose level of diabetic rats, which is descending respectively in the 1st day, 8th day, 15th day, 21st day, and 28th day. The recovering level of diabetes by CoQ10 is much greater than the recovering level of glibenclamide. The level of glucose in drug alone group is possessed to show normal level.
Fig. 2

Effect of CoQ10 on glucose of STZ-induced rats. Each value represents the mean ± SD of six rats. Comparisons were made as follows: a—group 1 vs groups 2, 3, 4, 5; b—group 2 vs groups 3, 4, 5; c—group 3 vs groups 4, 5; d—group 4 vs group 5. The symbols represent statistical significance at *p < 0.05. Statistical analysis was calculated by one-way ANOVA followed by the Student Newman–Keul’s test

Effect of CoQ10 on renal enzyme markers of STZ-induced rats

Diabetic-induced group possessed a significant (p < 0.05) increase in urea, creatinine, and uric acid (Table 1). CoQ10-treated diabetic group was able to reduce significant (p < 0.05) level of the serum renal function markers, which is comparatively better than the glibenclamide-treated diabetic rats. CoQ10 alone–treated rats possessed the normal level of renal markers. Our result showed a significant (p < 0.05) elevation in the level of creatinine, urea, and uric acid (Table 1).
Table 1

Effect of CoQ10 on serum renal function markers of STZ-induced rats

Serum parameters

Group 1

Normal

Group 2

STZ (50 mg/kg b.w.)

Group 3

STZ + COQ10 (10 mg/kg. b.w.)

Group 4

STZ + GLB (0.6 mg/kg b.w.)

Group 5

COQ10 (10 mg/kg b.w.)

Urea (mg/dL)

25.11 ± 1.47

42.27 ± 1.19a*

30.55 ± 1.31a*b*

35.67 ± 1.37a*b*c*

26.57 ± 1.45b*c*d*

Creatinine (mg/dL)

0.600 ± 0.364

2.316 ± 0.289a*

0.548 ± 0.412b*

0.591 ± 0.335b*

0.484 ± 0.366b*

Uric acid (mg/dL)

0.748 ± 0.290

2.481 ± 0.300a*

0.450 ± 0.379b*

1.307 ± 0.288b*c*

0.567 ± 0.406b*d*

Each value represents the mean ± SD of six rats. Comparisons were made as follows: a—group 1 vs groups 2, 3, 4, 5; b—group 2 vs groups 3, 4, 5; c—group 3 vs groups 4, 5; d—group 4 vs group 5. Statistical analysis was calculated by one-way ANOVA followed by the Student Newman–Keul’s test

*Statistical significance at p < 0.05

Effect of CoQ10 on serum assays of STZ-induced rats

Total cholesterol, triglyceride, and HbA1C possessed a significant (p < 0.05) elevation in the diabetic-induced group. HDL and total protein possessed decrease in the diabetic-induced group (Table 2 and Table 3). CoQ10- and glibenclamide-treated diabetic group were able to normalize the significant (p < 0.05) level of serum assay.
Table 2

Effect of CoQ10 on serum total cholesterol, HDL, and triglyceride of STZ-induced rats

Serum parameters

Group 1

Normal

Group 2

STZ (50 mg/kg b.w.)

Group 3

STZ + COQ10 (10 mg/kg. b.w.)

Group 4

STZ + GLB (0.6 mg/kg b.w.)

Group 5

COQ10 (10 mg/kg. b.w.)

Total cholesterol (mg/dL)

78.63 ± 1.51

132.25 ± 1.74a*

90.37 ± 1.62a*b*

83.60 ± 1.42a*b*c*

81.70 ± 1.62b*c*

HDL (mg/dL)

30.55 ± 1.22

24.39 ± 1.34a*

29.42 ± 1.34a*b*

27.87 ± 1.57b*c*

31.65 ± 1.27b*c*d*

Triglyceride

63.94 ± 2.08

79.47 ± 1.29a*

69.99 ± 1.62a*b*

67.57 ± 1.43a*b*

61.64 ± 1.36b*c*d*

Each value represents the mean ± SD of six rats. Comparisons were made as follows: a—group 1 vs groups 2, 3, 4, 5; b—group 2 vs groups 3, 4, 5; c—group 3 vs groups 4, 5; d—group 4 vs group 5. Statistical analysis was calculated by one-way ANOVA followed by the Student Newman–Keul’s test

*Statistical significance at p < 0.05

Table 3

Effect of CoQ10 on blood Hb A1C and serum total protein of STZ-induced rats

Blood parameters

Group 1

Normal

Group 2

STZ (50 mg/kg b.w.)

Group 3

STZ + COQ10 (10 mg/kg. b.w.)

Group 4

STZ + GLB (0.6 mg/kg b.w.)

Group 5

COQ10 (10 mg/kg. b.w.)

Hb A1C (%Hb)

4.50 ± 1.37

13.34 ± 1.49a*

6.59 ± 1.34b*

7.16 ± 1.44b*

5.45 ± 1.38b*

Total protein

7.05 ± 0.02

4.85 ± 0.08a*

6.44 ± 0.03a*b*

5.08 ± 0.05a*b*c*

7.54 ± 0.02a*b*c*d*

Each value represents the mean ± SD of six rats. Comparisons were made as follows: a—group 1 vs groups 2, 3, 4, 5; b—group 2 vs groups 3, 4, 5; c—group 3 vs groups 4, 5; d—group 4 vs group 5. Statistical analysis was calculated by one-way ANOVA followed by the Student Newman–Keul’s test

*Statistical significance at p < 0.05

Effect of CoQ10 on antioxidant of STZ-induced rats

The levels of antioxidants like SOD (Fig. 3), catalase (Fig. 4), and liver glycogen (Fig. 5) were measured to know the efficacy of CoQ10. Diabetic-induced group possessed significant (p < 0.05) decrease in the level of antioxidants. CoQ10 and glibenclamide were able to increase the levels significantly (p < 0.05) which are almost similar to the normal group. Group treated with CoQ10 alone has possessed normal antioxidant levels.
Fig. 3

Effect of CoQ10 on SOD in liver and kidney tissue homogenates of STZ-induced rats. Each value represents the mean ± SD of six rats. Comparisons were made as follows: a—group 1 vs groups 2, 3, 4, 5; b—group 2 vs groups 3, 4, 5; c—group 3 vs groups 4, 5; d—group 4 vs group 5. The symbols represent statistical significance at *p < 0.05. Statistical analysis was calculated by one-way ANOVA followed by the Student Newman–Keul’s test

Fig. 4

Effect of CoQ10 on Catalase in liver and kidney tissue homogenates of STZ-induced rats. Each value represents the mean ± SD of six rats. Comparisons were made as follows: a—group 1 vs groups 2, 3, 4, 5; b—group 2 vs groups 3, 4, 5; c—group 3 vs group 4, 5; d—group 4 vs group 5. The symbols represent statistical significance at *p < 0.05. Statistical analysis was calculated by one-way ANOVA followed by the Student Newman–Keul’s test

Fig. 5

Effect of CoQ10 on liver glycogen of STZ-induced rats. Each value represents the mean ± SD of six rats. Comparisons were made as follows: a—group 1 vs groups 2, 3, 4, 5; b—group 2 vs group 3, 4, 5; c—group 3 vs groups 4, 5; d—group 4 vs group 5. The symbols represent statistical significance at *p < 0.05. Statistical analysis was calculated by one-way ANOVA followed by the Student Newman–Keul’s test

Effect of CoQ10 on liver histopathology of STZ-induced rats

Normal central vein and normal hepatocytes were observed in the group 1. Diabetic-induced rats were observed to possess periportal inflammation, periportal fatty infiltration, and pyknotic nuclei (Fig. 6).
Fig. 6

Effect of CoQ10 on liver histopathology of STZ-induced rats. Liver histopathology (H&E staining). a Group 1 shows normal liver histology with normal central vein and normal hepatocytes. b Group 2 liver section shows periportal inflammation, periportal infiltration, and few pyknotic nuclei. The lobular architecture is maintained. c Group 3 shows normal central vein and normal hepatocyte morphology. d Group 4 shows some pyknotic nuclei and mild periportal inflammation. e Group 5 shows normal hepatocytes and central vein

Effect of CoQ10 on kidney histopathology of STZ-induced rats

Normal control group is observed to show normal glomerulus, which is also observed in the CoQ10 treatment group (Fig. 7), whereas diabetic rats possessed an inflammation in glomerulus with proteinuria, tubular damage, and spillage in Bowman ’s capsule. Glibenclamide-treated diabetic group possessed normal glomerulus with mild inflammation and also mild proteinuria. Group treated with CoQ10 alone has showed normal tubules.
Fig. 7

Effect of CoQ10 on kidney histopathology of STZ-induced rats. Kidney histopathology (H&E staining). a Group 1 shows normal renal tissue morphology with normal glomerulus. b Group 2 shows tubular damage with proteinuria and periglomerular inflammation. c Group 3 shows normal renal tissue morphology. d Group 4 shows mild proteinuria and mild periglomerular inflammation. e Group 5 shows normal renal tissue morphology

Effect of CoQ10 on pancreas histopathology of STZ-induced rats

STZ-induced diabetic rats were observed to possess damage in the islets (Fig. 8). The CoQ10-treated diabetic group possessed to recover the damaged islets, which is also similar in glibenclamide-treated group. Group treated with CoQ10 alone has shown normal islets.
Fig. 8

Effect of CoQ10 on pancreas histopathology of STZ-induced rats. Pancreas histopathology (H&E staining). a Group 1 shows normal pancreas histology of beta cells and islets. b Group 2 damaged islets. c Group 3 shows the recovery of islets. d Group 4 shows the recovery of islets. e Group 5 shows normal islets. The lobular architecture is maintained

Discussion

Our study reveals that the CoQ10 has effectiveness in recovering the STZ-induced rats. The complication in STZ-induced rats includes polydipsia (excess intake of water), hyperphagia (increased food intake), hyperglycemia, and severe weight loss [5]. Severe and continuous weight loss was observed in our study (Fig. 1).

Elevations in serum glucose, creatinine, urea, and uric acid are the major causes for diabetic nephropathy [22]. These elevations in creatinine and uric acid are due to the impaired function, and the significant (p < 0.05) elevation in urea is due to greater protein catabolism which shows the positive sign for hyperglycemia and nephropathy [23]. In our studies, CoQ10-treated diabetic rats were able to recover the renal marker enzyme due to the antioxidant property and its ability to regulate glycemia which possesses the better renal function [24, 25, 26]. The betterment of renal function is also due to the glycemic state by reduction of gluconeogenesis which reduces protein reduction [26]. STZ-induced rats also cause weight loss due to loss or degradation of the protein [13, 27].

In HbA1C, HDL and total protein CoQ10 are effective compared to glibenclamide, whereas in total, cholesterol and triglyceride glibenclamide possessed effectiveness compared to COQ10. In our studies, STZ-induced rats possessed a significant (p < 0.05) elevation in the level of total cholesterol, triglyceride, and decrease in the level of HDL (Table 2); this is due to dyslipidemia in untreated diabetic rats. This result was also observed in other studies on rat model [28].

SOD is used to eliminate the ROS by dismutation of superoxide radicals [29]. Excess formation of ROS is due to the depleted endogenous antioxidant; this will result in the reduction of SOD and the increase in lipid peroxidation [13]. Our studies showed a decrease in the level of SOD, catalase, and liver glycogen (Figs. 3, 4, and 5). The significant (p < 0.05) reduction in the level of antioxidant enzyme activity is due to the glycation of this enzyme, which occurs in elevated blood levels [13, 24, 25]. Decreases in the level of antioxidant level were also observed in various studies of STZ-induced rats [30]. The CoQ10-treated diabetic group possessed an increase in the level of antioxidant, which is due to the increased production of superoxide and H2O2 [31].

Diabetic group with the treatment of CoQ10 is possessed to normalize the changes caused by STZ. There is a mild periportal inflammation, and some pyknotic nuclei were observed in the standard group. CoQ10 alone group has not shown any changes in its histopath. The alteration in kidney function would lead to proteinuria. Due to the glomerulus damages, kidney histopathology possessed tubular damages and Bowman’s capsule in STZ-induced rats which are also observed in other studies [2]. The diabetic histopathology is known to cause the thickness in glomerulus basement membrane, which may lead to microalbuminuria, hyperfilteration, and increase in the extracellular matrix [32].

STZ is known to damage the pancreatic insulin secreting β cells. This also leads to the damages in the kidney [2, 7, 33]. This damage is able to be recovered by CoQ10 which is observed in histopath of the pancreas. Many herbal plants are reported to cause the increase in pancreatic β cells by regenerating the cells [34]. STZ-induced rats are known to cause increases in blood glucose level which is also known to cause depletion in pancreatic β cells [35, 36, 37].

Our study confirms the effectiveness of CoQ10, which is able to recover STZ-induced diabetic rats. CoQ10 has shown a beneficial effect when compared to the rat treated with the standard drug. CoQ10 alone–treated rats have not shown any adverse or side effect which demonstrates its potential efficacy. Some marketed drugs are reported to show physical weakness abdominal pain, muscle pain, diarrhea, gastrointestinal disorder [38, 39], low blood sugar level, and lactic acidosis [40]. The CoQ10 has not shown low blood sugar level, instead showed the normal level of blood sugar. Study on CoQ10 has reported not to have any adverse effect on long-term usage that was demonstrated in cardiovascular disorder, kidney disease, deficiency, diabetes, aging, inflammation, neurodegenerative disease, and fertility [41]. CoQ10 has a relation in both type 1 and type 2 as it is mediated by beta cells that could be effective in both type 1 and type 2 DM [42]. As a result of our study, we are concluding the antidiabetic activity of CoQ10 against STZ-induced diabetes in Wistar albino rats. This can be furthered studied in molecular level to know the molecular mechanism of CoQ10 against STZ-induced diabetes.

Notes

Acknowledgements

The authors are thankful to VIT University for providing the necessary facilities to carry out this research project.

Compliance with ethical standards

The experiment was carried out under the guidelines of CPCSEA, and the ethical clearance number is VIT/IAEC/11th/October 10th/No. 26.

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Research Society for Study of Diabetes in India 2019

Authors and Affiliations

  • Jerine S. Peter
    • 1
  • Shalini M
    • 2
  • Giridharan R
    • 1
  • Kadar S. Basha
    • 1
  • Udhaya B. Lavinya
    • 1
  • Sabina Evan Prince
    • 1
    Email author
  1. 1.School of Biosciences and TechnologyVIT UniversityVelloreIndia
  2. 2.ACS Medical College and HospitalChennaiIndia

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