2016

NPC Natural Product Communications Vol. 11

No. 10
Natural Triterpenoids for the Treatment of Diabetes Mellitus: 1579 - 1586
A Review
Han Lyu, Jian Chen and Wei-lin Li*

Institute of Botany, Jiangsu Province and Chinese Academy of Sciences, Nanjing 210014, China

lwlcnbg@mail.cnbg.net

Received: January 28th, 2016; Accepted: July 18th, 2016

Triterpenoids, an important group of secondary metabolites, are widely distributed in nature. Many triterpenoids have been found with potential therapeutic
effect against diabetes mellitus. However, the use of triterpenoids for the treatment of diabetes has not been systematically discussed previously. This review
summarized the anti-diabetic activity of natural triterpenoids reported since the late 1980s with the emphasis on the molecular mechanisms.

Keywords: Natural triterpenoids, Diabetes mellitus.

Diabetes Mellitus (DM) is a multi-cause metabolic disease
characterized by hyperglycemia resulting from defects in insulin
secretion, insulin action, or both. On the basis of etiology, diabetes
mellitus is categorized into two main types. Type 1 DM, also
known as insulin-dependent diabetes mellitus (IDDM), arises from
little or no endogenous insulin secretory capacity. Type 2 DM, or
non-insulin-dependent diabetes mellitus (NIDDM), is a much more
prevalent category and often results from a combination of
resistance to insulin action and an inadequate compensatory insulin
secretory response [1].
triterpenoid analogs or triterpenoids derived from animal and
microbial species are not included), this review will highlight their
anti-diabetic mechanisms, especially potential molecular
mechanisms. Given the diverse mechanistic insights of these
compounds, this review is structured according to the suggested
antidiabetic mechanisms of triterpenoids.
R2O
HO
H

R
Insulin and oral antidiabetic agents such as sulfonylureas,
biguanides, α-glucosidase inhibitors, and glinides are often used as HO R1 O
monotherapy or in combination to treat diabetes [2]. However,
many of the existing synthetic antidiabetic drugs have serious side 1. R1 = glc (1→2)-glc, R2 = H 5. R = CH3 (lupeol)
(ginsenoside Rg3) 6. R = COOH (betulinic acid)
effects. There is an increasing demand for more effective and safer 2. R1 = glc (1→2)-glc, R2 = glc (1→6)-glc Lupane-type triterpenoids
novel antidiabetic agents. Many natural products, such as (ginsenoside Rb1)
triterpenoids and flavonoids, have been extensively explored in the 3. R1 = glc (1→2)-glc, R2 = ara (1→6)-glc(p)
field of drug discovery and have led to remarkable successes [3-6]. (ginsenoside Rb2)
4. R = glc, R2 = H (ginsenoside Rh2)
Dammarane-type
Triterpenoids, a large class of natural products, are a rich reservoir
of candidate compounds for drug discovery. More than 20,000
triterpenoids exist in nature [7]. Triterpenoids are composed of six R2
isoprene (C5H8)6 units; they often occur as free triterpenoids, H COOH
triterpenic glycosides (saponins), or their esters. Triterpenoids are R1
R1
H COOH
structure-wise mainly classified into two chemical types, tetracyclic
HO
and pentacyclic. Triterpenoids can further be sub-classified into R2 HO
diverse groups including dammaranes, cycloartanes, lanostanes,
7. R1 = H, R2 = CH3 (oleanolic acid) 10. R1 = H, R2 = H (ursolic acid)
cucurbitanes (tetracyclic triterpenoids), lupanes, oleananes, ursanes, 8. R1 = OH, R2 = CH3 (maslinic acid) 11. R1 = OH, R2 = H (corosolic acid)
friedelanes (pentacyclic triterpenoids), and miscellaneous 9. R1 = OH, R2 = CH2OH (arjunolic acid) 12. R1 = OH, R2 = OH (tormentic acid)
compounds [8]. Oleanane-type triterpenoids 13. R1 = H, R2 = OH (pomolic acid)
Ursane-type triterpenoids
Triterpenoids have been proven to have a broad spectrum of Figure1: Structures of some active triterpenoids
pharmacological activities: anti-diabetic, anti-cancer, anti-
inflammatory, analgesic, antiviral, anti-HIV, antimicrobial, Antidiabetic activity of triterpenoids in vivo
antiplasmodial, cardioprotective and hepatoprotective effects Increasing studies have suggested that various triterpenoids
[4,5,7,8]. Among them, a large number of studies were focused on exhibited antidiabetic activity in normal or/and diabetic animal
their anti-diabetic properties. Pharmacological activities in diabetes models (Table 1). Triterpenoids were shown to reduce the plasma
and diabetic complications of some pentacyclic triterpenoids have glucose level and enhance glucose tolerance of experimental
been discussed earlier [4]. By collecting evidence in vitro and in animals [9-33]. These findings, which strongly suggest the
vivo bioassay of triterpenoids (tetracyclic triterpenoids and antidiabetic potential of triterpenoids, have initiated increasing
pentacyclic triterpenoids) of plant origin (semi-synthetic efforts in the field to explore the molecular mechanism responsible.
1580 Natural Product Communications Vol. 11 (10) 2016 Lyu et al.

Table 1: Antidiabetic activities of triterpenoids tested in animal models.

Compounds (type*) Model Antidiabetic activities Plant resource (family) References
ginsenoside Rg3(D) db/db diabetic mice ↓plasma glucose Panax ginseng C. A. Mey. (Araliaceae) [9]
↑insulin secretion
ginsenoside Rb2(D) STZ-induced rats ↓plasma glucose Panax ginseng C. A. Mey. (Araliaceae) [10]
↑hepatic glycogen
↓G6Pase
ginsenoside Rh2(D) fructose-rich-fed STZ-rats ↓plasma glucose Panax ginseng C. A. Mey. (Araliaceae) [11]
normal rats ↑response to exogenous insulin
↓plasma glucose
↑insulin secretion
ginsenoside Rg1(D) alloxan-diabetic mice ↓plasma glucose Panax ginseng C. A. Mey. (Araliaceae) [12]
normal mice ↑hepatic glycogen
ginsenoside Re(D) STZ-induced diabetic rats ↓plasma glucose Panax ginseng C. A. Mey. (Araliaceae) [13]
phanoside(D) normal rats ↓plasma glucose Gynostemma pentaphyllum (Thunb.) Mak. [14]
↑insulin secretion (Cucurbitaceae)
isoastragaloside I(Cy), db/db diabetic mice ↑adiponectin level Astragalus membranaceus (Fisch.) Bunge [15]
astragaloside II(Cy) ↑AMPK activity (Leguminosae)
↑insulin sensitivity
astragaloside IV(Cy) STZ-induced daibtetic rats ↓plasma glucose, HbA1C Astragalus membranaceus (Fisch.) Bubge [16]
↑insulin secretion (Leguminosae)
momordicoside S, T(Cu) normal and high-fat-fed mice ↑glucose tolerance Cucumis sativus L.( Cucurbitaceae) [17]
gymnemic acid II(O), STZ-diabetic mice ↓plasma glucose Gymnema sylvestre R. BR. [18]
gymnemic acid III(O), ↓sugar absorption in small intestinal (Asclepiadaceae)
gymnemasaponin V(O),
gymnemoside-f(O)
senegin II(O), normal mice ↓plasma glucose Polygala senega L. var. latifolia Torr. et Gray [19]
senegin III(O) KK-Ay diabetic mice (Polygalaceae)
kaikasaponin III(O) STZ-induced diabetic rats ↓plasma glucose Pueraria thunbergiana Benth. [20]
(Leguminosae)
arjunolic acid(O) STZ-induced diabetic rats ↓plasma glucose Terminalia arjuna (Roxb.) Wight & Arn. [21]
↓TNF-α,NO (Combretaceae)
↑antioxidant enzymes in pancreas
momordin Ic(O), normal rats ↓plasma glucose Kochia scoparia (L.) Schrad. [22,23]
oleanolic acid 3-O-glucuronide(O) ↓sugar absorption in small intestinal (Chenopodiaceae)
18 β-glycyrrhetinic acid(O) STZ-induced diabetic rats ↓plasma glucose,HbA1C Glycyrrhiza uralensis Fisch. [24]
↑insulin secretion (Leguminosae)
oleanolic acid(O) normal rats ↓plasma glucose Cornus officinalis Sieb. et Zucc. [25]
↑insulin secretion (Cornaceae)
maslinic acid(O), normal rats ↓plasma glucose Eriobotrya japonica (Thunb.) Lindl. [26]
pomolic acid(U) db/db/Ola diabetic mice ↓glycosuria (Rosaceae)
elatosides E(O) normal rats ↓plasma glucose Aralia elata (Miq.) Seem. (Araliaceae) [27,28]
escins-IIa(O), normal rats ↓plasma glucose Aesculus hippocastanum L. [29]
escins-IIb(O) (Hippocastanaceae)
tormentic acid(U) normal rats ↓plasma glucose Eriobotrya japonica (Thunb.) Lindl. [30]
↑insulin secretion (Rosaceae)
ursolic acid(U) high-fat diet mice ↓plasma glucose Cornus mas L. (Cornaceae) [31]
NA-STZ-induced diabetic mice ↑insulin secretion
↑hepatic glycogen
corosolic acid(U) normal mice ↓plasma glucose Lagerstroemia speciosa L. (Lythraceae) [32]
↓gluconeogenesis
euscaphic acid(U) normal rats ↓plasma glucose Eriobotrya japonica (Thunb.) Lindl. [33]
alloxan-diabetic mice (Rosaceae)
*In this review, the first appearance of a triterpenoid will be followed with the abbreviation of its chemical type in a parenthesis, D=dammarane-type, Cy=cycloartane-type,
Cu=cucurbitane-type, La=lanostane-type, Lu=lupane-type, O=oleanane-type, U=ursane-type, T=Taraxastane-type

Stimulation of insulin secretion
Insulin is a metabolic hormone secreted from pancreatic islet β-
cells. The main function of insulin is to maintain normal glucose
homeostasis. Insulin stimulates hepatic glycogen synthesis,
decreases glycogenolysis and the release of glucose from hepatic
gluconeogenesis. Insulin also promotes glucose uptake in the
skeletal muscle and adipose tissue. Patients with Type 1 DM, who
have little or no endogenous insulin secretory capacity, require
insulin therapy to maintain normoglycaemia. Insulin therapy has
also been used to prevent or slow the progression of diabetic
microvascular complications in patients with type 2 DM [34,35].
Several triterpenoids were reported to be able to increase the plasma
insulin level in normal or diabetic animals (Table 1). These findings
were also recapitulated in vitro studies. Phanoside at a dose up to
500 μM stimulated insulin secretion in isolated rat pancreatic islets
[14]. Oleanolic acid (50 µM) and oleanolic aldehyde (O) (6.25-50
mg/mL) enhanced insulin secretion in INS-1 832/13 pancreatic β-
cells. Oleanolic acid (30 µM) also enhanced acute glucose-
stimulated insulin secretion in isolated rat islets. Chronic treatment
with oleanolic acid increased total cellular insulin protein and
mRNA levels [36,37]. In spite of the well-documented activities, it
remains unclear how these triterpenoids stimulated insulin secretion.
Insulin secretion is modulated by several hormones and
neurotransmitters, among which acetylcholine (ACh) is an
important mediator [38]. Ginsenoside Rh2 (1.0 mg/kg) and oleanolic
acid (5, 10 and 20 mg/kg ) increased plasma insulin levels of Wistar
rats by releasing ACh from nerve terminals and then stimulating
muscarinic M3 receptors in pancreatic cells [11,25].
ATP-sensitive K+ channels (KATP channels) in the pancreatic β-
cells take part in cell energy metabolism by coupling cell
metabolism to electrical activity. The KATP channels in pancreatic
β-cells are critical in the regulation of glucose-induced and
sulfonylurea-induced insulin secretion. The opening of KATP
channels will suppress β-cells hyperpolarization and insulin
secretion [39]. 20(S)-Ginsenoside Rg3 (2-8 μM) enhanced the
insulin secretion in HIT-T15 cells in vitro, which was likely
associated with the closure of the KATP channels in β-cells [9].
Anti-diabetic natural triterpenoids Natural Product Communications Vol. 11 (10) 2016 1581

Table 2: Inhibitory activities of PTP1B.

Compdouds (type) IC50 (μM) Plant resource(family) References
ursolic acid 3.8 Symplocos paniculata (Thunb.) Miq. (Symplocaceae) [49]
2.3 Phoradendron reichenbachianum (Seem.) Oliv. (Santalaceae) [50]
3.1 Diospyros kaki Thunb. (Ebenaceae) [51]
corosolic acid 7.2 Symplocos paniculata (Thunb.) Miq. (Symplocaceae) [49]
7.0 Rhododendron brachycarpum G. Don (Ericaceae) [55]
rotungenic acid(U), 10.9 Diospyros kaki Thunb. (Ebenaceae) [51]
pomolic acid(U), 3.9
24-hydroxyursolic acid(U), 12.8
19α,24-dihydroxyurs-12-en-3-on-28-oic acid (U) 8.1
2a,3b-dihydroxy-24-nor-urs-4(23),11-dien-28,13b-olide (U), 29.1 Weigela subsessilis (Nakai) L.H.Bailey (Caprifoliaceae) [52]
2a,3b-dihydroxy-24-nor-urs-4(23),12-dien-28-oic acid (U) 5.3
3β-hydroxyurs-12-en-27-oic acid (U) 4.9 Astilbe koreana (Kom.) Nakai (Saxifragaceae) [54]
3-oxoolean-12-en-27-oic acid (O), 6.8 Astilbe koreana (Kom.) Nakai (Saxifragaceae) [54]
3β-hydroxyolean-12-en-27-oic acid (O), 5.2
3α, 24-dihydroxyolean-12-en-27-oic acid (O), 11.7
3β, 6β-dihydroxyolean-12-en-27-oic acid (O) 12.8
moronic acid (O), 13.2 Phoradendron reichenbachianum (Seem.) Oliv. (Santalaceae) [50]
morolic acid (O) 9.1
3β-acetoxyolean-12-en-28-acid (O), 7.8 Styrax japonica Sieb. et Zucc. (Styracaceae) [53]
3β-acetoxyolean-12-en-28-aldehyde (O) 9.3
oleanolic acid 9.5 Phoradendron reichenbachianum (Seem.) Oliv. (Santalaceae) [50]
7.6 Diospyros kaki Thunb. (Ebenaceae) [51]
spathodic acid (O) 18.8 Diospyros kaki Thunb. (Ebenaceae) [51]
rhododendric acid A (T) 6.3 Rhododendron brachycarpum G. Don (Ericaceae) [55]
lupeol (Lu), 13.7 Sorbus commixta Hedl. (Rosaceae) [56]
lupenone (Lu) 3.7
betulinic acid (Lu), 0.7 Saussurea lappa C.B.Clarke (Compositae) [57]
betulinic acid methyl ester (Lu) 0.9

Reversing insulin resistance
Insulin resistance is a pathologic state in which target cells fail to
respond to normal levels of circulating insulin. Reduced insulin
sensitivity may result in inappropriate insulin levels, impaired
fasting glucose or defective glucose tolerance. The resistance of
target tissues to insulin is the major pathophysiological event
resulting in the development of type 2 DM [40].
Studies showed that triterpenoids could reverse insulin resistance. In
animal studies, ginsenoside Rh2 (1 mg/kg) could increase the
responses to exogenous insulin and delay insulin resistance
induction by fructose-rich chow in streptozotocin (STZ)-induced
diabetic rats [41]. As the pathophysiological process accounting for
insulin resistance is still unclear, to fully understand the molecular
basis of these compounds will rely on in-depth mechanistic studies.
Below describes that how insulin resistance is possibly reversed by
triterpenoids treatment, including the activation of insulin signaling,
increasing adiponectin level, inhibiting protein tyrosine phosphatase
1B etc.
Activation of insulin signaling molecules： Insulin receptor
signaling is initiated by insulin binding to its cell surface receptor,
followed by receptor autophosphorylation, and activation of
receptor tyrosine kinases, which result in tyrosine phosphorylation
of insulin receptor substrates and successive activations of
phosphoinositide 3-kinase (PI3K), 3-phosphoinositidedependent
protein kinases (PDK-1 and PDK-2), Akt/protein kinase B (PKB)
and atypical protein kinase C λ and ζ (PKCλ/ζ). These complex
actions stimulate insulin-mediated translocation of glucose
transporter type 4 (GLUT4) from intracellular vesicles to the plasma
membrane. Mitogen activated protein (MAP) kinase and the PI3K
signaling are two major pathways involved in insulin-receptor
signaling, and the metabolic response to insulin is primarily
mediated via the PI3K pathway [42]. Defects in insulin receptor
signaling may contribute to impaired GLUT4 translocation and
insulin resistance [42,43].
Triterpenoids could act as an insulin sensitizer by influencing either
the upstream signaling pathway or the downstream mediators.
Ginsenoside Rb1 (D) (0.001-1 μM) stimulated basal and insulin-
mediated glucose uptake in 3T3-L1 adipocytes and C2C12
myotubes. Ginsenoside Rb1 (1 μM) promoted GLUT1 and GLUT4
translocations to the 3T3-L1 adipocytes cell surface and enhanced
translocation of GLUT4 in Chinese Hamster Ovary (CHO) cells.
Meanwhile, ginsenoside Rb1 increased the phosphorylation of
insulin receptor substrate-1 and PKB, and facilitated receptor [44].
It was also suggested that ginsenoside Rb1 (at up to 10 μM)
enhanced basal and insulin-mediated glucose uptake accompanied
by the up-regulation of mRNA and protein level of GLUT4 in 3T3-
L1 adipocytes [45]. These data together may suggest the compounds
multiple functions in modulating the insulin signaling pathway.
Ursolic acid increased the activity of insulin on tyrosine
phosphorylation of the insulin receptor β-subunit and the number of
insulin-activated IRs in CHO/IR. Ursolic acid potentiated insulin-
mediated tyrosine phosphorylation of the IR β-subunit,
phosphorylation of Akt, glycogen synthase kinase-3β, and enhanced
translocation of GLUT4 in 3T3-L1 adipocytes [46]. Likewise, 250
nM of corosolic acid enhanced glucose uptake in L6 myotubes and
facilitated GLUT4 translocation in Chinese-hamster ovary cells
expressing human IR cells. These actions could be blocked by PI3K
inhibitor and regulated by insulin pathway activation [47].
Inhibition of protein tyrosine phosphatase: Dephosphorylation of
signaling molecules by protein tyrosine phosphatases (PTPs) play a
critical negative regulatory role in insulin signal transduction. The
enhanced activity of one or more PTPs may lead to insulin
resistance. Current data indicate that inhibition of PTP1B, a member
of the PTP family, in peripheral tissues may be useful for treating
metabolic-related disorders such as obesity and type 2 DM [48].
A large number of triterpenoids showed PTP1B inhibitory activities
in vitro [49-57] (Table 2).These triterpenoids mainly belong to the
oleanane- and ursane-types. Structure-activity relationship findings
suggest that a hydroxyl group at C-3 and a carbonyl group at either
C-28 or C-27 of the oleanane-and ursane-type triterpenoids may be
essential structural features to exert the PTP1B inhibitory activity.
Triterpenoids with a 3β-hydroxy group may show a better inhibitory
activity than those with a 3α-hydroxy moiety [51].
1582 Natural Product Communications Vol. 11 (10) 2016
Increasing adiponectin level: Adiponectin is an adipocyte-secreted,
insulin-sensitizing hormone. Reduced circulating levels of
adiponectin may be exhibited in conditions of insulin resistance and
diabetes. Administration of recombinant adiponectin may increase
glucose uptake, hepatic glucose production in liver and ameliorate
whole body insulin resistance [58].
Isoastragaloside I and astragaloside II (5 μg/mL each) increased
adiponectin concentration in 3T3-L1 adipocytes. The same action
was found in mouse primary adipocytes after treatment with these
compounds. These actions were confirmed in animal tests:
Isoastragaloside I and astragaloside II induced significant increases
in serum adiponectin, which resulted in alleviation of
hyperglycemia, glucose tolerance and insulin resistance in db/db
mice and dietary mice [15].
Increasing the activity of AMP-activated protein kinase:
Adenosine 5'-monophosphate-activated protein kinase (AMPK)
plays an important role in mediating cell energy metabolism.
AMPK is involved in the stimulation of glucose uptake by muscle
contraction. AMPK also regulates insulin synthesis and secretion in
pancreatic islet β-cells. Increased activity of AMPK may be
effective in correcting insulin resistance in patients with forms of
impaired glucose tolerance and Type 2 DM [59].
Chronic treatment with (50 mg/kg) isoastragaloside I and
astragaloside II for 6 weeks resulted in a significant elevation in
phosphorylation of AMPK in both liver tissue and soleus muscle of
db/db mice [15].
Ten μM momordicoside Q, R, S, and T (Cu), and karaviloside XI
(Cu) isolated from Momordica charantia L. (Cucurbitaceae) (bitter
melon), stimulated GLUT4 translocation to the cell membrane in
both L6 myotubes and 3T3-L1 adipocytes, associated with an
increased activity of AMPK [17].
Ursolic acid, betulinic acid, oleanolic acid, and 30-norhederagenin
(T), isolated from the methanol extract of the bark of Paeonia
suffruticosa Andr. (Ranunculaceae) (Moutan Cortex), increased
glucose uptake and enhanced glycogen synthesis in HepG2 cells
under high glucose conditions. Ten μM concentrations of these
compounds significantly stimulated AMPK, glycogen synthase
kinase-3β and ACC phosphorylation [60].
Activation of peroxisome proliferator-activated receptors:
Peroxisome proliferator-activated receptors (PPARs) are a group of
nuclear receptor proteins that function as transcription factors. The
PPAR family consists of 3 subtypes of proteins encoded by separate
genes: PPAR α (NR1C1), PPAR β/δ (NR1C3) and PPAR γ (also
known as γ or NR1C2). PPARs regulate lipid and lipoprotein
metabolism, and glucose homeostasis. PPAR α and PPAR γ are
essential for the actions of the many insulin sensitizers [61,62].
Ginsenoside Rb1 (10 μM) increased the expression of mRNA and
the protein of PPARγ in 3T3-L1 adipocytes [45].
Ten μM 20(S)-protopanaxatriol (D) increased PPARγ-
transactivation activity in 3T3-L1 adipocytes by increasing the
expression of PPARγ target genes such as aP2, LPL and PEPCK, in
parallel with a significant increase in expression of GLUT4 [63].
Decreasing free fatty acid: Increased plasma free fatty acid (FFA)
levels, a common symptom in individuals with obesity or type 2
DM, have been considered as an important factor associated with
insulin resistance. Increased FFA can reduce insulin-stimulated
Lyu et al.
skeletal muscle glucose uptake. In liver, elevated FFA can impair
insulin-mediated suppression of hepatic glucose output. TNFα is a
cytokine largely expressed in adipose tissue, which may be linked
with increased plasma FFA level and impaired insulin sensitivity in
obesity and type 2 DM [42,64].
One hundred μM astragaloside IV antagonized TNFα-induced
insulin resistance and increased insulin stimulated 2-deoxy-D-[1-
3
H]-glucose uptake in 3T3-L1 adipocytes [65].
Promoting glycogen synthesis and inhibiting glycogen
degradation
In most mammalian cells, glycogen is stored as a reserve for the
production of glucose 6-phosphate as a metabolic fuel for
glycolysis. Storage of available glucose to supply the tissues is
found principally in the liver. A defect in glycogen synthesis is a
potential factor contributing to postprandial hyperglycemia in
patients with type 2 DM [66]. Glycogen phosphorylase (GP) is a
key enzyme involved in glycogen breakdown to produce glucose
and related metabolites for energy supply. Pharmacological
inhibition of GP has been regarded as a promising therapeutic
approach for treating diabetes [67].
Administration of ginsenoside Rb2 (10 mg/rat/d) for six days
produced a significant decrease in blood glucose level in STZ-
induced rats. A moderate increase in the hepatic glycogen content
and a significant decrease in the activity of glucose-6-phosphatase, a
gluconeogenic enzyme in liver, were found at the same time [10].
Ginsenoside Rg1 (200 mg/kg) promoted the synthesis of liver
glycogen in normal mice. In vitro, 0.1 µg/mL of ginsenoside Rg1
stimulated the uptake of 3H-glucose in isolated rat hepatocytes [12].
Ursolic acid supplement (0.01, 0.05 g/100 g diet) increased hepatic
glycogen content by decreasing hepatic glucose-6-phosphatase
activity, increasing glucokinase activity, and the
glucokinase/glucose-6-phosphatase ratio in nicotinamide-
streptozotocin-induced diabetic mice [68].
Hederagonic acid (O), gypsogenin (O), echinocystic acid (O),
oleanolic acid, hederagenin acid (O) and gypsogenic acid (O),
isolated from the ethanol extract of the roots of Gypsophila
oldhamiana Miq. (Caryophyllaceae), were found to be inhibitors of
GP in vitro; percent inhibition (10 μM) of these compounds were
11.1, 45.1, 19.0, 73.1, 73.1 and 45.1%, respectively [69].
Maslinic acid inhibited phosphorylase GP activity in homogenates
of cultured astrocytes with an IC50 value of 5.7 μM. Moreover, pre-
incubation with maslinic acid increased cellular glycogen content
and prevented norepinephrine-induced excessive glycogenolysis
[70].
At a dose of 100 mg/kg, methyl-3β-hydroxylanosta-9,24-dien-21-
oate (La), isolated from the chloroform extract of the stem bark of
Protorhus longifolia (Bernh. ex C. Krauss) Engl. (Anacardiaceae),
increased hepatic glycogen content with increases both in
hexokinase and glucokinase activity and a decrease in glucose-6-
phosphatase activity in STZ-induced diabetic rats [71].
Suppression of hydrolysis of starch and glucose transport in
small intestine
Glycosidase enzymes, such as α-glucosidase and α-amylase, have
the ability to degrade dietary starch and promote the rate of blood
sugar absorption from the small intestine. The inhibition of α-
glucosidase and α-amylase enzymes can significantly reduce the
Anti-diabetic natural triterpenoids
postprandial increase in blood glucose. Inhibition of α-glucosidase
and α-amylase can be used in patients with predominately
postprandial hyperglycemia. α-Glucosidase inhibitors, such as
acarbose, voglibose and miglitol, were developed in the 1990s and
commonly used in clinical therapy [72,73].
Corosolic acid (10 mg/kg) significantly reduced the hydrolysis of
sucrose in the small intestine of mice [74].
An oleanolic acid and ursolic acid (2:1) mixture was a potent
α-amylase inhibitor with an IC50 value of 4 μM in vitro. Oleanolic
acid, ursolic acid (1, 2.5, 5 μg/mL) and lupeol (5 μg/mL) showed
inhibitory effects against α-amylase [75].
Bartogenic acid (O), isolated from the seeds of Barringtonia
racemosa Roxb. (Lecythidaceae), showed both α-glucosidase (IC50
= 168.1 μg/mL) and α-amylase inhibitory properties [76].
Cichoridiol (18α,19β-20(30)-taraxasten-3β,21α-diol) (T), isolated
from Cichorium intybus L. (Asteraceae), showed an α-glucosidase
inhibitory activity (IC50 = 51.9 μM) [77].
α-Amyrin-3-O-β-(5-hydroxy) ferulic acid (U) and lupine (Lu),
isolated from the root bark of Euclea undulata Thunb. var. myrtina
(Ebenaceae), inhibited α-glucosidase (IC50 = 7.76, 14.69 μM,
respectively) [78].
2,3-Seco-20(29)-lupene-2,3-dioic acid (Lu), isolated from leaves
and twigs of Fagus hayatae Palib. ex Hayata (Fagaceae), showed an
α-glucosidase inhibitory activity (IC50 = 62.1 μM) [79].
Pistagremic acid (D), isolated from galls of Pistacia integerrima
J.L. Stewart ex Brandis (Anacardiaceae), showed inhibitory activity
against both yeast α-glucosidase (IC50 = 89.1 μM), and rat intestinal
α-glucosidase (IC50 = 38.9 μM) [80].
Inhibition of nutrient absorption is the basis of an agent used
clinically to inhibit intestinal catabolism of complex carbohydrates.
Agents that can delay or inhibit glucose absorption may have a
promising impact in managing diabetes [81].
Gymnemic acids II, III, and IV (O) (0.5 mM), gymnemasaponin V
(O) and gymnemoside-f (O), isolated from the leaves of Gymnema
sylvestre, showed an inhibitory effect on sugar absorption in rat
small intestinal fragments [82].
Momordin Ic (25 and 50 mg/kg) and oleanolic acid 3-O-glucuronide
(50 mg/kg) suppressed gastric emptying in rats. An in vitro study
showed that these compounds inhibited glucose uptake in rat small
intestine, concentration dependently, from 0.005-0.5 mM [22,23].
Inhibition of gluconeogenesis
Gluconeogenesis is a metabolic pathway that results from the
synthesis of glucose from other organic compounds. Individuals
with type 2 DM often show an increase in gluconeogenesis.
Gluconeogenesis inhibitors are potential therapeutic agents in the
treating of diabetes [83]. Corosolic acid decreased gluconeogenesis
in perfused rat liver and in isolated hepatocytes in a dose range of
20 to 100 μM [84].
Inhibition of 11β-hydroxysteroid dehydrogenase type 1
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is the
enzyme that converts inactive 11-ketoglucocorticoids into active
11β-hydroxyforms in metabolically relevant tissues such as the
liver, adipose tissue, skeletal muscles and pancreatic β-cells.
Prolonged exposure to elevated glucocorticoids as a result of
Natural Product Communications Vol. 11 (10) 2016 1583
increased 11β-HSD1 activity may lead to metabolic syndrome,
obesity, insulin resistance, type 2 DM and cardiovascular
complications [85]. Selective inhibition or down-regulation of
11β-HSD1 results in a decrease of excessive hepatic glucose
production in hyperglycemia and diabetes mellitus, and exerts a
positive effect on insulin sensitivity in diabetic subjects [86].
Ursolic acid, 3-epi-orosolic acid methyl ester (U), tormentic acid
methyl ester (U) and 2α-hydroxy-3-oxours-12-en-28-oic acid (U),
isolated from leaves of Eriobotrya japonica (Thunb.) Lindl. (Rosaceae),
selectively inhibited 11β-HSD1 with IC50 values of 1.9, 5.2, 9.4 and
17 μM, respectively [87].
Masticadienonic acid (La) and isomasticadienonic acid (La),
isolated from the oleoresinous gum of Pistacia lentiscus var. chia
(L.) (Anacardiaceae), selectively inhibited 11β-HSD1 (IC50 values
(2.51 and 1.94 μM) [88].
Inhibition of dipeptidyl peptidase-4
Dipeptidyl peptidase 4 (DPP-4) is involved in various physiological
processes by cleaving dipeptides from various peptide hormones,
neuropeptides and chemotactic agents. Glucagon-like peptide 1
(GLP-1) and glucose dependent-insulinotropic polypeptide (GIP)
are two incretin hormones released from enteroendocrine cells of
the intestine. GLP-1 and GIP are important insulin secretion
stimulators in postprandial blood glucose level control. DPP-4 could
inactivate the insulin-releasing effect of GLP-1 and GIP by removal
of His-Ala and Tyr-Ala dipeptides from the N-terminal end [89].
Several DPP-4 inhibitor drugs have been clinically used to treat
type 2 diabetes.
Six triterpenoids isolated from the leaves of Cyclocarya paliurus
(Batal.) Lljinsk. (Juglandaceae), cyclocariosides D, E, F, G and H
(D), and cyclocarin A (D) (10 μM), exhibited inhibitory activities
against DPP-4 [90].
Quinovic acid (U), quinovic acid-3β-O-β-D-glycopyranoside (U),
quinovic acid-3β-O-β-D-glucopyranosyl-(28→1)-β-D-
glucopyranosyl ester (U) {from Fagonia cretica L.
(Zygophyllaceae)} and lupeol {from Hedera nepalensis K. Koch
(Araliaceae)} inhibited DPP-4 with IC50 values of 30.7, 57.9, 23.5
and 31.6 µM, respectively [91].
Conclusion and future directions
Natural products have been the most productive source of bioactive
molecules in drug discovery because of their diverse structures and
functions in numerous physiological processes [92]. Triterpenoids
are widely distributed in the plant kingdom. Currently, triterpenoids
have become a focus in drug research and development for their
numerous biological and pharmacological properties.
Many plants with triterpenoids as their major components are used
in various countries as traditional antidiabetic medicines. A large
number of investigations have confirmed their positive impact as
potential pharmaceutical agents in the treatment of diabetes. As
demonstrated in this review, natural triterpenoids exhibit a wide
spectrum of pharmacological activities against diabetes mellitus.
Some triterpenoids also showed multi-target pharmaceutical effects.
Ursolic acid could stimulate insulin secretion and reverse insulin
resistance at the same time. Its properties involve multiple
mechanisms including activation of insulin signaling pathway;
inhibition of PTP1B, GP, 11β-HSD1, α-glucosidase and α-amylase;
and activation of AMPK and PPARs.
1584 Natural Product Communications Vol. 11 (10) 2016 Lyu et al.

All reported experimental results strongly suggest that triterpenoids
are promising candidates for the development of novel therapies for
diabetes mellitus. However, only very few compounds have been
evaluated in preclinical animal models. The complex pathology of
diabetes is a major challenge to develop suitable animal models.
Many studies showed that triterpenoids, especially some
triterpenoid glycosides, were metabolized and restructured into new
compounds by intestinal bacteria [93,94]. Further experimental and
clinical studies are required to elucidate and verify the active
compounds in vivo and detailed anti-diabetic molecular
mechanisms. Toxicity of these compounds needs further
examination before they can be used as potential sources for novel
drug development.
Acknowledgements - This work was funded by a project of the
National Natural Science Foundation of China (21102058), Natural
Science Foundation of Jiangsu Province of China (BK20141387),
and a Jiangsu Province Science and Technology Infrastructure
Construction plan (BM2011117).

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