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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Funding sources
  9. Competing interests
  10. References

Diabet. Med. 29, 1480–1492 (2012)

Abstract

Aims  Diabetes is a leading cause of morbidity and mortality worldwide. Studies have frequently looked at dietary components beneficial in treatment and prevention. We aim to systematically evaluate the literature on the safety and efficacy of Cinnamomum zeylanicum on diabetes.

Methods  A comprehensive search of the literature was conducted in the following databases; PubMed, Web of Science, Biological Abstracts, SciVerse Scopus, SciVerse ScienceDierect, CINAHL and The Cochrane Library. A meta-analysis of studies examining the effect of C. zeylanicum extracts on clinical and biochemical parameters was conducted. Data were analysed using RevMan v5.1.2.

Results  The literature search identified 16 studies on C. zeylanicum (five in-vitro, six in-vivo and five in-vivo/in-vitro). However, there were no human studies. In-vitro C. zeylanicum demonstrated a potential for reducing post-prandial intestinal glucose absorption by inhibiting pancreatic α-amylase and α-glucosidase, stimulating cellular glucose uptake by membrane translocation of glucose transporter-4, stimulating glucose metabolism and glycogen synthesis, inhibiting gluconeogenesis and stimulating insulin release and potentiating insulin receptor activity. The beneficial effects of C. zeylanicum in animals include attenuation of diabetes associated weight loss, reduction of fasting blood glucose, LDL and HbA1c, increasing HDL cholesterol and increasing circulating insulin levels. Cinnamomum zeylanicum also significantly improved metabolic derangements associated with insulin resistance. It also showed beneficial effects against diabetic neuropathy and nephropathy, with no significant toxic effects on liver and kidney and a significantly high therapeutic window.

Conclusion  Cinnamomum zeylanicum demonstrates numerous beneficial effects both in vitro and in vivo as a potential therapeutic agent for diabetes. However, further randomized clinical trials are required to establish therapeutic safety and efficacy.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Funding sources
  9. Competing interests
  10. References

Diabetes mellitus is a leading cause of morbidity and mortality worldwide, with an estimated 346 million adults worldwide being affected in year 2011 [1]. The prevalence is expected to double between the years 2005–2030, with the greatest increases expected in low- to -middle-income developing countries of Africa, Asia and South America [1,2]. The health-care expenditure for diabetes in 2010 was 11.6% of the world’s total health-care costs [3]. Eighty per cent of the worlds’ population with diabetes live in low- to middle-income countries, resulting in a significant economical strain on these developing economies [1,3]. Diabetes is also associated with a host of life-threatening and potentially disabling macrovascular and microvascular complications [4]. Hence, there is also a much larger economical burden in the form of lost productivity as a result of restricted daily activity, reduced work efficiency and permanent disability.

Ninety per cent of those with diabetes have the Type 2 diabetes, characterized by insulin resistance, hyper insulinaemia, β-cell dysfunction and subsequent β-cell failure [5]. Present pharmacological therapies aim at correcting/overcoming these defects [6]. In the USA, 84% adults with diabetes are on either oral medication or insulin, while 16% were not taking any allopathic treatment [7]. Studies have consistently demonstrated that patients’ adherence to present therapeutic regimes are poor [8]. Regime complexity, hypoglycaemia and other side effects, lack of confidence in immediate or future benefits and patients’ education/beliefs are among the common reasons limiting compliance [9–12]. Inadequacies in current treatment regimes have resulted in 2–3.6 million people in USA relying on complementary and alternative medicines for management of diabetes [13]. In addition, recent estimates show that > 80% of the people living in developing countries still prefer to depend on complementary and alternative medicines [14]. Even in developed countries such as the USA 71.8% use complementary and alternative medicines for treatment of diabetes [15]. Diet plays an important role on the incidence, severity and management of diabetes [16]. Hence studies have frequently focused on dietary components beneficial in prevention and treatment. Recent studies have demonstrated that many herbal/natural products have beneficial effects in patients with diabetes by improving glucose and lipid metabolism, antioxidant status and capillary function [17].

The genus Cinnamomum comprises of about 300 species, of which four species are used to obtain the spice ‘cinnamon’ [18]. Ceylon/’True’ cinnamon (Cinnamomum zeylanicum) and Chinese Cassia cinnamon (Cinnamomum aromaticum) are the most widely available varieties [18]. Studies have demonstrated many beneficial health effects of cinnamon, such as anti-inflammatory properties, anti-microbial activity, blood glucose control, reducing cardiovascular disease, boosting cognitive function and reducing risk of colonic cancer [19,20]. Previous studies have demonstrated anti-diabetic effects of C. aromaticum extracts in vivo and in vitro [21,22], however results from recent meta-analysis has been equivocal [23]. Cinnamomum zeylanicum, also known as Ceylon cinnamon or ‘true cinnamon’ is indigenous to Sri Lanka [18]. One significant difference between the two varieties is their coumarin content [24]. Coumarins are naturally occurring plant compounds with strong anticoagulant, carcinogenic and hepato-toxic properties [25]. The levels of coumarins in C. aromaticum appear to be very high and pose health risks if consumed regularly in higher quantities. In contrast, coumarin can only be found in trace amounts in C. zeylanicum [26]. This has resulted in several agencies advocating against the regular use of C. aromaticum as a supplement in diabetes [26]. Although there are systematic reviews summarizing the therapeutic use of C. aromaticum in diabetes [23], presently there are no scientific reviews exploring the therapeutic efficacy of C. zeylanicum on diabetes. The present study aims to systematically evaluate the literature on the effects of C. zeylanicum extracts on diabetes and document potential toxic effects.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Funding sources
  9. Competing interests
  10. References

Literature search

A systematic review of published studies reporting the effects of C. zeylanicum on diabetes was undertaken in accordance with the Meta-analysis of Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement for systematic reviews of interventional studies [27]. A comprehensive search of the literature was conducted in the following databases; PubMed, Web of Science (v.5.3), Biological Abstracts, SciVerse Scopus, SciVerse ScienceDirect, CINAHL and The Cochrane Library for studies published before 1 August 2011. We used the following medical subject headings and keywords: ‘Cinnamomum zeylanicum’, ‘Ceylon cinnamon’, ‘True cinnamon’ and ‘Sri Lankan cinnamon’ in combination with ‘diabetes’, ‘type-2 diabetes’, ‘type-1 diabetes’, ‘diabetes mellitus’, ‘glucose’ and ‘insulin’. Results were limited to studies in English, while conference proceedings and commentaries were excluded.

In the second stage the total hits obtained from searching the databases using the above search criteria was screened by reading the ‘full copy’ or ‘abstracts’. Studies not satisfying the inclusion criteria were excluded at this stage. To obtain additional data a manual search was performed using the reference lists of articles included and relevant websites/sources. Wherever possible, forward citations of the studies retrieved during the literature search was traced and screened for possible inclusion. This search process was conducted independently by two reviewers and the final group of articles to be included in the review was determined after an iterative consensus process.

Data extraction and analysis

A meta-analysis of studies examining the effect of C. zeylanicum extracts on clinical and biochemical parameters was conducted if the parameter of interest was reported in three or more studies. Hence the meta-analysis was performed on the following clinical and biochemical parameters; weight loss (WL), fasting blood glucose (FBG), total cholesterol (TC), high density lipoprotein-cholesterol (HDL-C), triglycerides (TAG) and insulin. Weight loss and fasting blood glucose were calculated as the difference between values at conclusion of experiment and day 0. In the remaining parameters the differences between means of control and experimental group at conclusion of experiment was used. Where studies used more than one dose of C. zeylanicum the most effective dose, as deemed by the authors of the particular study for the given parameter, was used. A fixed effect analysis was initially conducted for all comparisons. Heterogeneity was assessed using a χ2 test on Cochrane’s Q statistic [28] and by calculating I2 [29]. If significant heterogeneity was present (< 0.05 from the χ2 test) a random effects meta-analysis was carried out. Potential sources of heterogeneity were investigated by comparing study designs. Forest plots were used to illustrate the study findings and meta-analysis results. Data were analysed using revman version 5.1.2 (Review Manager, Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011) statistical software package. In all analyses a P-value < 0.05 was considered statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Funding sources
  9. Competing interests
  10. References

Literature search

The literature search using the above search criteria identified the following number of articles in the respective databases – PubMed (= 21), Web of Science (= 13), Biological Abstracts (= 12), SciVerse Scopus (= 32), SciVerse ScienceDirect (= 16), Cochrane (= 5) and CINHAL (= 4) – of which 13 satisfied the inclusion and exclusion criteria [30–42]. Three additional articles were identified by manually searching the reference lists and forward citations of papers included [43–45]. Hence, the total number of articles included in the present review is 16, which included five in-vitro studies, six in-vivo animal studies and five in-vivo/in-vitro studies. We were unable to identify any in-vivo human studies on C. zeylanicum. The search strategy is summarized in Fig. 1 and a description of the studies included is provided in Table 1. The in-vivo studies were conducted on Wistar rats, with diabetes mellitus being induced either by streptozotocin (= 9) or alloxan (= 2). In addition, the in-vivo studies evaluated the effects of either a single-administration (= 2) of C. zeylanicum or daily administration over a period of time (= 9), with the durations varying from 10 to 60 days. Authentication of the cinnamon specimen was done only in 6 of the 16 studies (37.5%).

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Figure 1.  Summarized search strategy.

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Table 1. Description of the studies included
Authors [reference]Study designStudy descriptionParameters studiedCZ dose (mg/kg)Substances used
  1. LD50, median lethal dose.

Adisakwattana et al. 2011 [43] in vitro’ ThailandPorcine α-amylase and rat intestinal acetone powder (intestinal α-glucosidase)Inhibitory activity on intestinal α-glucosidase and pancreatic α-amylase Not applicableFour types of cinnamon (including Cinnamomum zeylanicum) and acarbose
Al-Logmani et al. 2009 [30] in vivo, Saudi ArabiaWistar rats: streptozotocin-induced diabetes (= 40) and healthy (= 10); five groups; duration 21 daysBody weight; fasting blood glucose; LDL-cholesterol; HDL-cholesterol; triglycerides; total protein; blood urea; creatinine; uric acid; aspartate aminotransferase; alanine aminotransferase;Not mentioned Nigella sativa L. and C. zeylanicum blume oils
Anand et al. 2010 [31] in vivo and in-vitro, IndiaWistar rats: streptozotocin-induced diabetes (= 18) and healthy (= 6); four groups; duration 60 days In vivo: body weight; fluid intake; organ weight; fasting blood glucose; HbA1c; insulin; LD50 In vitro: pancreatic insulin release; glycogen content; pyruvate kinase and phosphoenolpyruvate carboxykinase activity and mRNA level; muscle glucose transporter-4 level20Cinnamaldehyde from C. zeylanicum blume and glibenclamide
Gumy et al. 2009 [32] in vitro, Switzerland11β-hydroxysteroid dehydrogenase activity of cultured HEK-293 cells Inhibition of 11β-hydroxysteroid dehydrogenaseNot applicable Cinnamomum zeylanicum blume and five plant extracts
Kannappan et al. 2006 [44] in vivo, IndiaWistar rats: HFD (= 18) and normal diet (= 12); five groups; duration 60 daysBody weight; fluid intake; fasting blood glucose; oral glucose tolerance test; insulin; HbA1c; triglycerides; free fatty acids; total cholesterol; phospholipids; enzyme assay10 and 100 Cinnamomum zeylanicum blume
Mishra et al. 2010 [33] in vivo and in vitro, IndiaWistar rats; alloxan-induced (= 36) and healthy (= 6); seven groups; duration 14 daysfasting blood glucose; total cholesterol; HDL-cholesterol; blood urea; glutathione levels; catalase activity; renal histology and lipid peroxidation5, 10 and 20 Cinnamomum zeylanicum blume and glipizide
Rajbir et al. 2009 [34] in vivo, IndiaWistar rats: alloxan-induced (= 42) and healthy (= 6); eight groups; duration 14 daysfasting blood glucose; thermal hyperalgesia (tail-immersion and hot-plate tests)5, 10 and 20 Cinnamomum zeylanicum blume, glipizide and fluoxetine
Ranilla et al. 2010 [35] in vitro, ChilePorcine pancreatic α-amylase, baker’s yeast α-glucosidaseTotal phenolic content; inhibitory effect on α-amylase, α-glucosidase and angiotensin-converting enzymeNot applicable Cinnamomum zeylanicum blume and 26 plant extracts
Roffey et al. 2006 [36]in-vitro, CanadaCultured 3T3-L1 adipocytesGlucose uptake and adiponectin secretion in 3T3-L1 adipocytesNot applicable Cinnamomum zeylanicum blume and insulin
Shen et al. 2010 [37] in vivo and in vitro, JapanWistar rats: streptozotocin-induced diabetes (= 20) and healthy (= 10); six groups; duration 22 days; cultured 3T3-L1 adipocytes In vivo: body weight; organ weight; fasting blood glucose; Insulin; total cholesterol; triglycerides; free fatty acids; HDL; creatinine; total protein; renal histology In vitro: glucose uptake3, 30 and 100 Cinnamomum zeylanicum blume
Shihabudeen et al. 2011[45] in vivo and in vitro, IndiaWistar rats: streptozotocin-induced diabetes (= 36) and healthy (= 30); 11 groups; single administration; yeast and rat intestinal α-glucosidase In vivo: blood glucose at 30, 60 and 120 minutes after maltose, sucrose or glucose loading dose In vitro: inhibition on yeast and rat intestinal α-glucosidase, mode of inhibition and reversibility300 Cinnamomum zeylanicum blume and acarbose
Soonham et al. 2010 [38] in vivo and in vitro, Saudi ArabiaWistar rats: streptozotocin-induced diabetes (= 40) and healthy (= 10); five groups; duration 10 days In vivo: fasting blood glucose; insulin; total cholesterol; triglycerides In vitro: liver and intestinal phosphofructokinase-1 activity2500 and 5000 Cinnamomum zeylanicum blume and insulin
Subash Babu et al. 2007 [39] in vivo, IndiaWistar rats: streptozotocin-induced diabetes (= 48) and healthy (= 16); seven groups; duration 45 daysBody weight; food intake; fasting blood glucose; insulin; HbA1c; total cholesterol; HDL; triglycerides; aspartate aminotransferase/alanine aminotransferase; alkaline phosphatase; acid phosphatase; lactate dehydrogenase; liver glycogen content; LD505, 10 and 20Cinnamaldehyde from C. zeylanicum blume and glibenclamide
Taher et al. 2006 [40] in vitro, MalaysiaCultured 3T3-L1 adipocytesActive compound isolation; Phosphorylation of insulin receptor in 3T3-L1 adipocytesNot applicable Cinnamomum zeylanicum blume
Verspohl et al. 2005 [41] in vivo, GermanyWistar rats: healthy (4–5), single administrationBlood glucose and insulin at 0, 15, 60, 120 and 240 minutes5.96 Cinnamomum zeylanicum and Cinnamomum cassia
Zari et al. 2009 [42] in-vivo, Saudi ArabiaWistar rats: streptozotocin-induced diabetes (= 20) and healthy (= 20); four groups; duration 49 daysfasting blood glucose; triglycerides; total cholesterol; HDL-cholesterol; LDL-cholesterol; total protein; creatinine; uric acids; blood urea; aspartate aminotransferase; alanine aminotransferaseNot mentioned Cinnamomum zeylanicum blume

In-vitro effects

Regulation of enzymes of carbohydrate metabolism, glycolysis and gluconeogenesis

Adisakwattana et al. [43] evaluated the inhibitory activity on intestinal α-glucosidase (maltase and sucrase) and pancreatic α-amylase of four types of cinnamon species (including C. zeylanicum) and their combination effect with acarbose. They demonstrated that all four types of cinnamon inhibited maltase, sucrase and pancreatic α-amylase. Thai cinnamon (Cinnamomum bejolghota) extract was the most potent inhibitor against the intestinal maltase. Cinnamomum zeylanicum was the most effective intestinal sucrase and pancreatic α-amylase inhibitor with IC50 (half maximal inhibitory concentration) values of 0.42 ± 0.02 and 1.23 ± 0.02 mg/ml, respectively. However, this inhibitory activity was less potent than acarbose against pancreatic α-amylase, intestinal maltase and intestinal sucrase. When combined with acarbose the cinnamon extracts produced an additive inhibitory effect against all three enzymes than when used alone. Ranilla et al. [35] demonstrated that C. zeylanicum extracts posses a high dose-dependent α-glucosidase inhibitory activity (100% at 2.5 mg and 95% at 0.5 mg of dried sample) and a high α-amylase inhibitory activity (77%, 72% and 51% at 25 mg, 12.5 mg and 5 mg of dried sample, respectively). Shihabudeen et al. [45] indicated that the inhibitory activity of α-glucosidase is dose-dependent, competitive (enzyme kinetics data fit to Lineweaver–Burk plot) and reversible (membrane dialysis experiment).

The effect of C. zeylanicum extracts and glibenclamide on pyruvate kinase and phosphoenol pyruvate carboxykinase activity and their m-RNA expression in diabetes-induced rat liver and kidney was evaluated by Anand et al. [31]. The pyruvate kinase activity in liver and kidney in untreated diabetes rats was significantly reduced compared with healthy controls, whereas treatment with cinnamon and glibenclamide for 60 days restored it to near-normal values in the respective treatment groups, with cinnamon being more effective than glibenclamide. Pyruvate kinase m-RNA expression of liver was significantly decreased by 64% in the untreated group, treatment of diabetic rats with cinnamon and glibenclamide resulted in reversal of pyruvate kinase m-RNA levels in liver to 95.5% and 89%, respectively; similar results were observed in kidney pyruvate kinase m-RNA expression. In diabetic untreated animals a significantly (< 0.01) increased activity of phosphoenol pyruvate carboxykinase was observed in comparison with healthy controls (liver 60%; kidney 85%). Treatment with cinnamon and glibenclamide in diabetic rats resulted in reversal of phosphoenol pyruvate carboxykinase activity to values still slightly above normal, while cinnamon was superior to glibenclamide. Phosphoenol pyruvate carboxykinase m-RNA expression in liver and kidney also showed a similar pattern.

The fructose-fed rat was used as an animal model of insulin resistance by Kannappan et al. [44]. The increased activities of glucose-6-phosphatase and fructose-1,6-bisphosphatase in liver, kidney and skeletal muscle in untreated fructose-fed rats was not observed in the group treated with cinnamon extracts at 2 ml/day per rat for 60 days. Similarly, the reduced glucose-6-phosphate dehydrogenase activity in untreated fructose-fed rats was near normal in those treated with cinnamon. However, lower doses of cinnamon (0.2 ml/day per rat) did not demonstrate these effects. Soonham et al. [38] demonstrated that the liver phosphofructokinase-1 activity was significantly increased by 33% and 39%, respectively, in rats treated with 0.5 g and 1.0 g cinnamon compared with untreated controls, with a 30% decrease in activity. Similarly, intestinal phosphofructokinase-1 activity also increased by 14% and 36%, respectively, with the same doses.

Stimulation of cellular glucose uptake and glycogen content

Roffey et al. [36] evaluated the effect of cinnamon on glucose uptake in cultured adipocytes. In the absence of insulin, adipocytes exposed to 0.2 mg/ml cinnamon showed an approximate twofold increase in glucose uptake relative to controls. No effect of cinnamon on glucose uptake was noted in the presence of 0.5 nm insulin, whereas two higher concentrations (0.3mg/ml and 0.4 mg/ml) of cinnamon showed a significant dose-dependent decrease in glucose uptake in the presence of 50 nm insulin. Treatment of the adipocytes with 50 nm wortmannin, an irreversible inhibitor of insulin-dependent glucose uptake, was associated with complete inhibition of the stimulated glucose uptake induced by 0.2 mg/ml of cinnamon. Shen et al. [37] demonstrated that cinnamon extracts stimulated glucose transporter-4 production and translocation to plasma membrane in muscles and brown adipose tissue in a dose-dependant manner. A similar effect was observed in cultured adipocytes. This effect was quantified by Anand et al. [31]. They demonstrated that in the membrane fractions of untreated diabetic rats, the translocation of glucose transporter-4 was only about 42.8% when compared with healthy controls. Treatment with cinnamon resulted in the reversal of membrane glucose transporter-4 levels to 73.1% in comparison with the healthy controls.

Hepatic and skeletal muscle glycogen contents were significantly decreased in untreated diabetic rats when compared with controls (61.6% and 63.1% respectively, P < 0.001) [31]. Treatment with cinnamon led to an insignificant decrease in liver (17.6%) and muscle glycogen contents (18.1%) compared with healthy control animals [31]. Subash Babu et al. (39) also demonstrated a similar effect, where cinnamaldehyde (20 mg/kg) from C. zeylanicum significantly increased hepatic glycogen content in diabetic rats: the observed increase was greater than for glibenclamide (0.6 mg/kg).

Stimulation of insulin release and insulin receptor signalling

The incubation of islets from normal healthy rats with cinnamon in the presence of 10 mm glucose for 2 h resulted in a significant (< 0.001) stimulation of the release of insulin, which was (41.2 ± 1.3 pm/IEQ islets) more than twofold that of control (18.7 ± 0.8 pm/islet equivalent) and even slightly greater than glibenclamide treated islets (39.5 ± 1.1 pm/islet equivalent) (31). Taher et al. (40) isolated a proanthocyanidin, cinnamtannin B1, from the stem bark of C. zeylanicum. Cinnamtannin B1 (0.11 mm) activated the phosphorylation of insulin receptor β-subunit on 3T3-L1 adipocytes. This effect was significantly greater than with insulin alone (100 nm). In addition, similar to insulin, cinnamtannin B1 stimulated phosphorylation of insulin receptors. The in-vitro effects are summarized in Fig. 2.

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Figure 2.  Summary of in-vitro effects of Cinnamomum zeylanicum. G6PD, glucose-6-phosphate; GLUT-4, glucose transporter-4; PEPCK, phosphoenol pyruvate carboxykinase; PFK-1, phosphofructokinase; +, stimulation/upregulation; –, inhibition/downregulation.

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In-vivo effects

Results of meta-analysis: weight loss, fasting blood glucose, total cholesterol, HDL-cholesterol, triglycerides and serum insulin

A forest plot of the studies comparing weight loss (= 3) associated with streptozotocin-induced diabetes in rats treated with C. zeylanicum and controls is shown in Fig. 3a. The pooled mean difference from random effects analysis is 15.79 (95% CI 6.39, 25.19; P = 0.001). The significant overall effect indicates that C. zeylanicum attenuates weight loss associated with diabetes. The forest plot for fasting blood glucose (= 6) also shows a similar distinct reduction in the cinnamon-treated group in comparison to controls (Fig. 3b). However, statistical heterogeneity of the data prevents the evaluation of a pooled estimate for fasting blood glucose. Total cholesterol (= 4) does not show a distinct pattern: the rise in levels with C. zeylanicum demonstrated by several studies have been contradicted by others (Fig. 3c). The forest plot of HDL-cholesterol (= 5) demonstrates a significant increase in cholesterol levels associated with C. zeylanicum treatment (Fig. 3d). Triglycerides (= 4) also show a similar distinct reduction in the cinnamon-treated group in comparison with controls (Figure 3e). However statistical heterogeneity, as indicated by I2 = 94% (P < 0.01) prevents further evaluation of a combined effect. Serum insulin (= 3) also demonstrated an increase associated with C. zeylanicum treatment (Fig. 3f).

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Figure 3.  Forest plot showing (a) weight loss (WL), (b) fasting blood glucose (FBG), (c) total cholesterol (TC), (d) high-density lipoprotein (HDL), (e) triglycerides (TAG) and (f) serum insulin associated with streptozotocin-induced diabetes in rats. CZ, Cinnamomum zeylanicum; IV, inverse variance; BWL, body weight loss.

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Reduction in LDL, HbA1c and insulin resistance

Al-Logmani et al. [30] demonstrated that streptozotocin-induced diabetes significantly increased LDL-cholesterol levels by 62.5% compared with the controls. However, treatment of C. zeylanicum resulted in a significant (< 0.01) decrease in the levels of LDL-cholesterol compared with untreated diabetic rats. Zari et al. [42] also demonstrated a similar statistically significant (< 0.001) reduction in LDL-cholesterol in cinnamon-treated rats in comparison with untreated streptozotocin-induced diabetic rats.

The effects of C. zeylanicum on HbA1c was studied by Anand et al. [31]; HbA1c remained more or less the same in healthy controls (from 23 ± 0.23 to 25 ± 0.30 mmol/mol) but was significantly increased (P < 0.001) in untreated diabetic rats (from 32 ± 0.49 to 115 ± 0.46 mmol/mol). The elevation of HbA1c was less and similar in both glibenclamide- (from 30 ± 0.5 to 46 ± 0.37 mmol/mol) and cinnamon-treated (from 29 ± 0.47 to 49 ± 0.43 mmol/mol) animals. A 40.2% reduction in HbA1c associated with administration of cinnamon when compared to untreated diabetic rats was shown by Subash Babu et al. [39].

Kannappan et al. [44] used a high-fructose diet fed rats as a model of insulin resistance and determined the metabolic effects associated with cinnamon treatment. The mean value of fasting blood glucose was higher in high-fructose diet fed rats compared with control rats. The value was significantly decreased in high-fructose diet fed rats treated with cinnamon (2 ml/day per rat; 20 mg/day) compared with the untreated high-fructose diet fed rats. There was a significant elevation in insulin and HbA1c at the day 60 of fructose feeding. Treatment with cinnamon significantly reduced the levels insulin and HbA1c to near normal values. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was elevated in high-fructose diet fed untreated rats, but in cinnamon treated rats the levels were near normal. A high-fructose diet caused a significant elevation of total cholesterol, triglycerides, free fatty acids and phospholipids in plasma of control and experimental animals; cinnamon administration resulted in a normal lipid profile. However, these effects were not seen with low-dose cinnamon administration (0.2 ml/day per rat; 0.2 mg/day).

The α-glucosidase inhibitory potential of cinnamon extract to control postprandial blood glucose levels in maltose and sucrose loaded streptozotocin-induced diabetic rats was studied by Shihabudeen et al. [45]. In normal rats the, the total glycaemic response associated with maltose loading was reduced by 65.1% with cinnamon treatment. Similarly in diabetic rats, compared with controls, the total glycaemic response was reduced by 78.2%, 86.3% and 54.2% when treated with 300 mg/kg of cinnamon, 600 mg/kg of cinnamon and 5 mg/kg of acarbose, respectively. Sucrose loading in normal and diabetes-induced rats also resulted in a 42.5% and 52.0–67.5% reduction in total glycaemic response, respectively, with cinnamon treatment. This effect was comparable to the effect of 5 mg/kg of acarbose. However, cinnamon treatment did not affect glycaemic response associated with glucose loading in both normal and diabetes-induced animals.

Complications of diabetes: neuropathy and nephropathy

The effects of cinnamon supplementation on alloxan-induced diabetic neuropathy by tail-immersion and hot-plate nociceptive threshold testing were studied by Rajbir et al. (34). Treatment with cinnamon oil at 5, 10 and 20 mg/kg doses was found to increase the nociceptive threshold in tail immersion test significantly in a dose-dependent manner in the treated rats compared with that of untreated diabetic control rats. The protective effect produced by cinnamon oil on thermal hyperalgesia was found to be more than that of the standard dug fluoxetine in the tail immersion test. In addition, treatment with cinnamon oil also increased the nociceptive threshold in hot-plate test significantly in a dose-dependent manner in treated rats compared with controls; this protective effect was found to be more than that of the standard drug fluoxetine.

Shen et al. (37) demonstrated that streptozotocin-induced diabetes results in hypertrophy of renal glomeruli with increased interstitial and tubular volumes. Cinnamon administration ameliorated such hypertrophy and glomerular volume was reduced to near-normal level. This effect did not demonstrate a dose–response relationship with doses of 30 mg/kg.day and 100 mg/kg.day both demonstrating similar effects. Mishra et al. [33] studied the effects of cinnamon oil on alloxan-induced renal damage. Histological studies of kidney demonstrated the protective effect of cinnamon oil by reducing the glomerular expansion, eradicating hyaline casts and decreasing the tubular dilatations; the protection that it conferred was dose-dependent.

Safety

Anand et al. (31) studied the effect of 5 (100 mg/kg), 10 (200 mg/kg) and 20 (400 mg/kg) times the effective dose (20 mg/kg) of cinnamon on healthy Wistar rats. They observed no behavioural changes (excitement, nervousness, dullness, alertness, ataxia or death). Values of aspartate aminotransferase, alanine aminotransferase, creatinine, total bilirubin and alkaline phosphatase remained within the normal range throughout the study. The insignificant increase in aspartate aminotransferase, alanine aminotransferase and alkaline phosphates values observed in animals administered with 20 times the effective dose after 72 h returned to their initial values within 120 h of cinnamon administration. The administered doses are comparable to a human adult dose of 600–2400 mg/kg based on the formula:

  • image

The 50% median lethal dose value (LD50) of orally administered cinnamon was 1850 ± 37 mg/kg [39]. Hence, based on the above formula, the LD50 for an adult human would be 11.4 ± 0.2 g/kg. They also demonstrated that the significantly elevated levels of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, acid phosphatase and alkaline phosphatase in streptozotocin-induced diabetic controls were restored to near normal levels after administration of cinnamon for 45 days [39]. Al-logmani et al. [30] also demonstrated similar finding, where in streptozotocin-induced diabetic rats the activities of blood aspartate aminotransferase and ALT were significantly (< 0.001) increased by 49.3% and 96.0% respectively, compared to their normal levels. Treatment of the streptozotocin-induced diabetic rats with C. zeylanicum oil for 3 weeks caused reduction in the activity of aspartate aminotransferase by 27.2% and alanine aminotransferase by 40.9% compared with the mean values of the untreated diabetic group. Zari et al. (42) also demonstrated similar reductions in aspartate aminotransferase and alanine aminotransferase levels in rats with cinnamon treatment for 7 weeks. Shen et al. [37] evaluated the effects of cinnamon on serum creatinine and demonstrate a significant reduction in creatinine levels with 30 mg/kg of cinnamon when compared with untreated streptozotocin-induced diabetic rats. However, in contrast, Al Logmani et al. [30] and Zari et al. [42] showed that streptozotocin-induced diabetic rats treated with cinnamon showed a significant increase in blood urea and uric acid when compared with controls.

In addition, Anand et al. [31] demonstrated that the weight of the liver of untreated streptozotocin-induced diabetic rats was significantly decreased by 45.8% after 60 days in comparison with controls rats, and treatment with cinnamon and glibenclamide increased the liver weights to near normal values. After 60 days the kidney weight of the untreated diabetic rats increased significantly by 178% compared with the healthy controls. In the cinnamon- and glibenclamide-treated groups the kidney weight increased only slightly, by 23.5% and 52.2%, respectively. Shen et al. (37) demonstrated that the weight of brown adipose tissue was significantly decreased (80%) in untreated streptozotocin-induced rats, whereas in those treated with cinnamon at 100 mg/kg it increased significantly by 200%.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Funding sources
  9. Competing interests
  10. References

This first comprehensive systematic evaluation on the effects of C. zeylanicum extracts on diabetes demonstrates numerous beneficial effects both in vitro and in vivo. In vitro, C. zeylanicum has demonstrated a potential for reducing post-prandial intestinal glucose absorption by inhibiting the activity of enzymes involved in carbohydrate metabolism (pancreatic α-amylase and α-glucosidase) [35,43,45], stimulating cellular glucose uptake by membrane translocation of glucose transporter-4 [31,36,37], stimulating glucose metabolism and glycogen synthesis [31,39], inhibiting gluconeogenesis by effects on key regulatory enzymes [31,38,39] and stimulating insulin release and potentiating insulin receptor activity [31,39,40]. Cinnamtannin B1 was identified as the potential active compound responsible for these effects [40]. The beneficial effects of C. zeylanicum in vivo includes; (1) attenuation of weight loss associated with diabetes [30,31,37,39,44];(2) reduction of fasting blood glucose [30,31,37–39,42];(3) reducing LDL and increasing HDL cholesterol [30,37,39,42];(4) reducing HbA1c [31,39,44]; and (4) increasing circulating insulin levels [31,37–39,41,44]. Cinnamomum zeylanicum also significantly improved metabolic derangements associated with insulin resistance [44]. In addition C. zeylanicum also showed beneficial effects against diabetic neuropathy and nephropathy [33,34,37]. In-vivo studies have also highlighted lack of significant toxic effects on liver and kidney, with a significantly high therapeutic window [30,39,42]. In addition, although the mechanisms of blood glucose reduction have been explored in detail in previous studies, the mechanism for the lipid lowering effects is not clearly described in the literature. Probable mechanisms for this effect include the high dietary fibre content of cinnamon, which reduces intestinal lipid absorption, and the high vitamin and anti-oxidant [47] content, which increases lipid metabolism. Furthermore, insulin plays a key role in lipid metabolism and it may be postulated that consumption of cinnamon improves lipid levels through its stimulatory effect on insulin, as demonstrated by increased serum insulin levels following C. zeylanicum administration.

The attenuation of weight loss in diabetes associated with C. zeylanicum probably results from improved glycaemic control after initiation of cinnamon treatment. The decrease in body weight of diabetic rats occurs because of catabolism of fats and protein. Owing to insulin deficiency, protein content is decreased in muscular tissue by proteolysis [48]. Oral administration of C. zeylanicum improved body weight in diabetic rats and probably occurs because of its insulin stimulatory effect.

In addition to the direct potential effects of C. zeylanicum on diabetes highlighted above, it is also known to possess many other beneficial properties that may have an indirect impact on the deleterious pathophysiology of diabetes. The phenolic constituents of C. zeylanicum have demonstrated anti-oxidant activity in vitro [47], which may be effective in reducing atherogenesis and its progression. Recent reports have highlighted a probable causal relationship between inflammation with obesity and insulin resistance [49]; C. zeylanicum has shown strong anti-inflammatory properties in vitro and in vivo and may have a role in preventing progression of diabetes [50]. Accumulation of advanced glycation end-products (AGEs) in vivo has been implicated as a major pathogenic process in diabetic microvascular and macrovascular complication. Proanthocyanidins which occur cinnamon are known to inhibit the formation of specific advanced glycation end-products [51] and hence may be useful in reducing the morbidity associated with diabetes by preventing its disabling complications. In addition, studies using an aqueous extract of cinnamon (high in type A polyphenols) have also demonstrated improvements in fasting glucose, glucose tolerance and insulin sensitivity in women with insulin resistance associated with the polycystic ovary syndrome [52].

Medicinal plants are being studied once again for the treatment of diabetes. Many conventional drugs have been derived from prototypic molecules in medicinal plants. Metformin exemplifies an efficacious oral glucose-lowering agent. Its development was based on the use of Galega officinalis to treat diabetes. Galega officinalis is rich in guanidine, the hypoglycaemic component that prompted the development of metformin [53]. To date, over 400 traditional plant treatments for diabetes have been reported, although only a small number of these have received scientific and medical evaluation to assess their efficacy [54]. Indeed, many formulations based on these herbal products are widely available in the market and are used regularly by diabetic patients, sometimes in preference over allopathic treatment [13,54]. The major obstacle preventing the use of herbal medication for treatment of diabetes in allopathic medicine is the lack of scientific and clinical data proving their efficacy and safety. There is a need to conduct clinical research on herbal drugs to evaluate their pharmacological and toxicological usefulness, and to develop animal models for toxicity and safety evaluation. It is also important to establish the active component/s from these plant extracts in order to develop efficacious medications.

Systematic reviews perform a vital role in bridging the scientific gap between traditional and allopathic medical practices; they bring together the existing scientific knowledge and highlight potential areas that require further evaluation. The present review has several strengths and limitations. The strengths of the present review include the comprehensive search of all leading databases on medicine, health and allied sciences (= 6), manual reference search and forward citation evaluation, availability of a comprehensive group of in-vitro and in-vivo studies evaluating the effects of C. zeylanicum, meta-analysis of key biochemical and anthropometric parameters and the exclusion of only a minimal number of studies based on strict exclusion criteria (= 3). Studies that were not included in this systematic review include commentaries (= 1) [55] and studies where the type of cinnamon used is not mentioned (= 2) [56,57], and where we were unable to verify from the respective authors the types of cinnamon used for the study. In addition, all 16 articles included in the review were from recently conducted studies (published in or after 2005).

We acknowledge several limitation to the extent to which conclusions can be drawn from the present systematic review. The C. zeylanicum specimen was authenticated in only six of the 16 studies (37.5%). However, considering that a majority of the studies (= 9, 56.2%) were conducted in countries where C. zeylanicum is cultivated, it is likely that the species used were ‘True’ cinnamon. In addition the presence of significant heterogeneity among the studies prevented estimation of a pooled effect for weight loss, fasting blood glucose, total cholesterol, HDL, triglycerides and serum insulin. However, a distinct pattern was observable for these parameters in the experimental groups receiving cinnamon in comparison with control groups. The heterogeneity could have resulted from variation in sample size, different methods used in induction of diabetes, differences in methods of cinnamon extraction, differing guidelines used to classify an animal as having diabetes and variations in duration of study (10–60 days). There were no studies evaluating the effects of C. zeylanicum in humans, hence care needs to be taken when generalizing the conclusions to the human population. However, considering the in-vitro studies that demonstrate beneficial effects on key regulatory enzymes involved in glucose metabolism it is reasonable to assume a similar effect in humans. In addition the funnel plot of the studies (Fig. 4) evaluating effects of C. zeylanicum on fasting blood glucose shows some asymmetry, indicating potential publication bias. Similar results were also seen for the other parameters used in the meta-analysis (results not shown).

image

Figure 4.  Funnel plot of mean difference in fasting blood glucose (FBG) from Cinnamomum zeylanicum-treated rats and control with 95% CI. SMD, standardized mean difference.

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Complexity of regimes, lack of significant therapeutic efficacy and side effects are among the common reasons for recent interest in alternative treatment strategies for diabetes [8,13]. There is compelling evidence highlighting the efficacy of C. zeylanicum on glucose metabolism and diabetes. However, lack of human trials has compromised our knowledge on common side effects, drug interactions and efficacy in humans. Hence, further randomized double-blinded placebo-controlled clinical trials are required to establish therapeutic safety and efficacy of C. zeylanicum as a pharmaceutical agent in diabetes.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Funding sources
  9. Competing interests
  10. References

This comprehensive systematic review and meta-analysis shows that Cinnamomum zeylanicum demonstrates numerous beneficial effects both in vitro and in vivo as a potential therapeutic agent for diabetes mellitus. It promotes better glycaemic control and healthy lipid parameters, reduces insulin resistance, potentiates the action of insulin and ameliorates common complications associated with diabetes. In addition preclinical in-vivo studies have not shown any significant toxic effects. However, further randomized double-blinded placebo-controlled clinical trials are required to establish therapeutic safety and efficacy in humans.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Funding sources
  9. Competing interests
  10. References
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