Hypoglycemic activity of a polyphenolic oligomer-rich extract of Cinnamomum parthenoxylon bark in normal and streptozotocin-induced diabetic rats.
Cinnamon bark has been reported to be effective in the alleviation of diabetes through its antioxidant and insulin-potentiating activities. The water-soluble polyphenolic oligomers found in cinnamon are thought to be responsible for this biological activity. In this study, the hypoglycemic activity of a polyphenolic oligomer-rich extract from the barks of Cinnamomum parthenoxylon (Jack) Nees was studied in normal, transiently hyperglycemic, and streptozotocin (STZ)-induced diabetic rats. Oral administration of the extract at doses of 100, 200, and 300 mg/kg body wt. caused significant changes in body weight loss and fasting blood glucose levels of normal rats. In STZ-induced diabetic rats, after administration of the extract at doses of 100, 200, and 300 mg/kg body wt. over 14 days, the blood glucose levels were decreased by 11.1%, 22.5%, and 38.7%, respectively, and the plasma insulin levels were significantly increased over pre-treatment levels. In an oral glucose tolerance test, the extract produced a significant decrease in glycemia 90 min after the glucose pulse. These results suggest that Cinnamomum parthenoxylon polyphenolic oligomer-rich extract could be potentially useful for post-prandial hyperglycemia treatment.
[c] 2009 Published by Elsevier GmbH.
Keywords: Cinnamon; Diabetes; Hypoglycemic activity; Cinnamomum parthenoxylon; Polyphenolic oligomers
Diabetes mellitus is a chronic metabolic disorder characterized by deregulation of carbohydrate, protein, and fat metabolism (O'Brien and Granner, 1996). Such alterations result in increased blood glucose, which causes long-term complications in many organs. Despite important progress in the management of diabetes using synthetic drugs, many traditional plant treatments are still used throughout the world. The World Health Organization (WHO) has recommended that this practice should be encouraged, especially in developing countries (WHO Expert Committee, 1980). However, few traditional antidiabetic plants have received proper scientific validation.
Cinnamon is a traditional Chinese medicine that has been used for thousands of years. The bark of Cinnamon cassia is often added to food preparations to improve taste and aroma. In recent years, this herb has been reported to possess potent antioxidant (Mancini-Filho et al., 1998; Singh et al., 2007), antimicrobial (Singh et al., 2007; Mau et al., 2001; Kalemba and Kunicka, 2003), and antipyretic (Kurokawa et al., 1998) properties. Much attention has also been paid to the influence of cinnamon on insulin action, which may provide benefits for diabetic patients. Interest in cinnamon as a potentially useful treatment for type-2 diabetes began almost 20 years ago (Khan et al., 1990). Since that time, numerous in vitro and in vivo studies have elucidated cinnamon's effect on insulin signal transduction (Karalee et al., 2001; Imparl-Radosevich et al., 1998; Broadhurst et al., 2000; Qin et al., 2003, 2004; Lee et al., 2003; Kim et al., 2006). Most experiments claimed that cinnamon is a natural insulin sensitizer (Anderson, 2008) and an inhibitor of advanced glycation end-products (AGEs; Peng et al., 2008). Moreover, cinnamon has the ability to decrease serum glucose, triglyceride, LDL cholesterol, and total cholesterol in people with type-2 diabetes (Khan et al., 2003).
The search for active compounds in cinnamon now are focused on the procyanidins, which are a class of polyphenols compounds and may be present as individual monomers or, in some cases, as oligomeric units. After testing a number of phenolic compounds derived and approximately 50 related plant extracts, Anderson et al. (2004) claimed that unique polyphenols oligomers are the compounds responsible for the biological activity.
The raw plant of TCM cinnamon used in China is commonly the bark of C. cassia. Other species such as C. japonica, C. burmannii, and C. chingii are also used as cinnamon in some places in China. Cinnamomum parthenoxylon (Jack) Nees is a kind of large tree that grows widely in central and southern China. It is familiar to people because of its distinctive aroma and its ability to disperse insects such as cockroaches. In addition to the bark, the leaves and fruits of C. parthenoxylon are also used as TCM, to treat rheumatoid arthritis, pertussis, and dysentery as recommended in the traditional medicinal system (Jiangsu New Medical College, 1977). A previous study on the chemical constituents of C. parthenoxylon focused on the essential oils, including safrole, eugenol, and cinnamic aldehyde, isolated from the essential oil fraction (Cinnamon research group, 1965). C. parthenoxylon is in the same genus as that of C. cassia, etc., and our primary investigation found the aqueous extracts of C. parthenoxylon also contained rich polyphenols oligomers. No antidiabetic properties, however, have been determined in the polyphenols oligomers in C. parthenoxylon extracts. The purpose of the present study was to examine the effect of a polyphenols oligomer-rich extract of C. parthenoxylon on blood glucose levels in normal glycemic, transient hyperglycemic, and streptozotocin (STZ)-induced diabetic rats.
Materials and methods
Bark of C. parthenoxylon was collected in November from a suburb of Nanchang, Jiangxi province, China, and air dried. The plant material was botanically authenticated by Professor Guanyun Gu and a voucher specimen (No. RG002) was deposited at the Herbarium of the Department of TCM Chemistry, School of Pharmacy, Shanghai University of TCM, Shanghai, China.
Preparation of the polyphenolic oligomer-rich extract of C. parthenoxylon barks
Two kilograms of dried powdered barks of C. parthenoxylon were ground continuously with 101 of 50% acetone-water at room temperature for 2 h, after which the solution was filtered and the residue was ground with same solvent under the same conditions once more. The combined extract was concentrated in vacuo to a quantity of 500 ml. It was then partitioned with ether (500 ml x 3). The water layer was removed in vacuo for a moment to get rid of the ether and then subjected to macro resin column chromatography eluted with water and different concentrations of ethanol. The 30% EtOH part was removed in vacuo at 50 [degrees]C to around 200 ml and subjected to freeze drying. The extract yield after freeze drying was 86 g and was named RG-4.
HPLC/MS analyses of polyphenols
A HPLC method was developed to check the principal components of the extract, in which 10 mg of RG-4 sample powder was added to a 10 ml volumetric flask, along with 8 ml of 0.1 N HAC, sonicated for 3 min, cooled to room temperature, and diluted to the volume. The solution was then filtered for HPLC injection.
Chromatographic analyses were performed on an HP 1100 series HPLC instrument equipped with an autosampler/injector, quaternary HPLC pump, column heater, diode array detector, and HP Chem-Station for data collection and manipulation. Reversed-phase separations of the procyanidin oligomers were performed on a 5-[mu]m Luna silica column (250 x 4.6 [mm.sup.2]; Phenom-enex, Torrance, CA). Samples were analyzed with a linear gradient from 85% solvent A (water with 0.2% formic acid) and 15% solvent B (100% acetonitrile) to 5% solvent A and 95% solvent B for 40 min at a flow rate of 0.5ml/min. UV data were collected using a diode array detector set at 280 nm. For HPLC/MS analyses, the HPLC apparatus was interfaced to an HP series 1100 mass-selective detector (model G1946A) equipped with an atmospheric pressure ionization electrospray chamber. Ten millimolar ammonium acetate in methanol was used as an ionization reagent at a flow rate of 0.1 ml/min and added via a tee in the eluent stream of the HPLC apparatus just prior to the mass spectrometer by an auxiliary HP 1100 series HPLC pump. Conditions for analysis in the negative ion mode included a capillary voltage of 3.5 kV, a fragmentor voltage of 85 V, a nebulizing pressure of 25 psig, and a drying gas temperature of 350 [degrees]C. Data were collected on an HP Chem-Station using scan mode over a mass range of m/z 220-2200 at 2.12s per cycle.
Adult male albino rats of Wistar strain weighing about 220[+ or -]60 g each were purchased from the Laboratory Animal Center (Shanghai, China) and maintained on a 12 h light/dark cycle in a temperature- and humidity-controlled room for 1 week prior to the experiment. They were fed with a standard laboratory diet. All procedures were carried out in accordance with the Chinese legislation on the use and care of laboratory animals and were approved by the respective university committees for animal experiments.
Effects of RG-4 on blood glucose levels in normal rats
Fasted rats were divided into four groups of ten animals each. Group I served as a control and received distilled water orally. Groups II-IV received RG-4 orally at a dose of 100, 200, and 300 mg/kg body wt., respectively. Animals were treated once a day for 14 days. Blood samples were obtained by amputation of the tail tip. Glyeemia was measured using an automated chemistry analyzer (Olympus, Japan), following the manufacturer's instructions.
Effects of RG-4 on blood glucose and plasma insulin levels in diabetic rats
The rats were adapted for 7-10 days and then fasted for 12 h before an intramuscular injection of streptozotocin (STZ, Sigma Chemical Company) dissolved in 10 mM sodium citrate buffer (pH 4.5), at a dose of 45 mg/kg body wt. After 3 days, only the animals with glycemia of >350 mg/dl were considered diabetic and were employed in the study. The rats were divided randomly into five groups (n = 10 per group): a control group treated with distilled water, three groups with different doses of 100, 200, and 300 mg RG-4/kg body wt. per day, and a group receiving glymepirids (Shanghai Jiangbei Pharmaceutical Co., Ltd., China) (5mg/kg body wt./day). All samples were administered daily for a period of 14 days. Fasting blood glucose levels were determined throughout the experimental period as described above. Plasma insulin level was assayed with an enzyme immunoassay (ELISA) using a monoclonal anti-insulin antibody (Boehringer-Mannheim, Mannheim, Germany).
Glucose tolerance test in normal rats
The rats were divided into five groups of ten animals each. Group I received orally distilled water and was kept as a control. Groups II-IV were administered orally RG-4 100, 200, and 300 mg/kg body wt./day, respectively. Group V was given the reference drug glymepiride (5 mg/kg body wt./day). Thirty minutes later, a 50% (W/V) glucose solution was administered orally (2g/kg body wt.) to each rat. Blood samples were taken at 0 min (just before glucose administration) and at 30, 60, 90, 120, and 180 min for the determination of blood glucose, as described above.
Each data value was expressed as mean [+ or -]SE. The data were subjected to analysis of variance (one-way ANOVA) to determine the significance of changes. Dunnett's multiple comparisons were made to analyze the significance of difference within the experimental groups, and p values of 0.05 or less were considered statistically significant.
This study was carried out in order to elucidate the effect of a polyphenols oligomer-rich extract of C. parthenoxylon (RG-4) on blood glucose levels in normal and STZ-diabetie rats. To the best of our knowledge, this is the first report addressing the hypoglycemic activity of a polyphenolic oligomer-rich extract of this plant.
The main components of RG-4
The common oligomeric procyanidins in plants are of two types. A-type oligomeric procyanidins have doubly linked bonds between the upper catechm/epicatechin unit and the middle/lower unit, like the compounds described by Anderson et al. (2004) and Foo et al. (2000); mass spectra of these compounds reveal molecular masses of 576 Da for dimer, 864 Da for trimer, and 1152 Da for tetramer (Anderson et al., 2004). B-type oligomeric procyanidins have a singly linked bond between the upper catechin/epicatechin unit and the middle/lower unit, like the compounds described by Sun and Miller (2003). Since there is one bond fewer than in the A type, the B type has two more protons in the structure; mass spectra of these compounds reveal molecular masses of 578 Da for dimer, 866 Da for trimer, and 1154 Da for tetramer (Sun and Miller, 2003).
The HPLC fingerprint of RG-4 is shown in Fig. 1. The positive and negative MS features of main peaks in RG-4 are shown in Fig. 2. As illustrated in Fig. 2, the protonated molecular ion [M + H] peak at 579.2 in the positive MS spectra and deprotonated molecular ion [M - H] peak at 577.5 in the negative MS spectra clearly show that the molecular mass at chromatographic peak at retention time 6.19 min was 578 Da. These should be the dimer polyphenolic oligomers. In the same way, the main two peaks at retention times 9.85 and 11.55 min represent components with molecular mass 866 Da and should be the trimer polyphenolic oligomers. The peak at retention time 13.43 min represents components with molecular mass 1154 Da, and should be the tetramer polyphenolic oligomers. The molecular masses and some fragments of oilgomers in RG-4 MS spectra indicate that the oligomeric procyanidins in RG-4 are mainly of B type. Therefore, the main components of RG-4 are a mixture of B-type polyphenols oligomers.
[FIGURE 1 OMITTED]
[FIGURE 2 OMITTED]
Effects of RG-4 on rat body weight
Under the conditions of the present work, STZ caused a 26% weight loss after 14 days. Treatment with RG-4 (100, 200, and 300 mg/kg body wt.) in the treateddiabetic group caused body weight decreases of 18%, 14%, and 9%, respectively. There was significant improvement in body weight under treatment with RG-4. The ability of RG-4 to protect against weight loss seems to be due to its hypoglycemic activity. Likewise, the oral administration of RG-4 caused no changes in gross behavior and none of the animals died. it can be stated that there were no harmful effects in rats following the oral administration of RG-4.
Hypoglycemic effect in normal rats
Table 1 shows the hypoglycemic effects of different doses of RG-4 on fasting glucose levels in normal rats for a period of 14 days. As shown, RG-4 induced significant (p < 0.05 and p < 0.01) hypoglycemic effects in a dose-dependent fashion. The glucose levels in rats treated with distilled water showed no significant changes. This suggests that RG-4 possesses an important anti-hypoglycemic activity.
Table 1. Effects of RG-4 on fasting plasma glucose levels in normal rats. Groups Fasting plasma glucose (mg.d1) Before treatment 14 days after treatment Control 84.2[+ or -]3.6 83.7[+ or -]2.8 RG-4 (100 mg/kg body 85.0[+ or -]4.2 79.3[+ or -]3.7* wt.) RG-4 (200 mg/kg body 84.6[+ or -]3.5 77.4[+ or -]2.6* wt.) RG-4 (300 mg/kg body 84.7[+ or -]4.0 74.3[+ or -]3.2** wt.) Each value represents mean[+ or -]SE of 10 rats per group. *p<0.05. **p<0.01 compared to pre-treatment levels.
Hypoglycemic effect on streptozotocin-induced diabetes in rats
STZ-induced diabetes has been deseribed as a useful experimental model to study the antidiabetic activity of several agents (Junod et al., 1969; Fisher, 1985). In the present study, the STZ dose (45 mg/kg body wt.) was selected in order to partially destroy the pancreatic [beta]-cells. Under these conditions, insulin was secreted, but not in amounts sufficient to regulate blood glucose levels and, consequently, the rats became permanently diabetic.
In the above experimental model of diabetes, blood glucose levels were significantly higher than those in normal rats. Table 2 shows the results of blood glucose value in STZ-induced diabetic rats. After daily treatment with RG-4 (100, 200, and 300 mg/kg body wt.) for 14 days, significant decreases in the blood glucose levels of 11.1%, 22.5%, and 38.7%, respectively, were observed as compared to pre-treatment levels. No significant changes were seen in diabetic controls before and after distilled water treatment. Glymepiride (5 mg/kg body wt.) decreased glucose levels by 65.2% after 14 days. The possible mechanism of action of the hypoglycemic effect of RG-4 may be stimulation of insulin secretion from the remaining panereatic [beta]-cells, as evidenced by the significant increase in plasma insulin levels following administration of RG-4 (Table 3). The plasma-glucose-lowering effects of RG-4 can be explained by the fact that it might have increased glucose utilization in diabetic animals by promoting insulin secretion.
Table 2. Effects of RG-4 on blood glucose levels in streptozotocin- induced diabetic rats. Groups Blood glucose levels (mg/d1) Before treatment 14 days after treatment Control 468[+ or -]32 465[+ or -]22 RG-4 (100 mg/kg body wt.) 457[+ or -]18 406[+ or -]15** RG-4 (200 mg/kg body wt.) 462[+ or -]16 357[+ or -]14** Glymepiride (5 mg/kg body wt,) 469[+ or -]27 163[+ or -]11** Each value represents mean[+ or -]SE of 10 rats per group. **p<0.01, statistically significant difference vs. control group. Table 3. Effects of RG-4 on plasma insulin levels in streptozotocin- induced diabetic rats. Groups Plasma insulin levels ([mu]IU/m1) Before treatment 14 days after treatment Control 5.08[+ or -]0.23 4.85[+ or -]0.31 RG-4 (100 mg/kg body wt.) 5.12[+ or -]0.34 13.69[+ or -]2.50** RG-4 (200 mg/kg body wt.) 5.20[+ or -]0.42 15.20[+ or -]2.29** Glymepiride (5 mg/kg body 5.11[+ or -]0.27 18.32[+ or -]3.05** wt.) Each value represents mean[+ or -]SE of 10 rats per group. **p<0.01, statistically significant difference vs. control group.
Effects of RG-4 on glucose tolerance test in normal rats
Fig. 3 shows that the oral administration of RG-4 caused a rapid decrease in the hyperglycemic peak after glucose loading in normal rats. Doses of 200 and 300 mg/kg body wt. caused a significant decrease in the blood glucose levels 90min after the glucose pulse; l00 mg/kg body wt. led to a slight reduction in glycemia compared to the strong effect above. These facts demonstrate a dose-dependent activity for RG-4 in the glucose tolerance test and decrease in blood glucose levels during the glucose tolerance test in a similar manner to glymepiride. This result led us to suppose that the effect of RG-4 could take place through a sulfonylurea-like mechanism.
[FIGURE 3 OMITTED]
Literature reports indicate that the cinnamon extract has no role in the alteration of body weight, food intake, and FER in native db/db mice (Kim et al., 2006). In this study, although the RG-4 improved body weight loss in STZ-induced diabetic rats, the oral administration of RG-4 caused no changes in gross behavior and none of the animals died. These results suggest that RG-4 has no effect on the body weight of normal rats.
The molecular weight data from mass spectroscopic studies suggest that polyphenolic oligomers in RG-4 are rich in B-type procyanidin oligomers, different from the A-type oligomers reported by Anderson et al. (2004). Here, a significant reduction of blood glucose levels in normal and STZ-induced rats was observed after 2 weeks of treatment with RG-4. Antidiabetic properties have also been reported for Vaccinium angustifolium, the Canadian lowbush blueberry, which also contains oligomeric procyanidins as possible antidiabetic agents (Martineau et al., 2006). The experiments also suggested that the possible mechanism of its hypoglycemic action is from potentiating the effect of insulin in serum or increasing either the pancreatic secretion of insulin from the existing beta celis or its release from the bound form. The relationship between the type form of procyanidin oligomers and anti-hyperglycemic activity in cinnamon species requires further investigation, and animal activity data must be validated in the future clinical trials to determine whether the cinnamon extract can offer an alternate treatment for type-2 diabetes.
This research was supported by a special appointment (Eastern Scholar) at the Shanghai Institutions of Higher Learning and the Shanghai Program for the Establishment of TCM Pharmaceutics (J50302).
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Q. Jia (a),(1), X. Liu (b),(1), X.Wu (a), R.Wang (a), X.Hu (a), Y. Li (a),(*), C.Huang (b),(*) (*)
(a) School of Pharmacy, Shanghai University of TCM, Shanghai 201203, China
(b) Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China
* Corresponding author. Tel.: + 86 21 51322181; fax: + 86 21 51322193.
** Also for correspondence. E-mail addresses: email@example.com, firstname.lastname@example.org (Y. Li), email@example.com (C. Huang).
(1) These authors contributed equally to this paper.
0944-7113/$ - see front matter[C]2009 Published by Elsevier GmbH.
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|Author:||Jia, Q.; Liu, X.; Wu, X.; Wang, R.; Hu, X.; Li, Y.; Huang, C.|
|Publication:||Phytomedicine: International Journal of Phytotherapy & Phytopharmacology|
|Date:||Aug 1, 2009|
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