Accepted Manuscript

Title: Cinnamaldehyde in diabetes: A review of

pharmacology, pharmacokinetics and safety

Authors: Ruyuan Zhu, Haixia Liu, Chenyue Liu, Lili Wang,

Rufeng Ma, Beibei Chen, Lin Li, Jianzhao Niu, Min Fu,
Dongwei Zhang, Sihua Gao

PII: S1043-6618(17)30072-5
DOI: http://dx.doi.org/doi:10.1016/j.phrs.2017.05.019
Reference: YPHRS 3602

To appear in: Pharmacological Research

Received date: 7-2-2017

Revised date: 4-5-2017
Accepted date: 21-5-2017

Please cite this article as: Zhu Ruyuan, Liu Haixia, Liu Chenyue, Wang Lili,
Ma Rufeng, Chen Beibei, Li Lin, Niu Jianzhao, Fu Min, Zhang Dongwei, Gao
Sihua.Cinnamaldehyde in diabetes: A review of pharmacology, pharmacokinetics and
safety.Pharmacological Research http://dx.doi.org/10.1016/j.phrs.2017.05.019

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Cinnamaldehyde in diabetes: A review of pharmacology,
pharmacokinetics and safety

Ruyuan Zhu1+, Haixia Liu1+, Chenyue Liu2, Lili Wang1, Rufeng Ma1, Beibei Chen1,
Lin Li1, Jianzhao Niu1, Min Fu3, Dongwei Zhang4*, and Sihua Gao4*

Running title: Cinnamaldehyde and Diabetes

1. Preclinical Medicine School, Beijing University of Chinese Medicine, Beijing 100029, China;

2. Chinese Material Medica School, Beijing University of Chinese Medicine, Beijing 100029, China;

3. The Research Institute of McGill University Health Center, Montreal, Quebec H4A 3J1, Canada;

4. Diabetes Research Center, Beijing University of Chinese Medicine, Beijing 100029, China;

+ Equally contributed

This submission includes 1 table and 5 figures.

* Correspondences to:
Dongwei Zhang, MD & PhD Sihua Gao, MD

Associate Professor of Diabetes Research Center Diabetes Research Center

Beijing University of Chinese Medicine Beijing University of Chinese Medicine

Beijing 100029. PR China Beijing 100029，PR China

Phone: (8610) 6428-6915 Phone: (8610) 6428-6929

Fax: (8610) 6428-6929 Fax: (8610) 6428-6929

Email: dongwei1006@gmail.com Email: gaosihua1216@163.com

Graphical abstract

Abstract

Cinnamaldehyde, one of the active components derived from Cinnamon,

has been used as a natural flavorant and fragrance agent in kitchen and

industry. Emerging studies have been performed over the past decades to

evaluate its beneficial role in management of diabetes and its

complications. This review highlights recent advances of cinnamaldehyde

in its glucolipid lowering effects, its pharmacokinetics, and its safety by

consulting the Pubmed, China Knowledge Resource Integrated, China

Science and Technology Journal, National Science and Technology

Library, Wanfang Data, and the Web of Science Databases. For the

inquiries, keywords such as Cinnamon, cinnamaldehyde, property,

synthesis, diabetes, obesity, pharmacokinetics, and safety were used in

various combinations. Accumulating evidence supports the notion that

cinnamaldehyde exhibits glucolipid lowering effects in diabetic animals

by increasing glucose uptake and improving insulin sensitivity in adipose

and skeletal muscle tissues, improving glycogen synthesis in liver,

restoring pancreatic islets dysfunction, slowing gastric emptying rates,

and improving diabetic renal and brain disorders. Cinnamaldehyde exerts

these effects through its action on multiple signaling pathways, including

PPARs, AMPK, PI3K/IRS-1, RBP4-GLUT4, and ERK/JNK/p38MAPK,

TRPA1-ghrelin and Nrf2 pathways. In addition, cinnamaldehyde seems to

regulate the activities of PTP1B and α-amylase. Furthermore,

cinnamaldehyde has the potential of metalizing into cinnamyl alcohol and

methyl cinnamate and cinnamic acid in the body. Finally, there is a

potential toxicity concern about this compound. In summary,

cinnamaldehyde supplementation is shown to improve glucose and lipid

homeostasis in diabetic animals, which may provide a new option for

diabetic intervention. To this end, further scientific evidences are required

from clinical trials on its glucose regulating effects and safety.

Key words ： Cinnamaldehyde; Diabetes; Obesity; Pharmacology;

Pharmacokinetics; Safety.
Contents

1. Introduction

2. The pharmacological activities of cinnamaldehyde in the treatment of

diabetes

2.1 Effect of cinnamaldehyde on glycaemia in animal models of diabetes

2.2. Cinnamaldehyde and adipose tissue

2.3 Cinnamaldehyde and skeletal muscle

2.4 Cinnamaldehyde and liver

2.5 Cinnamaldehyde and kidney

2.6 Cinnamaldehyde and pancreas

2.7 Cinnamaldehyde and gastro-intestinal tract and hypothalamus

2.8 The other biological effects of Cinnamaldehyde in diabetes

3. The recent advances in the pharmacokinetics of cinnamaldehyde

4. The other major constituents of Cinnamon in diabetes

5. Safety assessment of cinnamaldehyde

5.1 Acute toxicity

5.2 Long term toxicity

5.3 Hepatotoxicity

5.4 Respiratory toxicity

5.5 Skin sensitization

6. Conclusions and outlook

Acknowledgement
Conflict of interests

References

Abbreviations

Ach: acetylcholine;
Acsl4: acyl-CoA synthetase 4;
AUC0–t: area under the curve to termination time;
AMPK: 5′-adenosine monophosphate-activated protein kinase;
BAT: brown adipose tissue;
BDNF: brain-derived neurotrophic factor;
CARTPT: cocaine and amphetamine-related transcript;
CCK: cholecystokinin;
CEBP-α: CCAAT/enhancer-binding protein-α;
Cmax: maximum plasma concentration;
COX-2: cyclooxygenase-2;
Cpt1a: carnitine palmitoyltransferase 1A;
ERK/JNK/p38MAPK: extracellular signal-regulated kinase / c-Jun NH2-terminal
kinase/p38 mitogen-activated protein kinases;
FOXP2: forkhead box protein 2;
G3P: glycerol-3-phosphate
GLUT: glucose transporter;
GC-MS: gas chromatography–mass spectrometry;
HDL: high density lipoprotein-cholesterol;
HFD: high fat diet;
HFHS: High fat and high sucrose
HSL: hormone-sensitive lipase;
IL-6: interleukin-6;
IR: insulin receptor;
IRS-1: insulin receptor substrate-1;
JNK: c-Jun NH2-terminal kinase;
KCl: potassium chloride;
MCP-1: monocyte chemotactic protein 1;
MEF2: myocyte enhancer factors 2;
MGL: monoglyceride lipase;
NO: nitric oxide;
NQO1: NAD(P)H: quinone oxidoreductase 1
Nrf2: nuclear factor erythroid-2 related factor 2;
PEPCK: phosphine pyruvate carboxykinase;
PGC-1α: peroxisome proliferator-activated receptor γ coactivator 1α;
PI3K: phosphatidylinositol-3-kinase;
PK: pyruvate kinase;
PNPLA2: patatin phospholipase domain containing 2;
POMC: proopiomelanocortin;
PPAR: peroxisome proliferator-activated receptor;
PRDM16: PR domain containing 16;
PTP1B: protein tyrosine phosphatase1B;
RBP4: retinol binding protein 4;
SREBP1: sterol regulatory element-binding protein 1;
STZ: streptozotocin;
SME-cinnamaldehyde: submicrometer emulsions of cinnamaldehyde;
TG: triglyceride;
TGF-β: transforming growth factor-β;
Tmax: time at maximum plasma concentration;
TNF-α: tumor necrosis factor-α;
TRPA1: transient receptor potential-ankyrin receptor 1;
UCN: urocortin;
UCP1: uncoupling protein 1;
WAT: white adipose tissue;
1. Introduction

Cinnamaldehyde, an old flavourant derived from

Cinnamon trees and other species of the genus Cinnamomum [1], has now

attracted rising interests for its ability of preventing the development of

diabetes and its complications [2,3]. As a yellow and viscous liquid

(Figure 1), cinnamaldehyde constitutes 98% of essential oil of Cinnamon

bark, and was first isolated by Dumas and Péligot [4] and then

synthesized in the laboratory by the Italian chemist, Luigi Chiozza

(1828-1889) in 1854 [5]. In 2007, Subash et al. firstly reported a

hypoglycemic and hypolipidemic effect of cinnamaldehyde on

streptozotocin (STZ)-induced male diabetic Wistar rats [6].

Cinnamaldehyde has been since extensively studied in animal models of

diabetes and obesity. Here, we review recent progress of cinnamaldehyde

with regarding to its activities in management of diabetes and its

complications, its pharmacokinetics, and safety by consulting the Pubmed

(www.pubmed.com), Chinese National Knowledge Infrastructure

(www.cnki.net), National Science and Technology Library

(http://www.nstl.gov.cn/), China Science and Technology Journal

(http://en.cqvip.com/cstj.html), Wanfang Data

(http://www.wanfangdata.com.cn/) and web of science

(www.isiknowledge.com) databases.
2. The pharmacological activities of cinnamaldehyde in management

of diabetes

2.1 Effect of cinnamaldehyde on glycaemia in animal models of

diabetes

The hypoglycemic and hypolipidemic effects of cinnamaldehyde

have been extensively evaluated in animal experiments. We summarize

all the publications related to the applications of cinnamaldehyde in

diabetic rodent models by October, 2016 as shown in Table 1. Of these 13

experimental studies, male rats and mice are the most often used rodents

to assess glucolipid lowering effects of cinnamaldehyde, in which

diabetes models are often induced by high fat diet (HFD) plus STZ. It is

demonstrated that oral administration of cinnamaldehyde ranging from 20

mg/kg·body weight (BW) to 40 mg/kg·BW per day for a duration lasting

from 21 to 60 days resulted in a significant improvement in the levels of

blood glucose and glycosylated hemoglobin (HbA1C) as well as insulin

sensitivity in STZ-induced diabetic rats [7-10]. And 20 mg/kg·BW is

assumed to be the effective dose for preventing the development of

diabetes in animals.

Further, cinnamaldehyde treatment for 4 weeks increases plasma

insulin levels and liver glycogen content, as well as decreases triglyceride

(TG) and low density lipoprotein-cholesterol (LDL) levels in STZ and/or

HFD insulted male Wistar rats[11,12]. Furthermore, Camacho et al. found

that administration with cinnamaldehyde for 5 weeks to HFD fed

C57BL/6J mice significantly led to a reduction in body fat mass gain.

However, they claimed that cinnamaldehyde treatment did not alter

plasma fasting insulin levels and feed consumption [13]. The reason for

the inconsistence regarding insulin regulation could be attributed to that

genetic backgrounds of C57BL/6J mice are altered in some production

facilities [14,15]. The different substrains of mice may exhibit significant

differences in phenotypes [16-18]. In addition, cinnamaldehyde may

exhibit glucose lowering effect through improving insulin sensitivity in

the periphery in Camacho’s study [13].

Moreover, Cinnamon oil, which contains more than 98%

cinnamaldehyde, has also been demonstrated to reduce the fasting blood

glucose and total cholesterol as well as to elevate high density

lipoprotein-cholesterol (HDL) in a dose-dependent manner (5-20 mg/kg)

in response to aloxan challenge [19]. The similar results are also obtained

in using Cinnamon oil (25, 50 and 100 mg/kg) to treat KK-Ay mice for 35

days [20]. In this study, the authors also found that the administration of

Cinnamon oil decreased plasma C-peptide and improved glucose

tolerance and insulin sensitivity [20]. Thus, it is reasonable to assume that

cinnamaldehyde is one of main active components in Cinnamon oil

regarding blood glucose regulating.

 However, Hafizur et al. reported the contrasting results using STZ

(90 mg/kg) insulted 2-day-old Wistar rat pups [21]. In this study, they did

not found acute effects of blood glucose lowering and glucose tolerance

after single administration of cinnamaldehyde (10 mg/kg) to 3-month-old

diabetic rats [21]. And also cinnamaldehyde (50-200 μM) does not

promote insulin secretory activity in primary islets [21]. The reason for

this discrepancy may be attributed to that the dose of cinnamaldehyde

administered, treatment duration and the different culture conditions [22].

One dose of cinnamaldehyde is insufficient for attaining

glucose-lowering effect in diabetic rats. In addition, as mentioned above,

20 mg/kg of cinnamaldehyde and treatment duration of 4 weeks are

assumed to be effective in glucose regulating in diabetic animals.

Table 1: Diabetic animal models used in studying the effects of cinnamaldehyde

Animal Induction of diabetes Cinnamaldehyde (route and dose) Treatment Reference

(route and dose) duration
Mice High fat diet (HFD) Oral gavage; 5 and 10 mg/kg·BW 14 weeks [2]

Wistar rats HFD, i.p. of STZ Intragastric gavage; 40 mg/kg·BW 4 weeks [8]
(35mg/kg·BW)
KK-Ay mice Standard laboratory Intragastric gavage; 25, 50 and 100 35days [20]
diet mg/kg·BW
Male Wistar rats i.v. of STZ (65 Oral gavage; 40 mg/kg·BW 3 weeks [9]
mg/kg ·BW)
2-day-old Wistar i.p. of STZ (90 Oral gavage; 5 and 10 mg/kg·BW 1 day [21]
rat pups mg/kg·BW)
Male Wistar rats i.p. Of STZ Oral gavage; 20mg/kg·BW 60 days [7]
(50mg/kg·BW)
C57BL6/J mice HFD 0.2% cinnamaldehyde in diet 36 days [13]

Male C57BL/6 High fat and high 0.1%, 0.5%, and 1% 30 days [23]
 mice sucrose cinnamaldehyde in diet

Male Wistar rats i.p of STZ (50 Oral gavage; 20mg/kg·BW 6 weeks [10]
mg/kg·BW)
Male Wistar rats i.p of STZ (60 Oral gavage; 5, 10 and 45 days [6]
mg/kg·BW) 20mg/kg·BW
Wistar rats i.p of aloxan, 150 i.p; 5,10 and 20 mg/kg·BW 14 days [19]
mg/kg·BW
Wistar rats HFD, i.p of STZ (35 Intragastric gavage; 40 mg/kg·BW 4 weeks [11]
mg/kg·BW)
Male Wistar rats i.p of STZ (50 Oral gavage; 20 mg/kg·BW 28 days [12]
mg/kg·BW)

Note: i.p: intraperitoneal injection; i.v.: intravenous; BW: body weight.

Interestingly, several clinical trials demonstrate that Cinnamon and

its extracts achieve a therapeutic effect on patients with diabetes [24-27].

Since cinnamaldehyde is one of major extracts of Cinnamon, there is a

possibility to attain a glucose-lowering effect using cinnamaldehyde

treatment for patients with diabetes. Further, the biochemical results

obtained from in vitro cell cultures and/or in vivo animal experiments

may translate into human activities. However, there are several things that

need to be considered before additional clinical trials being performed.

First, cinnamaldehyde is not stable in the body, with the possibility of

metabolizing into cinnamic acid and transforming into cinnamyl alcohol

[28]. Therefore, the stability of cinnamaldehyde is the primary concern

for the druggability which may affect potent bioactivity of this compound.

Second, excessive doses of cinnamaldehyde may generate the toxic

response. In human, 3% cinnamaldehyde may cause skin irritation [29].

Third, the emerging cinnamaldehyde derivatives and novel approaches

such as encapsulation and submicromemter emulsion [30], may provide

more options to develop novel anti-diabetes drug candidates with better

activity and stability as well as lower toxicity, which allow the clinical

trials to be carried out successfully in the near future.

2.2 Cinnamaldehyde and adipose tissue

A weight of evidences support the concept that adipose tissues play

an important role in modulating insulin sensitivity, fat mass and body

weight [31-33]. Adipose tissues are classically distinguished into 2 types:

white adipose tissue (WAT) and brown adipose tissue (BAT) [34].

“Beiging” or “browning” of WAT contributes to a decrease in cell size

and an improvement of mitochondrial activity and body weight [35].

Using C57BL/6 mice on high fat and high sucrose (HFHS) diet for 1

month, Tamura et al. show that the addition of cinnamaldehyde (0.1-1.0%)

to HFHS diet induces a reduction of mesenteric adipose tissue weight,

and a tendency toward lowing perirenal and epididymal adipose tissues

weights in mice [23]. This is also confirmed in another independent study

performed by Khare et al [2], in which 5 and 10 mg/kg of

cinnamaldehyde was administrated to mice for 14 weeks, respectively.

Furthermore, cinnamaldehyde treatment (0.5 and 1.0% [23]; 10 mg/kg [2])

also reduces visceral fat deposition by stimulating BAT through

increasing protein expression of uncoupling protein 1 (UCP1) [36] and

gene levels of forkhead box protein 2 (FOXP2), bone morphogenetic

protein 4 (BMP4), and PR domain containing 16 (PRDM16) [2], which

facilitate energy metabolism and obesity prevention (Figure 2) [37].

In addition, cinnamaldehyde’s effectiveness in diabetes may partly

originate from its action on modulating adipose tissue metabolism

through promoting lipolysis and fatty acid oxidation (Figure 2) supported

by several lines of evidences. First, cinnamaldehyde (40 µM) could

enhance the expression of hormone-sensitive lipase (HSL), and suppress

the expression of perilipin and glycerol-3-phosphate dehydrogenase as

well as reduce adipocyte genes expression of peroxisome

proliferator-activated receptor (PPAR)-γ and CCAAT/enhancer-binding

protein-α (CEBP-α) in 3T3-L1 pre-adipocytes [2,38]. Second,

cinnamaldehyde (20 and 40 mg/kg for mice; 20 and 40 µM for cells [38])

also shows the capacity of increasing the gene levels of phosphorylated

AMP-activated protein kinase (p-AMPK) and acetyl-CoA carboxylase

(p-ACC) via decreasing its targeted genes expression of fatty acid

synthase (FAS), sterol regulatory element-binding protein 1 (SREBP1),

stearoyl-coenzyme desaturase-1 (SCD-1) and adipocyte fatty acid binding

protein αP2, and inhibiting glycerol-3-phosphate acyltransferase activity

in epididymal fat tissue of HFD insulted mice and in 3T3-L1 adipocytes.

Further, cinnamaldehyde (10 mg/kg) treatment increases

lipolysis-promoting genes expression (HSL, patatin phospholipase

domain containing 2 (PNPLA2), and monoglyceride lipase (MGL)) in

visceral adipose tissue of HFD insulted mice [2]. Third, cinnamaldehyde

treatment stimulates fatty acid oxidation by increasing mRNA expression

of carnitine palmitoyltransferase 1a (Cpt1a) and insulin receptor (IR) in

WAT as well as acyl-CoA synthetase 4 (Acsl4) in BAT [13]. It is known

that Cpt1a is a rate limiting enzyme in mitochondrial fatty acid oxidation

and enhanced expression of Cpt1a contributes to reducing triglyceride

content and inflammation, and improving insulin sensitivity in adipocytes,

as well as preventing endoplasmic reticulum stress and inhibiting reactive

oxygen species damage in macrophages of adipocyte tissue [39].

Meanwhile, inhibition of Acsl4 promotes free epoxyeicosatrienoic acid

production and impairs glucose-stimulated insulin secretion in INS

823/13 cells [40,41]. Acsl4 over-expression in BAT contributes to

thermogenesis in cold stimulated Acsl1 knockout mice [42]. Fourth,

cinnamaldehyde may also promote energetic metabolism and

thermogenesis by activation of transient receptor potential-ankyrin

receptor 1 (TRPA1) via stimulating the sympathetic nervous system

[23,43].

Enhancing glucose uptake in adipose tissues is an alternative option

to maintaining glucose homeostasis and improving fat metabolism [44].

Camacho et al. demonstrates that supplementation with cinnamaldehyde

(0.2% in diet) for 36 days induces an up-regulation of glucose transporter

(GLUT)1, GLUT12, and GLUT 8 in WAT of HFD insulted C57BL/6J

mice [13].

In addition, unhealthy adipose expansion leads to a release of

inflammatory molecules (interleukin-6 (IL-6) and tumor necrosis factor-α

(TNF-α)), which results in insulin resistance and increased concentration

of circulating free fatty acid [45]. Supplementation of cyclooxygenase-2

(COX-2) inhibitors to HFD induced obese rats and db/db mice reverses

the impaired glucose tolerance and insulin sensitivity as well as prevents

the increased monocyte chemotactic protein 1 (MCP-1) level [46]. It is

accepted that MCP-1 contributes to macrophage infiltration into adipose

tissue [47], and inhibition of MCP-1 signaling ameliorates insulin

resistance in mice [48]. In addition, cinnamaldehyde is demonstrated to

decrease serum IL-1β and inhibit inflammatory gene expression (COX-2,

MCP-1, TNF-α, and IL-6) in WAT of HFD insulted male Swiss albino

mice [2] and C57BLKS db/db mice [49]. Furthermore, cinnamaldehyde

has the ability of upregulating Cpt1a mRNA expression in WAT of HFD

insulted mice [13], while increased expression of Cpt1a protects against

pro-inflammatory adipokines release and promotes fatty acid oxidation,

which contributes to an improvement in insulin resistance [39,50,51].

PPARs are highly involved in the regulation of insulin resistance and

adipogenesis [52,53], and three isoforms of PPARs have been currently

discovered, including PPARα, PPARβ/δ, and PPARγ. PPARα is expressed

mostly in brown adipose tissue and liver, and activating PPARα lowers

plasma TG and elevates plasma HDL cholesterol levels. PPARγ is mainly

expressed in adipose tissue, and activation of PPARγ increases insulin

sensitivity. And PPARβ/δ is expressed universally in many tissues [54]. Li

et al. demonstrates that cinnamaldehyde increases expression of PPARδ

and PPARγ as well as its targeted genes such as aP2 and CD36 in 3T3-L1

differentiated adipocytes using quantitative real time-PCR, which serves

to improve insulin sensitivity and fatty acid β-oxidation [55]. However,

Huang et al. demonstrates that cinnamaldehyde treatment inhibits

pioglitazone-induced PPARγ gene expression and transcription activity in

cos-7 cells, and suppresses pioglitazone-induced 3T3-L1 cell

differentiation. Further, cinnamaldehyde treatment inhibits genes

expression of PPARγ and aP2 in epididymal fat tissue of HFD insulted

mice using reverse transcription PCR [38]. The reason for the discordant

results about cinnamaldehyde’s efficacy in regulation of PPARγ

expression may be attributed to differences between in vivo and ex vivo

experiments as well as different cell models. In the former study, TSA201

cells (human embryonic kidney cell line) were employed to study the

transient expression of PPARγ. In the latter study, full-length PPARγ

expression plasmid was transfected into COS-7 cells (fibroblast-like cell

lines derived from monkey kidney tissue) using the luciferase reporter

gene assay.
 In short, cinnamaldehyde has the capacity of improving diabetic

adipose tissues by reducing visceral fat deposition, and promoting

lipolysis and fatty acid oxidation and thermogenesis, which is associated

with an upregulation of energy expenditure genes (UCP1, FOXP2,

BPMP4 and PRDM16), an inhibition of PPARγ/CEBP-α and SREBP1, an

upregulation of HSL and PNPLA2 and MGL, an induction of AMPK

phosphorylation, and an increase in Cpt1a in WAT and Acsl4 in BAT, as

well as a stimulation of the sympathetic nervous system (Figure 2). In

addition, cinnamaldehyde prevents inflammatory genes expression, and

improves GLUTs expression in diabetic animals. Regarding the

regulation of PPARγ expression, there is no consistent conclusion of

cinnamaldehyde so far.

2.3 Cinnamaldehyde and skeletal muscle tissue

Muscular tissue is one of the major insulin-target tissues for glucose

metabolism that consumes more than 85 % of body glucose [56,57].

Insulin insufficiency or resistance leads to a decrease in GLUT4

translocation and subsequent glucose uptake in skeletal muscle in the

development of diabetes [58]. Cinnamaldehyde has been evidenced to

improve glucose metabolism in skeletal muscle tissue by several

investigators (Figure 3). Firstly, Prachi et al. demonstrates that

cinnamaldehyde treatment for 2 months increases glycogen content in

skeletal muscle by restoring GLUT4 levels in STZ induced rats [7].

Further, Juan et al. reveals that cinnamaldehyde treatment upregulates

mRNA expression of GLUT4 through increasing phospho-Akt (Thr308)

expression in skeletal muscle of C57BLKS db/db mice [49]. Similarly,

Nikzamir et al. also demonstrates that exposure of C2C12 skeletal muscle

cells to cinnamaldehyde (10, 20, and 50 µM) exhibits dose-dependently

increasing GLUT4 mRNA expression by 1.25, 1.6 and 3.01 folds,

respectively [58].

Furthermore, an experiment performed by Gannon et al.

demonstrates that cinnamaldehyde (40 µM) treatment increases GLUT4

expression via activating peroxisome proliferator-activated receptor γ

coactivator 1α (PGC-1α) and triggering its downstream effector myocyte

enhancer factors 2 (MEF2) in C2C12 cells [59]. In addition, the authors

also claimed that cinnamaldehyde treatment regulated oxidative

metabolism through increasing expressions of 5′-adenosine

monophosphate-activated protein kinase (AMPK), NAD+-dependent

deacetylases sirtuin 1, PGC-1α and cytochrome C as well as improving

PPARα and PPARβ/δ expression, which contributes to mitochondrial

biogenesis. However, cinnamaldehyde is demonstrated to inhibit

mitochondrial metabolism by reducing basal and chemically-induced

peak myotube oxidative metabolism in C2C12 cells [60]. Further,

cinnamaldehyde treatment increases fatty acid synthesis without elevating

PPARγ and SREBP-1c expression in C2C12 cells, suggesting that the

mechanisms of cinnamaldehyde on metabolic diseases are perplexing

[60]. But the authors did not provide the further evidences from in vivo

experiments to demonstrate these observations.

In addition, oral administration of cinnamaldehyde to STZ induced

diabetic rats for 2 months resulted in decreasing serum retinol binding

protein 4 (RBP4) level and increasing GLUT4 expression in muscle and

adipose tissue [61], suggesting that cinnamaldehyde may improve glucose

uptake through RBP4-GLUT4 pathway.

Moreover, diabetes disturbs phosphatidylinositol-3-kinase (PI3K)

pathway by upregulating expression of PI3K adaptor subunits p85/55/50

and decreasing insulin receptor substrate (IRS)-1 [62]. Li et al.

demonstrates that cinnamaldehyde treatment increases IRS-1 and

decreases PI3K adaptor subunit p85α expression in the gastrocnemius of

type 2 diabetic rats, which further leads to improvement on insulin

signaling [11].

In a word, cinnamaldehyde may protect against diabetes by

improving insulin sensitivity and glucose uptake through regulating

PI3K/IRS-1 and RBP4-GLUT4 pathway in skeletal muscle tissue, as well

as regulating mitochondria metabolism through PGC-1α/MEF2/GLUT4

pathway in C2C12 cells (Figure 3). Since boosting mitochondrial

function favors the amelioration in insulin resistance [63], and current in

vitro experiments suggest a counterproductive effect of cinnamaldehyde

in mitochondrial biogenesis and oxidative metabolism and fatty acid

synthesis. Further studies may also require elucidating the mechanisms of

cinnamaldehyde on mitochondria metabolism in vivo, which would help

comprehensively understanding glucose lowering effect of this compound

in management of diabetes.

2.4 Cinnamaldehyde and liver

Diabetes may result in a reduction of liver glycogen synthase

thereby affecting the glycogen storage and synthesis [64,65]. Pyruvate

kinase (PK) and phosphine pyruvate carboxykinase (PEPCK) are two

major enzymes involved in glycogen synthesis via regulating glycolysis

and gluconeogenesis [66]. And insulin deficiency is clearly associated

with increased PEPCK and decreased PK activities [54].

In an experiment performed by Kumar et al. demonstrates that

administration of cinnamaldehyde (20mg/kg) to diabetic rats for 28 days

significantly increases liver glycogen content [12]. Further,

supplementation of STZ induced diabetic rats with cinnamaldehyde for 2

months resulted in restoring altered activities and mRNA levels of PK

and PEPCK in liver (Figure 4). The results may indicate that

cinnamaldehyde exerts its glucose-lowering effect potentially through a

stimulation of glycogen synthesis and inhibition of gluconeogenesis [7].

 Diabetes may also cause an increase in the activities of plasma

aspartate aminotransferase, alanine aminotransferase, lactate

dehydrogenase, alkaline phosphatase and acid phosphatase in the liver

[67]. Treatment of STZ-induced diabetic rats with cinnamaldehyde

induces a reduction in the activities of these enzymes toward the normal

levels [6].

In addition, RBP4 is mainly synthesized in the liver and adipose

tissues, which is elevated in serum and liver in response to high glucose

[68], and the abnormal elevation of RBP4 further impairs insulin

signaling and increases hepatic glucose output [69]. Cinnamaldehyde

treatment significantly decreases RBP4 levels in serum and liver, which is

suggestive of a beneficial role of cinnamaldehyde in improving diabetic

liver function [8].

In a word, cinnamaldehyde has positive effects on diabetic liver

through improving glycogen syntheses by regulating activities of PK and

PEPCK and decreasing RBP4 level as well as normalizing the aberrant

liver enzymes, suggesting a beneficial role of this compound in glucose

metabolism and insulin sensitivity in diabetic liver.

2.5 Cinnamaldehyde and pancreas

Improvement of disordered pancreas islets and subsequent insulin

secretion is an essential step to resolve diabetes [18]. Currently,

cinnamaldehyde has been demonstrated to be involved in the regulation

of pancreas islets through the following means (Figure 4). First,

cinnamaldehyde (2 mg/ml) treatment doubly increases glucose stimulated

insulin-secretion in primary islets. And this effect is greater than

glibenclamide [7]. Second, oral administration of cinnamaldehyde to STZ

induced diabetic rats improves regeneration of islet cells and further

stimulates insulin secretion by protecting β-cells from free radicals insults

via preventing glycation of the antioxidant enzymes, such as superoxide

dismutase, catalase, and glutathione peroxidase [12,70], suggesting that

natural products with ameliorating oxidative stress may favor pancreatic

islets regeneration and insulin secretion. Therefore, the aforementioned

evidences may indicate that cinnamaldehyde plays a contributory role in

restorations of islet cells partly by improving insulin secretion via

inhibiting oxidative stress. However, whether cinnamaldehyde has the

ability of promoting islets hyperplasia and hypertrophy still requires

further investigation.

2.6 Cinnamaldehyde and gastro-intestinal tract and hypothalamus

Ghrelin is a potent orexigenic peptide secreted mainly from the

stomach and proximal small bowel, which stimulates food intake,

increases fat mass, and suppresses glucose-stimulated insulin release and

further improves glucose tolerance [71]. TRPA1 and ghrelin co-localize

in the gut, and regulates gastrointestinal functions through serotonin

release [72]. In addition, activation of TRPA1 induces adrenaline

secretion and subsequently increases energy consumption [73]. In

contrast, inhibition of TRPA1 impedes nerve fiber function in STZ

induced diabetic rats [36,74].

In an experiment performed by Camacho et al. [13] demonstrates

cinnamaldehyde (100 μM) treatment increases mRNA expression of

TRPA1 and IR, and decreases ghrelin protein expression in MGN3-1

stomach cells (Figure 4). In addition, a significant delay in gastric

emptying and a reduction of food intake were observed at 2 hours after a

single gavage of 250 mg/kg of cinnamaldehyde in mice. Further,

HFD-induced obese mice fed with cinnamaldehyde-containing diet for 5

weeks significantly reduces cumulative body weight gain and improves

glucose tolerance [13], suggesting that cinnamaldehyde has the ability of

improving glucose metabolism through delaying of gastric emptying via

regulating TRPA1-ghrelin pathway.

In another experiment performed by Khare et al. [2] reveals that

cinnamaldehyde treatment (10 mg/kg) decreases body weight gain by

reducing the circulating leptin and leptin/ghrelin ratio via increasing

proopiomelanocortin (POMC), urocortin (UCN), brain-derived

neurotrophic factor (BDNF), cocaine and amphetamine-related transcript

(CARTPT), and cholecystokinin (CCK) expression in hypothalamus of

HFD fed mice. It is accepted that ghrelin, POMC, BDNF, UCN, CARTPT,

and CCK are closely related to the hunger-satiety interplay [75-77]. In

addition, Khare et al. [2] claimed that cinnamaldehyde treatment (5 and

10 mg/kg) did not affect the abundances of selected gut microbial

communities (Lactobacillus, Bifidobacteria, and Roseburia species).

However, the results cannot rule out the possibility of cinnamaldehyde in

regulation of other bacterial genera in management of diabetes. Therefore,

a meta-genomic study is wanted to further explore whether

cinnamaldehyde improves global gut microbial derangement in diabetes.

2.7 Cinnamaldehyde and kidneys

Diabetes may cause kidney dysfunction by disturbing renal

glomeruli and glomerular filtration barrier [78]. Currently,

cinnamaldehyde is demonstrated to exert renal protective effects via the

following means (Figure 4). First, cinnamaldehyde treatment prevents an

increase in kidneys weights through downregulating the activities and

mRNA levels of PK and PEPCK in STZ induced diabetic rats [7]. Second,

cinnamaldehyde attenuates high glucose-induced renal interstitial cells

hyperplasia and hypertrophy as well as decreases protein expression of

collagen IV, fibronectin, and α-smooth muscle actin (α-SMA) through the

regulation of extracellular signal-regulated kinase (ERK)/c-Jun

NH2-terminal kinase (JNK)/p38 mitogen-activated protein kinases

(MAPKs)(ERK/JNK/p38MAPK) signaling pathway [79]. Third,

cinnamaldehyde is reported to relieve renal damage and preserve renal

function via targeting the activator of nuclear factor erythroid-2 related

factor 2 (Nrf2) and its downstream Phase II enzymes (NAD(P)H: quinone

oxidoreductase 1 (NQO1), heme oxygenase-1, catalase and

γ-glutamylcysteine synthetase (γ-GCS)) in STZ-induced diabetic mice, as

well as in high glucose insulted human renal mesangial cells [80,81] and

human umbilical vein endothelial cells [82]. It is known that Nrf2 is

involved in regulating antioxidant protein detoxifying enzymes and stress

response [83], and high glucose induces redox imbalance through

inhibiting Nrf2-dependent signaling pathway via induction of Phase II

enzymes [84,85]. Activation of Nrf2 could ameliorate metabolic disorders

by augmenting antioxidant capacity. Therefore, it is not surprisingly that

cinnamaldehyde supplementation is associated with reduced oxidative

stress and attenuated induction of the profibrotic mediator transforming

growth factor-β (TGF-β), cyclin-dependent kinase inhibitor p21, and

extracellular matrix proteins in diabetic kidneys [80]. However, the

intriguing results that cinnamaldehyde regulates stress response by

activating Nrf2 pathway related detoxifying enzymes also has not been

confirmed in humans and therefore requires appropriate investigations.

Long-term hyperglycemia and hyperlipidemia may cause diabetic

hypertension [86]. El-Bassossy et al. demonstrates for the first time that
cinnamaldehyde administration protects against diabetic hypertension

through normalization of vascular contractility and insulin secretion. In

this study, the investigator used STZ (50 mg/kg) or fructose (10%) to

establish insulin deficiency or insulin resistance models, which is

evidenced by elevating blood pressure through an increase in response to

potassium chloride (KCl) and an inflation of KCl-induced Ca2+ influx as

well as an inhibition of nitric oxide (NO) generation in aortas.

Supplementation of cinnamaldehyde (20 mg/kg) to diabetic rats for 6

weeks prevents blood pressure elevation and reverses impaired vascular

reactivity through decreasing response to KCl and restoring normal Ca2+

influx as well as increasing acetylcholine (Ach)-induced NO release [10],

indicating a protective role of cinnamaldehyde in management of diabetic

hypertension.

Collectively, cinnamaldehyde has been demonstrated to protect

diabetic nephropathy through harmonizing activities of PK and PEPCK,

as well as regulating ERK/JNK/p38MAPK and Nrf2 pathways. Further,

cinnamaldehyde treatment improves vascular reactivity by normalizing

K+- Ca2+ response and increasing NO release in aortas of diabetic rats.

2.8 The others biological activities of cinnamaldehyde in diabetes

Emerging evidence also suggests that cinnamaldehyde has additional

roles in preventing the development of diabetes. First, cinnamaldehyde

exhibits beneficial effects in improving diabetic cognitive dysfunction

[87]. Using STZ (35 mg/kg, i.p.) and HFD (18 weeks) induced diabetic

rats, cinnamaldehyde treatment for 3 weeks (from 15th week to 18th

week) is demonstrated to reduce hyperglycemia and reverse amelioration

of behavioral deficits by improving brain Ach esterase activity and

neurotransmitter levels (glutamate and gamma aminobutyric acid) as well

as reducing IL-6 and TNF-α levels [88].

Second, using high-resolution α-amylase inhibition assay,

cinnamaldehyde is demonstrated to inhibit α-amylase activity in vitro

[89]. It is well known that α-amylase is one of the major secretory

products of the pancreas, and is able to catalyze the cleavage of α-D-1,4

glyosidic bonds of amylose and amylopectin in the lumen of the small

intestine [90].

Last but not least, since aldehydes provide a general core structure

for PTP inhibitors [91], the constituents of Cinnamomum burmannii is

demonstrated to inhibit protein tyrosine phosphatase 1B (PTP1B) activity

[92]. It is well known that PTP1B is able to dephosphorylate activated IR

or IRS [92,93], and inhibition of PTP1B contributes to preventing the

development of diabetes [94]. However, Sartorius et al. [95] performed

an experiment to study the effect of cinnamaldehyde on PTP1B

expression in primary murine astrocytes. Contrary to the expectation,

cinnamaldehyde treatment does not inhibit PTP1B expression in

insulin-stimulated astrocytes. Further, cinnamaldehyde reduces glycogen

formation in the presence or absence of insulin stimulation. Meanwhile,

cinnamaldehyde attenuates the promoting effect of eugenol on

insulin-mediated glycogen formation. Both cinnamaldehyde and eugenol

does not interfere with insulin signaling in hepatoma Fao cells. It should

be noted that the authors did not evaluate the interactions of

cinnamaldehyde and PTP1B in other cells and in diabetic animal models.

Therefore, it is premature to reach far-reaching conclusion about possible

interactions between cinnamaldehyde and PTP1B in management of

diabetes.

3. The recent advances in the pharmacokinetics of cinnamaldehyde

Cinnamaldehyde naturally exists in trans-cinnamaldehyde form [96].

In an experiment performed by Zhao et al. evaluates the

pharmacokinetics of cinnamaldehyde in rats using relative sensitive

approach of gas chromatography–mass spectrometry (GC-MS) via oral

(500 mg/kg) and intravenous injection (i.v.,20 mg/kg) administration [97].

The results reveals that AUC0-t of cinnamaldehyde via oral administration

and via i.v. administration are 1984 ± 531 and 355 ± 53 ng h/ml,

respectively. The T1/2 and Tmax of cinnamaldehyde are longer for oral

administration (6.7 ± 1.5 h and 1.6 ± 0.5 h) than for i.v. administration

(1.7 ± 0.3 h and 0.033 h). The Cmax is 249±36 ng/ml for oral
administration, and 547±142 ng/ml for i.v. administration, respectively.

The results indicate that the bioavailability of cinnamaldehyde is better

improved by i.v. administration than by oral administration.

Further, the authors demonstrate that Cmax and AUC0–t are

proportional to the dose (from 125 to 500 mg), whereas Tmax and mean

residence time does not change in response to dose escalation [97]. Given

that cinnamaldehyde and cinnamyl alcohol could transform into each

another in rats [97], the authors also analyzes pharmacokinetic property

of cinnamyl alcohol in rats plasma. The pharmacokinetic data of

cinnamyl alcohol are 1105±337 ng·h/ml for AUC0–t, 6.7±2.8 h for T1/2,

1.5±0.7 h for Tmax, and 221±66 ng/ml for Cmax, at oral dosage of 500

mg/kg. Interestingly, methyl cinnamate has also been discovered in the

metabolites. For pharmacokinetic property of methyl cinnamate,

interested readers are encouraged to consult Zhao et al. article [97].

Further, it should be alert that the investigation conducted by

Sapienza et al. [98] may not truly reflect the pharmacokinetic property

using radiolabel assay and liquid chromatography, because the methods

are insensitive and inaccurate compared to GC-MS. And also the previous

determination of cinnamaldehyde distribution is not reliable using the

cinnamic acid in blood or hippuric acid in urine to predict

cinnamaldehyde metabolism. Therefore, cautions must be excised when

consulting the previous literatures pertaining to the data on absorption,

distribution, and metabolic detoxification of cinnamaldehyde [98-101]. In

addition, cinnamaldehyde is a reactive aldehyde with the capacity of

converting to cinnamyl alcohol [28], which is vulnerable to β-oxidation

as their cinnamic acid derivatives [102]. It also has been reported that

cinnamaldehyde is partly metabolized into cinnamic acid in stomach and

small intestine, and is almost completely metabolized into cinnamic acid

in the liver after oral administration of decoction of Cinnamomi Ramulus

to rats [101].

Furthermore, in order to improve the stability and bioavailability,

Zhao et al. develops a novel intravenous injection of submicrometer

emulsions of cinnamaldehyde (SME-cinnamaldehyde). The

pharmacokinetic data reveals that SME-cinnamaldehyde (20 mg/kg)

treatment induces a significant increase in AUC0−t and Cmax in

comparison with the previous cinnamaldehyde solution (589 ± 59.2 vs

375 ±83.5 ng h/L and 1052 ± 184 vs 547 ± 142 ng/mL, respectively). In

addition, the volume of distribution of SME-cinnamaldehyde is decreased

in comparison with the previous cinnamaldehyde solution [30].

Cinnamaldehyde and its metabolites are found to be distributed in heart,

liver, spleen, lung, kidney, and brain. Further, SME-cinnamaldehyde

improves tissue distribution in kidney, liver, spleen, and brain, as well as

enhanced accumulation in liver and kidneys [30]. In addition,

SME-cinnamaldehyde exhibits an increase in stability and penetrability.

Therefore, SME-cinnamaldehyde may have the higher capacity of

lowering blood glucose than cinnamaldehyde.

In short, cinnamaldehyde is well distributed throughout the body after

absorption. Cinnamaldehyde has an option to transform into cinnamyl

alcohol and also can be oxidized to cinnamic acid after entering the body

(Figure 1). In order to fully understand pharmacokinetic properties of

cinnamaldehyde, methyl cinnamate and cinnamyl alcohol should also be

determined in the plasma. However, the instability of cinnamaldehyde

calls into question that the bioactivity of cinnamaldehyde is likely due to

the sum of its metabolites. Therefore, further attempts are expected to

address the potential concerns. In addition, the newly developed

SME-cinnamaldehyde with improved bioavailability also needs further

investigation of anti-diabetic effect.

4. The other major constituents of Cinnamon in diabetes

As mentioned above, cinnamaldehyde is one of main ingredients in

Cinnamomum cassia in which more than 200 compounds have been

identified according to the Chinese Academy of Sciences Chemistry

(www.organchem.csdb.cn) and Chinese Herbal Drug Databases. Among

these, cinnamaldehyde, cinnamic acid, eugenol, and polyphenols have

been well evidenced to exhibit promising effects in preventing the

development of diabetes [103,104]. In an attempt to observe the

anti-diabetic activities of cinnamaldehyde and cinnamic acid, the results

obtained showed that cinnamic acid has greater advantage over

cinnamaldehyde in improving glucose tolerance in diabetic rats, and in

enhancing glucose-stimulated insulin secretion in isolated islets [21].

Like cinnamaldehyde, cinnamic acid and its derivatives also have

beneficial effects against diabetes and its complications [105]. However,

as discussed in the previous chapter, cinnamaldehyde is vulnerable to be

metabolized into cinnamic acid during absorption [101].

Further, it is demonstrated that eugenol is able to promote

insulin-mediated glycogen formation in primary astrocytes. In contrast,

cinnamaldehyde not only inhibits glycogen formation, and but also

attenuates eugenol mediated glycogen formation in primary astrocytes

[95]. Furthermore, eugenol ameliorates hyperglycemic induced oxidative

stress in SHSY5Y cells and in brain regions of STZ induced diabetic rats

[106]. In addition, eugenol treatment restores the altered levels of Ach

esterase and calcium in the brain of diabetic rats, suggesting the role of

eugenol in alleviating diabetic complications.

Furthermore, Cinnamon polyphenols, such as catechin, epicatechin,

and procyanidin B2, and phenol polymers, have shown to be effective in

increasing GLUT4 levels and IRβ [107] as well as inhibiting the

formation of advanced glycation end-products [108], indicating a

potential benefit in preventing the development of diabetes and its

complications. However, the bioavailability of polyphenols demands

improvement so as to meet therapeutic use when human trials are

considered [84].

5. Safety assessment of cinnamaldehyde

Even now, cinnamaldehyde is still assumed to be a safe natural

ingredient agent and well tolerated in human and animals [109,110]. The

concept is also well accepted by FDA and the council of Europe with

suggestion of the acceptable daily intake of 1.25 mg/kg. Here, we briefly

review the toxicity studies of this compound over the past decades.

5.1 Acute toxicity

Cinnamaldehyde is reported to have the high margin of safety [6],

and administered 20 times of effective dose (20 mg/kg) of this compound

did not cause abnormal behavioral signs and disturbed serum chemistry

values throughout the study [7]. The acute toxicity of cinnamaldehyde is

low, with oral median lethal dose (LD50) values ranging from a low of 0.6

g/kg BW to a high of 3.4 g/kg BW in different species [111].

5.2 Long term toxicity

Several studies have been performed to detect the potential long

term of toxicity and carcinogenesis by exposing male and female F344/N

rats and B6C3F1 mice on a diet containing cinnamaldehyde for three

months (4100, 8200, 16,500, or 33,000 ppm of microencapsulated

cinnamaldehyde) or two years (1000, 2100, or 4100 ppm of

microencapsulated cinnamaldehyde) [112]. The results of the three-month

studies show that body weights are reduced in female rats exposed to

16,500 or 33,000 ppm and in female mice exposed to 8200 ppm or greater.

In addition, feed consumption is reduced in all exposed groups of rats and

in the highest dose group of mice. Further, exposure to cinnamaldehyde

(8200 ppm or greater in rats and 33,000 ppm in female mice) increases

the incidence of squamous epithelial hyperplasia of the forestomach. In

addition, mice exposed to cinnamaldehyde (males and females exposed to

16,500 ppm and females exposed to 33,000 ppm) also exhibit increased

incidence of olfactory epithelial degeneration of the nasal cavity. All rats

survived throughout the three-month study.

Furthermore, the results from the two-year study demonstrate that

cinnamaldehyde treatment reduces body weight gain in mice exposed to

2100 or 4100 ppm, and in rats and mice exposed to 4100 ppm. Survival

of male rats and male B6C3F1 mice at 4100 ppm dose were less than that

of controls. However, cinnamaldehyde exposure does not cause

neoplasms or other clinical findings in rats or B6C3F1mice.

5.3 Hepatotoxicity

Cinnamaldehyde may also show cytotoxicity effects in F344 rat

hepatocytes evidenced by depleting glutathione levels [113], and in

HepG2 cells evidenced by increasing micronucleus numbers [114]. In

addition, the frequency of micronuclei was increased in hepatocytes in

both rats (1100 mg/kg/BW) and mice (850 and 1700 mg/kg/BW) [115].

The results suggest that high dose of cinnamaldehyde may induce genetic

alterations in hepatocytes.

5.4 Respiratory toxicity

As cinnamaldehyde is often used as a fragrance agent in e-cigarette,

Behar et al. [116] studied the potential toxicity of this product in human

embryonic and lung cells. The results demonstrate that cinnamaldehyde

treatment depolymerizes microtubules in human pulmonary fibroblasts.

Cinnamaldehyde also decreases cell proliferation and differentiation by

inhibiting cell growth and differentiation, and by altering cell morphology

and motility as well as increasing DNA strand breaks and cell death.

These data may suggest that cinnamaldehyde may impair homeostasis in

the respiratory system, and therefore cinnamaldehyde in e-cigarette is

cytotoxic and genotoxic.

5.5 Skin sensitization

In addition, further concerns are rising about the contact allergy of

cinnamaldehyde, which may limit its permissible uses in food [117],

cosmetics and drug. A study performed by Olsen et al. reveals that

cinnamaldehyde causes skin irritant by increasing cold pain threshold and

decreasing mechanical pain threshold as well as increasing skin

temperature and perfusion in human [118]. The skin sensitization of this

compound is also found in the local lymph node assay in mice [119] as

well as in percutaneous absorption assay in human [120]. The underlying

mechanism may be attributed to an upregulation of percentage of B cells

and an increase in mRNA expression of TGF-β1, IFN-γ and IL-2 in the

auricular lymph nodes of female B6C3F1 mice [121].

In summary, cinnamaldehyde consumption should limit at dose of no

more than acceptable daily intake. High and non-nutritional doses of

cinnamaldehyde may cause undesirable toxicity effects. Thus, cautions

must be excised when cinnamaldehyde is taken as a preventive measure.

Interested readers are also encouraged to consult Tilman Neudecker’s

[122], Panel et al’s [102] and Shreaz et al’s [29] reviews for further safety

information.

6. Conclusions and outlook

Mounting evidences demonstrate that cinnamaldehyde exhibits

beneficial effects in prevention and treatment of diabetes through the

regulation of blood glucose and lipids metabolism as well as

improvement of insulin sensitivity. Further, cinnamaldehyde also

improves diabetic disorders in different organs and/or tissues, including

gastro-intestinal tract, liver, kidney, pancreas, skeletal muscle tissue,

adipose tissue, and hypothalamus (Figure 5). The underlying mechanism

may lie in the regulation of PPARs, AMPK, PI3K/IRS-1, RBP4-GLUT4,

ERK/JNK/p38MAPK, TRPA1-ghrelin, and Nrf2 pathways. In addition,

cinnamaldehyde possesses the ability of regulating α-amylase and PTP1B

activities as well as improving diabetic cognitive dysfunction. However,

further studies are still needed to explore the exact mechanism of

favorable metabolic effects that cinnamaldehyde may harbor. Moreover,

cautions must be excised that cinnamaldehyde may surreptitiously

metabolize into methyl cinnamate, cinnamyl alcohol, and cinnamic acid.

These metabolites may have different properties and their own biological

activities, which may lead to misinterpret the actions of cinnamaldehyde.

However, despite broad spectrum of antidiabetic activities, clinical

evidences are still lack to support the applications of cinnamaldehyde in

management of patients with diabetes.

In addition, since cinnamaldehyde is always used as a flavorant, this

prompts researchers and scientists to think that cinnamaldehyde may be

used as an adjuvant in combination with already known pharmaceutical

drugs for diabetes and obesity. Therefore, clinical trials with strong

evidence are required to further evaluate sparing effect between

cinnamaldehyde and the marketed anti-diabetes drugs.

As a natural product derived from commonly used cinnamon in the

kitchen, cinnamaldehyde consumption at doses of no more than daily

acceptable intake presents no safety concerns. High and non-nutritional

consumption of cinnamaldehyde may induce genotoxicity and

hepatotoxicity effects. In addition, SME-cinnamaldehyde has an

improvement in bioavailability and stability, while further evidences

supporting the glucose-lowering effects in diabetic animals and clinical

trials of this preparation are still lacking. Taken together, the recent

advances in pharmacology and pharmacokinetics studies may highlight

the therapeutic potential of cinnamaldehyde in management of patients

with diabetes. Properly designed and well controlled prospective clinical

studies are badly needed to increase the credibility of this compound for

therapeutic intervention of diabetes.

Acknowledgement

This work was supported by Grants from Beijing Municipal Natural

Science Foundation (7172126), National Natural Science Foundation of

China (NSFC81274041, NSFC81273995), and key drug development

program of MOST (20122X09103201-005) as well as the 111 project of

MOE (B07007). The funding agencies have no roles in study design, data

analysis, drafting and submitting the article.

Conflict of Interest

The authors declare no conflict of interest regarding the publication of

this paper.
Figure Legends

Figure 1: Major metabolic pathways of cinnamaldehyde in the body. (A)

Cinnamaldehyde and cinnamyl alcohol mutually transforms into one

another. (B) Cinnamaldehyde can rapidly be oxidized to cinnamic acid.

(C) Methyl cinnamate is the methyl ester of cinnamic acid.

Figure 2. Cinnamaldehyde improves fat acid metabolism through

stimulating BAT, promoting lipolysis and oxidation, inhibiting

inflammatory molecules release, and increasing glucose uptake through

regulation of many genes and proteins in management of diabetes.

Abbreviations: Acsl4: acyl-CoA synthetase 4; BMP4: bone

morphogenetic protein 4; CEBP-α:CCAAT/enhancer-binding protein-α;

COX-2: cyclooxygenase-2; Cpt1a: carnitine palmitoyltransferase 1A;

FAS: fatty acid synthase; FOXP2: forkhead box protein 2; GLUT:

glucose transporter; G3PA: glycerol-3-phosphate acyltransferase; G3PD:

glycerol-3-phosphate dehydrogenase; HSL: hormone -sensitive lipase; IL:

interleukin; MCP-1: monocyte chemotactic protein 1; MGL:

monoglyceride lipase; IR: insulin receptor; p-ACC: phosphorylated form

of acetyl-CoA carboxylase; p-AMPK: phosphorylated forms of

AMP-activated protein kinase; PPARγ: peroxisome proliferator-activated

receptor γ; PNPLA2: patatin phospholipase domain containing 2;

PRDM16: PR domain containing 16; SCD-1: stearoyl-coenzyme

desaturase-1; SREBP1: sterol regulatory element-binding protein 1;

TNF-α: tumor necrosis factor-α; TRPA1: transient receptor

potential-ankyrin receptor 1; UCP1: uncoupling protein 1.

Figure 3. Cinnamaldehyde improves skeletal muscle metabolism through

increasing glycogen content and glucose uptake, improving insulin

sensitivity, and promoting mitochondrial biogenesis by regulating

PI3K/IRS-1, RBP4-GLUT4, PPARs, and PGC-1α/MEF2/GLUT4

pathway in management of diabetes.

Abbreviations: AMPK: 5′-adenosine monophosphate-activated protein

kinase; GLUT: glucose transporter; MEF2: myocyte enhancer factors 2;

IRS: insulin receptor substrate; PGC-1α: peroxisome

proliferator-activated receptor γ coactivator 1α; PI3K:

phosphatidylinositol-3-kinase; PPAR: peroxisome proliferator-activated

receptor; RBP4: retinol binding protein 4.

Figure 4. Cinnamaldehyde improves the functions of liver, pancreas,

gastro-intestinal tract, kidney, and hypothalamus through regulating lots

of genes and proteins in management of diabetes.

Abbreviations: ACP: acid phosphatase; ALP: alkaline phosphatase; ALT:

alanine aminotransferase; AST: aspartate aminotransferase; BDNF:

brain-derived neurotrophic factor; CARTPT: cocaine and

amphetamine-related transcript; CAT: catalase; CCK: cholecystokinin;

ECM: extracellular matrix proteins; ERK/JNK/p38MAPK: extracellular

signal-regulated kinase/c-Jun NH2-terminal kinase/p38 mitogen-activated

protein kinases; GPx: glutathione peroxidase; IR: insulin receptor; LDH:

lactate dehydrogenase; NO: nitric oxide; NQO1: quinone 1; Nrf2: nuclear

factor erythroid-2 related factor 2; PEPCK: pyruvate carboxykinase; PK:

pyruvate kinase; POMC: proopiomelanocortin; p21: p21/WAF1Cip1;

RBP4: retinol binding protein 4; SOD: superoxide dismutase; TGF-β:

transforming growth factor-β; TRPA1: transient receptor

potential-ankyrin receptor 1; UCN: urocortin; γ-GCS: γ-glutamylcysteine

synthetase.

Figure 5. Cinnamaldehyde improves the diabetic disorders in different

organs and/or tissues, including gastro-intestine, liver, kidney, pancreas,

skeletal tissues, adipose tissues and hypothalamus. In addition,

cinnamaldehyde inhibits α-amylase and PTP1B activities. Abbreviations:

PTP1B: protein tyrosine phosphatase1B.

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