Received: 19 September 2019 Revised: 22 December 2019 Accepted: 31 January 2020

DOI: 10.1002/ptr.6646

REVIEW

The effects of Ginkgo biloba on metabolic syndrome: A review

Farhad Eisvand1 | Bibi Marjan Razavi1,2 | Hossein Hosseinzadeh1,3

1
Department of Pharmacodynamics and
Toxicology, School of Pharmacy, Mashhad
University of Medical Sciences, Mashhad, Iran
2
Targeted Drug Delivery Research Center,
Pharmaceutical Technology Institute, Mashhad
University of Medical Sciences, Mashhad, Iran
3
Pharmaceutical Research Center,
Pharmaceutical Technology Institute, Mashhad
University of Medical Sciences, Mashhad, Iran
Correspondence
Hossein Hosseinzadeh, Pharmaceutical
Research Center, Pharmaceutical Technology
Institute, Mashhad University of Medical
Sciences, Mashhad, Iran.
Email: hosseinzadehh@mums.ac.ir
Abstract
The Ginkgo biloba (G. biloba), commonly known as ginkgo, brings considerable benefit
to common medicine, including weight loss effects, as well as antidiabetic, antihyper-
tensive, and antilipidemic properties that could be effective in the treatment of
Metabolic syndrome (MetS) associated with increased risk of cardiovascular disease
events. Major compounds of G. biloba are terpene lactones (bilobalide and
ginkgolides A, B, and C) and flavone glycosides (isorhamnetin, quercetin, and
kaempferol). We evaluated the most relevant original articles to indicate the effects
of G. biloba on different components of MetS, including obesity, high blood pressure,
dyslipidemia, and hyperglycemia. Several electronic databases (Scopus, PubMed,
Web of Science and Google Scholar) were searched and the articles that included
Ginkgo's effect on one or more of the criteria for MetS were selected. This review
indicated that G. biloba might be efficient in the improvement of MetS; however,
more studies especially clinical trials are needed to evaluate safety and efficacy of
G. biloba.

KEYWORDS
bilobalide, cardiovascular diseases, diabetes, Ginkgo biloba, ginkgolides, metabolic syndrome

1 | I N T RO DU CT I O N obesity (especially central body fatness), raised triglyceride (TG), and

Metabolic syndrome (MetS) is a cluster of interconnected detrimental
conditions leading to diabetes and cardiovascular disease (CVD)
(Alberti et al., 2009; P. L. Huang, 2009). These conditions include dys-
glycemia, low high-density lipoprotein cholesterol (HDL-C) levels,
Abbreviations: ACE, angiotensin converting enzyme; Adipo R1, lipid receptor R1; Akt, protein
kinase B; BMI, body mass index; BP, blood pressure; CAT, catalase; CI, confidence interval;
CVD, cardiovascular disease; DVP-RI, digital volume pulse reflection index; DVP-SI, digital
volume pulse stiffness index; eNOS, endothelial nitric oxide synthase; FPG, fasting plasma
glucose; FXR, farnesyl X receptor; G. biloba, Ginkgo biloba; GBE, Ginkgo biloba extract; GLUT4,
glucose transporter type 4; GPX, glutathione peroxidase; GSH, glutathione; HbA1c,
hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; HMG-CoA, 3-hydroxy-
3-methylglutaryl–coenzyme A; HOMA-IR, homeostatic model Assessment for insulin
resistance; hPXR, human pregnane X receptor; hs-CRP, high-sensitivity C-reactive protein; IL,
interleukin; iNOS, inducible NO synthase; IR, insulin receptor; IRS-1, insulin receptor
substrate 1; LDL-C, low-density lipoprotein cholesterol; LXR, liver X receptor; MD, mean
difference; MDA, malondialdehyde; MetS, metabolic syndrome; NF-κB, nuclear factor kappa
beta; NO, nitric oxide; pAIx, peripheral augmentation index; PL, pancreatic lipase; PPAR,
peroxisome proliferator-activated receptor; PTP-1B, protein tyrosine phosphatase 1B; PXR,
pregnane X receptor; SOD, superoxide dismutase; T2DM, type 2 diabetes mellitus; TC, total
cholesterol; TG, triglyceride; TNF-α, tumor necrosis factor-alpha; VLDL, very low density
lipoprotein.
hypertension (Alberti et al., 2009; Kaur, 2014). MetS has three or
more criteria as depicted in Figure 1 (Biesinger et al., 2016).
There exists a theory in pathophysiology indicating that a cascade of
reactions occurs as a result of imbalanced insulin and this, in turn, affects
other organs (Casqueiro, Casqueiro, & Alves, 2012; Goossens, 2008).
Insulin resistance is known as the inability of insulin to inhibit liver glucose
output and trigger glucose uptake in adipocytes and muscle cells. These
factors finally lead to glucose intolerance and type 2 diabetes mellitus
(T2DM) in susceptible people (Leroith, 2012; Reaven, 2011). Moreover,
inflammatory cytokines, such as interleukin (IL)-6, or tumor necrosis
factor-α (TNF-α) that usually exist in MetS and obesity, are revealed to
interfere with the receptors of insulin signaling pathway (Leroith, 2012).
In both developed and developing countries, MetS is viewed as a
major cause of morbidity and mortality (Tabeshpour, Razavi, &
Hosseinzadeh, 2017). The MetS outbreak around the world is within the
range of <10%–84% and depends on the characteristics of the target
population, such as gender, age, and race (Desroches & Lamarche, 2007;
Kolovou, Anagnostopoulou, Salpea, & Mikhailidis, 2007).

Phytotherapy Research. 2020;1–14. wileyonlinelibrary.com/journal/ptr © 2020 John Wiley & Sons, Ltd. 1
 2

FIGURE 1 Metabolic syndrome criteria

EISVAND ET AL.
EISVAND ET AL.
Herbal therapy plays a prominent role in medical treatment over the
world due to fewer side effects, cultural acceptability, efficacy, and safety
(Razavi & Hosseinzadeh, 2017; Tousian Shandiz, Razavi, & Hosseinzadeh,
2017). The effectiveness of medicinal herbs in the treatment of MetS has
been addressed in several studies. A few of these plants and their active
compounds include Nigella sativa (black seed) (Razavi & Hosseinzadeh,
2014); Allium sativum (garlic) (Hosseini & Hosseinzadeh, 2015); Vitis vinif-
era (grape) (Akaberi & Hosseinzadeh, 2016); Rosmarinus officinalis (rose-
mary) (Hassani, Shirani, & Hosseinzadeh, 2016); Berberis vulgaris
(barberry) (Tabeshpour, Imenshahidi, & Hosseinzadeh, 2017); Silybum
marianum (milk thistle) (Tajmohammadi, Razavi, & Hosseinzadeh, 2018);
Cinnamomum verum (cinnamon) (Mollazadeh & Hosseinzadeh, 2016); and
rutin (Hosseinzadeh & Nassiri-Asl, 2014).
Ginkgo biloba (G. biloba: Syn.: Salisburia biloba, Salisburia adiantifolia)
has been known as a valuable herb for mankind more than 2000 years
and regarded as a “living fossil” (Singh, Kaur, Gopichand, Singh, & Ahuja,
2008). It has been used as traditional medicine and studies have indi-
cated its beneficial effects including anti-inflammatory, photoprotective,
hepatoprotective, cardioprotective, and antioxidant (Priyanka et al.,
2017). The other features of the plant will be described in the following.
In this review, the most related in vitro, animal, and clinical trials
research projects concerning the role of G. biloba and GBE in cure of
FIGURE 2 Flow chart of literature search showing the excluded and included studies
3
different components of MetS including hypertension, high blood glu-
cose, obesity, and dyslipidemia were described.
All electronic databases (Scopus, PubMed, Web of Science
and Google Scholar) were searched thoroughly in an attempt to
identify in vivo, in vitro, and clinical studies on G. biloba and its com-
pounds with key words such as “G. biloba,” “ginkgolide,” “Metabolic
disorder,” “Metabolic syndrome,” “Dyslipidemia,” “Hyperlipidemia,”
“Obesity,” “Hypertension,” “Diabetes mellitus,” and “Hyperglyce-
mia.” Additionally, all the available articles on the effect of G. biloba
and GBE on MetS were taken into account. Furthermore, the refer-
ence lists of the included articles were surveyed to identify addi-
tional studies. The flow chart of the search process is depicted in
Figure 2.
1.1 | Botanical, chemical, and functional
characteristics of G. biloba
The ginkgo tree is native to Japan, Korea, and China, distributed in
several regions of America, Europe, the temperate areas of India,
New Zealand, and Argentina (Belwal et al., 2019). It was introduced to
Europe around 1,730 and is usually planted as a medicinal plant
4 EISVAND ET AL.
especially in Germany and France. The tree that exists in the Utrecht
botanical garden is among the first ones brought to Europe (Singh
et al., 2008).
1.2 | Morphology
Ginkgo is a gray-colored bark tree which can reach 30 m height with a
diameter of 7 m. Young ginkgo trees are forked and have a pyramidal
shape. Stem dimorphism leads to long and short shoots. The female
tree has a wide crown and spread shape, while the male tree usually
has a thin column form and is faintly longer. Ginkgo is a dioecious
plant, meaning that male and female reproductive organs are located
on different trees. Young leaves are light green, whereas mature
leaves are dark green turning golden yellow during senescence in
autumn (Huh & Staba, 1992).
1.3 | Chemical constituents
The main constituents of G. biboba leaf extract include biflavonoids,
flavonoids, terpenoids, polyprenols, and organic acids. Ginkgolides are
the primary terpenoids that exhibit the biological and pharmacological
activities attributed to G. biloba preparations (Belwal et al., 2019).
Standard extract of G. biloba includes almost 6% terpene lactones
(2.8–3.4% ginkgolides A, B, and C and 2.6–3.2% bilobalide) and 24%
flavone glycosides (isorhamnetin, quercetin, and kaempferol) (Profile,
2003; Unger, 2013) )Figure 3(.
Nature's Way Ginkgold is a dietary supplement manufactured
by Nature's Way factory in the US and sold as a standardized
extract of G. biloba leaves (the G. biloba extract[GBE]761 Formula)
(Profile, 2003). A 27-step extraction procedure was required for
GBE synthesis and one part of the extract is obtained by drying
liquid extract for each 50 parts of raw ginkgo leaves (Mei
et al., 2017).
1.4 | Pharmacokinetic
A study on the absorption of the radiolabeled GBE in rats reported
a minimum absorption of 60%. Since specific radioactivity in blood
peaked after 1.5 hr, the upper gastrointestinal tract was suspected
as a site of absorption. The pharmacokinetics of the GBE was char-
acteristic of a two-compartment model with first-order phase and a
half-life of 4.5 hr. Oral administration of GBE (100 mg−1 kg−1 day−1
for 4 days) significantly increased liver CYP450 content in rats and
altered metabolism of steroids. However, it exerted no effect on
the urinary steroid profile in humans after the intake of 240 mg/
day GBE for 28 days. Expired carbon14-carbon dioxides were
reported as 16% and 38% in 3 and 72 hr after oral treatment of rats
with GBE. Furthermore, 29% were eliminated in feces and 21% in
the urine (Heinonen & Gaus, 2015; Ude, Schubert-Zsilavecz, &
Wurglics, 2013).
1.5 | Therapeutic effects
The GBE is produced from the leaves of G. biloba or maidenhair (Unger,
2013) tree which were used in ancient Chinese medicine especially for
the treatment of asthma and bronchitis around 5,000 years ago. In a
few steps, the undesirable constituents are removed, while the effec-
tive ingredients are condensed (Yoshikawa, Naito, & Kondo, 1999).
Both the nuts and leaves of ginkgo have been used in traditional
Chinese medicine for several centuries. The nuts are known to treat
pulmonary diseases, such as cough and asthma, bladder inflammation,
and alcohol abuse, while the leaves have usually been consumed to
treat skin infections and heart dysfunctions (Mahadevan & Park, 2008).
The useful effects of G. biloba on symptoms related to stroke,
dementia, cerebrovascular disability, peripheral vascular disorders, and
Alzheimer's diseases have been proved (Napryeyenko & Borzenko,
2007; Sasaki et al., 2002) (Figure 4).
There is ample of experimental evidence that GBE has many
pharmacological effects. For instance, GBE was revealed to reduce
the risk of CVD. The other reported effects included prevention of
ischemia-induced oxidation (Akiba, Chiba, Mukaida, Tamura, & Sato,
2004; L.-H. Fan, Wang, & Cheng, 2006), improvement in cerebral
blood flow (Mashayekh et al., 2011), hepatoprotective activity (Naik &
Panda, 2007; Shinozuka et al., 2002), and antagonization of the action
of platelet-activating factor by GBE (Cho et al., 2016).
1.6 | Safety
The G. biloba is commercially formulated as tablets or capsules. The
European Pharmacopeia 6.1 has a monograph for GBE and the United
States Pharmacopeia 32 has monographs for GBE and Ginkgo tablets
and capsules (Dziwenka & Coppock, 2016). Acute toxicity studies on
the standardized GBE showed lethal dose (LD50) values >10,000,
1,100, or 2,100 mg/kg in rats and 7,700, 1,100, or 1900 mg/kg in
mice when administered by oral, intravenous, or intraperitoneal
routes, respectively (Mei et al., 2017).
The G. biloba is reported to be safe and well-tolerated in clinical stud-
ies; however, the extensive consumption of GBE in the elderly suffering
from some diseases such as, diabetes, rheumatism, or hypertension may
result in interactions with simultaneously used drugs (Herrschaft et al.,
2012; Ihl et al., 2011; McKenna, Jones, & Hughes, 2001). Moreover, the
ingestion of G. biloba supplements may prolong bleeding times in patients.
Furthermore, the administration of GBE during pregnancy or breastfeeding
is contraindicated due to the lack of safety data (Mahady, 2001).
2 | P RO T E C T I V E E FF E C T O F G . B I L O B A ON
LIP I D P RO FILE T HR O UGH A D J UST I N G L OW-
D E N S I T Y L I P O P R O T E I N , H I G H - D E N S I TY
LI P O P R O T E I N , A N D TG LE V E L S
The key characteristics of dyslipidemia are TG levels, decreased levels
of HDL-C, and an enhancement in the levels of LDL-C. Moreover,
EISVAND ET AL.
FIGURE 3 The structure of various compounds in Ginkgo biloba
obesity and insulin resistance are associated with hyperlipidemia
(Semenkovich, 2006). Additionally, increased secretion of VLDL from
liver cells causes insulin resistance resulting in hyperlipidemia
(Ginsberg, Zhang, & Hernandez-Ono, 2005).
The GBE is revealed to have a multidirectional impact on the lipid
profile of rat metabolome through the exertion of regulatory effect on
the profiles of polyunsaturated fatty acid, limitation in the absorption
of cholesterol, and deactivation of 3-hydroxy-3-methylglutaryl–
coenzyme A (HMG-CoA) (Zhang et al., 2009) )Table 1).
A meta-analysis study indicated that adjuvant therapy with
G. biloba appears to ameliorate TC (mean difference [MD] −0.61 mmol/
5
L; 95% confidence interval [CI] −0.90 to −0.33), TG (MD −0.32 mmol/
L; 95% CI −0.43 to −0.20), LDL-C (MD −0.32 mmol/L; 95% CI −0.48
to −0.16), and enhance HDL-C (MD 0.26 mmol/L; 95% CI 0.15 to
0.37), compared to statins therapy alone (Y. Fan et al., 2018).
As anticipated, a high-fat dietary intake significantly elevated
levels of plasma TG, whereas GBE treatment improved hyperglycemia
caused by high-fat diet. It was reported that GBE treatment did not
change levels of plasma TG, while phospholipids were slightly ele-
vated at the higher dose of GBE 761(Drieu et al., 2000; Tanaka, Han,
Zheng, & Okuda, 2004). In another study conducted on male rabbits,
G. biloba (10 mg−1 kg−1 day−1) treatment remarkably lowered plasma
6 EISVAND ET AL.
FIGURE 4 The effects of Ginkgo biloba on various organs of the body. CVD: cardiovascular disease; CYP450: cytochrome P-450
TG and cholesterol, while it increased HDL-C, compared to the
untreated group. Moreover, G. biloba was found to decrease MDA
levels and increase GSH levels of aortic tissue (Hussein et al., 2017).
The results of another experiment carried out on male rats gavaged
with ethanol 2.4 g/kg for 3 months and pretreated with a daily dose
of GBE 48 or 96 mg/kg indicated that intake of ethanol caused a
time-dependent rise in plasma LDL-C, TC, TG, and MDA levels, and
reduced the ratio of HDL-C/TC. In this study, the ethanol group rats
received 2.4 g/kg (30%, v/v, 10 ml/kg) ethanol 1 hr after ingestion of
normal saline (10 ml/kg) and GBE groups received EGB 48 mg/kg and
96 mg/kg 1 hr prior to administration of ethanol 2.4 g/kg. Prophylac-
tic treatment with GBE (48 and 96 mg/kg) especially in high doses sig-
nificantly elevated HDL-C amount, and normalized peroxidation, as
well as unusual lipid index in comparison with rats fed with ethanol
(Yao et al., 2007).
Accordingly, it can be inferred that GBE has an adjusting effect
on LDL, HDL, and TG levels. Moreover, it can prevent oxidative dam-
age and metabolites of lipid peroxidation, such as MDA (Figure 5).
3 | P R O T E C T I V E E F F E C T O F G. BIL O BA O N
O B E S I T Y TH R O U G H I N C R E A S E D E N E R G Y
CONSUMPTION AND DECREASED FOOD
INTA KE
High-fat foods contribute directly to obesity pathogenesis since it
changes central nervous system control of peripheral metabolism and
food intake resulting in enhanced insulin resistance, body weight gain,
and other metabolic disorders (Buettner, Schölmerich, & Bollheimer,
2007; Jiang et al., 2005). It was anticipated that one-third of the
world's population will be obese in 2030 (Knaapen et al., 2013).
The association of obesity with chronic diseases, such as insulin
resistance, Type2 diabetes, and subclinical inflammation, has caused
widespread concern over the prevalence of obesity (Federico et al.,
2010).The GBE was found to successfully decrease body weight in
overweight rats fed on high-fat food diet. In related research con-
ducted on high-fat diet-fed rats for 8 week with a 2-week administra-
tion of a 500 mg/kg of GBE, GBE treatment was revealed to reduce
both body weight gain and food/energy intake, in contrast to the
untreated rats. The food intake evaluation was calculated by the dif-
ference between the amount of meal offered and the residual volume
after 24 hr. Since the environmental conditions have been similar,
reducing food intake could be considered as GBE consumption. More-
over, a considerable increase was reported in lipid receptor R1 (Adipo
R1), insulin receptor (IR), IL-10 gene expressions, and protein kinase B
(Akt) phosphorylation which can stimulate insulin signaling cascade.
On the other hand, TNF-α levels and NF-κB p65 phosphorylation
were obviously decreased. The adverse effects of the excessive con-
sumption of high-fat diets may be reduced by the anti-inflammatory
effect of GBE through the reduction of TNF-α retroperitoneal fat
depot levels (Hirata et al., 2015). All of the biflavones in G. biloba,
including ginkgetin, sciadopitysin, isoginkgetin, and bilobetin, dis-
played strong to medium inhibitory effects on pancreatic lipase
(PL) with the half maximal inhibitory concentration (IC50) range of
2.90 μM to >12.78 μM. These results provided further evidence on
the effects of G. biloba on obesity, while inhibitory effects of G. biloba
on PL could serve as lead compounds for the expansion of
biflavonoid-type inhibitors for PL (Liu et al., 2018). In a study con-
ducted by Banin et al. (2014), GBE was reported to decrease obesity
and food intake, while it preserved dyslipidemia and hyperglycemia in
overweight rats fed on fatty foods. Furthermore, GBE increased insu-
lin sensitivity in contrast to rats gavaged with saline, while it repaired
insulin-induced Akt phosphorylation, decreased PTP-1B levels, and
increased IRS-1 in gastrocnemius muscle. Akt phosphorylation is a
necessary stage needed for GLUT4 translocation to the cytomem-
brane and finally for the ability of tissue to glucose uptake. Addition-
ally, PTP-1B was revealed to be associated with reduced IR tyrosine
phosphorylation and subsequently, insulin signaling defect (Banin
et al., 2014). The effect of ginkgolide Bon hepatic steatosis and body
weight in obese C57BL/6 male high-fat diet-fed mice, indicated that
TABLE 1 Summary of the effects of Ginkgo biloba in metabolic syndrome

Pharmacological
effects Compound Study protocol Results References
EISVAND ET AL.

Hypolipidemic GBE (40 mg/kg) In vivo, rats (p.o single dose) #TC, #LDL, "HDL, "activity of LPLand HL, (Zhang et al., 2009)
effects GBE 761(50 and 100 mg/kg) In vivo, rats (p.o for 10 days) "PUFAs, #SI, "phospholipids, improved (Drieu et al., 2000)
response to oxidative damage
GBE (48 and 96 mg/kg) In vivo, rats (p.o for 90 days) prophylactic "HDL-C, #TG, #LDL, #MDA (Yao et al., 2007)
medication
GBE (10 mg−1 kg−1 day−1) In vivo, rabbits (p.o for 6 weeks) #TC, #TG, "HDL-C, #MDA, "GSH (Hussein, Assad, & Rabeea, 2017)
A variety of doses Human patients #TG, #TC, #LDL-C, "HDL-C (Y. Fan, Jin, Man, & Gong, 2018)
Antiobesity GBE (500 mg/kg) In vivo, rats (p.o for 14 days) #food/energy intake, #BW, "adipo R1 and (Hirata et al., 2015)
effects IL-10 gene expressions, "IR and Akt
phosphorylation, #NF-κB p65
phosphorylation, #TNF-α levels
GBE (500 mg/kg) In vivo, rats (p.o for 14 days) #food/energy intake, "insulin sensitivity, (Banin et al., 2014)
"Akt phosphorylation, "IRS-1, #PTP-1B
levels in gastrocnemius muscle
Ginkgolide B 0.1% (w/w) or 0.1 g/100 g In vivo, C57BL/6 mice (p.o for 7 weeks) "mRNA expression of PXR (Luo et al., 2017)
Ginkgolide C (3–100 μM) In vitro, HepG2 hepatocytes #lipid accumulation, "mRNA expression of (W.-C. Huang, Chen, Liu, Wu, & Liou,
ATL, "lipolysis 2018)
Isoginkgetin, bilobetin, ginkgetin and In vitro, pancreatic lipase Inhibit pancreatic lipase (Liu et al., 2018)
sciadopitysin (2.90 μM to 12.78 μM)
Hypotensive GBE (0.05%–0.5%) In vivo, rats (p.o for 30 days) #SBP, "endothelial intracellular Ca2+ level (Kubota et al., 2006a)
effects GBE(0.5%) In vivo, rats (p.o for 24 days) #SBP (Kubota et al., 2006b)
GBE 761 (60 and 120 mg/kg) In vivo, rats (p.o for 3 weeks) #BP, Antithrombotic, Antioxidant effects, (Sasaki et al., 2002)
"expression of eNOS, mRNA
GBE 761 (100 mg−1 kg−1 day−1) In vivo, rats (p.o for 12 weeks) #BP, "mRNA eNOS expression, "protein (Abdel-Zaher, Farghaly, El-Refaiy, &
expressions of iNOS, TNF-α, IL-6 and Abd-Eldayem, 2017)
IL-1β in the kidney, #MDA, #nitrite levels,
"GSH
GBE (0.03 to 3 mg/ml) terpenoids (0.1 to In vitro, rat aorta ring strips Vasorelaxation (Nishida & Satoh, 2004)
100 μmol/L) flavonoids (0.1 to 100 μmol/
L)
Gibidyl forte® Human, healthy(p.o for 6 weeks) Dilate forearm blood vessels without (Mehlsen, Drabaek, Wiinberg, &
changing blood pressure Winther, 2002)
GBE(60 mg/day) Human, healthy(p.o single dose) #BP (Keheyan, Dunn, & Hall, 2011)
GBE (240 mg/day) Human, elderly men and women Not reduce BP (Brinkley et al., 2010)
(Continues)
7
 8

TABLE 1 (Continued)

Pharmacological
effects Compound Study protocol Results References
Antidiabetic GBE 761 (50 mg−1 kg−1 day−1) or bilobalide In vivo, rats (p.o for 15 days) "glucose uptake, "glycogen content (Rapin, Yoa, Bouvier, & Drieu, 1997)
effects (2 mg−1 kg−1 day−1)
GBE (100, 200 and 300 mg/kg) In vivo, rats (p.o for 30 days) #FBG, "SOD, GSH-Px and CAT activity, (Cheng, Liang, & Li, 2012)
"GSH "insulin expression "insulin
sensitivity "glucose consumption
Ginkgolide B (5 mg−1 kg−1 day−1) In vivo, rats (p.o for 8 weeks) Vasorelaxation "SOD and eNOS activities, (G. G. Wang, Chen, Li, Lu, & Zhao,
"H2S production, #MDA, "mRNA, 2015)
expression of GPX1, "protein expressions
of CBS and CGL
Bilobalide (10, 20 & 50 μM) In vitro, 3 T3-L1 preadipocytes #NF-κB/JNK activation, #adipokine (Priyanka et al., 2017)
secretion, "Adiponectin
GBE (10 mg/L) In vitro, hepatocyte L-02 cells Prevent hepatic insulin resistance "IRS-2 (Zhou, Meng, Qian, & Yang, 2011)
expression, #SRBEP1c expression
Green tea GBE Human, T2DM patients (p.o for 9 and #HbA1c (Lasaite, Spadiene, Savickiene, Skesters,
18 months) & Silova, 2014)
GBE(120 mg/day) Human, T2DM patients(p.o for 90 days) #HbA1c, #FBG, #plasma insulin, levels, (Aziz et al., 2018)
#BMI, #waist circumference, #VAI
GBE(120 mg/day) Human, normal glucose-tolerant individuals #SBP, "FI, "C-peptide (Kudolo, 2000)
(p.o for 90 days)
GBE(120 mg/day) Human, non-insulin-dependent diabetes "C-peptide, #plasma insulin levels, (Kudolo, 2001)
mellitus (NIDDM) (p.o for 90 days) "pancreatic β-cell function

Abbreviations: ", increase; #, decrease; ACE, angiotensin converting enzyme; Akt, protein kinase B; ATL, adipose triglyceride lipase; BP, blood pressure; BW, body weight; CAT, catalase; CBS, cystathionine β
synthetase; CGL, cystathionine γ lyase; eNOS, endothelial NO synthase; FBG, fasting blood glucose; FI, fasting insulin; FPG, fasting plasma glucose; GPX1, glutathione peroxidase 1; GSH, glutathione; GSH-Px,
glutathione peroxidase; HbA1c, hemoglobin A1c; HL, hepatic lipase; IL-10, interleukin- 10; IR, insulin receptor; IRS-1, increased insulin receptor substrate 1; LDL-C, low-density lipoprotein cholesterol; LPL,
lipoprotein lipase; MDA, malondialdehyde; PL, pancreatic lipase; p.o., per os (orally); PPARγ, peroxisome proliferator-activated receptor γ; PTP-1B, protein tyrosine phosphatase 1B; PUFAs, polyunsaturated fatty
acids; PXR, pregnane X receptor; SBP, systolic blood pressure; SI, saturation index; SOD, superoxide dismutase; SREBP, Sterol regulatory element-binding protein; TC, total cholesterol; TG, triglyceride; TNF-α,
tumor necrosis factor; VAI, visceral adiposity index.
EISVAND ET AL.
EISVAND ET AL.
FIGURE 5 Pharmacological effects of Ginkgo biloba and its related mechanisms
ginkgolide B (orally, 0.1% [w/w] daily for 7 weeks) activated hPXR in a
dose-dependent activity, although it did not alter PPARα, PPARβ,
PPARγ, farnesyl X receptor (FXR), as well as liver X receptor (LXR)α,
and LXRβ trans-activities. Furthermore, ginkgolide B decreased levels
of plasma TG and body weight, and improved hepatic steatosis. This
investigation reported that ginkgolide B enhanced the mRNA expres-
sion of pregnane X receptor (PXR) genes in diet-induced obesity in
mouse liver (Luo et al., 2017). In an in vitro study conducted on
HepG2 liver cells, 3–100 μM ginkgolide C significantly reduced
lipid accumulation in HepG2 cells in 1 day. Moreover, ginkgolide C
increased the hormone-sensitive lipase phosphorylation level and the
expression of adipose TG lipase to elevate the TG decomposition. The
current study indicated that ginkgolide C increased lipolysis and
decreased lipid accumulation through the SIRT1–AMPK cascade in
fatty liver induced by oleic acid (W.-C. Huang et al., 2018).
Based on available evidence, anti-obesity mechanisms of GBE
increases energy expenditure and decreases food intake. On the other
hand, it increases the sensitivity of different cells (e.g., muscle cells
and adipocytes) to insulin resulting in energy consumption.
4 | P R O T E C T I V E E F F E C T O F G. BIL O BA O N
HIGH BLOOD PRESSURE THROUGH
E N H A NC E D E X P R E S S I O N O F E N D O T H E L I A L
NOS mRNA
Hypertension is a chronic disease (Lopez-Carreras, Fernandez-
Vallinas, Miguel, & Aleixandre, 2014) and a major worldwide public-
9
health challenge, which can cause major complications such as
chronic heart failure, stroke, and acute coronary syndromes (Sliwa,
Stewart, & Gersh, 2011). The mechanisms of pathophysiology in this
disorder include such factors as inflammation, renin-angiotensin sys-
tem, autoimmune vascular dysfunction, and oxidative stress (Konta
et al., 2014; Mykkänen et al., 2014). It has been claimed that the
MetS is present in up to one third of high-blood pressure patients.
Blood pressure levels are related to insulin resistance and visceral
obesity, which are the main pathophysiological characteristics under-
lying the MetS (Yanai et al., 2008). However, some of the patients
with hypertension have turned to traditional medicine (J. Wang &
Xiong, 2012) for an improvement in clinical outcome regarding blood
pressure (BP) reduction and uncontrolled BP-associated symptoms,
including fatigue, headache, and dizziness, with low side effects
(Mansoor, 2001).
The G. biloba hypotensive effects have been reported in several
animal models. In a study on the effects of daily long-term oral use of
GBE on BP (containing 0.05%–0.5% ginkgo for 1 month), the G. biloba
significantly decreased systolic BP in spontaneously hypertensive rats.
Furthermore, this treatment significantly elevated acetylcholine-
induced maximal relaxation and diminished the EC50 value (Kubota
et al., 2006b).
Another study conducted on hypertensive Dahl rats revealed
that the GBE diet did not alter the heart rate; however, it signifi-
cantly reduced systolic BP. The rats were given an 8.0% NaCl plus
0.5% GBE diet or an 8.0% NaCl diet for 24 days (Kubota et al.,
2006a). Thereafter, terpenoids (bilobalide, ginkgolides A, B, and C)
(0.1 to 100 μmol/L), GBE (0.03 to 3 mg/ml), and flavonoids
10
(quercetin and rutin) (0.1 to 100 μmol/L) were separately tested
using rat aorta ring strips (isolated aorta). A vasorelaxant effect was
observed in all the constituents of GBE but the percentage contri-
bution of GBE-induced vasodilation is complicated (Nishida & Satoh,
2004). In another study performed on rats with damaged kidney,
the hypotensive and renoprotective effects of GBE 761 were
reported through the inhibition of renal NO overproduction, as well
as reduction in TNF-α and IL-6 levels in kidney tissues (Abdel-Zaher
et al., 2017).
In addition, the results of an experiment on stroke-prone spon-
taneously hypertensive rats signified that GBE 761 (orally, 60 and
120 mg/kg daily for 21 days) reduced BP and mediated strong anti-
thrombotic and antioxidant effects. Moreover, these results indi-
cated that urinary NO metabolites and nitrite/nitrate were visibly
elevated after GBE 761 treatment. Furthermore, the mRNA expres-
sion of endothelial NOS (eNOS) in the GBE 761 group (120 mg/kg)
was notably greater, compared to the control group (Sasaki
et al., 2002).
®
In a clinical study on the effect of GBE (Gibidyl Forte containing
2.4 mg terpen lactones and 9.6 mg ginkgoflavon glucoside per tablet)
on forearm hemodynamics in 16 healthy people (orally, for 6 weeks)
indicated that oral treatment with GBE could cause vasodilation in
forearm blood vessels and increase regional blood flow without alter-
ation in the BP level (Mehlsen et al., 2002).
In another clinical pilot investigation, the cardiovascular risk fac-
tors and homeostatic model assessment for insulin resistance
(HOMA-IR) were assessed in patients with MetS treated with
G. biloba (240 mg/day) for 60 days. The results demonstrated that
G. biloba decreased IL-6, hs-CRP, HOMA-IR, and reduced CVD total
mortality risk (Siegel, Ermilov, Knes, & Rodríguez, 2014).
In a randomized controlled crossover trial study, reflection index
(DVP-RI), stiffness index (DVP-SI), and peripheral augmentation
index (pAIx) were measured by monitoring the digital volume pulse.
The radial pulse wave was recorded at the baseline, as well as
120, 240, and 360 min after administration of GBE (240 mg/day). It
was denote that DVP-SI was slightly higher 120 min after GBE treat-
ment, compared to control group, while such factors as heart rate
and blood pressure were not affected by GBE exposure (Keheyan
et al., 2011). However, in another study G. biloba did not decrease
BP or the hypertension occurrence among the elderly. Three thou-
sand and sixty nine people (mean age 79 years and 54% male) that
participated in this clinical trial were hypertensive (54%), pre-
hypertensive (28%), and normotensive (17%). It should be consid-
ered that the age of the population could be an important factor in
the lack of GBE hypotensive effects. Indeed, it is possible that
enhanced aortic hardness may decrease the antihypertensive effects
of GBE (Brinkley et al., 2010).
According to these studies, NO decreases blood pressure by
dilating blood vessels and GBE hypotensive effect can be due to
enhancement of eNOS expression and NO production. Further-
more, Ginkgo enhanced the elevation of the endothelial intracellular
Ca2+ level and endothelium-dependent vasodilation that led to
hypotension.
EISVAND ET AL.
5 | P RO T E C T I V E E FF E C T O F G . B I L O B A ON
HI GH GLUC OSE L EV EL THROU GH
ELEVATION OF GLUCOSE UPTAKE AND
C O N S U M P T I O N , A S W E LL A S I N S U LI N
SENS ITIVI TY
Diabetes mellitus (DM) is a worldwide complicated disease with a
global outbreak of 366 million people in 2011 and is anticipated to
rise to 552 million by 2030 (Whiting, Guariguata, Weil, & Shaw,
2011). The DM is a metabolic disorder with several etiologies, includ-
ing chronic high glucose level, as well as abnormalities of protein, lipid,
and carbohydrate metabolism resulting from deficient insulin action,
insulin secretion, or both (Nayak & Roberts, 2006).
Several in vivo studies denoted the antidiabetic effect of GBE.
Accordingly, the oral administration of GBE 761 significantly elevated
the levels of muscle and liver glycogen, and moderately decreased the
suppression of glucose usage in streptozotocin-induced T2DM rats.
Rats received oral administration of GBE 761 (50 mg−1 kg−1 day−1)
for 15 days. The GBE 761 effects might be attributed to its free radi-
cal scavenging activity against streptozotocin cytotoxic function
(Rapin et al., 1997). Additionally, the antidiabetic effect of GBE as an
adjuvant therapy to metformin was studied in a clinical investigation.
In a randomized, multicenter, and double-blinded study in 60 T2DM
subjects, the patients were randomly assigned into two groups (GBE
120 mg/day or placebo [starch] 120 mg/day) for 3 months. The GBE
was revealed to markedly reduce FPG, insulin levels, blood HbA1c,
waist circumference, BMI, and visceral adiposity index (Aziz
et al., 2018).
Furthermore, in a clinical study, 56 T2DM patients were randomly
received GBE, placebo capsules, or green tea dry extract for
18 months (in the first 9 months patients used two capsule per day,
and in the second 9 months, three capsules per day). GBE capsules
contain 80 mg of standardized dry extract of G. biloba leaves. The
GBE was revealed to stimulate insulin secretion and decrease HbA1c
level among the GBE group. Additionally, the perceptions of stress
levels were significantly reduced after 9 months (p = .038) and
18 months (p = .030). In all three groups, the psychological well-being
and quality of life significantly improved after using GBE for
18 months (p = .019) (Lasaite et al., 2014).
In another study, diabetes was induced by the injection of
streptozotocin (60 mg/kg b.w.) intraperitoneally in male rats. The
administration of GBE (100, 200, and 300 mg/kg) for 1 month
enhanced the CAT, SOD, GPX activity, and GSH level in the pancreas
and liver of diabetic rats. Furthermore, the reduction of blood glucose
was revealed to be dose- and time-dependent (Cheng et al., 2012).
It was suggested that bilobalide protected lipid cells from oxygen
deficiency-induced insulin resistance and inflammation by improving
secretion of adiponectin, reducing inflammatory adipokine secretion,
inhibiting serine phosphorylation of IRS-1 receptors of insulin signal-
ing cascade, and lowering NF-κB/JNK activation (Priyanka
et al., 2017).
The results of a research on male Sprague–Dawley rats signified
that ginkgolide B(orally, 5 mg−1 kg−1 day−1 for 8 weeks) improved
EISVAND ET AL.
acetylcholine vasorelaxation and phenylephrine vasoconstriction. In
addition, it restored SOD and eNOS activities, as well as H2S pro-
duction, and decreased MDA level. Moreover, ginkgolide B
enhanced lessened nicotinamide adenine dinucleotide phosphate
oxidase subunits and GPX1 protein expression, as well as the
expression of cystathionine β-synthetase and cystathionine γ-lyase
protein (G. G. Wang et al., 2015).
Kudolo suggested that a 90 day-administration of GBE (120 mg,
single-dose, orally) enhanced the function of pancreatic β-cell. This
effect was time-and dose-dependent. Diminution of blood glucose
can be attributed to either enhanced plasma insulin level in diabetic
rats, increasing blood glucose transport to peripheral tissue or the
stimulation of pancreatic insulin secretion from β-cells in Langerhans
islets (Kudolo, 2000, 2001).
It is suggested that GBE enhanced sensitivity to insulin principally
by increasing transcription of IR substrate 2 and inhibiting insulin
resistance (Zhou et al., 2011).
Accordingly, it could be concluded that the use of GBE not only
increases glucose uptake and consumption, and insulin sensitivity but
also decreases FPG and HbA1c. In addition, GBE elevates the GSH
level in the liver and pancreas and prevents oxidative stress.
6 | C O N CL U S I O N
The use of medicinal plant products and supplements has dramatically
increased during last decades. Some herbs are currently applied for
the treatment of diabetes and CVD. In the light of abundant evidence,
the health benefits of plants are ascribed to their bioactive constitu-
ents, such as polyphenols, terpenoids, and alkaloids exerting several
physiological effects on human body. in vitro and in vivo studies dem-
onstrated the effects of G. biloba and GBE on different parts of MetS,
including CVD, hypertension, obesity, dyslipidemia, and T2DM. The
G. biloba regulates fatty acid profile by lowering the levels of LDL and
TG and increasing the levels of HDL in blood. The GBE also decreases
BP through increasing the expression of eNOS. Furthermore, it
reduces blood glucose by increasing glucose consumption and insulin
sensitivity.
In addition, several databases were searched to include all avail-
able articles. However, only articles written in English were reviewed,
and articles in other languages (especially Chinese) were excluded that
this elimination imposed a limitation on the current study.
It is suggested that further studies be conducted to demonstrate
the mechanism of action of GBE at the molecular and cellular levels.
Furthermore, small sample size was a limitation to reach a valid con-
clusion. Accordingly, the conduction of studies with larger sample size
would produce more reliable results. Furthermore, due to the limited
studies performed on G. biloba compounds in isolation and their
effects on MetS, it is suggested that these compounds be separated
and used in in vivo and in vitro studies.
CONF LICT OF IN TE RE ST
The authors declare no conflicts of interest.
11
OR CID
Farhad Eisvand https://orcid.org/0000-0002-2216-6728
Bibi Marjan Razavi https://orcid.org/0000-0002-7450-9286
Hossein Hosseinzadeh https://orcid.org/0000-0002-3483-851X
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How to cite this article: Eisvand F, Razavi BM,
Hosseinzadeh H. The effects of Ginkgo biloba on metabolic
syndrome: A review. Phytotherapy Research. 2020;1–14.
https://doi.org/10.1002/ptr.6646