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Effects Of Ginkgo Biloba And Panax Ginseng On Metabolism Of Carbohydrate, Lipids And Insulin Receptor Genes In Diabetic Rats

By: Mahrukh Naseem (2011-VA-531) | Dr. Muhammad Quaid Zaman.
Contributor(s): Dr. Imtiaz Rabbani | Dr. Hafsa Zaneb.
Material type: materialTypeLabelBookPublisher: 2014Description: 121p.Subject(s): Department of Physiology | Phd. ThesesDDC classification: 2260-T Dissertation note: Diabetes is a major public health issue. As conventional pharmaceutical agents have greater incidences of adverse effects so the interest in the natural remedies has increased greatly in the last few decades. Ginkgo biloba leaf extract (GBE) and Panax ginseng root extract (PGE) are ancient Chinese herbal drugs that have prominent position in the list of the best-selling natural remedies and are increasingly being used for the treatment of diabetes. The anti-diabetic effect of GBE is attributed to flavonoides while that of PGE is attributed to ginsenosides. In this study, GBE and PGE in combination showed significantly higher anti-diabetic effects than individual extracts in diabetic rats. Adult Wistar rats were allowed to feed on a high fat diet (HFD: 12.7% maize starch, 6.5% dextrose, 3.9% sunflower oil, 31.3% beef tallow and 28.6% casein by weight) for two weeks. The rats were divided into seven groups (08 rats in each group): Non-diabetic control group, Diabetic group, Diabetic + 100 mg/kg G. biloba leaf extract treated group (GBE), Diabetic + 300 mg/kg, P. ginseng root extract treated group (PGE), mixed 1 group : Diabetic + combination of both GBE and PGE at dose of 200 mg/kg/day (50mg/kg/day of GBE and 150mg/kg/day of PGE), mixed 2 group : Diabetic + combination of both GBE and PGE at dose of 400mg/kg/day (100mg/kg/day of GBE and 300mg/kg/day of PGE), mixed 3 group : Diabetic + combination of both GBE and PGE at dose of 600mg/kg/day (150mg/kg/day of GBE and 450mg/kg/day of PGE). At the end of the 14th day, the rats were kept in fasting condition overnight and then a single intra-peritoneal injection of alloxan monohydrate (Sigma, USA) dissolved in 0.5 ml of saline solution at a dose of 120-130 mg/Kg body weight was injected in all rats except for the non-diabetic group which were injected with an equal volume of normal Summary 79 saline. Body weight (BW) and blood glucose were measured at week 1 and week 14. At the end of the experimental period, blood samples in fasting/ basal state were collected from heart puncture for the biochemical parameters. Liver, muscles and adipose tissue were also collected for mRNA expression of genes involved in carbohydrate and fat metabolism. Results were expressed as Means ± S.E.M. Statistical analyses was performed using Statview software (SAS Institute Inc., SAS Campus Drive, Cary, NC, USA). Two-ways repeated measure ANOVA followed by PLSD Fisher's test was performed for BW and blood glucose to assess the effects of time and herbal drugs. For the rest of the parameters, one-way ANOVA followed by PLSD Fisher's test was performed to assess the effect of herbal drugs. Differences were considered significant at P < 0.05. A significant (P < 0.0001) reduction in the BW of the diabetic group was recorded compared to non-diabetic rats and a significant reduction in BW was observed after treatment in all the five treated groups compared to diabetic group. Glycemia was significantly higher in the diabetic rats (P < 0.0001) compared to non-diabetic rats and a significant reduction in the blood glucose level was recorded in all the five treated groups (P < 0.0001) group in comparison to the diabetic group. A significant reduction for fasting serum glucose (FSG) (P < 0.0001) was recorded for all the five treated groups compared to the non-treated diabetic rats. We linked the reduction in hyperglycemia to the mRNA expression of genes involved in glucose metabolism. In particular, we studied the gene expressions of GLUT-4, insulin receptor (IR), insulin receptor substrate-1 (IRS-1) and phosphoenolpyrovate carboxykinase (PEPCK) in liver, muscle and adipose tissue. A significant up-regulation for the mRNA expression of GLUT-4 was observed only in muscle in all the five treated groups, i.e. GBE (P < 0.001), PGE (P < 0.001), mixed 1 (P < 0.0001), mixed 2 (P < 0.0001) and mixed 3 (P < 0.0001). We found a significant down- Summary 80 regulation in the mRNA expression of IR in muscle (P < 0.0001) and adipose tissue (P < 0.05) in the diabetic group compared to non-diabetic rats, however, a significant up-regulation was found in mixed 3 group in muscle (P < 0.001) and adipose tissue (P < 0.05). We found a significant down-regulation (P < 0.001) for IRS-1 in liver in diabetic state and a significant up-regulation was recorded in GBE (P < 0.05) and mixed 3 (P < 0.05) groups only. We found a significant down-regulation of IRS-1 in muscle (P < 0.0001) and adipose tissues (P < 0.0001) in the diabetic group. None of the treated group showed significant results in muscles however, a significant up-regulation was found only in PGE (P < 0.001) and in the mixed 3 group (P < 0.0001) in adipose tissue. A significant up-regulation was recorded for PEPCK in GBE (P < 0.05), mixed 1 (P < 0.05), mixed 2 (P < 0.05) and mixed 3 (P < 0.05) groups in liver. A significant increase of blood cholesterol was found in rats in the diabetic state (P < 0.0001) and a significant reduction was found only in the mixed 3 (P < 0.001) treated group. A significant decrease was found for VLDL-C in mixed 1 (P < 0.05), mixed 2 (P < 0.0001) and mixed 3 (P < 0.0001) groups. A significant decreased was observed for LDL-C in mixed 1, mixed 2 and mixed 3 (P < 0.0001) groups which previously found to be enhanced in diabetic condition. In case of HDL-c a significant decreased was found for GBE (P < 0.001), PGE (P < 0.05), mixed 1 (P < 0.001), mixed 2 (P < 0.0001) and mixed 3 (P < 0.0001) which was previously found to be increased in the diabetic group (P < 0.0001). Conversely, a significant increase was seen for TG (P < 0.0001) in the diabetic state and a significant reduction was found in all the five treated groups (P < 0.0001). We further studied genes involved in lipid metabolism. A significant up-regulation was found for SREBP-1c in diabetic group (P < 0.0001) and a significant down-regulation was found to occur in mixed 2 (P < 0.05) and mixed 3 (P < 0.001) treated groups compared to untreated diabetic rats. In the liver, a significant up-regulation Summary 81 in the mRNA expression of FAS was found only in mixed 2 (P < 0.05) and mixed 3 (P < 0.05) treated groups which found to be down regulated in the untreated diabetic group (P < 0.001). A significant down-regulation in the mRNA expression of PPAR-α was found in diabetic rats skeletal muscle (P < 0.05), however, a significant up-regulation was found in GBE (P < 0.001), PGE (P < 0.05) mixed 1 (P < 0.001), mixed 2 (P < 0.001) and mixed 3 (P < 0.001) treatment groups in comparison to diabetic rats. We studied PPAR-γ in adipose tissue and found a significant up-regulation in PGE (P < 0.05), mixed 1 (P < 0.001), mixed 2 (P < 0.001) and mixed 3 (P < 0.0001) groups which had previously been found to be down regulated (P < 0.001) in diabetic rats compared to non-diabetic rats. We found that the body of the diabetic rats suffer with oxidative stress and measured a significant decrease for CAT (P < 0.0001) in diabetic group and significant increase was found in GBE (P < 0.05), PGE (P < 0.05), mixed 1 (P < 0.05), mixed 2 (P < 0.05), mixed 3(P < 0.05) groups compared to diabetic rats. Whereas, a significant decreased was recorded for MDA in GBE (P < 0.05), PGE (P < 0.05), mixed 1 (P < 0.001), mixed 2 (P < 0.001) and mixed 3 (P < 0.0001) groups, which previously showed a significant increased (P < 0.001) in diabetic group compared to non-diabetic. We linked oxidative stress with TNF- α and found a significant up-regulation (P < 0.0001) for all the three studied organs in diabetic groups compared to the non-diabetic group. In case of liver a significant down-regulation was found for GBE (P < 0.0001), PGE (P < 0.0001) and mixed 3 (P < 0.0001) groups compared to untreated diabetic rats. A significant down-regulation in the expression of TNF- α in muscle was recorded only in the mixed 2 (P < 0.001) and mixed 3 (P < 0.0001) groups compared to diabetic rats. However, a significant down-regulation in the expression of TNF- α in adipose tissue was observed for all the treated groups (P < 0.0001 for all groups) in comparason to the diabetic group. Summary 82 For serum creatinine a significant enhancement was observed for PGE (P < 0.05), mixed 1 (P < 0.05) and mixed 3 (P < 0.05) groups which were previously found to be reduced in diabetic rats. A significant increase for AST was found in diabetes (P < 0.0001) compared to non-diabetic rats, while a significant reduction was found to occur only for PGE (P < 0.05), mixed 2 (P < 0.05) and mixed 3 (P < 0.001) treated groups in comparison to the untreated diabetic group. Like AST a significant reduction was recorded for ALT in the diabetic group (P < 0.001) and only GBE (P < 0.001), PGE (P < 0.05) and mixed 3 (P < 0.05) showed a significant decreased in ALT level compared to untreated diabetic rats. In conclusion, we found that both GBE and PGE have strong individual anti-hyperglycemic, anti-hyper-triglyceridemic and anti-oxidative effects in an alloxan monohydrate induced rat model of diabetes. Both also showed strong influence on the activation on the expression of genes involved in the metabolic pathways of glucose and lipid which previously became dysfunctional in diabetic rats. When both these natural remedies were given in combination, synergistic effects were recorded in a dose dependent manner. Further work is needed to evaluate the way by which human beings suffering from diabetes are safely treated with these herbal remedies.
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Diabetes is a major public health issue. As conventional pharmaceutical agents have greater incidences of adverse effects so the interest in the natural remedies has increased greatly in the last few decades. Ginkgo biloba leaf extract (GBE) and Panax ginseng root extract (PGE) are ancient Chinese herbal drugs that have prominent position in the list of the best-selling natural remedies and are increasingly being used for the treatment of diabetes. The anti-diabetic effect of GBE is attributed to flavonoides while that of PGE is attributed to ginsenosides. In this study, GBE and PGE in combination showed significantly higher anti-diabetic effects than individual extracts in diabetic rats.
Adult Wistar rats were allowed to feed on a high fat diet (HFD: 12.7% maize starch, 6.5% dextrose, 3.9% sunflower oil, 31.3% beef tallow and 28.6% casein by weight) for two weeks. The rats were divided into seven groups (08 rats in each group): Non-diabetic control group, Diabetic group, Diabetic + 100 mg/kg G. biloba leaf extract treated group (GBE), Diabetic + 300 mg/kg, P. ginseng root extract treated group (PGE), mixed 1 group : Diabetic + combination of both GBE and PGE at dose of 200 mg/kg/day (50mg/kg/day of GBE and 150mg/kg/day of PGE), mixed 2 group : Diabetic + combination of both GBE and PGE at dose of 400mg/kg/day (100mg/kg/day of GBE and 300mg/kg/day of PGE), mixed 3 group : Diabetic + combination of both GBE and PGE at dose of 600mg/kg/day (150mg/kg/day of GBE and 450mg/kg/day of PGE). At the end of the 14th day, the rats were kept in fasting condition overnight and then a single intra-peritoneal injection of alloxan monohydrate (Sigma, USA) dissolved in 0.5 ml of saline solution at a dose of 120-130 mg/Kg body weight was injected in all rats except for the non-diabetic group which were injected with an equal volume of normal
Summary
79
saline. Body weight (BW) and blood glucose were measured at week 1 and week 14. At the end of the experimental period, blood samples in fasting/ basal state were collected from heart puncture for the biochemical parameters. Liver, muscles and adipose tissue were also collected for mRNA expression of genes involved in carbohydrate and fat metabolism.
Results were expressed as Means ± S.E.M. Statistical analyses was performed using Statview software (SAS Institute Inc., SAS Campus Drive, Cary, NC, USA). Two-ways repeated measure ANOVA followed by PLSD Fisher's test was performed for BW and blood glucose to assess the effects of time and herbal drugs. For the rest of the parameters, one-way ANOVA followed by PLSD Fisher's test was performed to assess the effect of herbal drugs. Differences were considered significant at P < 0.05.
A significant (P < 0.0001) reduction in the BW of the diabetic group was recorded compared to non-diabetic rats and a significant reduction in BW was observed after treatment in all the five treated groups compared to diabetic group. Glycemia was significantly higher in the diabetic rats (P < 0.0001) compared to non-diabetic rats and a significant reduction in the blood glucose level was recorded in all the five treated groups (P < 0.0001) group in comparison to the diabetic group. A significant reduction for fasting serum glucose (FSG) (P < 0.0001) was recorded for all the five treated groups compared to the non-treated diabetic rats. We linked the reduction in hyperglycemia to the mRNA expression of genes involved in glucose metabolism. In particular, we studied the gene expressions of GLUT-4, insulin receptor (IR), insulin receptor substrate-1 (IRS-1) and phosphoenolpyrovate carboxykinase (PEPCK) in liver, muscle and adipose tissue. A significant up-regulation for the mRNA expression of GLUT-4 was observed only in muscle in all the five treated groups, i.e. GBE (P < 0.001), PGE (P < 0.001), mixed 1 (P < 0.0001), mixed 2 (P < 0.0001) and mixed 3 (P < 0.0001). We found a significant down-
Summary
80
regulation in the mRNA expression of IR in muscle (P < 0.0001) and adipose tissue (P < 0.05) in the diabetic group compared to non-diabetic rats, however, a significant up-regulation was found in mixed 3 group in muscle (P < 0.001) and adipose tissue (P < 0.05). We found a significant down-regulation (P < 0.001) for IRS-1 in liver in diabetic state and a significant up-regulation was recorded in GBE (P < 0.05) and mixed 3 (P < 0.05) groups only. We found a significant down-regulation of IRS-1 in muscle (P < 0.0001) and adipose tissues (P < 0.0001) in the diabetic group. None of the treated group showed significant results in muscles however, a significant up-regulation was found only in PGE (P < 0.001) and in the mixed 3 group (P < 0.0001) in adipose tissue. A significant up-regulation was recorded for PEPCK in GBE (P < 0.05), mixed 1 (P < 0.05), mixed 2 (P < 0.05) and mixed 3 (P < 0.05) groups in liver.
A significant increase of blood cholesterol was found in rats in the diabetic state (P < 0.0001) and a significant reduction was found only in the mixed 3 (P < 0.001) treated group. A significant decrease was found for VLDL-C in mixed 1 (P < 0.05), mixed 2 (P < 0.0001) and mixed 3 (P < 0.0001) groups. A significant decreased was observed for LDL-C in mixed 1, mixed 2 and mixed 3 (P < 0.0001) groups which previously found to be enhanced in diabetic condition. In case of HDL-c a significant decreased was found for GBE (P < 0.001), PGE (P < 0.05), mixed 1 (P < 0.001), mixed 2 (P < 0.0001) and mixed 3 (P < 0.0001) which was previously found to be increased in the diabetic group (P < 0.0001). Conversely, a significant increase was seen for TG (P < 0.0001) in the diabetic state and a significant reduction was found in all the five treated groups (P < 0.0001). We further studied genes involved in lipid metabolism. A significant up-regulation was found for SREBP-1c in diabetic group (P < 0.0001) and a significant down-regulation was found to occur in mixed 2 (P < 0.05) and mixed 3 (P < 0.001) treated groups compared to untreated diabetic rats. In the liver, a significant up-regulation
Summary
81
in the mRNA expression of FAS was found only in mixed 2 (P < 0.05) and mixed 3 (P < 0.05) treated groups which found to be down regulated in the untreated diabetic group (P < 0.001). A significant down-regulation in the mRNA expression of PPAR-α was found in diabetic rats skeletal muscle (P < 0.05), however, a significant up-regulation was found in GBE (P < 0.001), PGE (P < 0.05) mixed 1 (P < 0.001), mixed 2 (P < 0.001) and mixed 3 (P < 0.001) treatment groups in comparison to diabetic rats. We studied PPAR-γ in adipose tissue and found a significant up-regulation in PGE (P < 0.05), mixed 1 (P < 0.001), mixed 2 (P < 0.001) and mixed 3 (P < 0.0001) groups which had previously been found to be down regulated (P < 0.001) in diabetic rats compared to non-diabetic rats.
We found that the body of the diabetic rats suffer with oxidative stress and measured a significant decrease for CAT (P < 0.0001) in diabetic group and significant increase was found in GBE (P < 0.05), PGE (P < 0.05), mixed 1 (P < 0.05), mixed 2 (P < 0.05), mixed 3(P < 0.05) groups compared to diabetic rats. Whereas, a significant decreased was recorded for MDA in GBE (P < 0.05), PGE (P < 0.05), mixed 1 (P < 0.001), mixed 2 (P < 0.001) and mixed 3 (P < 0.0001) groups, which previously showed a significant increased (P < 0.001) in diabetic group compared to non-diabetic. We linked oxidative stress with TNF- α and found a significant up-regulation (P < 0.0001) for all the three studied organs in diabetic groups compared to the non-diabetic group. In case of liver a significant down-regulation was found for GBE (P < 0.0001), PGE (P < 0.0001) and mixed 3 (P < 0.0001) groups compared to untreated diabetic rats. A significant down-regulation in the expression of TNF- α in muscle was recorded only in the mixed 2 (P < 0.001) and mixed 3 (P < 0.0001) groups compared to diabetic rats. However, a significant down-regulation in the expression of TNF- α in adipose tissue was observed for all the treated groups (P < 0.0001 for all groups) in comparason to the diabetic group.
Summary
82
For serum creatinine a significant enhancement was observed for PGE (P < 0.05), mixed 1 (P < 0.05) and mixed 3 (P < 0.05) groups which were previously found to be reduced in diabetic rats. A significant increase for AST was found in diabetes (P < 0.0001) compared to non-diabetic rats, while a significant reduction was found to occur only for PGE (P < 0.05), mixed 2 (P < 0.05) and mixed 3 (P < 0.001) treated groups in comparison to the untreated diabetic group. Like AST a significant reduction was recorded for ALT in the diabetic group (P < 0.001) and only GBE (P < 0.001), PGE (P < 0.05) and mixed 3 (P < 0.05) showed a significant decreased in ALT level compared to untreated diabetic rats.
In conclusion, we found that both GBE and PGE have strong individual anti-hyperglycemic, anti-hyper-triglyceridemic and anti-oxidative effects in an alloxan monohydrate induced rat model of diabetes. Both also showed strong influence on the activation on the expression of genes involved in the metabolic pathways of glucose and lipid which previously became dysfunctional in diabetic rats. When both these natural remedies were given in combination, synergistic effects were recorded in a dose dependent manner. Further work is needed to evaluate the way by which human beings suffering from diabetes are safely treated with these herbal remedies.

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