Non-Insulin Secretion Relative Hypoglycemic Effect of Neonatal Streptozotocin-induced Diabetic Rats by Gavage Feeding Antrodia cinnamomea (Agaricomycetes)
Background and Objective: Antrodia cinnamomea (AC) is an endemic medicinal fungus in Taiwan that has been shown to have anti-insulin resistance activity in previous studies. However, the therapeutic mechanism of AC in diabetes is unclear. The purpose of this study was the first time to determine the hypoglycemic effects of AC in a neonatal STZ-induced diabetic rat, a partial insulin deficiency state while exploring the impact of the plasma FFA level and insulin signal pathway. Materials and Methods: The neonatal STZ-induced (T2D) rats were randomly assigned to two experimental groups (EGs: AC 200 and AC 500) where they had gavage feeding of 200 or 500 mg kg1 AC, respectively and one control group (CG) where saline was orally administered. Blood samples were collected from the femoral vein to investigate plasma glucose, insulin and FFA levels. Results: The data showed that AC decreased plasma glucose levels at 60 min, while their plasma free fatty acid (FFA) levels were also lowered significantly (p<0.01). However, there were no significant elevations in the plasma insulin levels of the two experimental groups (EGs). Also, the levels of insulin signalling proteins (IRS-1, GLUT-4 and PI3K) were significantly elevated after administration of AC 500 mg kg1 (p<0.05). Conclusion: The hypoglycemic effect of AC in neonatal STZ-induced diabetic rats with no significant elevation of plasma insulin may be due to decrease plasma FFA levels and increased expression of intracellular insulin signalling proteins (IRS-1, GLUT-4 and PI3K).
to cite this article:
Bing-Rong Ji, Chi-Wen Huang, Ying-I Chen, Wai-Jane Ho, Shu-Wei Chang, Shih-Liang Chang and Chin-Hsien Chang, 2022. Non-Insulin Secretion Relative Hypoglycemic Effect of Neonatal Streptozotocin-induced Diabetic Rats by Gavage Feeding Antrodia cinnamomea (Agaricomycetes). International Journal of Pharmacology, 18: 1605-1612.
Copyright: © 2022. This is an open access article distributed under the terms of the creative commons attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.
Non-insulin-dependent diabetes mellitus (T2D) is a chronic metabolic disorder associated with the defect of insulin secretion and impaired insulin resistance1. Insulin resistance is defined as impaired sensitivity to insulin that leads to reduced plasma glucose uptake by the muscles, liver and adipose tissue2. Several factors have been proposed to explain the mechanisms of insulin resistance, including obesity, lipodystrophy, fatty liver, inflammation, hyperinsulinemia, hyperlipidemia, gene, ageing, hypoxia and pregnancy3.
Impaired suppression of free fatty acid (FFA) from adipose tissue and enhanced lipolysis both elevate plasma glucose levels4. As a result, the pancreas produces excessive insulin to help with plasma glucose reabsorption, which causes high plasma insulin levels whether plasma glucose is in the normal range or not5. In the previous reports, the decreased plasma FFA of AC contributes to improving insulin resistance6 and the hypoglycemic activity of electroacupuncture to decrease insulin resistance by elevating insulin signal proteins had a similar mechanism to AC7. Chronic hyperglycemia also gradually leads to a paradoxical “glucotoxic” loss of β-cell mass and insulin content that has typically been attributed to enhanced β-cell apoptosis, glycosylation and then dysfunction8.
Antrodia cinnamomea (AC) is a treasured endemic Taiwanese medicinal mushroom, known in Chinese as “Niu-Chang-Chih”9. In addition to the liquid-state cultured mycelium of AC, the solid-state is also commercially available in Taiwan. By using a submerged cultured method, useful metabolites can be obtained from its cultured mycelia, including triterpenoids, alkaloids and exopolysaccharides10,11, which possess antioxidative12, anti-inflammatory13, neuroprotective14 and hepatoprotective properties, even the ethnomedicine information had been reviewed recently15,16. The previous study has confirmed the hypoglycemic effect of AC and its ability to decrease plasma FFA levels in dexamethasone-induced insulin-resistance rats. The increased expression of insulin signalling proteins may play an important role in hypoglycemic activity. This AC also elevated the expression of Insulin Receptor Substrate 1 (IRS-1), Phosphoinositide 3-Kinase (PI3K) and glucose transporter type 4 (GLUT-4) which made insulin resistance of SIIR improve6.
However, the therapeutic mechanism of AC is complex in diabetes mellitus (DM). For the past five years, the antidiabetic effects of AC had been proved in several studies17-23. To realize a hyperglycemic signalling pathway in an insulin deficiency state, we used a neonatal streptozotocin (STZ)-induced diabetic rat in this research. The STZ is a diabetogenic chemical agent to create animal models of diabetes by selective damage of pancreatic β-cells and has been extensively used to induce insulin-dependent DM in large doses21. If lower doses or neonatal is given, then a type 2 diabetic animal model is obtained due to the mild impairment of insulin secretion24. Therefore, the purpose of this study was the first time to determine the hypoglycemic effects of AC in a neonatal STZ-induced diabetic rat, a partial insulin deficiency state while exploring the impact of the plasma FFA level and insulin signal pathway.
MATERIALS AND METHODS
Study area: The study was carried out at the Key Laboratory of College of Biotechnology and Bioresources, Da Yeh University, Changhua, Taiwan from 1 January to 31 December, 2017.
Animal models: The normal Wistar rats (age: 8-10 weeks, body weight: 250-300 g, number: 50) were brought from BioLASCO Taiwan Co., Ltd., that was fed in the animal centre at 25±1°C room temperature with 65±5% relative humidity and adapted in an environment with alternating half-light and half-dark cycle in 24 hrs and free access to standard rat chow and water. The Institutional Animal Care and Use Committee (IACUC) of Da-Yeh University approved the protocol of this research (permit number: 105028) according to the guide for the care and use of laboratory animals.
A previously published study was followed to set up the diabetic model. A type 2 (non-insulin-dependent) diabetic model was prepared by neonatal STZ-induced diabetic rats via intraperitoneal (i.p.) injection of 60 mg kg1 STZ (Sigma Company, USA) to neonatal male Wistar rats (within 2 days of birth)1. Eight weeks after, the plasma glucose level in rats was checked. If the plasma glucose level was greater than 150 mg dL1, then the rat was included in type 2 (non-insulin-dependent) diabetic model25.
Experimental sample: The AC powder sample was provided by Chair Professor Wai-Jane Ho, Da-Yeh University, Changhua, Taiwan. This study applied the same batch AC mycelium powder sample to our previous study for further exploration. Also, the active components (eburicoic acid and dehydroeburicoic acid, sulphurenic acid and dehydrosulphurenic acid and EK100) had been analyzed in methanol extract by High-Performance Liquid Chromatography (HPLC) method in the previous study6.
Experimental protocols: The neonatal STZ-induced diabetic rats were divided into three groups (n = 6 of each group) and performed the following experiments once: Control Group (CG): 1 mL kg1 gavage feeding saline, Experimental groups (Egs): Including AC 200, gavage feeding AC 200 mg kg1 and AC 500, gavage feeding AC 500 mg kg1 referring to the previous report by Chung et al.6. Before each feeding, every AC powder sample in saline was shock homogenized.
Blood samples obtained from animals in the CG and two EGs were assayed for the plasma glucose level to make sure successful induction of the T2D model, whereas, blood sample withdrawn from animals in all groups of this study was used to determine the plasma glucose, plasma FFA and plasma insulin levels for exploring the hypoglycemic effect mechanism of AC.
Plasma glucose assay: After fasting for 12 hrs, experimental animals were prepared after intraperitoneal injection (i.p.) with pentobarbital (40 mg kg1) as anaesthesia. The rats were withdrawing the blood sample 0.3 mL from the femoral vein with a 1 mL syringe containing heparin 0.05 mL at baseline 0, 30 and 60 min after feeding AC or saline 30 min. Then, the blood samples were put into Eppendorf tubes shaken lightly and stored on ice. The stored blood sample was centrifuged for 5 min at 13000×g. Then the Glucose HK stable liquid reagent (Randox Laboratories Ltd., Crumlin, UK) was applied to detect the plasma glucose levels (mg dL1) levels, a commercial enzymatic method which was determined by a spectrophotometer (COBAS system, Roche, Switzerland).
The calculation formula is:
The hypoglycemic activities of each group were determined using this formula and compared with their differences among groups.
Plasma insulin assay: An Enzyme-Linked Immunosorbent Assay (ELISA) kit, (EZRMI-13K, Linco Research, Inc., USA) was applied to detect plasma insulin levels. In brief, plasma samples were incubated for 2 hrs at about 24°C in a shaker and then exposed to a peroxidase conjugate and antibodies bound to a microtitration well. The conjugates were detected by reaction with a chromogenic substrate, 3,3',5,5'-tetramethylbenzidine (TMB) and adding acid to stop the reaction. The mixture was shaken to produce a colorimetric endpoint that was read by a spectrophotometer (TECAN SunriseTM ELISA Reader, Switzerland). The unit of data was presented as pmoL L1 by TECAN Magellan software.
Plasma FFA assay: A non-esterified fatty acids (NEFA) assay by Randox Laboratories Ltd. was used to detect plasma FFA levels. Plasma FFAs were transformed into a purple colour adduct by ELISA kit and using a spectrophotometer, Roche’s Cobas Mira chemistry analyzers (Roche Diagnostics International) to detect the plasma FFA level as described in our previous study7,26.
Western blot analysis: The skeletal muscle samples were homogenized by an ultrasonic processor (VCX 750, Sonics and Materials Inc.) in a lysis buffer, RIPA with PMSF (Santa Cruz Biotechnology, Inc.). Then, the centrifuged and the supernatants of the sample were detected by spectrophotometer. Further, the SDS-PAGE method was used to separate proteins and then transfer proteins to a PVDF membrane that was immersed in non-fat milk to decrease the nonspecific binding sites on the membranes and incubated overnight at 4°C with antibodies IRS-1 (sc-559), PI3K (sc-376112) and GLUT-4 (sc-7938) (Santa Cruz Biotechnology, Inc.). Finally, added with Goat Anti-Rabbit IgG antibody (HRP) (GTX213110-01) (GeneTex, Inc.) and an ECL detection kit (Bio-Rad Laboratories, Inc.). The 4.0 version of Gel-Pro Analyzer (Media Cybernetics, Inc.) was applied to determine the specific bands quantified by optical densitometry. The actin bands were selected as an internal loading control and the result of signal proteins was shown as the ratio of signal to actin6,7.
Statistical method: The data style of each group was expressed as “Mean±SE”. One-way Analysis of Variance (ANOVA) statistical method was performed using a commercial program SPSS. Two independent groups were compared using the post hoc method of Duncan’s Multiple Range Test. Statistically significant differences were set at p<0.05.
Hypoglycemic effect: The neonatal STZ-induced diabetic rats in the two EGs (AC 200 and 500) rats were treated with 200 or 500 mg kg1 AC and the CG rats were treated with normal saline. At 30 min, the hypoglycemic activities in the AC 200 and 500 were 14.54 and 15.31%, respectively. After 60 min, the hypoglycemic activities of the AC 200 (24.61%) and 500 (27.91%) both were greater than that of the CG significantly (p<0.05). The above results indicated that 60 min after gavage feeding 500 mg kg1 AC mycelium was better than gavage feeding 200 mg kg1 AC mycelium for the observation of hypoglycemic effect (Fig. 1).
||Hypoglycemic activity of AC in neonatal STZ-induced diabetic rats
AC: Antrodia cinnamomea, AC 200: Gavage feeding AC 200 mg kg1, AC 500: Gavage feeding AC 500 mg kg1, *p<0.05 and **p<0.001 vs saline, analyzed by ANOVA with Duncan’s Multiple Range Tests
||Plasma insulin levels after administration of AC to the neonatal STZ-induced diabetic rats
AC: Antrodia cinnamomea, AC 200: Gavage feeding AC 200 mg kg1 and AC 500: Gavage feeding 500 mg kg1, analyzed by ANOVA with Duncan’s Multiple Range Test
Impact on plasma insulin levels: For oral administration AC, the insulin level was analyzed in a serum sample obtained from the femoral vein by an ELISA method. The insulin level slightly increased from 0.13±0.02-0.20±0.05 pmol L1 at 60 min after 200 mg kg1 AC treatment, but no statistically significant elevation. Also, the insulin levels were not significant elevation at 60 min after 500 mg kg1 AC treatment. However, the plasma insulin levels were not statistically significant elevation than the basal level after 60 min of the EGs and CG (Fig. 2).
Impact on plasma FFA levels: At 60 min of AC 500 group, the serum FFA level had significantly decreased to 1.54±0.19 mmol L1 compared with the level of baseline (p<0.01), But after oral administration of 200 mg kg1 AC and the same volume of saline to neonatal STZ-induced diabetic rats did not significantly reduce the plasma FFA level 60 min (Fig. 3).
Expression of insulin signal proteins: The levels of the insulin signal proteins GLUT 4 (AC 500: Saline = 0.55±0.17: 0.04±0.03), PI3K (AC 500: Saline = 0.95±0.15: 0.12±0.04) and IRS-1 (AC 500: Saline = 0.72±0.03: 0.29±0.02) were significantly elevated after 500 mg kg1 AC administration compared with those in the saline group, p<0.01. The fold changes (EG/CG) were 12.6, 8.1 and 2.5, respectively. Also, after 200 mg kg1 AC administration compared with those in the saline group these three signal proteins were significantly elevated, p<0.05 (Fig. 4 and 5).
||Impact of AC on plasma FFA levels of neonatal STZ-induced diabetic rats
AC: Antrodia cinnamomea, AC 200: Gavage feeding AC 200 mg kg1, AC 500: Gavage feeding 500 mg kg1, *p<0.05 and **p<0.01 by ANOVA with Duncan’s Multiple Range Test
||Change of signalling proteins by the AC-administered neonatal STZ-induced diabetic rats
IRS 1: Insulin receptor substrate 1, PI3K: Phosphoinositide 3 kinase, GLUT 4: Glucose transporter 4, AC: Antrodia cinnamomea, AC 200: Gavage feeding AC 200 mg kg1, AC 500: Gavage feeding 500 mg kg1, *p<0.05 and **p<0.01 vs saline by ANOVA with Duncan’s Multiple Range Tests
||Hypoglycemic signalling pathway of Antrodia cinnamomea mycelium powder in neonatal STZ-induced diabetic rats
Non-insulin-dependent diabetes mellitus also known as T2D is a heterogeneous disease with defects of insulin sensitivity, impaired insulin resistance or deficiency of insulin secretion27. Most oral hypoglycemic agents and insulin sensitizers, such as thiazolidinedione (TZDs), have several side effects and these drugs limit their use28. Diabetic patients are eager for an agent with fewer side effects that perfectly manage plasma glucose levels and improve insulin resistance. Antrodia cinnamomea (AC) is a valuable medicinal mushroom exclusively grown in Taiwan. In recent years, several studies have demonstrated that AC possesses anti-inflammatory, antioxidant, immunomodulatory, hepatoprotective, hypolipidemic, antidiabetic, antiaging and antitumor activities29-31.
In this prior research, we revealed the hypoglycemic and hypolipidemic effects of 200 and 500 mg kg1 AC in the Steroid-Induced Insulin-Resistant (SIIR) animal model after oral administration6,17,20,32,33. This study followed these doses to explore the hypoglycemic effect in the insulin-deficient model, we injected STZ (i.p.) to neonatal Wistar for building an animal model with partially impaired insulin secretion to simulate the clinical T2D state (Fig. 1).
The most commonly used chemicals to induce diabetes in experimental rats are alloxan and STZ which selectively destroy pancreatic beta cells34. The STZ impairs glucose oxidation and decreases insulin biosynthesis and secretion35, resulting in a model of T2D insulin resistance. If high doses (i.e., 200 mg kg1 for mice) are applied, then the model will have irreversible damage to β-cells that mimics human T1D. If lower doses (i.e., 60 mg kg1 for mice) are given, then the conditions resemble T2D due to the mild impairment of insulin secretion24.
To establish the model, neonatal rats were injected with 60 mg kg1 STZ and grow up 8-10 weeks, 250-300 g then gavage feeding two doses of AC (200 or 500 mg kg1) as the EGs. The extraction method of active ingredients from Antrodia cinnamomea was demonstrated in the recent article by Huang et al.36. The reason we analyzed the insulin level of serum after oral administration AC 30 and 60 min is that the insulin resistance was performed in 30 min in our previous dexamethasone induced insulin resistant animal model6. After 60 min, the hypoglycemic activities in all the EGs (AC 200 = 24.61% and AC 500 = 27.91%) were significantly different from the saline group, p<0.05, but at 30 min the hypoglycemic activity of EGs (AC 200 = 14.54% and AC 500 = 15.31%) did not significantly different from CG. So the optimal feeding dose to have a hypoglycemic effect was determined to be 500 mg kg1 AC for 60 min in this insulin-deficient state (Fig. 1).
The plasma insulin levels were no significant elevation at 60 min after 200 or 500 mg kg1 AC administration in this insulin-deficient model (Fig. 2), also the same trend was obtained in the SIIR rats with improving insulin resistance6, lowering the value of HOMA-IR index, that indicated AC improving insulin resistance with a hypoglycemic effect almost not relative the insulin secretion.
In a previous study, ergostatrien-3β-ol (EK100) was isolated by HPLC from our AC powder sample6. This study believes EK100 is the curial component causing the hypoglycemic effect of AC by increasing insulin sensitivity in insulin-deficient rats6,19. Also, dehydrosulphurenic acid, dehydroeburicoic acid and eburicoic acid possessed stronger α-glucosidase inhibitory effect37. Steroids are frequently prescribed to treat inflammatory diseases and their impairment of insulin sensitivity is a problematic side effect, especially in patients with T2D. In the present experiment, we demonstrated that the hypoglycemic effect was mediated by the same signalling pathway in neonatal STZ-induced diabetic rats as in SIIR `rats. However, the crucial phytosterols causing the hypoglycemic effect of AC in T2D rats are still unknown.
The FFA elevation is often associated with hyperlipidemia, which is a risk factor for insulin resistance3. Administration of 500 mg kg1 AC to neonatal STZ-induced diabetic rats resulted in lower plasma glucose levels at 60 min, which was closely relative to a significant decrease in the serum FFA level. The previous study also showed that 200 mg kg1 AC improved insulin resistance by elevating the levels of insulin signalling proteins (IRS 1, PI3K and GLUT 4) and decreasing plasma FFA levels6. In this study, 500 mg kg1 AC can significantly decrease plasma FFA levels, but 200 mg kg1 AC cannot significantly decrease plasma FFA levels which may be due to different pathogenesis between SIIR rats and neonatal STZ-induced diabetic rats (Fig. 3).
The AC also caused increases in IRS 1, PI3K and GLUT 4, which is to a previous study showing that insulin signalling acts in skeletal muscle by insulin binding to subunits of the insulin receptor on the surface of the cell (Fig. 4-5)6. Previous series studies that the insulin receptor autophosphorylated and activates Insulin Receptor Substrates (IRS) in skeletal muscle38, it is mainly IRS-1 which activates PI3K, then prompts the GLUT 4 translocation from the cytoplasm to the cytoplasmic membrane and engages in the active transport of plasma glucose into skeletal muscle39,40. Therefore, AC stimulates IRS-1 to enhance GLUT 4 performance due to decreasing the plasma FFA level and may not be relative to insulin secretion, which enhances the insulin signalling pathway, resulting in a hypoglycemic effect in STZ neonatal induced diabetic rats39,41. This study believes that AC possesses hypolipidemic and non-insulin relative hypoglycemic effects, which may help the treatment of diabetic and overweight patients more effective and efficiently. The greater sample sizes and related signal pathway explorations are needed in further research.
The AC is a potent diabetes medicine due to its hypoglycemic effects mediated by lowering the plasma FFA levels and increasing the levels of insulin signalling proteins (IRS 1, PI3K and GLUT 4) without a significant change in plasma insulin level, thus a non-insulin secretion relative hypoglycemic effect of neonatal STZ induced diabetic rats could be summarized. The crucial components of AC that cause the hypoglycemic effect still need to be determined. Therefore, AC has the potential to become a functional food or further become an oral hypoglycemic agent for improving insulin resistance to lowering plasma glucose levels in type 2 diabetic patients.
Antrodia cinnamomea (AC) is a valuable medicinal mushroom found in the forests of Taiwan. In recent years, several studies have demonstrated that AC possesses several bioactivities. This study was the first time to determine the hypoglycemic effects of AC in the neonatal STZ-induced diabetic rat model, a partial insulin deficiency state while lowering the plasma FFA level and enhancing several insulin signal proteins.
We would like to thank the primary effort of an undergraduate student, Mr. Shih-Hong Liao.
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