Trends in Food Science & Technology 88 (2019) 46–56

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Trends in Food Science & Technology

journal homepage: www.elsevier.com/locate/tifs

Review

Recent advances in the development of sesquiterpenoids in the treatment of T

type 2 diabetes
Lei Chena,1, Xu Lua,1, Hesham El-Seedib,∗∗, Hui Tenga,∗
a
College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, Fujian, 350002, China
b
Pharmacognosy Group, Department of Medicinal Chemistry, Uppsala University, Biomedical Centre, Box 574, 751 23 Uppsala, Sweden

A R T I C LE I N FO A B S T R A C T

Keywords: Background: Treatment of type 2 diabetes mellitus (T2DM) through dietary terpenoids is receiving a promising
β-Cell dysfunction interest and sesquiterpenoids’ importance for food and pharmaceutical industries is mainly based on the existed
Insulin resistance scientific works.
Sesquiterpenoids Scope and approach: Sesquiterpenoids might contribute to prevent or delay T2DM by inhibiting key enzymes
Type 2 diabetes
relevant for hyperglycemia, modulating β-cells function, targeting insulin signaling route, etc. Sesquiterpenoids
Key enzyme
also have been demonstrated to stimulate glucose uptake by enhancing glucose transport, repressing glucose
production, or improving lipid metabolism.
Key findings and conclusions: In this review, we summarized the latest developments of sesquiterpenoids in the
treatment of type 2 diabetes as well as sesquiterpenoids-rich herbs against key enzymes relevant to hypergly-
cemia, and discussed their underlying molecular mechanisms of anti-diabetic potential. We also suggested a
better evaluation of the pharmacological profile of sesquiterpenoids and their derivate with a clear-cut choice of
possible human pathologies.

1. Introduction tissues to insulin (type 2 diabetes mellitus, T2DM or non-insulin de-

Diabetes mellitus (DM) is known as a sort of metabolic disturbance,
which is marked by a chronic hyperglycemic condition either caused by
an insulin deficiency of impaired insulin signaling and non-auto-
immune etiology, or due to a decreased insulin sensitivity present pri-
marily in the adipose tissues, liver, and skeletal muscles. Other serious
complications such as blindness, delayed wound healing, erectile dys-
function, ischemic heart disease, and stroke, and micro as well as
macro-vascular complications such as neuropathy, retinopathy, and
nephropathy are quite common in the case of long term diabetes.
The International Diabetes Federation (IDF) estimated that the
number of diabetes cases is expected to grow to 438 million globally in
2030 from 285 million people in 2009 (Bennett, 2018; Cao et al., 2018;
Zhao et al., 2018). The world health organization (WHO) has reported
that there are about 422 million people worldwide have diabetes in
2014 (Vinayagam, Xiao, & Xu, 2017). There are two major forms of the
syndrome, resulting from either lack of insulin secretion by beta cells of
the pancreas (type 1 diabetes mellitus, T1DM or insulin dependent
diabetes mellitus, IDDM), or caused by decreased sensitivity of target
pendent diabetes mellitus, NIDDM). Conversely, Type 1 diabetes re-
presents only 10% of all cases of diabetes, affecting approximately 20
million people worldwide of all age groups, pointedly 4–5 years, or in
their teens and early adulthood. The major pathophysiological event
contributing to the development DM is T2DM accounting at least 90%
of all cases of diabetes mellitus. The incidence of T2DM upsurge with
age, with most cases being diagnosed after the age of 40 years. This is
parallel to a lifetime risk of developing diabetes of 1 in 10.
A widely held notion is that T2DM is a heterogeneous and polygenic
disorder resulting fromgenetic susceptibility, characterized by impaired
insulin signaling, also known as insulin resistance, as well as a relative
insulin deficiency of non-autoimmune etiology, and environmental
factors such as obesity, over eating, lack of exercise, and stress as well
as aging (Li et al., 2015). It is typically idiopathic diabetes involving
multiple genes and environmental factors to varying extents. Under
normal physiological conditions, insulin controls blood glucose home-
ostasis within a narrow range through the stimulation of glucose uptake
into peripheral tissues mainly skeletal muscle and fat tissue and by
suppressing the release of stored lipids from adipose tissue by liver

∗
Corresponding author.
∗∗
Corresponding author.
E-mail addresses: hesham.el-seedi@ilk.uu.se (H. El-Seedi), tenghui850610@126.com (H. Teng).
1
Authors contributed equally to this work.

https://doi.org/10.1016/j.tifs.2019.02.003
Received 11 December 2018; Received in revised form 25 January 2019; Accepted 2 February 2019
Available online 05 February 2019
0924-2244/ © 2019 Published by Elsevier Ltd.
L. Chen, et al. Trends in Food Science & Technology 88 (2019) 46–56

Abbreviations IL interleukin
iNOS inducible nitric oxide synthase
AMPK AMP activated protein kinase IR insulin receptor
ATP adenosine triphosphate IRE1α inositol-requiring enzyme 1α
CD sconjugated dienes JNK c-Jun N-terminal Kinase
COX-2 cyclo-oxygenase-2 MAPK mitogen-activated protein kinase
CRP C-reactive protrein LOOH lipidperoxides
ERK extracellular regulated kinase NF-κB nuclear factor kappa B
FAS fatty-acid synthase Nrf2 nuclear factor erythroid 2-related factor
GK glucokinase NF-kB nuclear factor kappa-B
GLUT glucose transporter PB2 procyanidin B2
GPx glutathione peroxidase PC protein carbonyls
GR glutathione reductase PERK PKR-like ER-regulated kinase
Grb-2 growth factor receptor-bound protein 2 PEPCK phosphoenolpyruvate carboxykinase
GS glycogen synthase PGE2 prostaglandin E2
GSH glutathione PI3K phosphatidylinositol-3-kinase
GSK-3 glycogen synthase kinase-3 PKC protein kinase C
GST glutathione-S-transferase PPAR peroxisome proliferator activated receptor
HbA1c haemoglobin A1c PTP1B protein tyrosine phosphatase 1B
HFr high-fructose-fed rats PTL Parthenolide
HO-1 heme oxygenase-1 ROS reactive oxygen species
HOMA-B homeostatic model assessment of β-cell function SOD superoxide dismutase
HOMA-IR homeostatic model assessment of insulin resistance SREBP1-c sterol-regulatory-element-binding protein-1-c
HPPA 3-hydroxyphenylpropionic acid TNF tumor necrosis factor
IFN-γ interferon-γ TBARS thiobarbituric acid reactive substances
IκB inhibitor of nuclear factor-κB T2DM type 2 diabetes mellitus
IKK IκB kinase

despite wide fluctuations in supply and demand. In T2DM, this me-
chanism is halted when insulin secretion is impaired through a dys-
function of the pancreatic β-cell, and compromised insulin action
through insulin resistance therefore leads to multiple metabolic ab-
normalities.
Thus, the major contributor to the pathogenesis of T2DM is insulin
resistance. Clinically, the terminology of insulin resistance is a condi-
tion in which insulin in the body does not exert sufficient action pro-
portional to its blood concentration to conserve a normo-glyceamia. On
cellular level, it is defined as deficient insulin signaling strength from
downstream receptor to the final substrates in multiple and mitogenic
aspects of cellular functions. In insulin resistant plight, the impairment
of insulin action in major target organs such as liver and muscles does
not properly respond to insulin and by that inducing hyper-glycaemia
and a reactive escalation of insulin excretion by β cells of pancreas. At
those conditions, the poor insulin responsiveness can only be re-
imbursed for limited time only, which only further impairs insulin re-
sistance. This depraved cycle finally points to brawl of fragile balance
between insulin resistance and β cell functions, which leads to mani-
festation of T2DM.
Irrespective to the fundamental pathophysiological processes, the
metabolic amendments that result from hyperglycemia ultimately, lead
to functional and/or structural changes in virtually all tissues. The most
distinguished damage is to the endothelium, which plays an imperative
part in the pathogenesis of the macrovascular complications or due to
damage to larger blood vessels (coronary artery disease, peripheral
arterial disease, and stroke) and microvascular complications or due to
damage to small blood vessels (diabetic nephropathy, neuropathy, and
retinopathy). Though, other tissues are important as well as evinced, for
instance by the contribution of structural changes in connective tissue,
leading to impotence and diabetic foot disorders (which include severe
infections leading to amputation.
2. Sesquiterpenoids
Sesquiterpenoids are a category of terpenes consisting of three iso-
prene units sharing a structural formula of C15H24, which are significant
secondary metabolite in nature, and mostly existed by volatile oil.
Sesquiterpenes are extensively distributed in plants, microbes, marine
organisms and some insects, and they have important physiological
activities and functions (Table 1). Especially sesquiterpene lactones,
they have effects of cytotoxic, antimicrobial, anti-inflammatory, anti-
diabetic, anti-tumor and other functions. Sesquiterpenes are one of the
terpenoid compounds which have the most types of structural

Table 1
Biological activity of sesquiterpenes.
Compounds Type Sources Efficiency Reference

Bisabolol oxygenated sesquiterpene Commercial gastroprotection Rocha et al. (2011)

(+)-8-(15)-cedren-9-ol oxygenated sesquiterpene Commercial – Fenrick, Bhattacharya, and Willard (1981)
Costunolide oxygenated sesquiterpene Costus speciosus anti-diabetic Eliza et al. (2010a)
Dehydroleucodine oxygenated sesquiterpene Artemisia douglasiana gastroprotection Repetto and Boveris (2010)
Eremanthin oxygenated sesquiterpene Costus speciosus anti-diabetic Eliza et al. (2010a)
Farnesol oxygenated sesquiterpene Commercial – Fenrick et al. (1981)
Guaiol oxygenated sesquiterpene Commercial – Fenrick et al. (1981)
Huperzine-A oxygenated sesquiterpene Commercial neuroprotection Xiao, Wang, and Tang (2000)
Lindenenyl acetate oxygenated sesquiterpene Lindera aggregata neuroprotection Li et al. (2009a)
Guaiazulenum oxygenated sesquiterpene Commercial hepatoprotection Kourounakis, Rekka, and Kourounakis (1997)

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L. Chen, et al.
skeletons. Up to now, there are more than 200 kinds of skeletons, and
thousands of compounds have been formed. More than 300 kinds in
marine organisms and 1000 kinds in plants have been found. Sesqui-
terpene compounds can be divided into acyclic, monocyclic, bicyclic,
tricyclic and tetracyclic sesquiterpenes according to the number of
carbon rings. According to the classification of oxygen-containing
functional groups, sesquiterpenes can be divided into alcohols, alde-
hydes, ketones, lactones etc.
3. Advances in research on the anti-diabetic effect of
sesquiterpenes
3.1. Acyclic sesquiterpenes
Acyclic sesquiterpenes, including α and β-farnesene (1–2), farnesol
(3), nerol (4) and other compounds, have pleasant aroma and the role
of blenders and fixative. Among them, α-farnesene is present in the
volatile oil of loquat leaf, ginger and other plants, and the β-form is
found in the essential oil of patchouli, hops and ginger. The content of
farnesol is higher in neroli oil and lemongrass, and it is an advanced
perfume raw material (Fig. 1). Nerol has an apple odor and it is one of
the main ingredients of neroli oil. The current research rarely reported
the inhibition effect of acyclic sesquiterpenes on diabetes.
3.2. Sesquiterpene lactones
There are few reports on the anti-diabetic effects of monocyclic and
polycyclic sesquiterpenoids, while sesquiterpenoid derivatives are very
effective. Sesquiterpene lactones (SLs) are a group of secondary meta-
bolites extracted from compositae plants. The chemical structures of the
known SLs are more than 5000, which are the main active components
of compositae. SLs have a variety of biological effects, such as anti-
tumor, anti-inflammatory, antimicrobial, antigenic variation and other
functions, so sesquiterpene lactones has broad prospects for many dis-
eases therapies. Most studies are focus on the anticancer and anti-in-
flammatory effects of SLs, and the discovery of anti-inflammatory effect
is a significant milepost on the road to eventually make clear its me-
chanism.
Inflammation and oxidative stress lead to β-cell failure in insulin
resistance. As a chronic inflammatory disease, the pathogenesis of
diabetes is closely associated with the activation of NF-κB. PTL is a very
important natural substance in sesquiterpene lactones, which has been
proved as a specific suppressor to NF-kB. NF-kB is a key mediator in the
immune system, playing an important part in the regulation of in-
flammatory response. Meanwhile, NF-kB regulates genes involved in
cell apoptosis, survival, metabolism and angiogenesis. Therefore, the
abnormal regulation of NF-kB due to various causes can lead to multiple
diseases. For the treatment of related diseases, it is very important to
study and explore the drugs which can regulate NF-kB activation and its
associated signaling pathways. In addition, sesquiterpene lactones can
also be used to treat diabetes by inhibiting α-glucosidase, aldose re-
ductase, etc. The related effects of sesquiterpene lactones on diabetes
are shown in Table 2.
3.3. Acyclic sesquiterpenes
At present, thousands of sesquiterpenoids have been found in plants,
and many studies have shown that sesquiterpenoids extracted from
plants have good anti-hyperglycemic and anti-lipid effects.
Ponnusamy et al. (Ponnusamy, Ravindran, Zinjarde, Bhargava, &
Ravi Kumar, 2011) studied an Indian plant (Ayurvedic), the product
extracted from its tubers by isopropanol extraction can effectively in-
hibit the secretion of human pancreatic amylase (HPA). GC-MS analysis
showed that the main components of the crude extracts are curcumi-
noid, sesquiterpene and cinnamic acid, suggest that this Indian plant
has great potential of anti-diabetes.
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Trends in Food Science & Technology 88 (2019) 46–56
Yu-Ming Chung et al. (Chung et al., 2013) obtained three new bi-
sabolane-type sesquiterpenoids from the fermentation broth of fungus
Aspergillus sydowii, they are (7S)-(+)-7-O-methylsydonol (5), (7S,
11S)-(+)-12-hydroxysydonic acid (6) and 7-deoxy-7,14-didehy-
drosydonol (7), respectively. All of them show good anti-inflammatory
and anti-diabetic effects. Compounds 1 and 2 increased the glucose
consumption of the differentiated 3T3-L1 adipocytes in the culture
medium, which is mainly due to the presence of certain substituents
(methylene alcohol on C-3 and hydroxy group on C-7) in bisabolane-
type sesquiterpenes (as shown in Fig. 2).
Keskes et al. (2014) extracted natural compounds from the leaves of
Juniperus phoenicea L, and the main constituents were monoterpenoids
and sesquiterpenes including δ-Cadinene and Germacrene D. The re-
sults showed that the sesquiterpenoids extracted from this plant could
be a potential drug for anti-diabetes by inhibiting α-amylase and reg-
ulating blood glucose effectively. Escandón-Rivera et al. (2012) ex-
tracted a kind of sesquiterpene from the water extract of Brickellia ca-
vanillesii, which can be used as inhibitor of α-glucosidase, and the
structure of this compound is shown in Fig. 3. Compound 4 (8) binds to
the catalytic site enzyme with a Ki value of 0.30 μM, and the amino
acids involved in the binding or hydrogen bonding of calcium protein
are Glu304 and Ar349 (as shown in Fig. 3).
In another study, three kinds of sesquiterpenes were isolated from
Lactuca indica: sesquiterpene lactone (11), lactucain C (12) and fur-
ofuran lignan, lactucaside (13). The in vivo animal experiments in-
dicated that the extract exhibited ideal anti-hyperglycemic effects (Hou,
Lin, Cheng, & Hsu, 2003) (the structure of the compound is shown in
Fig. 2).
Basha and Sankaranarayanan (2014) isolated a natural sesqui-
terpene-caryophyllene, and it has been shown that caryophyllene reg-
ulates the glycemic index in diabetic mice by regulating the metabolism
of carbohydrates. The disaccharide metabolism is related to intestinal
α-glucosidase on the glycolysis of monosaccharide, so it can inhibit the
enzyme activity and act as an attractive drug target in the treatment of
diabetes, and can be used as the first line of defense to control post-
prandial hyperglycemia. High blood glucose levels will lead to the
formation and accumulation of sorbitol in diabetic patients, and aldose
reductase promote sorbitol accumulation mainly through polyol
pathway, therefore aldose reductase is another effective target. Protein
glycosylation is another undesirable consequence of hyperglycemia,
which is caused primarily by non-enzymatic reactions of glucose and
protein present in the blood, leading to the formation of advanced
glycation end products (AGEs), can induce other complications of dia-
betes such as Alzheimer's disease, cardiovascular disease and stroke.
Ajish et al., (2015) extracted kinds of natural plant ingredients from the
Zingiber zerumbet: four sesquiterpenes (14–17) and four flavonoids.
The in vitro results showed that the four sesquiterpenoid extracts could
effectively inhibit the effects of α-glucosidase, aldose reductase and
anti-protein saccharification, provide a new way for the treatment of
diabetic patients (Fig. 2).
Morikawa, Kishi, Pongpiriyadacha, Hisashi Matsuda, and
Yoshikawa (2003) isolated a new acylated eudesmane-type sesqui-
terpene, salasol A (18) from Salacia chinensis, which can play a role in
anti-diabetic by inhibiting aldose reductase polyol pathway. Aldose
reductase is a key enzyme in the polyol pathway that promotes the
conversion of glucose to sorbitol. In normal tissues, aldose reductase is
lower than glucose, so blood glucose is less likely to be catalyzed to
Fig. 1. The structure of partial acyclic sesquiterpenes.
L. Chen, et al. Trends in Food Science & Technology 88 (2019) 46–56

Table 2
Related studies on the anti-diabetic effect of sesquiterpene lactones.
Sources Type Anti-diabetic effect and its mechanism Reference

Yacon leaves Sesquiterpene lactones-
Enhydrin
Smallanthus macroscyphus Sesquiterpene lactones
Brickellia cavanillesii Sesquiterpene lactones
The rhizome of Costus Costunolide
speciosus
Foeniculum vulgare Mill Sesquiterpene lactones
Glucoside and decyl glucoside
– Sesquiterpene lactones
derivatives
– Sesquiterpene lactones and its
derivatives
Effectively reduce the secretion of postprandial glucose and inhibit the Genta et al. (2010)
activity of α-glucosidase.
Prevent carbohydrate absorption after food intake and reduce blood glucose Serra-Barcellona et al. (2014)
by inhibiting intestinal enzymes, including α-glucosidase and α-amylase.
The hyperglycemia in diabetic mice can be treated effectively by inhibiting Escandón-Rivera et al. (2012)
α-glucosidase.
Costunolide has a good effect of decreasing blood glucose and blood lipid, it Eliza, Daisy, Ignacimuthu, and
can inhibit the hepatic gluconeogenesis and promote glucose uptake and Duraipandiyan (2009)
metabolism, produce insulin-like effect on peripheral tissues by enhancing
glucose absorption ability in muscle and adipose tissue, stimulate the
regeneration process and restore the remaining β cell.
Anti-hyperglycemic effect Takayanagi, Ishikawa, and
Inhibition of α-glucosidase and α-amylase Kitajima (2003)
It can be used for the treatment of diabetes through the regulation of NF-κB Chen et al. (2016)
and MAPK signaling pathway.
Reduce the production of chemokines, such as MCP-1, TGF-β1 and FN, Jia et al. (2013)
activate NF-κB, and inhibit sugar-induced degradation of IκBα

sorbitol. However, for diabetic patients, the increase in glucose avail-
ability in insulin tissue, nerves and the retina results in an increase in
the formation of sorbitol through the polyol pathway. Sorbitol is not
easily diffused in the cell membrane and intracellular, and sorbitol
accumulation has been implicated in chronic diabetic complications
such as cataract, neuropathy, and retinopathy. Aldose reductase in-
hibitors could prevent the conversion of glucose to sorbitol and may
prevent or treat the complications of diabetes (Terashima et al., 1984).
Diacylglycerol acyltransferase (DGAT) is a key enzyme in the
synthesis of triglycerides in eukaryotes, and therefore the acyl-CoA
inhibitor has been proposed as a drug target for the treatment of obe-
sity, type II diabetes and metabolic syndrome. Park et al. (2008) ex-
tracted four sesquiterpenes from the buds of Tussilago farfara, they are
tussilagonone (19), tussilagone (20), 7-1r-(3-ethyl-cis-crotonoyloxy)
(2-methylbutyryloxy)3,14-dehydro-Z-notonipetranone (21), and 8-an-
geloylxy-3 4-epoxy-bisabola-7 (14),10-dien-2-one (22). Through the
detection of DGAT, rat liver microsomes and HepG2 cell microsomes,
results showed that all the compounds inhibited DGAT1 and IC50 va-
lues were 99.2, 18.8, 47.0, 211.1 μM (acting on rat liver microsomes),
and more than 1, 49.1, 160.7, 294.4 μM (acting on HepG2 cell micro-
somes). Compound 20 was the most potent inhibitor of liver micro-
somal DGAT1 derived from murine and human hepatocellular carci-
noma HepG2 cells, and it also significantly inhibited the synthesis of
triglycerides and inhibited acetic acid [14C] or glycerol [14C] in HepG2
cells converted into triglyceride. These findings suggest that tussilagone
is a potential candidate for the treatment of obesity and type 2 diabetes.
In addition, some of the structural features of terpenes seem to
provide a strong support to explain its antioxidant properties. Among
the sesquiterpenes, the allyl alcohol type is the most active antioxidant
compound. Costunolidec (23) and eremanthin (24), which are isolated
from Costus speciosus (Koen ex. Retz) Sm, have protective effects against
oxidative stress in streptozotocin-induced diabetic rats. The mechanism

Table 3
Related studies on the anti-diabetic effect of sesquiterpenes from marine organisms.
Compounds Structure Sources Efficiency Reference

Dysidine The sponge Reduce the sensitivity of catalase, inhibit phosphatase (PTP), prevent Zhang et al. (2009)
Dysidea villosa dephosphorylation reaction

O-methyl nakafuran- Hainan sponge inhibit the activity of PTP1B with IC50 value of 1.58 μmol/L Shao et al. (2006)
8 Dysidea
Lactone
unnamed Hainan Sponge All the compounds inhibited PTP1B, and compound were the strongest most Huang, Li, Li, Shi,
Dysidea septosa potent inhibitor of PTP1B with an IC50 value of 1.9 μg/mL and Guo (2008)

unnamed

unnamed

unnamed

Dysidine Hainan sponge It is a slow-binding inhibitor of PTP1B with the IC50 value of 6.70 μmol/L. It Li, Zhang, Shen, and
Dysidea villosa can activate the insulin signaling pathway and promote the transport of Guo (2009b)
glucose transporter 4 (GLUT4) on CHOK1 and 3T3-L1 cell membranes. The
glucose uptake of 3T3-L1 cells increased 2.3-fold.

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Fig. 2. (continued)
Fig. 2. Molecular structure of sesquiterpenoids from plant.

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L. Chen, et al. Trends in Food Science & Technology 88 (2019) 46–56

Fig. 3. Docking results using the structural model of the α-glucosidase: (A) site of binding of acarbose (blue), which comprises the catalytic site of the enzyme; (B)
binding conformation of compounds 9 (cyan), 8 (magenta), and 10 (orange). (For interpretation of the references to colour in this figure legend, the reader is referred
to the Web version of this article.)

of protection is to induce antioxidant SOD, CAT, GPx enzyme and non-
enzymatic antioxidant GSH to keep lipid peroxidation at a low level
(Eliza, Daisy, & Ignacimuthu, 2010b). In addition, sesquiterpene dimers
also exhibit similar effects in streptozotocin-induced mild and severe
diabetic mice (25) (Gutiérrez & Ramirez, 2016).
PPARs are members of the nuclear receptor superfamily, whose
activators are currently prescribed as anti-hyperlipidemia and anti-hy-
perglycemic drugs. Studies have shown that naturally-derived sesqui-
terpenes enhance PPAR-γ activation by directly binding to the ligand-
binding domain of PPAR-γ (PPAR-γ is commonly expressed in all tissues
of adult mammals), and sesquiterpenes also stimulate the transactiva-
tion of PPAR-dependent gene promoters (Nahvinejad, Pourrajab, &
Hekmatimoghaddam, 2016). Herb-derived sesquiterpene activator
could enhance PPAR-γ activity to induce its interaction with PPRE
(PPAR-γ response element), SHP and ABCA1 gene promoters, and had
significant dose-effect relationship. PPAR-γ activators not only improve
insulin sensitivity, but also reduce oxidative stress. PPAR-γ activator is
a major source to suppress the oxidants in vascular system, including
the phagocytosis of NADPH oxidase and endothelial NADPH oxidase-
mediated ROS-induced pancreatic β-cell apoptosis. The naturally-de-
rived sesquiterpenes enhance PPAR-γ activation by directly binding to
the ligand-binding domain of PPAR-γ. In addition, sesquiterpene sti-
mulates the transactivation of PPAR-dependent gene promoters.
Dorema aucheri extract (sesquiterpene containing α-eudesmol
(26) > 31.2%, δ-Cadinen (27) > 10.9%, β-caryophyllene
(28) ∼ 4.9%) exerts its biological effects through activation of PPAR-γ
and indicates that it can act as PPAR-α/γ dual activator. The sesqui-
terpenoids (triterpene lactones, tirotundin (29), tagitinin A (30),

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tagitinin C (31)) in Tithonia diversifolia have been reported to be PPAR-

Liu, Wen, Zheng, Zhang, and

Murakami et al., 2002, 2003

Chung, Cho, Bhuiyan, Kim,
α/γ dual activators, which is a potential mechanism for its therapeutic

Chao, Huang, Lin, Chang,

Whan Han et al., 2001
effect in the treatment of diabetes (Lin, 2012). This drug is involved in

Wang et al. (2015)

the anti-hyperglycemic effect of PPAR-γ, seems to be associated with its

and Chang (2016)

Jin et al. (2006)

and Lee (2010)

ability to enhance insulin sensitivity, which enhances the efficacy of
Han (2007)
insulin. In addition, the sesquiterpenes (32–38) in Tithonia diversifolia
Lin (2012)
Reference

have been found to enhance insulin sensitivity, and thus improve the
bioavailability of insulin.
The activation process of insulin receptor (IR) mainly includes
↓TNF-α, ↓IL-1β, ↓IL-6, ↓Nitrite production, ↓iNOS, ↓COX-2, ↓NF-κB, ↓p38, ↓

↓TNF-α, ↓iNOS, ↓COX-2, ↓free radical generation, ↓COX-2, ↓IκBα, ↓NF-κB, ↑

↑GLUT4, ↑PPARγ, ↑PPARα, ↑SREBP-1c, ↓glucose production, ↓Nrf2, ↓ p-ERK, phosphorylation of IR. Currently, IR and IRS1 can be dephosphorylated

↓iNOS, ↓COX-2, ↓NF-κB, ↓p38, ↓p65, ↓JNK, ↑IκBα, ↑GSH, ↓ GPx, ↓GR, ↓ p-
Nrf2, ↓ Nrf2, ↓ p-ERK, ↓p-JNK, ↓p-p38, ↑ glucose uptake, ↓ p (Ser)-IRS-1
↓NF-κB, ↓IκBα, ↓TNF-α, ↓IL-1β, ↓IL-6, ↓Nitrite production, ↓p65, ↓iNOS,

by several PTP enzymes, including PTP1B, PTPα, LAR, CD45, TC-PTP,

resulting in the impaired glucose uptake in peripheral tissues, which is

↓NO, ↓PGE2, ↓IL-1β, ↓TNF-α, ↓IL-6, ↓IL-12, ↑Nrf-2, ↑AMPK, ↓HO-1

↑glucose uptake, ↑GLUT4, = GLUT1 ↑AMPK, ↑PI3K/Akt, ↓TNF-α,

the main pathogenesis of type 2 diabetes. Sesquiterpenes showed strong
ability to enhance insulin sensitivity, and its mechanism mainly
↓iNOS, ↓COX-2, ↓NF-κB, ↑IFNγ, ↓ Nitrite production, ↓PGE2

through the insulin pathway, possibly through the inhibition of protein

tyrosine phosphatase (especially PTP1B), thereby improving GLUT4
mediated uptake of glucose. PTP-1B, a key negative regulator of insulin
signaling pathway, is thought to be a negative regulator of IR signaling
↓PGE2, ↓IκBα, ↓COX-2, ↓NF-κB, ↓p65, ↓iNOS,

and a promising drug target for the treatment of type 2 diabetes.

↓p-JNK, ↓p-p38, ↓PEPCK, ↓G6-pase, ↑GK

Sesquiterpenoid with PTP-1B inhibitory activity can block the tyrosine

phosphorylation of insulin-stimulated IR, thereby affecting the phos-
phorylation of IRS-1, sensitizing insulinoid and insulin, and decreasing
blood glucose (Zhang, Li, Guo, Jiang, & Shen, 2009). Ligularia fischeri is
p65, ↓JNK, ↑IκBα, ↓PGE2

very common in the southwest of China, and it is a traditional Chinese

medicine. Researchers isolated and purified a kind of sesquiterpene
↓ Nitrite production
↓PPARγ, ↓PPARα

from the roots of Ligularia fischeri, that is (3β, 6β, 8α, 10β) -3-acetyl-6, 8,
10-trihydroxyeremophil-7 (11)-eno-12, 8-lactone (39). This kind of
sesquiterpene could effectively inhibit PTP1B and its in vivo IC50 value
is 1.34 μmol/L (Deng, Dong, Jiao, & Lu, 2009). CB Clarke et al. isolated
Effect

IFN-γ

Mokko lactone (40) and Dehydrocostuslactone (41) from the roots of

Saussurea lappa, both of them could inhibit PTP1B and the IC50 values
12.5–100 μg/ml, 24 h

were IC50 = 1.41 ± 0.02 μg/mL and 6.51 ± 0.64 μg/mL, respec-
5 μM, 10–120 min;

tively.
0.1 μM-10 μM

0.5 μM-10 μM
−0.63 μg/ml
5 μM-20 μM
0.16 μg/ml

2.5–10 μM
Treatment

3.4. Specific inhibitors for PTP1B

5–40 μM
NA

NA

NA

In marine aquatic organisms, the anti-diabetic effect of sesqui-

terpenoids is mainly mediated by PTP1B pathway. Many studies have
Inulanolides, 1, 6α-dihydroxyeriolanolide, 1-acetoxy-6α-
Sesquiterpenes modulation of proteins involved in the anti-diabetic effect in cultured cells.

shown that sesquiterpenes in marine organisms can be used as potent

inhibitors of PTP1B. Abdjul et al. (2016) have isolated three novel
Bicyclogermacrene, Caryophyllene, Germacrene-D,

1-oxo-4aH-eudesma-5 (6), 11 (13)-dien12,8β-olide

sesquiterpenes (42–44) from the Dysidea sp. Marine Sponge. The hy-
droquinone compounds can be used as an inhibitor of PTP1B. Com-
pounds 42–44 inhibited the activity of PTP1B with IC50 values of 11,
9.5, and 6.5 μM, respectively. In addition, sponge is a kind of natural
Atractylenolide I, atractylenolide II

resources with important biological activity, which has a wide range of

Farnesene, γ-Elemene, Cadinene
hydroxyeriolanolide, eupatolide

chemical structure in marine metabolites (see Table 3).

Tirotundin, tagitinin A

4. Studies in cultured cells

Acetylbritannilactone

Lindenenyl acetate
Japonicones E-L

Despite an enormous amount of research, the exact pathogenetic

Sesquiterpenes

mechanisms leading to the complications of T2DM are still far from

Zerumbone

(JEUD-38)
Ergolide
Britanin

clear. Unifying theory where the root cause of T2DM is abnormalities in

both insulin action and secretion. This was supposed to be the initiating
step that led to direct consequence of obesity-associated exposure of
Human periodontal ligament (HPDL) cell

tissues to elevated dietary nutrients, resulting in the accumulation of

VSMCs (vascular smooth muscle cells)

toxic metabolic by-products. Nonetheless, research has indicated that

Colonic adenocarcinoma cell lines,

other factors may also be crucial, including inter-organ communication

Mouse skeletal muscle C2C12

networks that are mediated by peptide hormones and inflammatory

molecules (cytokines), and activation of intracellular stress response
pathways. Even though the detailed pathophysiological sequence which
leads to insulin resistance is still largely indefinite, studies have con-
tributed to a deeper understanding of the underlying molecular me-
Adipose tissue

chanisms. Cell cultural studies constitute an important tool to examine

RAW264.7
(ADC)

model
Raw264.7

Raw264.7
Raw264.7

Raw264.7
Cell type

the underlying molecular mechanisms of sesquiterpenoids by simu-

Table 4

HepG2

lating a diabetic condition in different cell lines coming or obtained

from main target tissues for the disease such as pancreas and insulin-

52
L. Chen, et al. Trends in Food Science & Technology 88 (2019) 46–56

sensitive/responsiveness tissues (liver, adipose tissue and skeletal

Murakami et al. (2003), Tanaka et al.

Basha and Sankaranarayanan, 2016

muscle) (Table 4). Impairment of insulin signaling can be associated

Peltonen-Shalaby, and Ali (2006)

Al-Amin, Thomson, Al-Qattan,
with several mechanisms such as tyrosine dephosphorylation, im-
balance of serine/threonine phosphorylation, or insulin receptor in-

Gunawan et al. (2016)

Gunawan et al. (2016)

ternalization. A various number of molecules allied to insulin resistance
Genta et al. (2010)

affect these mechanisms, and in this review covers adipose tissue, free

Liu et al. (2016)

Li et al. (2015)
fatty acids (FFAs), Interleukin 6 (IL-6), Tumor necrosis factor alpha
(TNF-alpha), peroxisome proliferator activated receptor gamma (PPAR
Reference

gamma), fuel oxidation, insulin secretion, Beta-cell mass and gluco-

(2001)

toxicity. Adipose tissue dysfunction holds a critical role in the insulin

resistance in T2DM. Obesity and abnormal distribution of fat in the
↓Blood glucose, ↓total cholesterol, ↓triglycerides, ↓urine output, ↓

body (lipodystrophy) causes insulin resistance in muscle. In addition,

↓8-hydroxy-2-deoksiguanosin, ↓oxidative stress, ↑GLUT4, ↓insulin

Pancreas: ↑β-cell mass, ↑Bcl-xL, ↓Bax, ↓caspase-3 activity, ↑SOD,

Kidney: = GSH, = GPx, = GR, =CAT, ↑ SOD, ↓GST, ↓TGF-β1, ↓

defective glucose transport by GLUT4 in adipose tissue leads to insulin

↑CAT, ↑GPx, ↑GR, ↑GST, ↑GHS, ↓TBARS, ↓LOOH, ↓PCO, ↓CD,

↓Blood glucose, ↓total cholesterol, ↓triglycerides, ↓blood urea

resistance in the muscle and liver. Emerging data imply that molecules
water intake, hypoglycaemic, hypocholesterolaemic and
Colonic mucosa: ↓TNF-α, ↓IL-1β, ↓IL-6, ↓PGE2, ↓COX-2

Liver: ↑GLUT4, ↑PPARγ, ↑PPARα, ↑SREBP-1c, ↓glucose

released from adipocytes, such as free fatty acids, TNF alpha, IL-6, in-
hibit insulin signaling and induce insulin resistance, and activate
serine/threonine kinases that phosphorylate the IRS proteins and in-
hibit their function. Up-surged FFAs are related with a reduction in
Retina: ↓p38 MAPK, ↓NF-κB p65, ↑Bcl-xL
↓p-JNK, ↓p-p38, ↓PEPCK, ↓G6-pase, ↑GK

insulin-stimulated IRS-1 phosphorylation and IRS-1-associated PI3K

activity at the molecular level. FFAs increases cellular diacylglycerol
↓ Glucose, ↓insulin, ↑hypoglycemic

concentrations by activation of cellular kinases and atypical protein

kinase C isoforms, which leads to activation of the inflammatory kinase
production, ↓Nrf2, ↓ p-ERK,
nitrogen, ↓serum creatinine

inhibitor kB (IKK) and c-jun-N-terminal kinases (C-JNK), increasing

serine/threonine phosphorylation of IRS-1 and reducing downstream
IRS-1 signaling. Tirotundin, tagitinin A (0.1–10 μM) by suppressing
hypolipidaemic

mitotic clonal expansion, which diminished mRNA levels of PPAR-ɣ

and PPARα in HepG2 cells (Lin, 2012). Sesquiterpenoids could also
resistance

contribute to alleviate diabetic complications induced in LPS-stimu-

NF-κB
Effect

lated Raw264.7. In this regard, pre-treatment with britanin, ergolide

(Whan Han et al., 2001), inulanolides, 6α-dihydroxyeriolanolide, 1-
acetoxy-6α-hydroxyeriol, anolide, eupatolide (Jin et al., 2006), japo-
250–1000 mg/kg/day, 8 weeks

nicones E-L, 1-oxo-4aH-eudesma-5 (Wang et al., 2015) inhibited the IL-

20–40 mg/kg/day, 2 weeks
0.1% diary, 2 weeks, diet
containing 0.01%–0.05%

500 mg/kg/day, 7 weeks

15 mg/kg/day, 12 weeks

200 mg/kg/day, 45 days

1β-induced expression of inducible nitric oxide synthase (iNOS) by

0.8 mg/kg b.w. 8 weeks

blocking the nuclear localization of the p65, p38-nuclear factor kappa B

zerumbone,5 weeks

(NF-κB) and partly restored the insulin in RAW264.7 cells.

Treatment

5. Studies in animal models

NA

Metabolism in T2DM is marked by an early irregularity of insulin

resistance, a malfunctioning state in which insulin is incapable to exert
its biological effects at circulation concentrations that are functional in
Yacon leaves extract with sonchifolin,

Germacrene-D, Farnesene, γ-Elemene,

normal case. Insulin resistance has been prospected as the key relating
Bicyclogermacrene, Caryophyllene,
Morus alba extract (sesquiterpene

Hibiscus leaf extract: α-humulen

Ginger extract: β-bisabolene and

factor for the metabolic disease cluster of glucose intolerance, hy-

uvedalin, enhydrin, fluctuanin

pertension and dyslipidemia. The intransigency of insulin action leads

Effects of sesquiterpenes products in animal studies as anti-diabetics a.

to impaired glucose uptake and glycogen synthesis in peripheral tissues

Sesquiterpenes products

[22]. In addition, defective suppression of hepatic glucose output,

Zerumbone (≥98%)

under both fed as well as the fasting state was observed in insulin re-
β-Caryophyllene
(−)-zingiberene

sistance. Resistance to the action of insulin towards anti-lipolytic also

Zerumbone

aid in triglyceride breakdown in fat tissue and the formation of free

Cadinene
lactones)

fatty acids, which inhibit insulin-stimulated glucose uptake and meta-

bolism in skeletal muscle, stimulate hepatic gluconeogenesis (Chen
et al., 2016) and hinder with insulin receptor signals. Changes in serum
colitis, azoxymethane (AOM)-induced colonic

adipokine concentrations are also contribute to the insulin resistant

Dextran sulfate sodium (DSS)-induced acute

state at the pre-onset of T2DM, resistance to the glucose-lowering ac-

tion of insulin tends to lead a slight increase of blood glucose con-
centration, which stimulates insulin secretion and causes hyper-
Streptozotocin (STZ)-diabetic rats

Streptozotocin (STZ)-diabetic rats

Streptozotocin (STZ)-diabetic rats

Streptozotocin (STZ)-diabetic rats

Streptozotocin (STZ)-diabetic rats

insulinemia and its initially able to overcome insulin resistance. The

aberrant crypt foci (ACF)

diabetic state develops when insulin secretion cannot longer be sus-

tained to compensate insulin resistance, and it is at this stage that
fasting and post-prandial hyperglycemia is apparent.
Alloxan-diabetic rats

Alloxan-diabetic rats

Immense elevation of circulating IL-6 is observed in insulin re-

sistance state and this condition in responses to physiologic insulin le-
Animal model

vels, decreases tyrosine phosphorylation of the IR substrate (IRS) 1, and

association of the p85 subunit of P3K with IRS-1. In addition, activation
Table 5

of Akt, is markedly inhibited and these events are mediated through

increases in the expression of the suppressor of cytokine signaling-3

53
L. Chen, et al.
(SOCS-3) protein [28]. TNF-alpha is a cytokine produced by adipocytes,
a causative factor in obesitylinked to insulin resistance and the patho-
genesis of type-2 diabetes. One of the mechanisms account for the
metabolic effects of TNF-alpha is induction of elevated free fatty acids
via stimulation of lipolysis, down regulation of genes that are required
for normal insulin action, such as GLUT4, direct effects on insulin sig-
naling, and negative regulation of PPAR gamma.
As shown in Table 5, in STZ-induced diabetic rats, the injection of
yacon leaves extract which consist of sonchifolin, uvedalin, enhydrin,
and fluctuanin, at 0.8 mg/kg/day for 8 weeks improved insulin sensi-
tivity and increased glucose uptake (Genta et al., 2010). At the mole-
cular level, zerumbone (Liu, Tzeng, & Liu, 2016) and β-caryophyllene
(Basha and Sankaranarayanan, 2016) intake prevented β-cell apoptosis
by increasing antiapoptotic proteins (Bcl-xL) and decreasing pro-
apoptotic proteins. Moreover, in the pancreatic tissue β-caryophyllene
diet at a dose of 200 mg/kg/day for 45 days enhanced antioxidant
defences (GPx and GR activities) to prevent the oxidative injury, i.e.
lipid and protein oxidative damage was reduced (Basha and
Sankaranarayanan, 2016). These results taken together suggest a de-
layed loss of functional β-cell mas and diabetes progression through a
sesquiterpenes-induced preventive effect by averting oxidative stress
and apoptosis in the pancreas.
As mentioned previously, liver also plays key role in T2DM.
Administration of bicyclogermacrene, caryophyllene, germacrene-D,
farnesene, γ-elemene, cadinene diabetic rats for 9 weeks improved the
liver insulin resistance by abolishing the glucose production (Gunawan,
Putra, & Widihati, 2016). The hypoglycemic effect of sesquiterpenes
seems to be also mediated through the decreased levels of hepatic
PEPCK and increased values of GK and GLUT-4. Moreover, zerumbone
-supplemented diet suppressed JNK and p38 activation caused by in-
sulin resistance and oxidative stress (Liu et al., 2016). Sesquiterpene
lactones-rich diet also suppressed blood glucose, total cholesterol, tri-
glycerides, blood urea nitrogen, and serum creatinine, as well as NF-ĸB
levels in Streptozotocin (STZ)-diabetic rats (Li et al., 2015). Similarly,
Fig. 4. Dietary sesquiterpenes exert their anti-diabetic effects by targeting various cellular signaling pathways in pancreas, liver, skeletal muscle and white adipose
tissues (⇧: Increase,➞Stimulate Decrease).
54
Trends in Food Science & Technology 88 (2019) 46–56
the intake of hibiscus leaf extract with α-humulen (15 mg/kg/day, 12
weeks) prevented 8-hydroxy-2-deoksiguanosin, oxidative stress, and
insulin resistance (Gunawan et al., 2016). These findings show that a
sesquiterpenes-enriched diet alleviates hepatic insulin resistance, redox
imbalance and lipid metabolism, which are all crucial alterations in the
development and progression of T2DM.
6. The structure-activity relationship
The relevant information suggesting that sesquiterpenoids posses-
sing more compact molecular structures ((−)-α-neoclovene and (−)-α-
copaene), low ramification (trans, β-farnesene, trans, trans-farnesol and
cis-nerolidol) and less symmetric (according to Gm-total symmetry of
the molecule) (trans-β-farnesene, trans, trans-farnesol, (−)-α-copaene,
cis-nerolidol and (−)-α-neoclovene) will be more effective for anti-
diabetes. Otherwise, compounds with electronegative substituents
(guaiazulene, trans, trans-farnesol, trans-β-farnesene, (+)-valencene
and (−)-α-copaene), less ramified structures (trans, trans-farnesol,
trans-β-farnesene, (−)-α-copaene and guaiazulene) and with more
symmetry (according to G2e-symmetry considering the second com-
ponent) with an electronegative terminal fragment (guaiazulene, trans-
β-farnesene and trans, trans-farnesol) seem to be more effective for the
induced effect. This knowledge can be useful for future valorisation of
plants or related materials containing such structures. Finally, it is
important to point out that the concentration tested to evaluate the
effects is higher than that usually observed for these compounds in
plant materials. Thus, this study supports the current tendencies of
valorisation of natural products as a source of bioactive compounds for
the formulation of foods and/or nutraceuticals enriched extracts.
7. Conclusion
Sesquiterpenoids have various capabilities such as antioxidant ac-
tivity, biological functions, and anti-diabetic properties. It seems that
L. Chen, et al.
sesquiterpenes exert their anti-diabetic effects by targeting various
cellular signaling pathways in pancreas, liver, skeletal muscle and white
adipose tissues (Fig. 4). In this paper, based on its activity in the
treatment of Type 2 Diabetes, we attempted to provide an overview of
recent developments in sesquiterpenoids in the treatment of type 2
diabetes. It can be foreseen that, with a deep understanding of the
health benefits of sesquiterpenoids, improvements in manufacturing
technologies, new strategies for stabilization of fragile nutraceuticals,
and the development of novel approaches to site-specific carrier tar-
geting will play an important role in increasing the efficacy of func-
tional foods or even pharmaceuticals, over the next decade.
Moreover, sesquiterpenoids can act as potential anti-diabetic agents
by protecting β-pancreatic cells and improving insulin secretion. In
insulin-sensitive tissues such as liver, adipose tissue and skeletal
muscle, sesquiterpenoids improve insulin sensitivity by regulating
glucose transport and key proteins of the insulin signaling pathway, as
well as by exerting a lipid-lowering effect. Sesquiterpenoids exerts
protective effects in the mentioned target tissues by preventing the
oxidative and inflammatory damages associated to the disease. This
also contributes to improve the insulin response and the glycaemic
control, and therefore, to prevent and/or slow down the onset and/or
development of T2DM. All studies presented propose a prominent role
for sesquiterpenoids in the protection against T2DM, as they could be
considered as a potential chemopreventive tool useful for the nutri-
tional management of this disorder. However, further efforts are needed
to fully evaluate the potential of cocoa in terms of β-cell functionality
and insulin-sensitizing effects, identification of targets and optimal
doses to prevent, delay or contribute to the treatment of T2DM.
Acknowledgments
This work is supported by the National Natural Science Foundation
of China (NSFC, Grant No. 31701520; 31801459), China Postdoctoral
Science Foundation Funded Project (No. 2018M642551), the Funds for
Distinguished Young Scientists (Grant No. kxjq17012) at Fujian agri-
culture and forestry university of China.
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