Journal of Diabetes & Metabolic Disorders

https://doi.org/10.1007/s40200-020-00628-8

REVIEW ARTICLE

Indian Traditional medicinal plants as a source of potent

Anti-diabetic agents: A Review
Vishakha Parab Gaonkar 1 & Kirankumar Hullatti 1

Received: 27 May 2020 / Accepted: 3 September 2020

# Springer Nature Switzerland AG 2020

Abstract
Objective The present review aims to provide an overview of traditional medicinal plants known to be of anti-diabetic potential.
Methods A literature search was conducted using the scientific databases including PubMed, EMBASE and google scholar and a
total of fifty herbs have been described and their possible mechanism of anti-diabetic action has been mentioned. Among them,
in-depth discussion on five most potent anti-diabetic herbs has been provided with respect to their mechanism of action, in-vivo
studies and clinical efficacies.
Results The present review has highlighted the usefulness of the herbal source for the treatment and management of diabetes
mellitus. With the help of previous literature published on In-vivo animal studies and human clinical studies; the effectiveness of
Gymnema sylvestre, Momordica charantia, Trigonella foenum graecum, Tinospora cordifolia and Curcuma longa in the
treatment and management of Diabetes has been proved.
Conclusion Based on this review it can be concluded that herbs can serve as more efficient, safer, and cost-effective adjuvant
therapy in the management and treatment of diabetes. Further investigations mainly focusing on the isolation of phytocompounds
from these herbs can lead to the discovery of newer antidiabetic agents.

Keywords Anti-diabetic . Diabetes mellitus . Herbs . Hyperglycaemia . Medicinal plants . Phytocompounds

Introduction around 463 million adults are currently living with diabetes
and estimates that there will be 578 million adults with diabe-
Diabetes mellitus is one of the most prevalent diseases found tes by 2030, and 700 million by 2045 [4].
in all parts of the world and is becoming a serious threat to The management of diabetes mellitus is considered a glob-
mankind’s health [1]. It is a complex heterogeneous group of al problem. In current allopathic therapy the oral
metabolic disorders including hyperglycemia and is associat- hypoglycaemic agents and insulin, are subsequently used to
ed with the imbalance in carbohydrate, protein, and lipid me- control the diabetic conditions, however, complications asso-
tabolism [2]. According to WHO, “Diabetes mellitus is a ciated with them, limited tolerability, cost, and other side ef-
chronic disease caused by inherited and/or acquired deficien- fects reduce its wide acceptance. This could be the main rea-
cy in production of insulin by the pancreas, or by the ineffec- son for the shift of common people to Ayurveda form allo-
tiveness of the insulin produced. Such a deficiency results in pathic system nowadays [5].
increased concentrations of glucose in the blood, which in turn Since ancient times traditional herbal drugs with multiple
damage many of the body’s systems, in particular the blood phytoconstituents and properties have been used as medicines
vessels and nerves” [3]. According to the recent data by for the treatment of a wide range of diseases [6]. Herbal med-
International Diabetes Federation (IDF) Atlas claims that icines have been considered to be intrinsically safe, due to
their natural occurrence, efficacy, and fewer side effects [7].
India has a long history of use of medicinal plants for the
* Kirankumar Hullatti management of diabetes. World ethnobotanical information
[email protected] has reported the usage of about 800 plants for the control of
1
diabetes mellitus, amongst them only 410 are experimentally
Department of Pharmacognosy and Phytochemistry, KLE College of
proven for having anti-diabetic properties but the complete
Pharmacy Belagavi, KLE Academy of Higher Education and
Research (KAHER), Belagavi, India mechanism of action is available only for about 109 plants
 J Diabetes Metab Disord

[8]. The treatment of diabetes using herbs has more advanta- provided with respect to their mechanism of action, in vivo
geous effects and does not cause much side effects. These studies and clinical efficacies. The rationale behind selection
herbal drugs act by different mechanisms and consequently of these five herbs owes to their traditional usage, easy avail-
protect the β-cells during the diabetic condition and reduce ability, effectiveness and most importantly to their proven
the amount of glucose level in the blood [9]. clinical significance. The selected plants are a choice of herbal
This review aims to provide an overview of the use of medicine in the treatment of diabetes. They are also utilized by
medicinal plants in the management of diabetes, focusing on multiple pharmaceutical herbal industries and most of the
their mechanism of action. Furthermore, an emphasis on the herbal anti-diabetic preparation consist of these herbs.
five most commonly available and potent anti-diabetic herbs Although there are other plants which are utilized in the dia-
has been given. These include Gymnema sylvestre, betes management as folklore medicine but their commercial
Momordica charantia, Trigonella foenum graceum, utilization is less as compare to the chosen five plants. Hence a
Tinospora cardifolia, and Curcuma longa. need has been felt for understanding their various mechanism
of actions and efficacy in management of diabetes.

Methods Gymnema sylvestre

A literature search was conducted using the scientific data- Gymnema sylvestre is an indigenous herb, belonging to the
bases including PubMed, EMBASE and google scholar. The family Asclepiadaceae. It is popularly known as “gurmar” for
aim was to identify published data on traditionally used me- its distinct property as sugar destroyer, it is a reputed herb in
dicinal plant for the treatment and management of Diabetes the Ayurvedic system of medicine. The plant is indigenous to
mellitus. The search terms used were “diabetes and plants”, western and central India, Australia, and tropical Africa [94].
“traditional plants”, “medicinal plants and diabetes”, “anti-hy-
perglycemic plants”, and “mechanism of anti-diabetic action”. Phytochemistry of G. sylvestre
Based on the above criteria extensive literature search was
carried out and a total of fifty herbs have been described with G. sylvestre is a good source of a large number of bioactive
their possible mechanism of anti-diabetic action. Amongst the substances. The leaves contain Triterpene saponins like
fifty herbs in-depth discussion on five most potent and easily gymnemic acids, gymnemasaponins, and gymnemasides.
available anti-diabetic herbs has been provided with respect to Apart from this, other phytoconstituents include flavones, an-
their mechanism of action, in-vivo studies and clinical thraquinones, pentatriacontane, hentri-acontane, α and β-
efficacies. chlorophylls, phytin, stigmasterol, dquercitol, resins, etc.
The major secondary metabolites present in Gymnema in-
cludes Gymnemic acid. The Gymnemic acids consist of nu-
Traditional anti-diabetic plants merous members termed as gymnemic acids I–VII,
gymnemasaponins, and gymnemosides A–F. Gurmarin is an-
Since the time of Charaka and Sushruta, traditional medicines other essential phytoconstituent isolated from G. sylvestre
have been used for the management of diabetes mellitus [10]. [95].
Medicinal plants have always been a valuable source of drugs
and many of the currently available drugs such as aspirin, Mechanism of Action
quinine, vincristine, vinblastine, and digitalis have been de-
rived directly or indirectly from them [11]. Most of the anti- Antidiabetic activity of Gymnemic acids appears to be due to
diabetic drugs derived from plants are from the phytochemical a combination of mechanisms. It acts through stimulation in
class of polyphenols, terpenoids, tannins, and steroids. These insulin secretion from the pancreas. It also shows a similar
affect various metabolic cascades, which further affect the effect by delaying the glucose absorption in the blood. In the
level of glucose in the human body [12]. intestine it attaches to the receptor present in the external layer
A list of medicinal plants used traditionally for diabetes of the intestine, thereby preventing the absorption of sugar
with proven anti-diabetic and related beneficial effects are molecules by the intestine, resulting in low blood glucose
compiled along with their family, active principles responsible levels [95]. In a study extract of the plant has showed its
for diabetes, mechanism of action and use (Table 1). effectiveness in regeneration of pancreatic β cells [66].
Amongst the fifty herbs described in Table 1 we have iden- Gymnemic acid the major phytocompounds present in the
tified five most potent and easily available anti-diabetic herbs plant is reported to interact with glyceraldehyde-3-phosphate
namely, Gymnema sylvestre, Momordica charantia, dehydrogenase (GAPDH), a key enzyme in glycolysis path-
Trigonella foenum graecum, Tinospora cordifolia and way [96]. Moreover, G. sylvestre has been reported to exhibit
Curcuma longa. In-depth discussion on these herbs has been significant inhibitory activity against α-glucosidase; Fig. 1.
Table 1 List of Traditional plants used in management and treatment of Diabetes

Plant name Family Parts used Active Principles Mechanism of action Uses Reference

Acacia arabica Leguminoceae Bark Gallic acid, pyrocatechol, (+)- Act as secretagouge to release insulin Hypoglycemic activity [13, 14]
catechin, (-)
epigallocatechin-7-gallate,
(-) epicatechin, quercetin,
J Diabetes Metab Disord

(+) catechin-5-gallate.
Achyranthes aspera Amaranthaceae Leaves, seeds. Betaine, achyranthine, β ecdysone Carbohydrate digestion and absorption Hypoglycemic effect [15, 16]
Adhatoda vasica Acanthaceae leaves Vasicine Vasicinol α-Glucosidase-inhibiting activity Antidiabetic [17, 18]
Aegle marmelose Rutaceae leaves Aegelin, marmesin and marmelosin Regeneration of pancreatic β cells and Hypoglycaemic effect [16, 19]
insulin secretion
Ageratum conyzoides Asteraceae leaves Mono- and sesquiterpenes Increase peripheral utilization of glucose Hypoglycaemic effect [20, 21]
Allium cepa Amaryllidaceae bulb S-methyl cysteine sulfoxide, S-allyl Stimulates pancreatic β-cells Hypoglycaemic effect [22, 23]
cysteine sulfoxide
Allium sativum Amaryllidaceae bulb Allicin, apigenin, alliin Stimulates pancreatic β-cells Antidiabetic and anti-oxidant [16, 23, 24]
Aloe barbadensis Asphodelaceae leaves Aloin, barbaloin, isobarbaloine, Insulin secretion and synthesis Hypoglycemic effect. [16, 25]
aloetic acid.
Andrographis paniculata Acanthaceae Whole plant Andrographolide, Regeneration of pancreatic β cells, insulin Antidiabetic & hepatoprotective. [26, 27]
secretion
Annona squamosa Annonaceae leaves Acetogenin Enhances insulin level from pancreatic islets, Hypoglycemic and antihyperglycemic activities [28, 29]
increased utilization of glucose in muscle.
Areca catechu Palmitaceae Leaves, flowers, Nitrosamines, arecoline, arecaidine Carbohydrate digestion and absorption Hypoglycemic [16, 30]
seeds
Azadirachta indica Meliaceae leaves Azadirachtin, Improves the insulin signaling molecules Antidiabetic, Antibacterial, antioxidant [31, 32]
nimbolinin, nimbin, and glucose utilization in the skeletal
nimbidin, quercetin. muscle.
Bacopa manneri Serophulariacea Aerial part Bacosine, brahmine, bacopaside I, II, Increase in peripheral glucose consumption Antihyperglycemic agent [33, 34]
III, IV and V.
Bauhinia forficuta Fabaceae leaves Kaempferitrin Glycolysis, insulinonematic activity. Hypoglycemic effect, antioxidant. [35, 36]
Berberis aristata Berberidaceae Stem bark, roots, Barberin, Glucose transport, carbohydrate digestion Hypoglycemic effect [37, 38]
leaves and absorption, DPP-IV inhibition
Boerhavia diffusa Nyctaginaceae leaves Punarnavine, Boeravinone A-F Increase in hexokinase activity, increase Antidiabetic [39, 40]
plasma insulin level, antioxidant
Camellia sinensis Thecaceae leaves Epigallocatechin-gallate, Free radical scavenging activity, Antihyperglycemic activity, antioxidant [41, 42]
gallocatechin, epicatechin, (+) insulinonematic activity
catechin, (−) epicatechin
Caseria esculenta Salicaceae roots Leucopelargonidin, Dulcitol, Beta Insulin secretion Antihyperglycemic activity [43]
sitosterole.
Cassia auriculata Fabaceae roots Bis (2-ethyl hexyl) phthalate α-Glucosidase-inhibiting activity Antihyperglycemic effect [44, 45]
Centella asiatica Apiaceae Whole plant asiaticoside Antihyperglycemic activity [46, 47]
Coccinia indica Cucurbitaceae Aerial parts - β- Amyrin Acetate, Lupeol, Initiate insulin secretion, carbohydrate Hypoglycemic effect. [48, 49]
Cucurbitacin B, Taraxerone, digestion and absorption.
Taraxerol, β-carotene, Lycopene,
Commelina communis Commelinaceae Leaves, stem 1-deoxynojirimycin, Inhibition of α-glucosidase Antihyperglycemic agent. [50, 51]
(2R,3R,4R,5R)2,5-bis(hydroxym-
ethyl)-3,4-dihydroxypyrrolidine
Curcuma longa Zingiberaceae rhizomes Curcumin, termerone, germacrone, Inhibition of α-glucosidase, inhibition of Antidiabetic, Antihyperlipidemic, antioxidant [52, 53]
zingiberene GSK-3β
Cyprus rotandus Cyperaceae Whole plant α cyperone, cyperene, cyperol. Inhibites intestinal glucose absorption and Hypoglycemic agent [54, 55]
promoting glucose consumption.
Emblica officinalis Euphorbiaceae fruits Gallic acid, ellagic acid, vitamin c. Hypoglycemic, Decreases lipid Hypoglycemic and antioxidant. [56, 57]
peroxidation, antioxidant.
Enicostema littorale Gentianaceae Whole plant Swertiamarin, apigenin, isovitexin, Glucose-induced insulin release through K(+ Hypoglymcemic effect. [58, 59]
swertisin, saponarin, 5-o )-ATP channel.
glucosylswertisin
Table 1 (continued)

Plant name Family Parts used Active Principles Mechanism of action Uses Reference

Ficus benghalensis Moraceae Bark, leaves Leucocyanidin, pelarogonidin Insulin secretion, glycogen synthesis Antidiabetic [60, 61]
Ficus racemosa Moraceae Bark, leaves β-sitosterol, racemosic acid, Glycogenolysis and gluconeogenesis Hypoglycemic activity [62, 63]
Bergenin.
Glycyrrhiza glabra Leguminoceae roots Glycyrrhizin, glycyrrhizic acid Potent PPAR-γ ligand binding activity thus, Hypoglycemic agent. [64, 65]
liquirtin, isoliquirtin. reduces the blood glucose level
Gymnema sylvestre Asclepidaceae leaves Gymnenic acid, Stigmasterol, Regeneration of pancreatic β cells, Antidiabetic agent. [66–68]
Gurmarin, betaine, α-glucosidase inhibitor, insulin secretion
gymnemosides.
Ginkgo biloba Ginkgoceae leaves Kaempferol, isorhamnetin Inhibition of α-amylase and α-glucosidase Hypoglycemic agent. [69]
activity
Mangifera indica Anacardiaceae leaves Mangiferin α-Glucosidase-inhibiting activity Hypoglycemic agent [70]
Momordica charantia Cucurbitaceae fruits Momordin, momordicine, charantin Insulin secretion, glycogen synthesis Hypoglycemic agent [71, 72]
Morus indica Moraceae leaves Chrysin, isoquercitrin Insulin secretion Hypoglycemic agent [73]
Ocimum sanctum Lamiaceae leaves Eugenol, trans-β ocimene, Insulin secretion, carbohydrate digestion and Hypoglycemic agent. [74, 75]
Carvacrol, linalool. absorption
Panax ginseng Araliaceae roots Ginsenosides Rg2, panaxan A, B, C, Regeneration of pancreatic β cells, free Antihyperglycemic activity [76, 77]
D, E radical scavenging
Phyllanthus amarus Phyllanthaceae leaves Brevifolin carboxylic acid, ethyl α-Amylase inhibitory activity Hypoglycemic, Anti-oxidant activity. [78]
brevifolin carboxylate
Pterocarpus marsupium Leguminoceae Stem wood Marsupsin, pterosupin, pterostilbene Insulinomematic activity Antidiabetic [79]
Swertia chirata Gentinaceae Whole plant Amarogentin, swerchirin, chirantin Stimulates insulin release from islets Antihyperglycemic agent [80]
Syzygium aromaticum Myrtaceae Flower buds Eugenol, Caryophylline Insulin secretion, carbohydrate digestion and Hypoglycemic agent [81]
absorption
Syzygium cumini Myrtaceae Bark, seeds Jambosine, jambolin, anthocyanins. α-Glucosidase-inhibiting activity Anti-hyperglycemic [82]
Terminalia arjuna Comberetaceae Stem bark Arjunic acid, arjunolic acid, gallic Stimulates insulin release from islets Hypoglycemic ativity [83]
acid.
Terminalia chebula Comberetaceae fruits Gallic acid, chebulic acid, Secretion of insulin from the β-cells. Hypoglycemic ativity [84]
chebulanin, ellagic acid,
chebulegic acid, chebulinic acid
Terminalia belerica Comberetaceae fruits ß- sitosterol, gallic acid, ellagic acid, Insulin secretion, carbohydrate digestion and Hypoglycemic ativity [85]
ethyl gallate, chebulaginic acid. absorption
Tinospora cardifolia Menispermaceae Leaves and stem Tinosporine, cordifolide, tinosporide, α-Glucosidase-inhibiting activity, glycolysis Antidiabetic agent. [86, 87]
Barberin.
Trigonella foenum graceum Fabaceae seeds Trigonellin, Fenugreekine. Regeneration of pancreatic β cells, insulin Antidiabetic activity. [88, 89]
secretion
Vinca rosea Apocynaceae Whole plant Catharanthine, vindoline, Regeneration of pancreatic β cells, insulin Hypoglycemic activity [90]
vindolinene vinblastine, release
vincristine
Vitis vinifera Vitaceae Leaves, stem E-resveratrol, E-ε-viniferin, Insulinonematic activity Anti-hyperglycemic activity [91]
anthocyanins.
Withania somnifera Solanaceae Leaves, roots Withaferin A, withanolides Insulin release from pancreatic β cells Hypoglycemic activity [92]
Zingiber officinalis Zingiberaceae rhizomes Gingirol, shoagol, zingerone. Increase insulin level & decrease Hypoglycemic activity [93]
fasting glucose level
J Diabetes Metab Disord
J Diabetes Metab Disord

Antidiabetic effects of Gymnema sylvestre momordin, cucurbitins, cucurbitacins momorcharins, etc.

[72]. Most of the anti-diabetic potential of M. charantia is
Various in vivo animal studies and clinical expeiments have ascribed to Charantin. The hypoglycemic activity of the com-
repeatedly shown hypoglycemic effects of leaves of G. pound is similar to that of insulin [99].
sylvestre. In a study, the methanol extract of G. sylvestre leaf
and callus showed pronounced anti-diabetic activity through
Mechanism of action
the regeneration of β-cells [97]. Sugihara Y., et al. reported
the antihyperglycemic effect of gymnemic acid IV, isolated
M. charantia exerts its hypoglycemic effects via multiple
from the leaves of G. sylvestre. The study reported that
mechanisms. The possible mechanism of the hypoglyce-
gymnemic acid IV decreased blood glucose levels by 13.5 −
mic action of M. charantia is mainly due to insulin secre-
60.0% within 6 hours of administration in comparison with
tion and glycogen synthesis [71, 72]. Some studies indicate
glibenclamide, also increased plasma insulin levels was ob-
that bitter melon may stimulate glucose utilization by pe-
served in STZ-diabetic mice at a concentration of 13.4 mg/kg
ripheral and skeletal muscle, inhibit intestinal glucose up-
due to gymnemic acid IV [66].
take, and increase hepatic glycogen synthesis [72]. Hsin-Yi
Lo et al., reported that seed extract of M. charantia regu-
Momordica charantia lates glucose metabolism mainly via the insulin signaling
pathway [100]. In an experimental study using cell-based
Momordica charantia also known as karela, the bitter guard is screening assay Hsueh-ling Cheng identified and reported
a flowering wine, belonging to family Cucurbitaceae. The that triterpenoids are the potential hypoglycaemic agents
herb is commonly used by Ayurvedic and other traditional responsible for anti-diabetic action of the plant, also the
systems of medicine as an anti-diabetic agent. The plant is underlying mechanism to bring about the action was attrib-
widely cultivated in Asia, India, East Africa, and South uted to AMP-activated protein kinase [101]; Fig. 2.
America [72].
Antidiabetic effects of M. charantia
Phytochemistry of M. charantia
Experimental studies have confirmed the hypoglycaemic ef-
Bitter melon is rich in constituents such as glycosides, sapo- fect of M. charantia on various animal models. A study dem-
nins, alkaloids, reducing sugars, resins, phenolic constituents, onstrated the dose-dependent hypoglycaemic activity exhibit-
fixed oil, and free acids [98]. The main phytoconstituents ed by methanolic fruit extract of M. charantia in alloxan-
present in M. charantia are charantine, charine, momordicin, induced diabetic rats [102]. Mahmoud MF et al., studied the

Fig. 1 Schematic representation of Probable molecular mechanism for anti-diabetic effect of G. sylvestre
 J Diabetes Metab Disord

Fig. 2 Schematic representation of Probable molecular mechanism for anti-diabetic effect of M. charantia

antidiabetic activity of M. charantia fruit juice in Mechanism of action

streptozotocin-induced diabetic rats [103]. In an investigation-
al study Joo-Hui Han et al., isolated four new cucurbitane-type The mode of action of the herb is through Regeneration of
triterpenoids (C1-C4) from the ethanol extract of M. charantia pancreatic β cells and insulin secretion [88, 89]. A study re-
and investigated whether the compounds affect insulin sensi- ported the inhibitory role of Trigonelline on the activity of
tivity both in vitro and in vivo models. The results reported glycogen synthase kinase isoforms in the regulation of glyco-
significant decreases in blood glucose level and enhanced gly- gen metabolism, to bring about the hypoglycaemic action
cogen storage by compound C2 in STZ‐injected mice [104]. [106]. Trigonelline has also been found to enhance glucose
and lipid hemostasis via the improvement of the insulin sig-
naling pathway [107]. Another possible mode of action of
Trigonella foenum graceum T. foenum graecum, are the Inhibition of glucose uptake,
GLUT-4 translocation, and improved insulin resistance [108,
Trigonella foenum graceum also known as fenugreek is used 109]; Fig. 3.
primarily as an alternative therapy for diabetes. A member of
the Fabaceae family, the plant cultivated in India and North
African countries. The herb has a long history of usage as a
potent anti-diabetic agent in Ayurvedic and folklore medicine Antidiabetic effects of T. foenum graecum
[94, 105].
The pharmacological studies have proven the anti-diabetic
potential of various extracts of T. foenum graecum. In a study,
Phytochemistry of T. foenum graceum the ethanolic extract of fenugreek seeds was investigated for
anti-diabetic action on streptozotocin-induced diabetic rats.
The phytochemical studies have largely been focused on The results demonstrated a significant decrease in serum glu-
seeds. The main chemical constituents of seeds are alkaloids cose, total cholesterol, triacylglycerol, while an increase in
approximately 36%, steroidal saponins, mucilage, fibers serum insulin in diabetic rats was observed [110]. Shah
[105]. Among the alkaloid content of fenugreek seed, et al., studied the hypoglycaemic effect of Trigonelline in
Trigonelline is major phytoconstituents which is responsible alloxan-induced diabetic mice. They reported a reduction in
for most of the activity of the herb. The mucilage (25–30%) is blood glucose level and identified the presence of islet cells in
mostly a galactomannan. Steroidal saponins such as diosgenin the pancreatic duct suggesting its beneficial effect on β cells
and yamogenin constitute about 0.1–2.2%. Fenugreekine a [111]. Multiple studies on seed extracts, raw powder, and
sapogenin peptide ester is also present in the seeds. The free active constituents by investigators have demonstrated the
amino acids in the seeds are present as 4-hydroxyisoleucine, hypoglycaemic action of the herb, confirming its use as a
which is reported to have directly stimulated insulin [94, 106]. potent herbal remedy for the management of diabetes.
J Diabetes Metab Disord

Fig. 3 Schematic representation of Probable molecular mechanism for anti-diabetic effect of T. foenum-graecum

Tinospora cordifolia effect of stem extracts of T. cordifolia by conducting experi-

ments with Ehrlich ascites tumor cell model. The study report-
Tinospora cordifolia (Willd.) Miers, belonging to family ed the ameliorotary effect of T. cordifolia on GLUT 1 and
Menispermaceae, is a potent herb used to combat diabetes. GLUT 3 transporters involved in basal glucose uptake; sug-
The herb reported to possess anti-diabetic activity in gesting it as a possible mechanism to exert the hypoglycemic
Ayurvedic literature and is present in many Ayurvedic formu- effect [113]. Another study reported the insulin-releasing, in-
lations. The herb is commonly known as Guduchi and is in- sulin-sensitizing, and inhibition of gluconeogenesis as the
digenous to the tropical areas of India, Myanmar, and Sri possible mechanism exhibited by an alkaloidal fraction of
Lanka [94]. T. cordifolia [114]; Fig. 4.

Phytochemistry of T. cordifolia
Antidiabetic effects of T. cordifolia
T. cordifolia consists of a variety of phytoconstituents belong-
ing to different classes such as alkaloids, glycosides, steroids The stem has been the maximum investigated part of the plant
diterpenoid, sesquiterpenoid, phenolics, proteins, etc. The ma- for its anti-diabetic activity. It has been reported that methanol
jor active constituents responsible for the anti-diabetic effect extract of T. cordifolia significantly reduces the fasting blood
belongs to a class of alkaloids; these consist of Berberine, glucose levels in streptozotocin-induced diabetic rats.
Palmatine, Tembetarine, Magnoflorine, Tinosporin. The other Improvement in the insulin and C-peptide levels were also
constituents present are Tinocordiside, Tinocordifolioside, reported which indicated the regeneration of β cells in the
Cordioside, Cordifolioside, Tinosporon, Tinosporides, etc. pancreas [115]. Manikkam et al. isolated a polysaccharide
[94, 112]. from methanolic extract of T. cordifolia stem and demonstrat-
ed the β-cell regenerative property of the isolated polysaccha-
Mechanism of Action ride in streptozotocin-induced diabetic rats suggesting its us-
age as a potent hypoglycemic agent [116].
T. cordifolia is reported to act by a different mechanism of
action. The possible mechanism to bring about hypoglycemic Curcuma longa
action is due to inhibition of α-glucosidase activity and gly-
colysis. In a study Chougale et al. reported the inhibitory ef- Curcuma longa Linn, belonging to family Zingiberaceae, is
fect of T. cordifolia on the α-glucosidase enzyme [86]. reported as a potent herb in Ayurveda system of medicine to
Joladarashi et al., proved the Glucose uptake-stimulatory combat diabetes. It is commonly known as Turmeric, Haldi,
 J Diabetes Metab Disord

Fig. 4 Schematic representation of Probable molecular mechanism for anti-diabetic effect of T. cordifolia

Haridra, etc. The herb is native to India and is widely cultivat- Demethoxycurcumin, and Bisdemethoxycurcumin among
ed particularly in West Bengal, Tamil Nadu, and Maharashtra this curcumin constitute about 60% of total curcuminoids.
[94]. Curcumin is a major active principle responsible for most of
the biological activity of C. longa [94].
Phytochemistry of C. longa
Mechanism of action
The rhizomes of C. longa consist of a large number of pheno-
lic compounds. Curcuminoids are the major active constitu- C. longa is known to exert the hypoglycemic action via dif-
ents present in the rhizomes. Curcuminoids are the mixture of ferent mechanisms, of which the most common being the
three related compounds namely Curcumin, inhibition of α-glucosidase and α-amylase enzyme [52, 117,

Fig. 5 Schematic representation of Probable molecular mechanism for anti-diabetic effect of C. longa
Table 2 Clinical studies on Anti-diabetic efficacy of selected five plants

Author (year) Plant name Study Duration Dose Number Outcome References
(Cases/ Control)
J Diabetes Metab Disord

Gaytan Martinez L. et al., (2020) G. sylvestre RCT 12 weeks 600 mg/day 15/15 ↓ 2-h OGTT (p = 0.003) and A1C [122]
Double-blind (GS capsule) (p = 0.025), ↑ insulin sensitivity
Al-Romaiyan A. et al., (2010) G. sylvestre Cohort study 2 months 1 gm/day 11 ↓ blood glucose [123]
(Novel GS extract) ↑plasma insulin and C-peptide levels
Nanda Kumar S. et al., (2010) G. sylvestre quasi-experimental design 3 months 500 mg/day 39/19 ↓ blood glucose (fasting and [124]
(GS capsule) post-prandial), and glycated
hemoglobin
Trakoon-osot W. et al., (2013) M. charantia RCT 16 weeks 6 g/day of MC dried-fruit pulp 19/19 ↓ A1C from baseline (p = 0.042, ↓ of [125]
Double-blind total advanced glycation end
products (AGEs) in serum
(p = 0.028)
Fuangchan A. et al., (2011) M. charantia Multicentric double-blind RCT 4 weeks G1-500 mg/day, G2-1000 mg/day, G1 = 33 ↓ fructosamine levels in G3 and G4. [126]
G3-2000 mg/day, dry fruit pulp G2 = 32
(G4-1000 mg/day metformin) G3 = 31
G4 = 33
Lim ST. et al., (2010) M. charantia RCT G1- 60 mg/kg/day G1 = 10 G3 showed a more rapid (15 [127]
double-blind G2-80 mg/kg/day G2 = 10 minutes) stimulation of insulin
G3-100 mg/kg/day G3 = 10 secretion than placebo
G4 = Placebo G4 = 10
Najdi RA. et al. (2019) T. foenum graecum RCT 12 weeks 2 gm/day TGF 6/6 ↑ fasting insulin level (P = 0.04). [128]
Verma N. et al., (2016) T. foenum graecum Multicentric double-blind RCT 3 month 1000 mg/day 154 ↓ fasting plasma, post-prandial blood [129]
Fenfuro (TGF seed extract) capsule sugar levels and HbA1c levels. ↑
fasting and post-prandial
C-peptide levels.
Kumar V. et al., (2015) T. cordifolia RCT 15 days 50 mg/ kg body weight/ day TC 90 ↓ fasting blood sugar [130]
stem powder
Roy K. (2015) T. cordifolia RCT 2 Months 500 mg/day encapsulated stem of 29/30 ↓ HbA1c levels [131]
TC
Rahimi HR. et al., (2016) C. longa RCT 3 months 80 mg/day Nano-curcumin (as 39/41 ↓ fasting blood sugar (p = 0.004) [132]
Double-blind nano-micelle) ↓ HbA1c levels (p = 0.02)
Chuengsamarn S. et al. (2012) C. longa RCT 9 months 1500 mg/day curcuminoids capsule 119/116 ↓ fasting plasma glucose and HbA1c [133]
Double-blind levels (p = < 0.01), better β cell
functions. ↑HOMA-β
(p = < 0.01)
Na LX. et al. (2012) C. longa RCT 3 months 300 mg/day curcuminoids 50/50 ↓ fasting blood glucose (p < 0.01), [134]
Double-blind HbA1c (p = 0.031),
and insulin resistance index
(HOMA-IR) (p < 0.01)
 J Diabetes Metab Disord

118]. Gutierres et al.., reported that increased levels of AKT usefulness in diabetes have been reviewed and a possible
phosphorylation and GLUT4 translocation in skeletal muscles mechanism of the action exerted by them to bring about
could be the possible mechanism responsible for the antidia- the anti-diabetic action has been highlighted. Among
betic activity of curcumin [53]. Kuroda et al., reported that the them, light has been shed upon 5 most potent anti-
hypoglycemic effect exerted by curcumin, demethoxycurcu- diabetic herbs with respect to their phytochemistry, under-
min, bisdemethoxycurcumin, and ar-turmerone is mainly at- lying mechanism of action, and anti-diabetic effect
tributed to PPAR-γ ligand-binding activity of the compound exerted by them.
[119]. In a molecular docking study Yasser et al., reported that From the evidences gathered from literature it is noticeable
the hypoglycemic effects of curcumin may be due to the that the herbs acts by various mechanism to bring about the
Inhibition of glycogen synthase kinase 3β [120]; Fig. 5. anti-diabetic effect. As evident from the literature a single
herbs displays multiple mechanism of action for example
Antidiabetic effect of C. longa Regeneration of pancreatic β cells, inhibition α-glucosidase
enzyme, insulin secretion, PPAR-γ ligand binding activity,
Various studies have shown the hypoglycemic activity of rhi- etc. this may be due to the presence of a variety of
zomes of C. longa. Seo et al. investigated the glucose- phytoconstituents in a herb. This can in turn bring about the
lowering potential of curcumin in diabetic db/db mice. A sig- synergistic effects leading to reduction in hyperglycaemic ac-
nificant decrease in blood glucose and HbA1c levels were tion. As described in the review, most of the reported mecha-
observed in animals treated with curcumin. A further study nism of actions exerted by the herbs have been described. In
reported the improvement in glucose homeostasis, glucose addition to that, more information on G. sylvestre, M.
tolerance, and elevated plasm insulin levels by the administra- charantia, T. foenum graecum, T. cordifolia and C. longa
tion of curcumin [121]. A study reported the suppression of has been provided owing to their extensive utilization by herb-
increased blood glucose levels in Genetically Diabetic KK-Ay al industries for development of anti-diabetic products. By
Mice by ethanolic extract of C. longa [119]. looking at the diverse phytoconstituents, their mechanism of
action, and clinical evidences it is clear that these herbs pos-
sess anti-diabetic effect.
Clinical studies Based on this comprehensive overview we can conclude
that herbal medicines can play a pivotal role in the manage-
Clinical trials plays an important role in accessing the safety ment and treatment of diabetes with fewer side effects. More
and efficacy of a particular medication in humans. Based on investigations mainly focusing on the isolation of
the literature obtained on the clinical efficacy of the selected phytocompounds from these herbs can lead to the discovery
five herbs, only recent publications from the year 2010 on- of newer anti-diabetic agents.
wards have been identified from the database search. The
details of clinical experiments for the investigation of anti- Acknowledgements The author are thankful to principal KLE College of
Pharmacy, Belagavi for his encouragement to write this review.
diabetic effects of the five herbs has been summarized in
Table 2.
Compliance with ethical standards

Conflict of interest The authors declare that they have no conflict of

Conclusion interest.

Diabetes mellitus is the most common endocrine disorder

marked by persistent hyperglycaemia resulting from impaired
insulin production or insulin resistance. Regardless of all the References
developments in therapeutics, diabetes still remains a major
cause of morbidity and mortality in the world. Allopathic 1. Onal S, Timur S, Okutucu B, Zihnioglu F. Inhibition of α-
Glucosidase by Aqueous Extracts of Some Potent Antidiabetic
therapies available currently for the treatment of diabetes have
Medicinal Herbs. Prep Biochem Biotech. 2005;35(1):29–36.
a number of serious side effects; consequently, there is a need 2. Lin Y, Sun Z. Current views on type 2 diabetes. J Endocrinol.
for investigation of more effective and safer hypoglycaemic 2009;204(1):1–11.
agents. Traditional medicine and ethno-botany have an ever- 3. WHO | Diabetes mellitus. https://www.who.int/mediacentre/
emerging role to play in the treatment and management of factsheets/fs138/en/. Accessed 7 Aug 2020.
diabetes mellitus. 4. Worldwide toll of diabetes. Diabetesatlas.org. 2020. https://www.
diabetesatlas.org/en/sections/worldwide-toll-of-diabetes.html.
The present review has highlighted the usefulness of Accessed 7 Aug 2020.
the herbal source for the treatment and management of 5. Parasuraman S, Thing G, Dhanaraj S. Polyherbal formulation:
diabetes mellitus. Around 50 herbs known for their concept of Ayurveda. Pharmacogn Rev. 2014;8(16):73.
J Diabetes Metab Disord

6. Calixto JB. Efficacy, safety, quality control, marketing and regu- 25. Yagi A, Hegazy S, Kabbash A, Wahab EA. Possible hypoglyce-
latory guidelines for herbal medicines (phytotherapeutic agents). mic effect of Aloe vera L. high molecular weight fractions on type
Braz J Med Biol Res. 2000;33(2):179–89. 2 diabetic patients. Saudi Pharm J. 2009;17:209–15.
7. Prabhakar P, Kumar A, Doble M. Combination therapy: A new 26. Komalasari T, Harimurti S. A Review of The Anti-diabetic
strategy to manage diabetes and its complications. Phytomedicine. Activity of Andrographis paniculata (Burm. f.) Nees based in-
2014;21(2):123–30. vivo Study. Int J Med Sci Public Health. 2015;4(4):265–263.
8. Prabhakar P, Doble MA. Target based therapeutic approach to- 27. Akhtar M, Bin Mohd Sarib M, Ismail I, Abas F, Ismail A, Lajis N.
wards diabetes mellitus using medicinal plants. Curr Diabetes Anti-diabetic activity and metabolic changes induced by
Rev. 2008;4(4):291–308. Andrographis paniculata plant extract in obese diabetic rats.
9. Jeeva S, Sheebha A. A review of antidiabetic potential of Molecules. 2016;21(8):1026.
ethnomedicinal plants. Med Aromat Plants. 2014;3(4):1–8. 28. Tomar RS, Sisodia SS. Antidiabetic activity of Annona squamosa
10. Kashikar VS, Kotkar T. Indegenous remedies for Diabetes Linn. In alloxan – induced diabetic rats. Int J Green Pharm.
mellitus. Int J Pharm Pharm Sci. 2011;3(3):22–9. 2014;8(4):237–41.
11. Jasmin R, Ganesh kumar R, Rajaram R. Probing the mechanism of 29. Davis JA, Sharma S, Mittra S, Sujatha S, Kanaujia A, Shukla G,
the anti-diabetic potential of terpenoids from Elephentopus scaber et al. Antihyperglycemic effect of Annona squamosa hexane ex-
L., an Indian ethanomedical plant in STZ diabetic rats In-vivo and tract in type 2 diabetes animal model: PTP1B inhibition, a possible
In-silico analysis. Indian J Biochem Biophys. 2018;55:384–88. mechanism of action. Indian J Pharmacol. 2012;44(3):326–32.
12. Zhang L, Reddy N. Bioactive molecules from medicinal herbs for 30. Mannan N, Boucher BJ, Evans SJW. Increased waist size and
life threating diseases. J Mol Sci. 2018;2(4):1–11. weight in relation to consumption of Areca catechu (betel-nut); a
13. Rajvaidhya S, Nagori BP, Singh GK, Dubey BK, Desai P, Alok S, risk factor for increased glycaemia in Asians in East London. Br J
Jain SA. Review on Acacia arabica - An Indian medicinal plant. Nutr. 2000;83:267–75.
Int J Pharm Sci Res. 2012;3(7):1995–2005. 31. Satyanarayana K, Sravanthi K, Shaker IA, Ponnulakshmi R.
Molecular approach to identify antidiabetic potential of
14. Hegazy GA, Alnoury AM, Gad HG. The role of Acacia Arabica
Azadirachta indica. J Ayurveda Integr Med. 2015;6(3):165–74.
extract as an antidiabetic, antihyperlipidemic, and antioxidant in
streptozotocin-induced diabetic rats. Saudi Med J. 2013;34(7): 32. Omnia M. Molecular and biochemical effect of neem extract on
727–723. experimental Diabetes. IOSR J Appl Chem. 2014;7(7):24–9.
15. Vijayaraj R, Sri Kumaran N. Evaluation of in vivo antidiabetic and 33. Ghosh T, Maity T, Singh J. Antihyperglycemic activity of
antioxidant activity of Achyranthes aspera Linn. seeds by bacosine, a triterpene from Bacopa monnieri, in alloxan-induced
streptozotocin induced diabetic rats. Int J Green Pharm. diabetic rats. Planta Med. 2011;77:804–8.
2018;12(1):29–37. 34. Kishore L, Kaur N, Singh R. Renoprotective effect of Bacopa
monnieri via inhibition of advanced glycation end products and
16. Bharti S, Krishnan S, Kumar A, Kumar A. Antidiabetic
oxidative stress in STZ-nicotinamide-induced diabetic nephropa-
phytoconstituents and their mode of action on metabolic path-
thy. Ren Fail. 2016. https://doi.org/10.1080/0886022X.2016.
ways. Ther Adv Endocrinol Metab. 2018;9(3):81–100.
1227920.
17. Gao H, Huang Y, Gao B, Li P, Inagaki C, Kawabata J. Inhibitory
35. Franco RR, Alves VH, Zabisky LF, Justino AB, Martins MM,
effect on α-glucosidase by Adhatoda vasica Nees. Food Chem.
Saraiva AL, et al. Antidiabetic potential of Bauhinia forficata
2008;108(3):965–72.
Link leaves: a non-cytotoxic source of lipase and glycoside hydro-
18. Kumar V, Prakash O, Kumar S, Narwal S. α-glucosidase inhibi-
lases inhibitors and molecules with antioxidant and antiglycation
tors from plants: A natural approach to treat diabetes. Pharmacogn properties. Biomed Pharmacother. 2020;123:1–8.
Rev. 2011;5(9):19.
36. Jorge AP, Horst H, de Sousa E, Pizzolatti MG, Silva FR.
19. Arawwawala M, Jayaratne M. Aegle marmelos (L.) Correa as a Insulinomimetic effects of kaempferitrin on glycaemia and on
potential candidate for treatment of diabetes mellitus: A review. J 14C-glucose uptake in rat soleus muscle. Chem Biol Interact.
Herbmed Pharmacol. 2017;6(4):141–7. 2004;149(2–3):89–96.
20. Rafe MR. A review of five traditionally used anti-diabetic plants 37. Al masri IM, Mohammad MK, Tahaa MO. Inhibition of
of Bangladesh and their pharmacological activities. Asian Pac J dipeptidyl peptidase IV (DPP-IV) is one of the mechanisms
Trop Med. 2017;10(10):933–9. explaining the hypoglycemic effect of berberine. J Enzyme
21. Nyunai N, Njikam N, Abdennebi EH, Mbafor JT, Lamnaouer D. Inhib Med Chem. 2009;24:1061–6.
Hypoglycaemic and antihyperglycaemic activity of Ageratum 38. Cicero AFG, Tartagni E. Antidiabetic Properties of Berberine:
conyzoides L. in rats. Afr J Tradit Complement Altern Med. From Cellular Pharmacology to Clinical Effects. Hosp Pract.
2009;6(2):123–30. 2012;40(2):57–63.
22. Vu NK, Kim CS, Ha MT, Mai Ngo TQ, Park SE, Kwon H, et al. 39. Alam P, Shahzad N, Gupta AK, Mahfoz AM, Bamagous GA, Al-
Antioxidant and antidiabetic activities of flavonoid derivatives Ghamdi SS, et al. Anti-diabetic Effect of Boerhavia diffusa L. root
from the outer skins of Allium cepa L. J Agric Food Chem. extract via free radical scavenging and antioxidant mechanism.
2020. https://doi.org/10.1021/acs.jafc.0c02122. Toxicol Environ Health Sci. 2018;10:220–7.
23. Sabiu S, Madende M, Ajao AA, Aladodo RA, Nurain IO, Ahmad 40. Brahima M, Eugene A, Justin B, Madjid A, Machioud S,
JB. The Genus Allium (Amaryllidaceae: Alloideae): Features, Rodrigue A, et al. The Effect of Methanolic Leaf Extract of
phytoconstituents, and mechanisms of antidiabetic potential of Boerhavia diffusa Linn. (Nictaginaceae) on the Activities of
Allium cepa and Allium sativum. In: Watson RR, Preedy VR, Antidiabetic, Anti-inflammatory and Antioxidant Enzymes in
eds. Bioactive food as dietary interventions for diabetes. Experimental Diabetes. J Pharm Res Int. 2018;24(5):1–25.
Cambridge: Academic; 2019. pp. 137–154. 41. Wang H, Shi S, Bao B, Li X, Wang S. Structure characterization
24. Mamun MA, Hasan N, Shirin F, Belal MH, Khan MAJ, Tasnin of an arabinogalactan from green tea andits anti-diabetic effect.
MN, et al. Antihyperglycemic and antihyperlipidemic activity of Carbohydr Polym. 2015;124:98–108.
ethanol extract of garlic (Allium sativum) in streptozotocin- 42. Hininger-Favier I, Benaraba R, Coves S, Anderson RA, Roussel
induced diabetic miceInternational. J Med Health Res. AM. Green Tea Extract Decreases Oxidative Stress and Improves
2017;3(2):63–6. Insulin Sensitivity in an Animal Model of Insulin Resistance, the
 J Diabetes Metab Disord

Fructose-Fed Rat. J Am Coll Nutr. 2009. https://doi.org/10.1080/ 60. Chikaraddy A, Maniyar Y. Evaluation and comparison of hypo-
07315724.2009.10718097. glycemic activity of bark and leaf of Ficus bengalensis linn. in
43. Prakasam A, Sethupathy S, Pugalendia KV. Antiperoxidative and alloxan induced diabetes in albino rats. Indian J Pharm Pharmacol.
antioxidant effects of Casearia esculenta root extract in 2017;4(3):138–42.
streptozotocin induced diabetic rats. Yale J Biol Med. 2005;78: 61. Khanal P, Patil BM. Gene set enrichment analysis of alpha-
15–23. glucosidase inhibitors from Ficus benghalensis. Asian Pac J
44. Govindasamy C, Al-Numair KS, Alsaif MA, Viswanathan KP. Trop Biomed. 2019;9(6):263–70.
Influence of 3-hydroxymethyl xylitol, a novel antidiabetic com- 62. Veerapur VP, Prabhakar KR, Thippeswamy BS, Bansal P,
pound isolated from Casearia esculenta (Roxb.) root, on glyco- Srinivasan KK, Unnikrishnan MK. Antidiabetic effect of Ficus
protein components in streptozotocin-diabetic rats. J Asian Nat racemosa Linn. stem bark in high-fat diet and low-dose
Prod Res. 2011;13(8):700–6. streptozotocin-induced type 2 diabetic rats: a mechanistic study.
45. Benalla W, Bellahcen S, Bnouham M. Antidiabetic medicinal Food Chem. 2012;132(1):186–93.
plants as a source of alpha glucosidase inhibitors. Curr Diabetes 63. Amin MM, Bhakta S, Das SK. Anti-diabetic potential of Ficus
Rev. 2010;6(4):247–54. racemosa: current state and prospect especially in the developing
46. Kabir AU, Samad MB, D’Costa NM, Akhter F, Ahmed A. countries. J Biosci Agric Res. 2015;05(02):65–72.
Hannan JM. Anti-hyperglycemic activity of Centella asiatica is 64. Karthikeson PS, Laxmi T. Anti-Diabetic Activity of Glycyrrhiza
partly mediated by carbohydrase inhibition and glucose-fiber glabra - An In vitro Study. Int J Pharm Sci Rev Res. 2017;44(1):
binding. BMC Complement Altern Med. 2014;18:14–31. 80–1.
47. Nugroho AE, Lindawati NY, Herlyanti K, Widyastuti L, Pramono 65. Harwansh RK, Parea KC, Pareta SK, Singh J. Pharmacological
S. Anti-diabetic effect of a combination of andrographolide- studies of Glycyrrhiza glabra- a review. Pharmacologyonline.
enriched extract of Andrographis paniculata (Burm f.) Nees and 2011;2:1032–8.
asiaticoside-enriched extract of Centella asiatica L. in high 66. Sugihara Y, Nojima H, Matsuda H, Murakami T, Yoshikawa M,
fructose-fat fed rats. Indian J Exp Biol. 2013;51(12):1101–8. Kimura I. Antihyperglycemic Effects of Gymnemic Acid IV, a
48. Jamwal A, Kumar S. Antidiabetic activity of isolated compound Compound Derived from Gymnema sylvestre Leaves in
from Coccinia indica. Indian J Pharm Educ. 2019;53(1):151–9. Streptozotocin-Diabetic Mice. J Asian Nat Prod Res. 2000;2:
49. Kohli S, Kumar PN. Combined effect of Coccinia indica leaf 321–7.
extract with acarbose in type II diabetes induced neuropathy in 67. Chen G, Guo M. Rapid Screening for α-Glucosidase Inhibitors
rats. J Innov Pharm Biol Sci. 2014;1(2):77–87. from Gymnema sylvestre by Affinity Ultrafiltration-HPLC-MS.
50. Youn JY, Park HY, Cho KH. Anti-hyperglycemic activity of Front Pharmacol. 2017;8:1-8.
Commelina communis L.: inhibition of alpha-glucosidase. 68. Dholi SK, Raparla R. Kannappan. In vivo anti diabetic evaluation
Diabetes Res Clin Pract. 2004;66:149-55. of gymnemic acid in streptozotocin induced rats. Pharma Innov J.
51. Shibano M, Kakutani K, Taniguchi M, Yasuda M, Baba K. 2014;3(7):82–6.
Antioxidant constituents in the dayflower (Commelina communis 69. Tanaka S, Han LK, Zheng YN, Okuda H. Effects of the flavonoid
L.) and their alpha-glucosidase-inhibitory activity. J Nat Med. fraction from Ginkgo biloba extract on the postprandial blood
2008;62(3):349–53. glucose elevation in rats. Yakugaku Zasshi. 2004;124(9):605–11.
52. Riyaphan J, Jhong C, Lin S, Chang C, Tsai M, Lee D, et al. 70. Ngo DH, Ngo DN, Vo TT, Vo TS. Mechanism of Action of
Hypoglycemic efficacy of docking selected natural compounds Mangifera indica Leaves for Anti-Diabetic Activity. Sci Pharm.
against α-Glucosidase and α-Amylase. Molecules. 2018;23:2260. 2019;87(13):1–12.
53. Gutierres V, Campos M, Arcaro C, Assis R, Baldan-Cimatti H, 71. Miura T, Itoh C, Iwamoto N, Kato M, Kawai M, Park SR, Suzuki
Pe cc in i ni R , et al . C u rc um in P h ar m ac o ki n et ic an d I. Hypoglycemic activity of the fruit of the Momordica charantia
Pharmacodynamic Evidences in Streptozotocin-Diabetic Rats in type 2 diabetic mice. J Nutr Sci Vitaminol. 2001;47(5):340–4.
Support the Antidiabetic Activity to Be via Metabolite(s). Evid 72. Joseph B, Jini D. Antidiabetic effects of Momordica charantia
Based Complement Alternat Med. 2015;1–13. (bitter melon) and its medicinal potency. Asian Pac J Trop Dis.
54. Singh P, Khosa RL, Mishra G, Jha KK. Antidiabetic activity of 2013;3(2):93–102.
ethanolic extract of Cyperus rotundus rhizomes in streptozotocin- 73. Pradeep Kumar R, Sujatha D, Mohamed Saleem TS,
induced diabetic mice. J Pharm Bioallied Sci. 2015;7(4):289–92. Madhusudhana Chetty C, Ranganayakulu D. Potential antidiabet-
55. Tran H, Nguyen MC, Le HT, Nguyen TL, Pham TB, Chau VM, ic and antioxidant activities of Morus indica and Asystasia
et al. Inhibitors of a-glucosidase and a-amylase from Cyperus gangetica in alloxan-induced diabetes mellitus. J Exp
rotundus. Pharm Biol. 2013. https://doi.org/10.3109/13880209. Pharmacol. 2010;2:29–36.
2013.814692. 74. Raja TAR, Reddy RV, Priyadharshini, Buchineni M. An evalua-
56. Fatima N, Hafizur RM, Hameed A, Ahmed S, Nisar M, Kabir N. tion of anti-hyperglycemic activity of Ocimum sanctum Linn
Ellagic acid in Emblica officinalis exerts anti-diabetic activity (leaves) in Wister rats. Pharma Innov. 2016;5(1):1–3.
through the action on β-cell of pancreas. Eur J Nutr. 2015. 75. Patil R, Patil R, Ahirwar B, Ahirwar D. Isolation and characteri-
https://doi.org/10.1007/s00394-015-1103-y. zation of anti-diabetic component (bioactivity-guided
57. Nain P, Saini V, Sharma S, Nain J. Antidiabetic and antioxidant fractionation) from Ocimum sanctum L. (Lamiaceae) aerial part.
potential of Emblica officinalis Gaertn. leaves extract in Asian Pac J Trop Med. 2011;4(4):278–82.
streptozotocin-induced type-2 diabetes mellitus (T2DM) rats. J 76. Qiu S, Yang WH, Yao CL, Shi XJ, Li JY, Lou Y, et al.
Ethnopharmacol. 2012;142(1):65–71. Malonylginsenosides with Potential Antidiabetic Activities from
58. Murali B, Upadhyaya UM, Goyal RK. Effect of chronic treatment the Flower Buds of Panax ginseng. J Nat Prod. 2017;80:899–908.
with Enicostemma littorale in non-insulin-dependent diabetic 77. Kang OH, Shon MY, Kong R, Seo YS, Zhou T, Kim DY. Anti-
(NIDDM) rats. J Ethnopharmacol. 2002;81(2):199–204. diabetic effect of black ginseng extract by augmentation of AMPK
59. Maroo J, Vasu VT, Aalinkeel R, Gupta S. Glucose lowering effect protein activity and upregulation of GLUT2 and GLUT4 expres-
of aqueous extract of Enicostemma littorale Blume in diabetes: a sion in db/db mice. BMC Complem Alter M. 2017;17(341):1–11.
possible mechanism of action. J Ethnopharmacol. 2002;81(3): 78. Adedapo AA, Ofuegbe SO. The evaluation of the hypoglycemic
317–20. effect of soft drink leaf extract of Phyllanthus amarus
J Diabetes Metab Disord

(Euphorbiaceae) in rats. J Basic Clin Physiol Pharmacol. 98. Saeed MK, Shahzadi I, Ahmad I, Ahmad R, Shahzad K, Ashraf
2014;25(1):47–57. M, et al. Nutritional analysis and antioxidant activity of bitter
79. Pant DR, Pant ND, Saru DB, Yadav UN, Khanal DP. gourd (Momordica charantia) from Pakistan.
Phytochemical screening and study of antioxidant, antimicrobial, Pharmacologyonline. 2010;1:252–60.
antidiabetic, anti-inflammatory and analgesic activities of extracts 99. Budrat P, Shotipruk A. Extraction of phenolic compounds from
from stem wood of Pterocarpus marsupium Roxburgh. J Intercult fruits of bitter melon (Momordica charantia) with subcritical wa-
Ethnopharmacol. 2017;6(2):170–6. ter extraction and antioxidant activities of these extracts. Chiang
80. Kavitha KN, Dattatri AN. Experimental Evaluation of antidiabetic Mai J Sci. 2008;35(1):123–30.
activity of Swertia Chirata – Aqueous Extract. J Pub Health Med 100. Lo H, Ho T, Lin C, Li C, Hsiang C. Momordica charantia and Its
Res. 2013;1(2):71–5. Novel Polypeptide Regulate Glucose Homeostasis in Mice via
81. Kuroda M, Mimaki Y, Ohtomo T, Yamada J, Nishiyama T, Mae Binding to Insulin Receptor. J Agric Food Chem. 2013;61:
T, et al. Hypoglycemic effects of clove (Syzygium aromaticum 2461–8.
flower buds) on genetically diabetic KK-Ay mice and identifica- 101. Hsueh-Ling C, Hsin-Kai H, Chi -IC, Chung-Pao T, Chang-Hung
tion of the active ingredients. J Nat Med. 2012;66(2):394–9. C. A Cell-Based Screening Identifies Compounds from the Stem
82. Kumar A, Ilavarasan R, Jayachandran T, Deecaraman M, of Momordica charantia that Overcome Insulin Resistance and
Aravindan P, Padmanabhan N, et al. Anti-diabetic activity of Activate AMP-Activated Protein Kinase. J Agric Food Chem.
Syzygium cumini and its isolated compound against 2008;56:6835–43.
streptozotocin-induced diabetic rats. J Med Plant Res. 102. Nkambo W, Anyama NG, Onegi B. In vivo hypoglycemic effect
2008;2(9):246–9. of methanolic fruit extract of Momordica charantia L. Afr Health
83. Barman S, Das S. Hypoglycemic effect of ethanolic extract of bark Sci. 2013;13(4):933–9.
of Terminalia arjuna Linn. In normal and alloxan–induced 103. Mahmoud MF, El Ashry FE, El Maraghy NN, Fahmy A. Studies
noninsulin-dependent diabetes mellitus albino rats. Int J Green on the antidiabetic activities of Momordica charantia fruit juice in
Pharm. 2012;6(4):279–284. streptozotocin-induced diabetic rats. Pharm Biol. 2017;55(1):758–
84. Akram N, Srivastava M, Mishra MK. Antidiabetic Activity of root 65.
of Terminalia chebula on alloxan induced diabetic rat. World J 104. Han JH, Tuan NQ, Park MH, Quan K, Oh J, Heo KS, et al.
Pharm Med Res. 2019;5(3):108–12. Cucurbitane Triterpenoids from the Fruits of Momordica
85. Sabu MC, Kuttan R. Antidiabetic and antioxidant activity of Charantia Improve Insulin Sensitivity and Glucose Homeostasis
Terminalia belerica Roxb. Indian J Exp Biol. 2009;47(4):270–5. in Streptozotocin-Induced Diabetic Mice. Mol Nutr Food Res.
86. Chougale AD, Ghadyale VA, Panaskar SN, Arvindekar AU. 2018;62(7):1700–769.
Alpha glucosidase inhibition by stem extract of Tinospora
105. Bahmani M, Shirzad H, Mirhosseini M, Mesripour A, Rafieian-
cordifolia. J Enzyme Inhib Med Chem. 2009;24(4):998–1001.
Kopaei M. A Review on Ethnobotanical and Therapeutic Uses of
87. Sharma R, Amin H, Galib, Prajapati PK. Antidiabetic claims of
Fenugreek (Trigonella foenum-graceum L). Evid Based
Tinospora cordifolia (Willd.) Miers: critical appraisal and role in
Complement Alternat Med. 2016;21(1):53–62.
therapy. Asian Pac J Trop Biomed. 2015;5(1):68–78.
106. Roshana Devi V, Sharmila C, Subramanian S. Molecular Docking
88. Yoshinari O, Igarashi K. Anti-Diabetic Effect of Trigonelline and
Studies Involving the Inhibitory Effect of Gymnemic Acid,
Nicotinic Acid, on KK-Ay Mice. Curr Med Chem. 2010;17:2196–
Trigonelline and Ferulic Acid, the Phytochemicals with
202.
Antidiabetic Properties, on Glycogen Synthase Kinase 3 (α and
89. Zhou J, Zhou S, Zeng S. Experimental diabetes treated with
β). J Appl Pharm Sci. 2018;8(04):150–60.
trigonelline: effect on β cell and pancreatic oxidative parameters.
Fundam Clin Pharmacol. 2011;27(3):279–87. 107. Amat-Alrazaq A, Aldakinah, Muhammad Y, Al-Shorbagy, Dalaal
90. Ahmed MF, Kazim SM, Ghori S, Mehjabeen SS, Ahmed SR, Ali M, Abdallah, et al. Trigonelline and vildagliptin antidiabetic ef-
SM, Ibrahim M. Antidiabetic activity of Vinca rosea extracts in fect: improvement of insulin signalling pathway. J Pharm
alloxan-induced diabetic rats. Int J Endocrinol. 2010;2010:1–6. Pharmacol. 2017:1–9.
91. Orhan N, Aslan M, Orhan DD, Ergun F, Yeşilada E. In-vivo 108. Jaiswal N, Maurya CK, Venkateswarlu K, Sukanya P, Srivastava
assessment of antidiabetic and antioxidant activities of grapevine AK, Narender T, Tamrakar AK. 4-Hydroxyisoleucine stimulates
leaves (Vitis vinifera) in diabetic rats. J Ethnopharmacol. glucose uptake by increasing surface GLUT4 level in skeletal
2006;108(2):280–6. muscle cells via phosphatidylinositol-3-kinase-dependent path-
92. Kumar V, Dey A, Chatterjee SS. Phytopharmacology of way. Eur J Nutr. 2012;51(7):893–8.
Ashwagandha as an Anti-Diabetic Herb, In: Kaul S., Wadhwa 109. Maurya CK, Singh R, Jaiswal N, Venkateswarlu K, Narender T,
R, editors. Science of Ashwagandha: Preventive and Tamrakar AK. 4-Hydroxyisoleucine ameliorates fatty acid-
Therapeutic Potentials. Berlin: Springer. 2017. induced insulin resistance and inflammatory response in skeletal
93. Otunola GA, Afolayan AJ. Antidiabetic effect of combined spices muscle cells. Mol Cell Endocrinol. 2014;395(1–2):51–60.
of Allium sativum, Zingiber officinale and Capsicum frutescens in 110. Eidia A, Eidib M, Sokhteha M. Effect of fenugreek (Trigonella
alloxan-induced diabetic rats. Front Life Sci. 2015. https://doi.org/ foenum-graecum L) seeds on serum parameters in normal and
10.1080/21553769.2015.1053628. streptozotocin-induced diabetic rats. Nutr Res. 2007;27:728–33.
94. Khare CP. Indian Medicinal Plants An Illustrated Dictionary. 111. Shah SN, Bodhankar SL, Badole SL, Kamble HV, Mohan V.
Berlin: Springer. 2008. Effect of trigonelline: An active compound from Trigonella
95. Kanetkar P, Singhal R, Kamat M. Gymnema sylvestre: A Memoir. foenum graecum Linn. In alloxan induced diabetes in mice. Cell
J Clin Biochem Nutr. 2007;41:77–81. Tissue Res. 2006;6(1):585–90.
96. Ishijima S, Takashima T, Ikemura T, Izutani Y. Gymnemic acid 112. Singh SS, Pandey SC, Srivastava S, Gupta VS, Patro B, Ghosh
interacts with mammalian glycerol-3-phosphate dehydrogenase. AC. Chemistry and medicinal properties of Tinospora cordifolia
Mol Cell Biochem. 2008;310:203–8. (Guduchi). Indian J Pharmacol. 2003;35:83–91.
97. Ahmed A, Rao AS, Rao M. In vitro callus and in vivo leaf extract 113. Joladarashi D, Chilkunda ND, Salimath PV. Glucose uptake-
of Gymnema sylvestre stimulate β-cells regeneration and anti- stimulatory activity of Tinospora cordifolia stem extracts in
diabetic activity in Wistar rats. Phytomedicine. 2010;17(13): Ehrlich ascites tumor cell model system. J Food Sci Technol.
1033–9. 2014;51(1):178–82.
 J Diabetes Metab Disord

114. Patel MB, Mishra S. Hypoglycemic activity of alkaloidal fraction 126. Fuangchana A, Sonthisombata P, Seubnukarnb T, Chanouanc R,
of Tinospora cordifolia. Phytomed. 2011;18:1045–52. Chotchaisuwatd P, Sirigulsatien V, et al. Hypoglycemic effect of
115. Rajalakshmi M, Eliza J, Cecilia E, Nirmala A, Daisy P. Anti- bitter melon compared with metformin in newly diagnosed type 2
diabetic properties of Tinospora cordifolia stem extracts on diabetes patients. J Ethnopharmacol. 2011;134:422–8.
streptozotocin- induced diabetic rats. Afr J Pharm Pharmacol. 127. Lim ST, Jimeno CA, Razon-Gonzales EB, Velasquez ME. The
2009;3(5):171–80. MOCHA DM study: The Effect of MOmordica CHArantia tablets
116. Rajalakshmi R, Roy A. b-cell regenerative efficacy of a polysac- on glucose and insulin levels during the postprandial state among
charide isolated from methanolic extract of Tinospora cordifolia patients with Type 2 Diabetes Mellitus. Philipp J Intern Med.
stem on streptozotocin-induced diabetic Wistar rats. Chem-Biol 2010;48(2):19–25.
Interact. 2016;243:45–53. 128. Najdi RA, Hagras MM, Kamel FO, Magadmi RM. A randomized
117. Ghani U. Re-exploring promising a-glucosidase inhibitors for po- controlled clinical trial evaluating the effect of Trigonella foenum-
tential development into oral anti-diabetic drugs: Finding needle in graecum (fenugreek) versus glibenclamide in patients with diabe-
the haystack. Eur J Med Chem. 2015;103:133–62. tes. Afr Health Sci. 2019;19(1):1594–601.
118. Jhong C, Riyaphan J, Lin J, Chia Y, Weng C. Screening alpha- 129. Verma N, Usman K, Patel N, Jain A, Dhakre S, Swaroop A, et al.
glucosidase and alpha-amylase inhibitors from natural compounds A multicenter clinical study to determine the efficacy of a novel
by molecular docking in silico. BioFactors. 2015;41(4):242–51. fenugreek seed (Trigonella foenum-graecum) extract (Fenfuro™)
119. Kuroda M, Mimaki Y, Nishiyama T, Mae T, Kishida H, in patients with type 2 diabetes. Food Nutr Res. 2016;60(1):
Tsukagawa M, et al. Hypoglycemic Effects of Turmeric 32382.
(Curcuma longa L. Rhizomes) on Genetically Diabetic KK-Ay 130. Kumar V, Mahdi F, Singh R, Mahdi A, Singh RK. A clinical trial
Mice. Biol Pharm Bull. 2005;28(5):937–9. to assess the antidiabetic, antidyslipidemic and antioxidant activi-
120. Bustanji Y, Taha MO, Almasri IM, Al-Ghussein M, Mohammad ties of Tinospora cordifolia in management of type – 2 Diabetes
MK, Alkhatib HS. Inhibition of glycogen synthase kinase by Mellitus. Int J Pharm Sci Res. 2016;7(2):757–64.
curcumin: Investigation by simulated molecular docking and sub-
131. Roy K, Shah R, Iyer U. Tinospora cordifolia stem supplementa-
sequent in vitro/invivo evaluation. J Enzyme Inhib Med Chem.
tion in diabetic dyslipidemia: an open labelled randomized con-
2009;24(3):771–8.
trolled trial. Funct Food Health Dis. 2015;5(7):265–74.
121. Seo K, Choi M, Jung U, Kim H, Yeo J, Jeon S, et al. Effect of
curcumin supplementation on blood glucose, plasma insulin, and 132. Rahimi HR, Mohammadpour AH, Dastani M, Jaafari MR,
glucose homeostasis related enzyme activities in diabetic db/db Abnous K, Mobarhan MG, et al. The effect of nano-curcumin
mice. Mol Nutr Food Res. 2008;52:995–1004. on HbA1c, fasting blood glucose, and lipid profile in diabetic
122. Gaytan Martinez L, Sanchez-Ruiz L, Zuniga L, Gonzalez-Ortiz subjects: a randomized clinical trial. Avicenna J Phytomed.
M, Martinez-Abundis E. Effect of Gymnema sylvestre 2016;6(5):567–77.
Administration on Glycemic Control, Insulin Secretion, and 133. Chuengsamarn S, Rattanamongkolgul S, Luechapudiporn R,
Insulin Sensitivity in Patients with Impaired Glucose Tolerance. Phisalaphong C, Jirawatnotai S. Curcumin Extract for
J Med Food. 2020. https://doi.org/10.1089/jmf.2020.0024. Prevention of Type 2 Diabetes. Diabetes Care. 2012;35(11):
123. Al-Romaiyan A, Liu B, Asare-Anane H, Maity C, Chatterjee S, 2121–7.
Koley N, et al. A novel Gymnema sylvestre extract stimulates 134. Na LX, Li Y, Pan HZ, Zhou XL, Sun DJ, Meng M, et al.
insulin secretion from human islets in vivo and in vitro. Curcuminoids exert glucose-lowering effect in type 2 diabetes
Phytother Res. 2010;24(9):1370–6. by decreasing serum free fatty acids: a double-blind, placebo-
124. Nanda Kumar S, Mani UV, Mani I. An Open Label Study on the controlled trial. Mol Nutr Food Res. 2012;56:1–9.
Supplementation of Gymnema sylvestre in Type 2 Diabetics. J
Diet Suppl. 2010;7(3):273–82. Publisher's Note Springer Nature remains neutral with regard to
125. Trakoon-osot W, Sotanaphun U, Phanachet P, Porasuphatana S, jurisdictional claims in published maps and institutional affiliations.
Udomsubpayakul U, Komindr S. Pilot study: Hypoglycemic and
antiglycation activities of bitter melon (Momordica charantia L.)
in type 2 diabetic patients. J Pharm Res. 2013;6:859–64.