Effect of Ganoderma lucidum spores intervention on glucose and lipid metabolism gene expression profiles in type 2 diabetic rats
© Wang et al.; licensee BioMed Central. 2015
Received: 5 January 2015
Accepted: 12 May 2015
Published: 22 May 2015
The fruiting body of Ganoderma lucidum has been used as a traditional herbal medicine for many years. However, to the date, there is no detailed study for describing the effect of G. lucidum spores on oxidative stress, blood glucose level and lipid compositions in animal models of type 2 diabetic rats, in particular the effect on the gene expression profiles associated with glucose and lipid metabolisms.
G. lucidum spores powder (GLSP) with a shell-broken rate >99.9 % was used. Adult male Sprague–Dawley rats were randomly divided into three groups (n = 8/group). Group 1: Normal control, normal rats with ordinary feed; Group 2: Model control, diabetic rats with ordinary feed without intervention; Group 3: GLSP, diabetic rats with ordinary feed, an intervention group utilizing GLSP of 1 g per day by oral gavages for 4 consecutive weeks. Type 2 diabetic rats were obtained by streptozocin (STZ) injection. The changes in the levels of glucose, triglycerides, total cholesterol and HDL-cholesterol in blood samples were analyzed after GLSP intervention. Meanwhile, gene expressions associated with the possible molecular mechanism of GLSP regulation were also investigated using a quantitative RT-PCR.
The reduction of blood glucose level occurred within the first 2 weeks of GLSP intervention and the lipid synthesis in the diabetic rats of GLSP group was significantly decreased at 4 weeks compared to the model control group. Furthermore, it was also found that GLSP intervention greatly attenuated the level of oxidative stress in the diabetic rats. Quantitative RT-PCR analysis showed up-regulation of lipid metabolism related genes (Acox1, ACC, Insig-1 and Insig-2) and glycogen synthesis related genes (GS2 and GYG1) in GLSP group compared to model control group. Additionally, there were no significant changes in the expression of other genes, such as SREBP-1, Acly, Fas, Fads1, Gpam, Dgat1, PEPCK and G6PC1.
This study might indicate that GLSP consumption could provide a beneficial effect in terms of lowering the blood glucose levels by promoting glycogen synthesis and inhibiting gluconeogenesis. Meanwhile, GLSP treatment was also associated with the improvement of blood lipid compositions through the regulation of cholesterol homeostasis in the type 2 diabetic rats.
Diabetes mellitus (DM) is a metabolic disorder caused by a lack of insulin and/or pancreatic dysfunction characterized by hyperglycemia. DM is a common, morbid and costly disease, affecting more than 1 in 10 adults in both United States and China . DM is the leading cause of new blindness, amputation and end-stage renal diseases and it also contributes to a host of other conditions. Although there is no published data for the medical cost of diabetes in China in recent years, the medical costs of managing DM and its complications exceeded $115 billion in the United States alone in 2011 and the indirect costs added another $58 billion . Evidence suggests that DM complications can be markedly attenuated with appropriate control of blood pressure and hyperglycemia and with successful treatment of hyperlipidemia. Thus, there is a great interest in novel approaches to indirect DM management. However, despite the increasing number of drugs available for DM treatment, significant improvements in the control of DM have not been observed .
Previous studies have confirmed that the treatment with natural antioxidants can reduce diabetic complications  and the continuous efforts to discover new antioxidants as useful drug candidates to combat diabetic complications are on-going. Ganoderma lucidum (Leyss; Fr) Karst. (Ganodermataceae) is a well-known Chinese traditional medicine which has been clinically used in China, Japan and Korea for more than 2000 years. Mushrooms of the genus Ganoderma have been shown to be a rich source of biologically active metabolites , containing many bioactive components, including triterpenoids, polysaccharides, nucleotides, sterols, steroids, peptides and other bioactive ingredients . G. lucidum spores contain high levels of ganoderic acids, ergosterol peroxide and pentadecanoate . Many are active against current major chronic diseases. For example, ganoderic acids, one group of triterpenoids existing in the fruiting body of G. lucidum showed anti-androgenic, anti-5 α-reductase, anti-inflammatory and anti-tumor and a range of other biological activities –.
Although the fruiting body of G. lucidum has been used as a traditional herbal medicine since ancient times, the spores were utilized only in the late 20th century . The spores contain many bioactive substances, including lanostane type triterpenes  and polysaccharides  similar to those in the fruiting body . Other characteristics of the bioactive compounds existing in the spores are those they are also rich in fatty acids, in particular long-chain C-19 fatty acids. Previous study demonstrated that these fatty acids could inhibit tumor cell proliferation and induce apoptosis in the HL-60, promyelocytic leukemic cell line . Meanwhile, other research also showed the potential anti-hyperglycemic effect in diabetic rats using polysaccharides extracted from G. lucidum fruiting body . However, to the date, few detailed studies described the effects of G. lucidum spores on blood glucose and lipid compositions in streptozotocin (STZ) induced diabetic rats and neither of the investigation of G. lucidum spores intervention on the gene expression of glucose and lipid metabolisms has been reported in above diabetic model. To the best of our knowledge, there are few reports in the literature evaluating the feasibility of using G. lucidum spores as a potential anti-diabetic agent and the descriptions of the molecular mechanism(s) involved in these processes are also very rare. Moreover, the co-existing of the multi-active compounds in G. lucidum spores might provide a stronger synergistic or positively effect on improving the diabetic status than the consumption of the single active compound. Therefore, in this study, STZ-induced-diabetic rats are used to investigate the changes in the expression levels of genes involved in lipid and glucose metabolisms after G. lucidum spores treatment.
Effect of GLSP intervention on the body mass of diabetic rats
There was no significant difference in the initial weights among the three groups (P = 0.6925) (Additional file 1: Table S1), indicating that the random grouping was acceptable. The body mass of the rats in the normal control group gradually increased at 4 weeks, suggesting that the dietary composition designed was appropriate. After the injection of STZ, the rats in the two diabetic groups (i.e. model control group and GLSP intervention group) displayed a reduction of body mass gain and the weight of the diabetic rats was lower than that of the normal control group (P > 0.01) during the 4 consecutive weeks, suggesting that the diabetic disease greatly affected the normal development of these rats. There was no significant difference in the body mass between the model control and GLSP intervention group (P = 0.6099) within the first 3 weeks. At the fourth week, the body mass of GLSP group was higher by 9.0 % (P > 0.05) compared to that of model group, indicating that GLSP consumption could partially recover the weight loss after 4 weeks treatment.
Effect of GLSP intervention on blood glucose and insulin levels in the diabetic rats
Effect of GLSP intervention on blood glucose level
Blood glucose level (mmol/L)
RMANOVA F value
5.96 ± 0.64b
5.80 ± 0.83b
5.72 ± 0.29b
5.82 ± 0.79b
6.20 ± 0.52c
32.28 ± 1.00a
30.00 ± 3.32a
24.12 ± 6.60a
30.96 ± 3.04a
32.22 ± 1.71a
30.79 ± 2.72a
28.19 ± 8.32a
25.27 ± 3.98a
25.52 ± 7.48a
24.31 ± 1.17b
Effect of GLSP intervention on blood lipid compositions
Effect of GLSP intervention on blood TG, TC and HDL-c in diabetic rats
0.29 ± 0.00c
2.96 ± 0.07c
2.90 ± 0.07a
2.92 ± 0.27b
5.57 ± 0.47b
1.32 ± 0.45b
1.49 ± 0.55a
4.58 ± 0.09a
2.57 ± 0.29a
Effect of GLSP intervention on oxidative stress level
Effect of GLSP intervention on the level of oxidative stress in diabetic rats
GSH-Px (U/mg prot.)
SOD (U/mg prot.)
6.49 ± 1.9a
53.96 ± 3.8a
1689.65 ± 220.1a
210.65 ± 7.7b
11.24 ± 0.2b
65.12 ± 7.6a
1223.26 ± 216.1b
179.26 ± 3.7c
9.68 ± 0.7a
61.12 ± 4.2a
1785.26 ± 259.7a
289.13 ± 4.0a
As compared with the model control group, the MDA level was 13.9 % lower at 4 weeks in the GLSP group (Table 3) (P < 0.05). Furthermore, there was also a reduction of ROS for GLSP intervention group compared to the model control, although the difference was not significant. Nevertheless, the levels of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were higher by 25.9 % (P < 0.05) and 38.0 % (P < 0.05), respectively, following the GLSP treatment compared to the model control group.
Expression of genes related to glucose metabolism
Expression of genes related to lipids metabolism
Although previous research has shown that the fruiting bodies of G. lucidum could reduce blood glucose and plasma cholesterol levels –, few studies have investigated the molecular mechanisms associated with these activities. Our study combines the data of biochemical analysis and gene expression and indicates that GLSP intervention could result in a partial recovery of body weight, reduction of blood glucose level and improvement of lipid compositions and even attenuation of oxidative stress in the STZ-induced diabetic rats. These improvements might be highly associated with the changes in the expression levels of the related genes.
The current study would suggest that GLSP intervention could manipulate hyperglycemic and hyperlipidemic status with a significant reduction of blood glucose level and the improvement of blood lipid compositions (TG, TC, HDL-c) in type 2 diabetic rats (P < 0.01). The GLSP dosage used in this study was 1 g per day, which was about 3 % of the total diet. Although this dosage did not achieve a completely functional recovery of the DM rats to a normal status, it could be used as a reference dosage for improving the symptoms of DM. In contrast, Winther et al. reported that G. lucidum as monotherapy lowered C-peptide significantly (P < 0.001), leaving HDL-c parameter unchanged.
As shown in Table 3, the level of oxidative stress in diabetic rats was improved with the reduction of MDA and the increase of SOD and GSH-Px following GLSP intervention. Meanwhile, The GLSP intervention also led to a reduction of ROS level compared to the model control, although the difference was not significant. Considering that MDA is produced from ROS, the higher level of MDA may promote polyunsaturated fatty acid peroxidation. Previous studies have also shown a strong relationship between MDA levels and different pathological stages of diabetes, because MDA concentration increased considerably in diabetes mellitus . Thus, the controlling of MDA concentration would be helpful in maintaining a suitable level of oxidative stress. Antioxidant enzymes, including SOD and GSH-Px are vital defenses against ROS and they are important in inhibiting oxygen radical formation and usually act as biomarkers for indicating ROS production. This study found that the activities of antioxidant enzymes SOD and GSH-Px were significantly decreased in the model control group compared to the normal controls, indicating a lower antioxidant defense caused by diabetes. However, the administration of GLSP significantly enhanced the activity of SOD and GSH-Px (Table 3), suggesting that the antioxidant compounds present in GLSP might enhance plasma antioxidant capacity in diabetic rats. One plausible mechanism for interpreting the anti-hyperglycemic function of GLSP might be through its scavenging ability to protect pancreatic cells from oxygen-radical damage, supporting an increased secretion of insulin. Previous research has also demonstrated that a high dosage of antioxidant compounds had a favorable effect on glucose homeostasis in obese subjects with the improvements in their Homeostasis Model Assessment (HOMA) index, thus exerting a positive effect on insulin sensitivity .
Previous reports have shown the anti-hyperglycemic activity of GLSP ,  and this function was further highlighted in this study (Table 1). A significant elevation of insulin levels in rats was also demonstrated after the administration of GLSP (unpublished data), which was also accompanied by a decreased blood glucose level. The current study is consistent with previously reported work . Thus, the current results could further support the evidence from previous studies on the anti-hyperglycemic effect of GLSP through decreased glucose level in animals accompanied with increased insulin levels and improvements in pancreatic cell function –. However, the mechanisms associated with this benefit are not completely clear. Therefore, in light of our current results, it might be hypothesized that the benefits derived from GLSP intervention in the diabetic rats could be partially associated with its roles in promoting glycogen synthesis although gluconeogenesis was not significantly affected (PECPK and G6PC1 in Fig. 1). Another plausible reason may be associated with insulin regulation. The expression level of insulin induced genes, in particular Insig-1, was enhanced significantly in GLSP intervention group compared to model control group. It has been shown that Insig-1 and Insig-2 play an important role in glucose homeostasis  and they also have a key function in the regulation of intracellular cholesterol and fat metabolism . Consistently, previous reports have confirmed that a lower glucose concentration could promote the expression levels of Insig-1 and Insig-2 genes  and Insig-1 inhibited lipid accumulation and free fatty acid (FFA) synthesis in a time-dependent manner . In addition, the hepatic over-expression of Insig-1 (or Insig-2) would also inhibit the activation of SREBP-1 c in the rat liver –, a key factor in the control of hepatic glucose metabolism and the manipulation of glucose homeostasis associated with insulin. Although there was no significant change in the expression level of SREBP-1 with the increased expression level of Insig genes in our study, post transcriptional regulation might play some roles as well.
In summary, this study has shown that G. lucidum spores could be used as an ingredient for attenuating diabetic mellitus through potential anti-hyperglycemic and anti-hyperlipidemic activities. More importantly, the relationships between GLSP intervention and the changes in the gene expression levels of the related glucose and lipid metabolic pathways might highlight a potential model for interpreting the action of GLSP treatment.
Materials and methods
G. lucidum spores powder (CLSP) with shell-broken rate >99.9 % was provided by Chongqing Biotechnology Institute (Chongqing, China).
Animals and diets
Twenty four healthy male Sprague–Dawley rats of ~200 g weight were purchased from the Animal Resource Centre, Medical College of PLA Military Science (Beijing, China). They were housed in wire-bottomed cages in a room with controlled temperature (23 °C) and lighting (a 12-h-light/-darkcycle) and allowed free access to food and water. The rats were randomly assigned to 3 groups (n = 8/group): normal control, model control and Ganoderma lucidum spores powder (GLSP) treatment. The rats were fed with a basic diet. After 1 week’s adaptive feeding with the basic diet, the rats were fasted for 12 h, followed by a single intravenous injection of 45 mg/ kgb.w STZ except the rats in normal control group. After 72 h injection of STZ, the blood glucose level was higher than 16.7 mmol/L demonstrating a successful induction of diabetes. Normal control and model control animals were fed with the basal diet for 4 weeks without any intervention. In contrast, GLSP was administered for the third group by oral gavages, using a feeding needle with 1 g per day for 4 consecutive weeks before they were sacrificed for the analysis. There were no casualties or obvious signs of toxicity throughout the course of the experiments and all rats involved survived. The basal diet contained 7 % fat and 13 % protein. Group food intakes and individual body weights were monitored daily throughout the study. Experimental procedures were approved by the Animal Ethics Committee of PLA Military Science and complied with the Chinese Code of Practice for the Care and Use of Animals for Scientific Purposes.
During the whole experiment (4 weeks), blood samples from all rats were collected from the tail vein (once a week) for blood glucose level analysis. At the end of the experiments, blood samples were collected from the femoral artery before animals were sacrificed by cervical dislocation. Blood collected was stored at −80 °C prior to chemical analyses. High-density lipoprotein-cholesterol (HDL-c) (North Kangtai Clinical Reagent Co., Beijing, China, F003-2), total cholesterol (TC) (Dong’ou Diagnosis Products Co Ltd, Zhejiang, China, F002-1) and triglyceride (TG) (Dong’ou Diagnosis Products Co Ltd, Zhejiang, China, F001-1) concentrations were measured according to the instructions of their corresponding kits, respectively. Plasma glutathione peroxidase (GSH-Px) (Jiancheng Biological Engineering Institute, Nanjing, China, A061-1), reactive oxygen species (ROS) (Sigma-Aldrich, USA, DCFH-DA, D6883) and superoxide dismutase (SOD) were measured by enzyme-linked immunosorbent assay (ELISA) (Jiancheng Biological Engineering Institute, Nanjing, China, A015). Commercially available ELISA kit was used to determine blood insulin levels (Beinglay Biotech Co., Ltd, Wuhan, China, DRE20732).
Following the cervical dislocation, the rats were dissected immediately with sterile scissors and the liver was removed, weighed and immediately frozen in liquid nitrogen and stored at −80 °C prior to RNA extraction.
Analysis of gene expression associated with lipid and glucose metabolisms
The primer of genes
Amplicon product (bp)
Annealing temperature (°C)
Results were expressed as means ± SD with SPSS software (version 13.0). The data were analyzed statistically using one-way ANOVA, repeated measures ANOVA and Tukey test (multiple comparisons). A value of P < 0.05 was considered as statistically significant.
This work was financially supported by the China-European research collaboration program (SQ2013ZOA100001), the Nature Science Foundation of China (No. 31471701) and Tianjin Research Program of Application Foundation and Advanced Technology (15JCZDJC34300).
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