2. Abstract Obesity levels have increased significantly in the past five decades, and are predicted to continue rising, resulting in important health implications. In particular, this has translated to an increase in the occurrence of type II diabetes mellitus (T2D). To alleviate associated problems, certain nutraceuticals have been considered as potential adjuncts or alternatives to conventional prescription drugs. Cinnamon, a commonly consumed spice originating from South East Asia, is currently being investigated as a potential preventative supplement and treatment for insulin resistance, metabolic syndrome and T2D. Extensive in vitro evidence has shown that cinnamon may improve insulin resistance by preventing and reversing impairments in insulin signalling in skeletal muscle. In adipose tissue, it has been shown that cinnamon increases the expression of peroxisome proliferator‐activated receptors including, PPARγ. This is comparable to the action of commonly used thiazolinediones, which are PPAR agonists. Studies have also shown that cinnamon has potent anti‐inflammatory properties. However, numerous human clinical trials with cinnamon have been conducted with varying findings. While some studies have demonstrated no beneficial effect, others have indicated improvements in cholesterol levels, systolic blood pressure, insulin sensitivity and postprandial glucose levels with cinnamon. However, the only parameter consistently improved by cinnamon consumption is fasting glucose levels. While it is still premature to suggest the use of cinnamon supplementation based on the evidence, further investigation into mechanisms of action is warranted. Apart from further characterization of genetic and epigenetic changes in model systems, systematic large‐scale clinical trials are required. Here we discuss the mechanisms of action of cinnamon in the context of T2D and we highlight some of the associated controversies. Introduction Obesity is increasingly becoming one of the most common metabolic disorders in the world. The proportion of people with obesity has risen dramatically in the past fifty years, not only in developed countries, but also in parts of the developing world (1, 2). This can be attributed by an increase in sedentary lifestyle and the growing reliance on convenient ‘fast’ and processed foods, which lack in nutrition and are rich in fats and sugars (3‐5). Numerous studies have demonstrated the important role of diet in the prevention of obesity. For example, it has been shown that a diet which promotes a pro‐inflammatory environment can increase the risk of developing obesity, in contrast to diets which promote an anti‐inflammatory environment (6‐10). Obesity can have very serious health implications. It has been associated with a greater risk of cardiovascular diseases, certain cancers such as colon, stomach, gall bladder and pancreatic cancers. Further, it is considered to be one of the factors that has lead to the significant rise in the incidence of insulin resistance, metabolic syndrome and type 2 diabetes mellitus (T2D) (11). With respect to obesity, the most important factors to address are lifestyle changes which include exercise and a healthy diet. Research into alternative methods such as the use of nutraceuticals has become increasingly common for the management of insulin resistance, metabolic syndrome and T2D (12). Nutraceuticals are naturally occurring compounds found in foods which may have physiological health benefits and protect against chronic disease, such as T2D. Nutraceuticals are an attractive option due to their natural occurrence in foods and the perceived decreased risk of side effects compared to certain prescription drugs. Many nutracuticals are increasingly becoming available commercially. For example, resveratrol, found in red grapes, is currently marketed as an anti‐cancer and anti‐inflammatory supplement, which is supported by extensive findings in cell culture and animal model studies (13, 14). A common spice which has been extensively researched as a potential treatment for T2D is cinnamon. Cinnamon supplements are already being sold as preventative or therapeutic supplement for various diseases, including T2D, metabolic syndrome, insulin resistance, asthma,
3. arthritis, cancer and elevated cholesterol. However, as with many other nutraceuticals the precise health benefits in humans are still controversial. Cinnamon is a spice produced from the bark of numerous trees from the genus Cinnamomum (Fig. 1). There are several species which are native to South East Asia. Sri Lanka has traditionally been the main exporter of cinnamon, with reports of exportation to ancient Egypt as far back as 1400 BCE. Cinnamon was introduced to Europe from Sri Lanka in the early 16th century by the Portuguese. This was the Cinnamomum zeylancium species, and is often referred to as true cinnamon. Cinnamon was originally harvested from naturally occurring trees until the Dutch East India Company became the main exporter of cinnamon following their capture of Sri Lanka from the Portuguese and began mass cultivation of cinnamon for trade. The process involves stripping the bark from the tree while it is still wet, after which the outer bark is disposed and the inner bark is allowed to curl into the familiar cinnamon quills after drying. Cinnamon has been used extensively in traditional medicines for many different ailments, including rheumatism, wounds, diarrhoea, headache and colds. It is also used as a natural food preservative. Biological effects of cinnamon The potential mechanisms of action of cinnamon in relevant metabolic pathways are summarized in Fig. 2. Numerous studies demonstrate potential beneficial effects of cinnamon, including potent antioxidant, anti‐inflammatory and anti‐bacterial properties (12, 15, 16). Research into the health benefits of cinnamon has focused mostly on its potential to treat or prevent insulin resistance, metabolic syndrome and T2D (17‐19). T2D is a complex metabolic disorder of impaired insulin sensitivity (insulin resistance) of peripheral tissue such as skeletal muscle and impaired insulin secretion (20, 21). The exact mechanism of insulin resistance is poorly understood, but involves defects in the insulin signalling pathway, such as impaired activation of phosphatidylinositol 3‐kinase (PI3K) and downstream signalling (22). As a result of insulin resistance, glucose is not taken up effectively by the peripheral tissue and since the pancreas cannot compensate for the insulin resistance by over producing insulin (hyperinsulineamia, which occurs in pre‐diabetic insulin resistance and metabolic syndrome), glucose concentration increases in the blood stream. T2D occurs in certain individuals as a result of lifestyle factors such as diet and obesity, as well as genetic predisposition (23). T2D can lead to severe and life threatening complications, including cardiovascular disease, retinopathy, nephropathy and non‐healing diabetic foot ulcers. The modern literature indicates that the potential anti‐diabetic properties of cinammon have been studied for over 20 years. An early in vitro study using the rat epididymal fat cell assay, indicated that cinnamon, or specifically, an unidentified water soluble component of cinnamon, potentiated insulin activity (16). However, cinnamon contains many different compounds such as cinnamaldehyde, eugenol, camphor and polyphenols as well as trace elements (calcium, chromium, copper, iodine, iron, manganese, phosphorus, potassium, zinc) and vitamins making it difficult to identify which compounds were mediating this effect. In a more recent study, which indicated a 20‐fold enhancement in insulin‐dependent glucose metabolism following treatment with cinnamon, active water soluble components were isolated, and found to be the components which mediate the beneficial effects (24). These components were identified as the double linked procyanidin type‐A polymers which usually occur as trimers and tetramers, of the flavanoids catechin and epicatechin and possess potent antioxidant properties.
4. Molecular mechanisms of action of cinnamon A main mechanism of action of cinnamon focuses on the ability of water soluble extracts to promote insulin signalling. Firstly, treatment with cinnamon polyphenols has been shown to increase the autophosphorylation of insulin receptors as well as decrease the activity of tyrosine phosphatase which inactivates the receptor in vitro (25). The combined effect of these actions is an increase in insulin sensitivity. It also increases the amount of IRβ, insulin receptor substrate‐1 and GLUT4, which allows glucose uptake into the cell, thus enhancing cellular glucose uptake (26, 27). Increased glycogen biosynthesis, activated glycogen synthase and inhibition of glycogen synthase kinase‐3β (GSK3 β) has also been observed (28). Furthermore, increased expression of tristetraprolin (TTP), an anti‐inflammatory compound, may be involved in the prevention of inflammation associated with adipose tissue in obesity (26). Another potential mechanism of action of cinnamon extract involves the activation of the transcription factors, peroxisome proliferator‐activated receptors (PPARs). PPARs have been shown to be involved in the regulation of insulin resistance and adipogenesis, and PPAR agonists such as thiazolinediones have long been used clinically in the treatment of T2D and insulin resistance (29‐31). In one study it was found that water soluble cinnamon extract was able to induce the expression of PPARγ and PPARα both in vitro and in vivo in mouse adipose cells (32). It was shown in 3T3‐L1 that there was an increase in the expression of PPARγ and PPARα and their target genes (GLUT4, CD36, LPL, FAS, ACO). Further, cinnamon extract caused the differentiation of 3T3‐L1 pre‐adipocytes to adipocytes (32). In vivo it was found that in a mouse model of diabetes where the mice were fed a high calorie diet, supplementation with cinnamon extract improves the results of an intra‐peritoneal glucose tolerance test compared to controls (32). Also, cinnamon extract improved hyperinsulinemia and reduced serum free fatty‐acid levels. However, increases in the expression of in PPARγ and the related genes CD36 and LDL in white fat tissue and PPARα and the target gene ACO in liver, were also observed. However, these effects have only been demonstrated in animal models and it has yet to be proven that cinnamon has similar effects in humans. In contrast, another study has shown that cinnamaldehyde, one of the main components of the essential oil of cinnamon, resulted in a decrease in the levels of PPARγ (33). Cinnamon may also mediate anti‐diabetic effects by preventing inflammation. In one study, it was found that treatment with cinnamon extract resulted in the decreased expression of IL‐1β, IL‐6 and TNF‐α mRNA, while increasing the expression of IR, IRS1, IRS2, PI3K and Akt1 in hamster enterocytes (34). Cinnamon extract also inhibited regulators of lipid metabolism CD36 and microsomal triglyceride transfer protein (MTTP) in enterocytes. Using an in vivo model of TNF‐α‐induced dyslipidemia in Triton WR‐1339 treated hamsters, it was found that diet supplementation with 50 mg/kg water soluble cinnamon extract resulted in a reduction in serum triglyceride levels and inhibition of the postprandial overproduction of intestinal apolipoprotein B48 containing lipoprotein. This indicates that cinnamon extract may be involved in the improvement of the postprandial state and intestinal dyslipidemia by its ability to counteract gene changes induced by the proinflammatory cytokine TNFα, one of the main contributors of obesity associated meta‐inflammation (34). Clinical studies with cinnamon Overall, a plethora of studies have demonstrated the beneficial metabolic effects of cinnamon and its components in vitro and in animal models. Numerous trials have been conducted in humans to determine the metabolic effects of cinnamon and the results remain controversial. We have reviewed sixteen studies that have been performed to investigate the biological effects of cinnamon in humans. Of those, only five found no significant affect on the parameters studied, while all of the other studies found significant beneficial changes caused by cinnamon. Of the studies conducted,
5. five investigated the effects of cinnamon consumption in healthy individuals and six studies investigated effects in individuals with T2D. The remaining studies have investigated the effects of cinnamon in people with type 1 diabetes mellitus (T1D), metabolic syndrome, impaired fasting glucose, postmenopausal women and women with polycystic ovarian syndrome. The first study to examine the effects of cinnamon in humans showed very promising results. A group of 30 men and 30 women with T2D being managed using sulfonylurea drugs were randomly allocated into six groups, and were instructed to consume either 1, 3 or 6 grams of cinnamon each day for 40 days, in the form of capsules. The remaining three groups were given placebos which corresponded with the number of cinnamon capsules being taken by the cinnamon group. After the 40 day period of cinnamon consumption, it was found that with all the different doses of cinnamon there was a decrease in fasting serum glucose levels (18‐29%), as well as the triglyceride, LDL cholesterol and total cholesterol levels, which was not matched by the placebo groups (17). Although many other studies have demonstrated beneficial effects of cinnamon, this study indicated the most striking results and changes. One reason for this may be that the patients were also taking sulfonylurea drugs which increase insulin secretion – this increased secretion coupled with the role of cinnamon in reducing insulin resistance may have lead to improved outcomes. There are five other studies performed in T2D patients, two of which indicated no significant effects with cinnamon. Of the studies that did show beneficial effects, Mang et al found that intake of 3 grams of water soluble cinnamon extract for 120 days resulted in decreased fasting glucose levels (35) while Crawford et al demonstrated that cinnamon (1 gram/day) decreased HbA1c (36). The study by Blevins et al did not show any significant effects as a result of cinnamon supplementation and neither did a study involving postmenopausal woman with T2D (37, 38). This may be a consequence of patients already taking various diabetic drugs, including metformin, thiazoledinedione and hydroxylmethylglutaryl‐coenzyme A reductase inhibitors (statins). Furthermore, duration may be an important issue. The duration of the study with postmenopausal women was only 6 weeks and other studies have indicated a lack of beneficial effects after 6 weeks, in contrast to 12 weeks (39‐41). In addition, one study was performed in patients with T1D, and no significant results were found with cinnamon supplementation. This result is expected as T1D is primarily a disease of insulin secretion and not insulin resistance (42). Of the five studies performed in healthy individuals, four showed some beneficical effects of cinnamon whereas only one did not. This negative study was designed to determine the effect of cinnamon consumption on oxalate excretion; however fasting plasma glucose, total cholesterol, and triacylglycerols levels were also measured, and no significant effect with cinnamon was found (43). In one study with seven healthy, lean young males, consumption of cinnamon lead to a decrease in the total plasma glucose response to an oral glucose test, which was found to be sustained effect for over 12 hours (44). In a follow up study where cinnamon was consumed over two 14 day periods, it was shown there was an improvement in both glucose and insulin sensitivity (45). Other studies showed that when 6 grams of cinnamon was taken simultaneously with food (rice pudding), there was a decrease in postprandial glucose and a decrease in gastric‐emptying rate (46), however the same effect was not found in a follow up study using 1 and 3 grams of cinnamon (47). These findings highlight the potential preventative effects of cinnamon. In a study with participants with metabolic syndrome, it was shown that 500 mg/day of Cinnulin PF® (a commercial aqueous extract of cinnamon containing the bioactive double linked procyanidin type‐A trimers and tetramers) resulted in improvements in the fasting blood sugar levels, as well in systolic blood pressure and body fat composition (40). In another study where participants had impaired fasting glucose, it was found that there was an improvement in impaired fasting glucose as well as an improvement in the antioxidant status and therefore reduction of oxidative stress which was attributed to cinnamon intake (39). A study in which women with PCOS, which is associated with
6. insulin resistance, also demonstrated that daily cinnamon consumption (1 gram/day Cinnulin PF) resulted in the improvement in insulin sensitivity. Although some studies with cinnamon did not show any effects, the majority of studies performed did consistently demonstrate beneficial effects of cinnamon on multiple parameters, especially decreasing fasting and postprandial glucose levels and improving insulin sensitivity. One meta‐analysis of the available literature indicated that cinnamon did cause a significant decrease in fasting blood glucose (48). However, another meta‐analysis concluded that cinnamon did not appear to improve A1C, FBG, or lipid parameters in patients with T1D or T2D highlighting the controversial nature of the field (49). Conclusions Overall, the potential beneficial metabolic effects of cinnamon remain controversial. There may be many different reasons for the discrepancies observed in human trials to date. One possibility may be the variation in the type of cinnamon used. There are many different species of cinnamon available commercially and these may differ in their properties and the effects they elicit. Further, the chemical composition of the same type of cinnamon may be affected based on geography and preparation. Most studies have used Cinnamomum cassia, although many did not specify. In some studies only the water soluble extract of cinnamon, rather than the whole spice, is used, which is likely to add variability. It is possible that use of the extract may help to concentration the active components. Furthermore, there was variation in the sample population chosen, which ranged from healthy individuals, to those with metabolic syndrome and T1D and T2D. Since cinnamon is believed to promote insulin sensitivity, it may be expected that the effectiveness would be greater in those whose disease state was more progressed such as in T2D, rather than those with milder insulin resistance, or minimal insulin resistance. Furthermore, it has yet to be established whether cinnamon polyphenols, believed to be the key active components are absorbed in the gut and whether they reach relevant concentrations in the plasma. It is also unclear whether they act directly to influence gene expression, or by other mechanisms. By considering the evidence it does appear that cinnamon has beneficial effects at least on fasting blood glucose. In contrast, the effects of cinnamon on other parameters have not been as consistent. Given the interest in nutraceuticals, undoubtedly further research will delineate the mechanisms of action of cinnamon in metabolism and systematic large‐scale human studies will resolve the current controversies. Acknowledgements The support of the Australian Institute of Nuclear Science and Engineering is acknowledged. TCK was the recipient of AINSE awards. Epigenomic Medicine is supported by the National Health and Medical Research Council of Australia. Supported in part by the Victorian Government’s Operational Infrastructure Support Program.
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10. Figure Legends Figure 1. Cinnamon has been a highly valued spice for its culinary and medicinal properties since antiquity. Both true cinnamon (Cinnamomum zeylancium) and cassia (depicted, Cinnamomum aromaticum) contain numerous bioactive compounds, a principle component being cinnamaldehyde. Contemporary research indicates that cinnamon may be beneficial in Type‐II diabetes. It is thought that the double‐linked, water‐soluble procyanidin Type‐A polymers of the potent catechin antioxidant are responsible for the favourable effects of cinnamon in diabetes.
11. Figure 2. In addition to genetic predisposition, lifestyle factors such as a sedentary lifestyle and poor diet are important determinants in the development of obesity and T2D. As depicted by the robust cartoon (blue font), obesity can have very serious health implications. It has been associated with a greater risk of cardiovascular diseases and cancer. It also results in an increase in free fatty acids and inflammation in adipose tissue. All these factors can contribute to insulin resistance of peripheral tissue such as skeletal muscle and impaired insulin secretion, and increase the chance of metabolic syndrome and type 2 diabetes mellitus (T2D). A cartoon depicting a healthy physique (black font), with an active lifestyle and healthy diet has opposing metabolic effects which include: effective glucose uptake, low adiposity and no insulin resistance. These factors decrease the risk of metabolic disorder such as obesity and T2D. The middle cartoon (green font) represents genetic/epigenetic predisposition to the development of diabetes and obesity. Alteration in lifestyle can impact the risk of developing metabolic disorders. The intake of nutraceuticals such as cinnamon, which may have health benefits in the context of diabetes (indicated in the pathways in red) may potentially decrease the risk. A potential mechanism of action of cinnamon extract involves the activation of the transcription factors, peroxisome proliferator‐activated receptors (PPARs). PPARs have been shown to be involved in the regulation of insulin resistance and adipogenesis, and PPAR agonists such as thiazolinediones have long been used clinically in the treatment of T2D and insulin resistance. (A) Increases in the expression of in PPARγ and the related genes CD36 and LDL in fat tissue. (B) In the liver, cinnamon extract increases PPARα and the target gene ACO. (C) Treatment with cinnamon polyphenols has been shown to increase the autophosphorylation of insulin receptors as well as to decrease the activity of tyrosine phosphatase which inactivates the receptor in skeletal muscle. The combined effect of these actions is an increase in insulin sensitivity. Cinnamon also increases the amount of IRβ, insulin receptor substrate‐1 and GLUT4, which allows glucose uptake into the cell, thus enhancing cellular glucose uptake, increased glycogen biosynthesis, activated glycogen synthase and inhibition of glycogen synthase kinase‐3β (GSK3 β). (D) Cinnamon may also mediate anti‐diabetic effects by preventing inflammation. Cinnamon extract may result in the decreased expression of IL‐1β, IL‐6 and TNF‐α mRNA, while increasing the expression of pro‐inflammatory cytokines in enterocytes.
12. Table 1. A summary of human studies where patients with type 2 diabetes, metabolic syndrome, impaired fasting glucose and associated diseases were treated with cinnamon. Condition Study Cohort Age (years) Country Medication Duration Amount of Baseline Glycemia Main findings (Male/ cinnamon used (fasting) reduction Female) per day glycemia T2D Khan 2003 60 52.2 ± 6.32 Pakistan Sulfonylurea drugs 40 days 1, 3, or 6 g of 7.8 ‐ 22.2 23 ‐ 30 % Significant reduction of (30/30) cinnamon mmol/L glucose, triglyceride, LDL (average 11.6‐ cholesterol, and total 13.0 mmol/L) cholesterol levels T2D Mang 2006 65 62∙8 ± 8∙37 Hannover, Anti‐diabetic drugs (metformin, 4 months ACE*, 9∙26 ± 2∙26 10% (8∙15 ± Significant reduction of (44/21) (cinnamon), Germany sulphonylureas, glinides, equivalent of 3 mmol/L 1∙65) glucose levels 63∙7 ± 7∙17 glitazones, combination g of cinnamon (placebo) therapies), or diet only. No powder insulin therapy T2D Vanschoonbeek 25 62.9 ± 1.5 Netherlands Sulfonylurea derivatives, 6 weeks 1.5 g, 8.37 ± 0.59 7.91 ± 0.71 No significant changes 2006 (‐/25) Post‐ thiazolidinediones, metformin Cinnamomum mmol/L mmol/L menopause derivatives, cassia or diet only T2D Blevins 2007 58 63.6 USA Variable anti‐diabetic 3 months 1 g cinnamon 132.9 ± 9.3 Δ glucose No significant changes (49/51) (cinnamon), medications (metformin, mg/dL 9.8 ± 5.9 58.0 thiazoledinedione, mg/dL (placebo) hydroxymethylglutaryl‐CoA reductase inhibitor) T2D Crawford 2009 109 60.5 ± 10.7 USA Insulin, variable anti‐diabetic 90 days 1 g cinnamon N/A N/A Significant reduction of HbA1C (64/45) (cinnamon), drugs (0.83%) 59.9 ± 9.2 (control) Metabolic Ziegenfuss 2006 22 46.0 ± 9.7 USA Not treated 12 weeks ACE, 0.5 g, 116.3 ± 12.8 106.5 ± 20.1 Significant reduction in fasting syndrome (11/11) equivalent of 10 mg/dL mg/dL glucose levels after 12 weeks, g of cinnamon and systolic blood powder pressure and body fat levels Polycystic Wang 2007 15 31.1 ± 2.0 USA Not treated 8 weeks ACE, 1 g 92.57 mg/dL 85.43 No significant changes in ovary (‐/15) mg/dL glucose levels. Significant syndrome increase in insulin sensitivity. Impaired Roussel 2009 22 45.6 ± 2.7 France Not treated 12 weeks ACE, 0.5 g, 114 ± 2.2 102 ± 4.3 Significant reduction in fasting fasting (cinnamon) equivalent of 10 mg/dL mg/dL glucose levels after 12 weeks glucose 45.8 ± 3.6 g of cinnamon years powder (placebo) *ACE: Aqueous cinnamon extract