Research on potential of Cinnamomum cassia to be developed into supplemental food in prevention and treatment of diabetes

Jing-Song Yan,Bin Han,Zhong Li,Huai-Yuan Qi,Kai-Ge Shi,Hai-Sheng Tu,Hui-Min Ye*

1Hubei Provincial Hospital of TCM, Wuhan 430000, China.2College of Traditional Chinese Medicine, Guangdong Pharmaceutical University,Guangzhou 510006,China. 3School of Chinese Materia Medica,Guangdong Pharmaceutical University,Guangzhou 510006,China.

Abstract Objective:To dig out potential of Cinnamomum cassia Presl to be developed into health tonics in regulating blood glucose from effectiveness and marketing, we designed this research.Methods: We searched from PubChem,CNKI, Web of Science, associated official websites, and other available resources to obtain information about Cinnamomum cassia Presl in blood glucose regulation.Results: Both volatile and non-volatile components of Cinnamomum cassia Presl were revealed as material foundation in blood glucose regulation.In addition, not only the production and utilization of blood glucose would be conditioned by Cinnamomum cassia Presl, but also the risk factors to diabetes as well as complications could be interfered by Cinnamomum cassia Presl.China,America,Australia, Canada and other countries have developed Cinnamomum cassia Presl-associated products to maintain healthy blood glucose level.Conclusion: Cinnamomum cassia Presl is effective in blood glucose regulation, and it’s of great potential to further develop Cinnamomum cassia Presl health products in the prevention and treatment of diabetes.

Key words:Cinnamomum cassia Presl,Blood glucose,Health product

Background

Diabetes is a kind of chronic metabolic disease with many complications [1].According to reports, the global prevalence of diabetes in 2015 was 410 million,an increase of about 260 million compared with 150 million in 2000;while it is estimated that by 2040, the incidence of diabetes will be as high as 640 million[2].According to the official report, the morbidity of diabetes in China is 11.2% in 2017, while only 36.5%of investigated people are of clear understanding of diabetes [3].It suggested that in addition to the available data, a great number of potential patients with diabetes is out of statistics.However, nothing has been well recognized to be effective to cure diabetes,and it is of great necessity to develop access to blood glucose regulation.

Cinnamomum cassiaPresl.(CA), also named as“cinnamon (Rou Gui in Chinese)” is the dried bark of Cinnamomum.It’s permitted to be used as spicery additive in cooking and as medicinal material.CA displays wide range of biological activities.The available studies have found that cinnamaldehyde, CA polyphenols, CA polysaccharides and other components are effective in diabetes regulation.This paper summarizes the material foundation and mechanism of CA in the prevention and treatment of diabetes, to provide basis for the further development of CA products for regulating blood glucose.

Material foundation

As shown in Table 1, the components of CA include the volatiles and the non-volatiles.Among them, the volatile components show higher concentration, being considered as the major effective substances of CA.The non-volatile components are consisted of flavonoids, polysaccharides, lignans, polyphenols,terpenes and other components.

Table 1 The main material foundation of Cinnamomum cassia Presl in diabetes prevention and treatment

Volatile oils

Chen Jingying [4] found that CA volatile oil has the potential to treat diabetes: after oral administration of CA oil at a dose of 0.9 mL/kg, the blood glucose level of insulin resistance mice, induced by high-fat diet,was controlled.The effect is compatible to that of the positive control group, in which the mice were treated with metformin hydrochloride enteric-coated tablets in 0.25 g/(kg·d),ig.

CA volatile oils is consisted of a variety of small molecular compounds, such as aldehydes, acids,olefins.Among them, cinnamaldehyde is the most important active ingredient in CA volatile oils with content about 87%of the total volatile oils[5].

Cinnamaldehyde, the yellow oily liquid, has been reported enjoying a variety of biological activities.A number of studies have shown that cinnamaldehyde is effective in preventing and treating diabetes.Hosni [6]found that cinnamaldehyde can reduce blood glucose levels in pregnant rats by inhibiting oxidative stress and inflammation.In addition to its direct effects on diabetes, cinnamaldehyde could also effectively balance the development of diabetes susceptibility factors and complications.By inhibiting the browning of white adipose tissue and avoiding the hypertrophy and hyperplasia of adipose tissue, cinnamaldehyde is available to balance the weight of mice.In addition,cinnamaldehyde is accessible to promote vasodilation and angiogenesis, delay the occurrence of cardiovascular complications [7, 8].What’s more, it’s reported that the functional damage of nerve caused by hyperglycemia was ameliorated after administration of cinnamaldehyde[9].

Cinnamic acid is an acidic component with high concentration in the volatile oils of CA.According to research, cinnamaldehyde would be metabolized into cinnamic acid,cinnamyl alcohol and methyl cinnamate after administration 10.It’s possible that cinnamic acid is the effective substance in blood glucose regulation.Besides, the available studies, in vitro or in animal models, have reported that cinnamic acid and its derivatives are essential in diabetes prevention or treatment through different pharmacological mechanisms [11].Hatice GülAnlar [12] designed experiments to feed streptozocin-induced diabetic albino Wistar rats with cinnamic acid, and finally found that cinnamic acid is potential in regulating lipid homeostasis and reducing oxidative stress levels.Cinnamic acid plays an important role in interrupting development of diabetic complications.

Non-volatile components

Flavonoids (including coumarin, kaempferol),polyphenols, polysaccharides, terpenoids are major non-volatile components in CA.Polyphenol components such as catechins, epicatechins, A-type proanthocyanidins Trimers have been discovered and confirmed in previous studies [13, 14].It has been revealed that the content of total flavonoids accounts for 44.48% (mass fraction) of the non-volatile parts of CA, and the total polyphenol content accounts for about 28.16%[15].While polysaccharides enjoy lower content, and Glucofuran was reported as the main component of CA polysaccharides with content about 38.64%of the total polysaccharide[16].

Flavonoids.Flavonoids are important functional components in Chinese herbal medicines.Studies have found that the flavonoids in CA have strong antioxidant activity and can be used for the prevention and treatment of chronic metabolic diseases [17].However, there is no research available to explore the importance of CA flavonoids in prevention and treatment of diabetes.

Polyphenols.Polyphenols is an important part of CA non-volatile components, with multiple biological activities such as antioxidant, anti-inflammatory, and hypoglycemic [18].Jiang Qiong [19] reported that CA total polyphenols enjoys better hypoglycemic effect on streptozocin-induced diabetic mice than metformin,which may be explained by CA polyphenols in protecting islet cells.The anthocyanins and catechins,the components of CA polyphenols, helping to protect pancreatic β cells and increase insulin sensitivity, are considered to account for the hypoglycemic activity of CA polyphenols[20].

Polysaccharide.The polysaccharide in CA was reported to be effective in hypoglycemic [21].Studies have found that CA polysaccharides could significantly reduce the blood glucose level of diabetic mice [22].But due to its low content and complicated extraction,the pharmacological effects of CA polysaccharides on diabetes still needs to be investigated.

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Pharmacological mechanism

As shown in Figure 1, the pharmacological mechanism of CA in diabetes prevention and treatment can be summarized as the following five parts.

Figure 2 Details of Cinnamomum cassia Presl Products for Blood Glucose Level Regulation.

Protect islet cells and promote release of insulin

Low insulin sensitivity (type 2 diabetes) and insufficient insulin secretion are the main features of diabetes.Multiple researches have suggested that CA is potential in diabetes treatment by protecting pancreatic islet cells and promoting insulin release.Li's team [23] and Liao Zuozhuang [24] both believed that CA polyphenols enjoys hypoglycemic bioactivity by repairing the function of islet cells.The former one believes that CA polyphenols inhibit the expression of nuclear transcription factor NF-κB, thereby inhibiting the synthesis of inducing nitric oxide synthase and reducing the toxicity of nitric oxide to islet cells.As a result, the damage islet cell in STZ-induced diabetic mice was improved and insulin secretion returned to normal.CA polyphenols could also reduce the damage of oxygen free radicals to islet cells by enhancing activity of superoxide dismutase and glutathione peroxidase, reducing concentration of malondialdehyde.While Liao found that CA polyphenols protect islet cells and promote insulin secretion, mainly by activation of protein kinase B in pancreatic cells, promotion of glucose transporter 4 transferring to the plasma membrane, inactivation of glycogen synthase 3.

Delay the absorption of carbohydrates in intestine

Starch, sucrose, maltose and other polysaccharides in food are broken down into glucose and other monosaccharides before absorption into blood.It’s believed that α-glucosidase plays an important role in polysaccharides decomposition, and the lower activity of α-glucosidase, the less decomposition of carbohydrates,with absorption of glucose and the level of postprandial blood glucose decreased.It’s reported that CA extract has strong α-glucosidase inhibitory activity, not only in in vitro experiments, but also in diabetic rat models [25].In addition to CA, cinnamon in other genus,including Ceylon Cinnamon,also enjoy α-glucosidase inhibitory activity.According to previous investigation, CA was recognized as the most active α-glucosidase inhibitors in various cinnamon genus, with IC50 5.3 μg/ml [26, 27].However, the certain components of CA that inhibit the activity of α-glucosidase have not been revealed.

Reduce gluconeogenesis

The production of blood glucose, in addition to the decomposition of polysaccharides, it can also be produced by the decomposition of glycogen (also known as gluconeogenesis).Lu Zhaolian [28] reported that CA polyphenols enjoyed bioactivity in gluconeogenesis inhibition.By inhibiting expression of phosphoenolpyruvate kinase and glucose-6-phosphate in liver cancer cells (HepG2), following by inactivation of phosphoenolpyruvate kinase, CA polyphenols reduced the conversion of endogenous glucose into blood glucose.Such conclusions were further confirmed by Cheng[29].

Regulate the metabolism of adipose to control weight

Since the development of diabetes is susceptible to obesity, regulation of adipose metabolism and keeping weight in balance are considered as important access to diabetes prevention and development.Cinnamaldehyde shows great potential in inhibiting the dissimilation of adipose tissue, regulating hormones homeostasis,further promoting the decomposition of adipose tissue.It’s suggested that cinnamaldehyde could increase the expression of lipolysis rate-limiting enzyme, hormone sensitive lipase, and inhibit expression of human perilipin,glycerol 3-phosphate dehydrogenase,avoiding the maturation and accumulation of adipocytes.In addition, cinnamaldehyde could also interfere gene expression.For example,cinnamaldehyde could reduce the expression of peroxisome proliferator-activated receptor γ (PPAR-γ),CCAAT/α-binding protein enhancer adipocyte marker genes, so as to decrease the synthesis and transformation of adipocytes [30].In the mice model treated with high fat diet and cinnamaldehyde, it was found that cinnamaldehyde was able to down-regulate the expression of CCAAT/α-binding protein enhancer gene, and up-regulate expression of lipolytic genes,including hormone sensitive lipase, fat triglyceride lipase, and recombinant human monoglyceride lipase.Besides, it was found that the transient receptor potential channel A1 was activated by promoting the expression of cholecystokinin, and leptin-ghrelin tended to be balanced.It suggested that cinnamaldehyde helps to promote lipolysis, prevent visceral fat accumulation, and improve the metabolism homeostasis of glucose-lipid[31].

Delay the occurrence of complications

CA enjoys more potential in prevention and treatment of diabetic complications in cardiovascular system and nervous system.Cardiovascular complications induced by hyperglycemia could be eased with administration of cinnamaldehyde, by reducing oxidative damage, inhibiting fibroblast proliferation, and promoting the release of vascular endothelial relaxing factors.Cinnamaldehyde also helps to activate the nuclear factor erythroid 2-related factor 2 signal and increase expression of hemoglobin oxygenase, glutathione peroxidase 1, quinone oxidoreductase in kidneys and aorta of diabetic mice to reduce oxidative stress, ameliorating vessels injury 7.Heart complications could also be improved since the proliferation of myocardial fibroblasts in hyperglycemic rats was inhibited by cinnamaldehyde[32].It was also reported that through phosphoinositol 3 Kinase/activation of protein kinase B and mitotic activated protein kinase signaling pathways,cinnamaldehyde is effective in increasing expression of vascular endothelial growth factor in vascular wounds, promoting angiogenesis, accelerating wound healing [33].CA is potential in diabetic cardiovascular diseases treatment, since cinnamaldehyde could activate nuclear factor erythroid 2-related factor 2 channel, regulate antioxidant response, inhibiting the proliferation and metastasis of vascular smooth muscle cells in Zucker diabetic obesity rats[34].

Patients with hyperglycemia in a long period are easier to be complicated with damage to central nervous system and peripheral nervous system.Cinnamaldehyde has been reported to increase release of neurotransmitter and improve cognitive dysfunction caused by diabetes in animal studies9.The available literature has found that cinnamaldehyde can reduce the activity of acetylcholinesterase in the cortex and hippocampus, increase the concentration of glutamate and γ-aminobutyric acid in the brain, up-regulate the excitability in brain of mice with diabetic cognitive impairment.While on the other hand, cinnamaldehyde also inhibits the activity of the inflammatory factors,including interleukin 6 and tumor necrosis factor α,protects the brain nerve cells from damage,ameliorating complications 9.Besides, cinnamic acid was found to be effective in learning ability improvement and cognitive impairment of diabetic mice by reducing oxidative stress and improving cholinergic dysfunction in brains[35].

Health products development

The official name of health product varies from countries to countries.In China, it’s named as Supplemental Food (“Bao Jian Shi Pin” in Chinese),and it’s defined as Dietary Supplement in America,Complementary Medicines in Australia,Natural Health Product in Canada.It’s divided into Supplemented Food and Dietary Supplement in New Zeland.In Janpan, health product is officially named as Health Food.

By searching the health product database in Yaozhi Website and the associated official websites,information of CA health products for regulating blood glucose were obtained.In this study, the associated products in China, America, Australia, Canada, New Zealand,Japan were screened,since these six countries are considered as countries with great sales of health products (China, America, Australia, Japan), or countries with advanced research and development of health products (Canada, New Zealand).(“Cinnamomum cassia” AND “blood glucose”) would be adopted as key words to screen the associated products.

While in New Zealand Medicines and Medical Devices Safety Authority website(https://www.medsafe.govt.nz/), no product about CA(CA as active ingredient) is discovered.In Japan, the Supplements & Health Support Food Data Base(http://www.kenshoku-toyaku.jp/) was brought to rest,and we failed to get the associated information.But we learn that it’s authorized that CA is effective in maintain healthy blood glucose and is beneficial in keeping fit(https://hfnet.nibiohn.go.jp/contents/detail508lite.html).The other information of CA health products for regulating blood glucose were summarized in Figure 2.It’s obviously that Australia controls the largest markets of CA registered health products, about 47%,while that is 14% in China (Figure 2A).In these products, CA is mostly used in the form of extracts,and little products are displayed with major components in extraction (Figure 2B).According to the research, CA products for glucose regulation are mainly in dosage form of capsules, tablets, liquids or powders (Figure 2C).It facilitates people to take these products, which conforms to the expectance of supplemental food development.

The registered CA health products for blood glucose regulation is worthy of reference, and it indicated that CA is of great potential in diabetes prevention as well as treatment.But it still needs to be developed, to be advanced,so as to take greatest advantage of CA.

Conclusion

CA enjoys a wide range of biological activities and can be compatible with other medicinal materials for treatment of diseases in clinical.It’s considered that the components of CA, such as cinnamaldehyde,polyphenols, and polysaccharides, are effective in diabetes treatment in various aspects, including reducing insulin resistance, increasing insulin release,regulating glycolipid homeostasis.A number of CA health products for blood glucose regulation have been registered, most of which are in form of oral tablets and capsules.Taking effectiveness .and marketing into consideration, it’s of great potential that CA is beneficial for diabetes prevention and treatment.It’s of interest to develop CA health products to assist blood glucose regulation.

On the whole, cinnamon enjoys multiple commercial genera, while most of the available literatures was lack of specific cinnamon indication.Besides, the purity of CA component in the study remains unknown, leading to results being incomparable among assemble literatures.There is still great potential for the development of CA non-volatile components in maintaining blood glucose homeostasis,no matter in theoretical research or product applications.And employing specific effective CA component in health product development might help to improve efficacy and increase the utilization efficiency of medicinal materials.