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Current Diabetes Reviews
ISSN: 1573-3998
eISSN: 1875-6417
SCIENCE
BENTHAM
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186
Current Diabetes Reviews, 2021, 17, 186-197
MINI-REVIEW ARTICLE
A Review on Natural Products and Herbs Used in the Management of
Diabetes
Deepshikha Patle1,2, Manish Vyas3 and Gopal L. Khatik2,*
1Faculty of Pharmaceutical Sciences - PCTE Group of Institutes, Jhande, VPO Baddowal, Ludhiana, Punjab, 142021,
India; 2Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Lovely Professional University,
Jalandhar- Delhi G.T. Road, Phagwara, Punjab, 144411, India; 3Department of Ayurveda, School of Pharmaceutical
Sciences, Lovely Professional University, Jalandhar, Delhi G.T. Road, Phagwara, Punjab, 144411, India
A R T I C L E H I S T O R Y
Received: January 02, 2 020
Revised: March 03, 2020
Accepted: March 24, 2 020
DOI:
10.2174/1573399816666200408090058
Abstract: Aim: We aimed to review the importance of the natural products and herbs used in the man-
agement of diabetes mellitus (DM) as medicinal agents.
Background: Naturally occuring phytoactive compounds and herbs are very important because they are
found to be effective against several diseases. DM is a commonly occurring endocrinological disorder,
with the incidences increased four times in the last 34 years. There are several oral hypoglycemic agents
available in the market, which in the long term, may lead to a high risk of secondary failure rate.
Objectives: This review focuses on natural products and herbs application for effective management of
diabetic conditions, and natural products that can be utilized as alternative therapy.
Methods: We searched the various online databases (PubMed, Bentham, ScienceDirect) and scientific
publications from the library using a qualitative systematic review. The criteria of the review were
based on natural products and herbs application for possessing medicinal value against diabetes and the
literature of previous thirty years has b een searched. The inclusion criteria of materials were based on
the quality and relevancy with our aim.
Results: We observed that owing to the potential of natural products and herbs, different research
groups are searching for the potent natural antidiabetic agents with minimal side effects. Recent re-
search showed that there is a decline in a number of new molecules that fail in clinical trials because of
toxicity thus, natural products and herbs are considered as the alternative. Currently, some of the natural
products and herbs like coixol, andrographolide, Tinospora cordifolia, polypeptide p, charantin, Annona
squamosa, and Nigella are being explored for their potential to be u sed successfully for the management
of type 2 diabetes.
Conclusion: The significance of natural products and herbs in the anticipation of diabetes and allied
complications are being described herein. We observed that a huge amount of work is being done to ex-
plore the natural products and herbs to manage the diabetes and this review gives the highlights of them.
Keywords: Natural products, herbs, flavonoid, diabetes mellitus, phytoactive compounds, endocrinological disorder.
1. INTRODUCTION
Diabetes Mellitus (DM), in the current years, has been
observed to be a serious issue, recognized through an imper-
fection in insulin development or in insulin activity on fringe
tissues promoting metabolic variations from the norm and
hyperglycemia [1, 2]. In 2015, it was assessed that 415 mil-
lion individuals had diabetes. However, this figure is relied
upon to ascend to 642 million in the following 25 years [3].
*Address correspondence to this author at the Department of Pharmaceuti-
cal Chemistry, School of Pharmaceutical Sciences, Lovely Professional
University, Jalandhar- Delhi G.T. Road, Phagwara, Punjab, 144411, India;
Tel: +91-9256336645; E-mail: gopal_niper@rediffmail.com
The WHO evaluated that around 346 million individuals
around the globe experience the effects of diabetes, which
will be multiplied constantly by 2030, representing a major
face up to the health care system [4]. The disease is isolated
in 2 major classes: insulin-dependent, also called type 1 dia-
betes and non-dependent, also known as type 2 diabetes [5].
It is characterized by anomalous large amounts of plasma
glucose in fasting situation or past association of glucose, all
through an oral glucose tolerance test. Diabetes is observed
by an absolute or relative insufficiency in the discharge of
insulin [6]. Diabetes type 1 consequences in insulin insuffi-
ciency are caused by a cell linked immune damage in β-cells
of the pancreas and found to be most developed in young
people [7]. Approximately 90 percent of diabetes is type 2,
1875-6417/21 $65.00+.00 © 2021 Bentham Science Publishers
A Review on Natural Products and Herbs Current Diabetes Reviews, 2021, Vol. 17, No. 2 187
which is the result of resistance in insulin and it’s lack [8].
However, type 2 diabetes is also found to be developed at an
earlier point of life, as observed through Maturity Onset
Diabetes of the Young (MODY). Diabetes mellitus type 2 is
nowadays impacted by solely genetic or ecological factor
ensuing improvement of resistance in insulin and dysfunc-
tion of β cell [9–11]. The involvement of hereditary and eco-
logical variables in the development of type 2 diabetes varies
amongst people.
Natural products and herbs keep on contributing to the
prevention and cure of a variety of ailments. They provide an
extensive resource for the discovery of new compounds with
specific arrangements in the structures that show great inter-
est in therapeutic activities for the treatment of a range of
ailments. Medications from these sources are typically
thought to be more secure, less expensive and effectively
accessible, cheaper, and occasionally more effective than
entirely synthetic moieties. In current years, researchers have
been in the search of safe and most effective drugs from
natural sources, especially through medicinal plants [12].
The globe is moving towards infestations of diabetes, es-
pecially type 2 diabetes mellitus, in an increasing order at a
disturbing pace [13–15]. Enhancement in glycemic man-
agement diminishes the possibility of diabetes mellitus [16].
The antidiabetic drugs, being utilized at present, are linked
with a few severe side effects, and henceforth it’s an urgent
requirement to search novel and effective potential agents of
elevated potency h aving fewer side effects (Fig. 1) [17].
2. DRUGGABILITY OF NATURAL PRODUCTS AND
HERBS
In developing countries, medicinal plants continue to be
the main source of medication. In China alone, 7,295 plant
species are utilized as medicinal agents. The World Health
Organization has estimated that foraround 3.4 billion people
in the developing world, plants represent the primary source
of medicine. This represents about 88% of the world's in-
habitants who rely mainly on traditional medicine for their
primary health care [18]. It is thus, a matter of utmost con-
cern to public health and indeed to human life that urgent
action is needed to be taken to prevent further diminution of
the actual and potential availability of medicinal and biologi-
cal agents. Natural remedies that, although undocumented,
may have been used for many thousands of years by the hu-
man race must be appropriately cataloged to ensure that vital
ethnomedical information is not lost forever. Farnsworth et
al. reported that at least 119 compounds derived from 90
plant species can be considered as important drugs currently
in use in one or more countries, with 77% of these being
derived from plants used in traditional medicine. The impor-
tance of natural products is also evidenced by the fact that in
the year 1991, nearly half of the best selling drugs were ei-
ther natural products or their derivatives [19].
Difficulties in the development of novel drugs are the
most part, experienced issues [20]. Following are the ideal
features for naturally obtaining compounds:
• Increased stereocomplexity.
• The lesser ratio of aromatic ring atoms.
• A number of oxygen atoms.
• The greater figure of a chiral center.
• Distribution of molecular properties like the diversity of
ring systems, mass number, and partition coefficient.
These special highlights represent a series of difficulties
for a medicinal scientist to work in the enlargement of me-
dicinal compounds, enhancement of absorption, and mini-
Fig. (1). Current treatment options for type 2 Diabetes.
188 Current Diabetes Reviews, 2021, Vol. 17, No. 2 Patle et al.
mizing toxicity can improve effectiveness [21].
3. NATURAL PRODUCTS AND HERBS AS ANTIDIA-
BETICS
3.1. Antidiabetic Properties of Pure Natural Products
Different medications have been utilized to treat Type 2
diabetes mellitus and a number of compounds are obtained
from plants and micro-organisms, such as phenols, galegine,
flavonoids, and anthocyanins, that show optimistic antidia-
betic action (Table 1) [20].
Flavonoids are derivatives of benzo-γ-pyrone. These are
groups of hydroxylated phenolic substances known to be
potent free radical scavengers, have attracted tremendous
interest for the treatment of diabetes mellitus these deriva-
tives are synthesized by plants in response to microbial in-
fection. Their classification is based on their side group posi-
tions and substitutions. The chemical properties of these
polyphenolic compounds depend upon their structure, substi-
tutions and conjugations, and degree of polymerization [22].
Flavonoids have attracted enormous attention among
therapeutics for the treatment of diabetes mellitus [22], and
their structure-activity relationship has been well studied
(Fig. 2). A pair of the hydroxyl group at position C-3' and C-
4'and C-5' are important for antioxidant and antidiabetic ac-
tivities, similarly C-2, C-3 double bond and keto group at C-
4 are also equally important whereas, methylation or acetyla-
tion of hydroxyl lead to decreased antidiabetic effects of
flavonoids. Flavonoids are also called as benzo-γ-pyrones
and obtained via plant sources. Their protective effects in
biological systems are attributed to their ability to exchange
hydrogen or electrons free radical [23], activation of inhibi-
tory enzymes of oxidation [24], metal catalysts [25], reduc-
tion of α-tocopherols [26] and inhibition of oxidase enzyme
[27] (Fig. 3).
Table 1. Some potential antidiabetic active compounds from natural products.
Active
Compounds Structures Sources Efficacy [References]
Procyanidin
B2
O
OH
OH
O
OH
OH
HO
OH
HO
OH
Grape (Vitisvi-
nifera)
Grape seed procyanidin B2 (GSPB2), a natural
polyphenol product, exhibited protective effects
on diabetic vasculopathy [20,34].
Gallic acid
OOH
HO OH
OH
Gallnut of Oak apple GA presents as the active compound in T. bel-
lerica, responsible for the regeneration of β-cells
and normalizing all the biochemical parameters
(decreased serum total cholesterol, triglyceride,
LDL-cholesterol, urea, uric acid, and creatinine
and show increased plasma insulin, C-peptide
and glucose tolerance level) [35].
Rutin
O
O
O
O
OO
HO
OH
OH OH
OH
OH
HO
OH
OH
OH
Sweet granadilla
(Passifloraligularis)
Rutin decreases the absorption of carbohydrates
from the small intestine, stimulates the secretion
of insulin from beta cells, protects Langerhans
islet against degeneration, increases glucose
uptake by tissues, and inhibits gluconeogenesis in
the liver [36].
(Table 1) Contd….
A Review on Natural Products and Herbs Current Diabetes Reviews, 2021, Vol. 17, No. 2 189
Active
Compounds Structures Sources Efficacy [References]
Delphinidin -
3-O-glucoside
O
OH
OH
O
OH
HO OH
OH
OH
OH
HO
HO
Maqui Berry (Aristo-
teliachilensis)
Hypoglycemic effect of delphinidin-3-glucoside
(Dp 3-glc), malvidin-3-glucoside (Mv-3-glc)
relative to blueberry anthocyanin-enriched ex-
tracts and metformin in insulin-resistant C57bl/6J
mice [37].
Mycaminose
O
H
OH OH
NH2
OH
Java Plum
(Syzygiumcumini)
The isolated compound, mycaminose at a dose
level of 50 mg/kg, also shows a significant de-
crease (p<0.05) in blood sugar level [38].
Ellagic acid
O
O
O
O
HO
HO OH
OH
Brazil plum (Spondi-
astuberosa); Cagaita
(Eugeniadysenterica
DC.); Acaçá Cam-
buci (Campomane-
siaphaea Berg.)
Ellagic acid in Emblica officinalis exerts anti-
diabetic activity through the action on β-cells of
the pancreas that stimulates insulin secretion and
decreases glucose intolerance [39].
Cyanidin
O
OH
OH
OH
OH
HO
Camu camu
Cyanidin 3-glucoside, a natural antioxidant may
prevent cardiovascular complications by amelio-
rating oxidative damage, inflammation, meta-
bolic dysfunctions and apoptosis pathways in
type 2 diabetes [40].
Catechin
O
OH
OH
HO
OH
OH
Star fruits (Aver-
rhoacarambola);
Graviola (Annona-
muricataL.)
The inhibitory effect of catechin against α-
glucosidase enzyme was evaluated and initially
demonstrated that catechin preferentially inhib-
ited maltase rather than sucrase in an immobi-
lized α-glucosidase inhibitory assay system [41].
Quercetin
O
OH
OH
OH
HO
OH O
Cambuci (Campo-
manesiaphaeaBerg.);
Araza Camucamu
Acaçá (Psidium-
guineensis Sw.);
Tucumã (Astro-
caryumaculea- tum)
Quercetin is reported to interact with many mo-
lecular targets in the small intestine, pancreas,
skeletal muscle, adipose tissue and liver to con-
trol whole-body glucose homeostasis. Mecha-
nisms of action of quercetin are pleiotropic and
involve the inhibition of intestinal glucose ab-
sorption, insulin secretory activities [42].
Kaempferol
O
OH
OH
HO
OH O
Cambuci
(Campomane-
siaphaea Berg.);
Acaçá (Psidium-
guineensis Sw.);
Panã(Annonacrassifo
lia Mart.); Cagaita
(Eugeniady senterica
DC.)
Among flavonoids, only kaempferol and quer-
cetin showed a high 50% inhibition concentration
(IC50) of xanthine oxidase at 8.07 μg/mL and
16.36 μg/mL, respectively [43].
(Table 1) Contd….
190 Current Diabetes Reviews, 2021, Vol. 17, No. 2 Patle et al.
Active
Compounds Structures Sources Efficacy [References]
Phlorizin
O
O
O
HO
OH
OH
OH
OH
HO
HO
Unripe Malus Phlorizin, a naturally occurring product found in
the bark of pear (Pyrus communis), apple,
cherry, and other fruit trees, is a competitive
inhibitor of sodium-glucose co-transporters
SGLT1 and SGLT2; it reduces renal glucose
transport and lowers blood glucose [44].
Phloretin
OH
HO
OH
OH
O
Apple tree leaves Daily oral treatment with Phloretin for 4 weeks
significantly (P<0.05) reduces postprandial blood
glucose and improves islet injury and lipid me-
tabolism. Glucose consumption and glucose
tolerance further improved by Phloretin via the
GOD-POD method [45].
Isorhamnetin
OOCH
3
OH
OH
OH
HO
O
Red turnip, golden-
rod, mustard leaf,
Isorhamnetin glycosides possess the antidiabetic
effect and their influence on lipid content, endo-
plasmic reticulum stress markers and the expres-
sion of enzymes regulating lipid metabolism
[46].
Chlorogenic
acid
O
OH
OH
OH
HO
HO COOH
O
Sour tea (Hibiscus
sabdariffa)
Chlorogenic acid (CGA) at a dose of 5 mg/kg
body weight exerts antidiabetic potential in
streptozotocin (STZ) (45 mg/kg b.w.) [47].
Curcumin
OCH3
HO
OOH
OHH3CO
Turmeric (Curcuma
longa)
Anti-diabetic activity of curcumin may be due to
its potent ability to suppress oxidative stress and
inflammation. Curcumin also reduces blood
glucose and the levels of glycosylated hemoglo-
bin in diabetic rats through the regulation of
polyol pathway [48].
Bisdemethoxy
curcumin
O O
HO OH
Turmeric (Curcuma
longa)
Bisdemethoxycurcumin is an active constituent
of Curcuma longa and shows antidiabetic as well
as antioxidant effects [49].
ar-turmerone
O
Turmeric (Curcuma
longa)
Proposed to inhibit microglia activation and
useful in treating neurodegenerative disease
[50].
Caffeine
N
NN
N
O
O
H
3
C
CH
3
CH
3
Green tea (Camellia
Sinensis)
Coffee and caffeine exerted an ameliorative
effect on high-fat-diet-induced impaired glucose
tolerance by improving insulin sensitivity [51].
Charantin
CH(CH
3
)
2
O
Glucose
Bitter melon Bitter melon is traditionally known for its me-
dicinal properties, such as antidiabetic, antican-
cer, anti-inflammation and cholesterol-lowering
effects. It contains many phenolic compounds
[52].
A Review on Natural Products and Herbs Current Diabetes Reviews, 2021, Vol. 17, No. 2 191
OOH
OH
O
OH
OH
H
3
C
O
O
OCH
3
bulky substituents led to decreased
antidiabetic properties
Hydroxyl involved in
increased antidiabetic
properties
Presence of double bond alongwith
keto group is important for
antidiabetic properties
Fig. (2). Key feature of flavonoid as an antidiabetic scaffold.
O
O
OH
OH
HO
Apigenin
OHO
OH
OH
OH
O
Luteolin
Fig. (3). Flavonoid derivatives i.e. Apigenin, Luteolin.
To oxidize cell proteins, nucleic acids, and lipids, reac-
tive oxygen species (ROS) are suitable. Clinical evidence
has demonstrated that the age of ROS increments in diabetes
is closely linked by means of oxidation and oxidative degra-
dation of glycine protein [28, 29]. Rise in reactive oxygen
species like superoxide of mitochondria into endothelium
cell [30], in addition to endoplasmic reticulum stress, follow
decline defense mechanism of antioxidant, which provokes
breakdown on the cellular and enzymatic level [31]. While
the mid-1980s, the possible effect of flavonoids for the
treatment of Type 2 diabetes has been intended mainly com-
pared with type-1 [32, 33].
3.2. Antidiabetic Properties of Extracts and Herbal For-
mulations
Drug designing is a move towards the discovery of drugs
on the basis of their target. A drug target is a molecule con-
cerned with pharmacokinetic and pharmacodynamic parame-
ters that are specific to an illness condition [53]. The devel-
opment of new medication is a tedious and expensive proc-
ess. The discovery of a new molecule in order to achieve its
potency roughly takes around 15 years, which involves more
than 1 billion $ of funds, according to the present scenario.
Fundamentally, the discovery of a novel molecule involves
the detection of new chemical entities (NCEs). An investiga-
tion among new medications as of the year 1981 to 2007
reveals that partially the drugs accepted ever since 1994,
which are natural products dependent. Through the year
2005 to 2007, approximately 13 compounds have been af-
firmed by natural products and herbs. There are different
studies available on the advancement of novel medications
from the plant source. Morphine was segregated through
opium (seeds of opium), around 200 years ago. Clinical trials
are continuous, in excess of 100 compounds derived from
natural sources. At least 100 molecules are beneath the pre-
clinical developmental level [54].
Hays et al. studied the importance of naturally obtained
compounds and one of the discoveries for the treatment of
type 2 diabetes. They looked into major pertinent therapeutic
plants and their effectiveness against diabetes [55]. Rios et
al. suggested that natural products widely show effect
against type 2 diabetes mellitus and further elaborated that
the number of screening of medicinal plants and preclinical
studies in animals are found to be useful for the treatment of
diabetes in several part of the world. Though, most curiosity
could be in the development of orderly research in clinical
trials [56]. An elaborated historical perspective of conven-
tional native medical practices done by Pan et al. stated the
use of Indian, Arabic and Chinese herbal compounds, which
relates to their important input towards the wellbeing of so-
cieties [57].
Said et al. combined four antidiabetic herbs used for the
conventional herbal medicine by Arabs, which was found to
maintain ‘Glucolevel’. Clinically satisfactory glucose level
was achieved throughout 2 to 3 weeks of treatment [58].
Likewise, a huge decrease in hemoglobin A1C amount was
found in patients treated with glucose levels. Sushama et al.
evaluated the antidiabetic, antihyperlipidemic, and antioxi-
dant actions of Buchanania lanzan on streptozotocin
prompted type 1 and 2 diabetic rats [59]. Streptozotocin ad-
ministered into the rats for about 21 days brought about a
considerable decrease in the level of blood glucose, com-
pared to control rats who had diabetes. It was concluded that
flavonoids' presence is the prime factor meant for its actions.
Bharti et al. suggested the antidiabetic activity on an extract
of tocopherol obtained through the seed of C. pepo and per-
formed validation of in-vivo and studied computational
docking. The in-vivo study was conducted against PX-407
induced diabetic rats, which was completely upheld through
molecular docking, further demonstrated that the extract of
C. pepo was found to be antioxidant and antidiabetic. Subse-
quently, the examination presents that C. pepo seed extract
192 Current Diabetes Reviews, 2021, Vol. 17, No. 2 Patle et al.
can be an addition in the current antidiabetic medications and
it limits changes of pre-diabetics into diabetics [60].
Chikhi et al. observed antidiabetic action into the leaf ex-
tract of A. halimus L., in the rats (induced by streptozotocin)
and results found a beneficial effect in lowering the raised
level of glucose present in the blood [61]. Chowdhury et al.
studied Buchanania lanza commonly known as char, achar,
and chironji as species of enormous potentials. The bulb of
B. lanza was found to be an important component as expec-
torant, carminative and diuretics. In addition, it shows anti-
hypertensive, antidiabetic ,and anticancer actions [62].
Leaf latex extract doses of A. megalacantha were ex-
plored for antidiabebetic efficacy in STZ-induced diabetic
mice which showed significant lowering of plasma glucose
after 14 days treatment with 100, 200, and 400 mg/kg daily
dose. It has been used as an Ethiopian folk medicine. A sig-
nificant reduction in total cholesterol, triglycerides, low den -
sity lipoprotein was also reported, which can be useful in
hyperlipidemic conditions [63].
Sekhon-Loodu et al., have reported the antidiabetic po-
tential of various plant extracts including sweet gale (Myrica
gale L.), roseroot (Rhodiola rosea L.), sheep sorrel (Rumex
acetosa L.), stinging nettles (Utrica dioica L.) and dandelion
(Taraxacum officinale L.) for their antioxidant, α-
glucosidase, α- amylase inhibitory activities. Among these,
ethanolic extract of Myrica gale were found to have high
phenolic content showing antioxidant activity with IC50 =
3.28 mg/L, inhibition of α-amylase with IC50 = 62.65 mg/L
and α-glucosidase with IC50 = 27.20 mg/L comparable to
acarbose drug, thus it suggested that the polyphenols present
could be useful in treatment of type 2 diabetes and
obesity[64].
In a recent study, an antidiabetic and antihyperlipidemic
potential of aqueous extract of Sigesbeckia orientalis L. (St.
Paul’s Wort) was reported in an alloxan-induced diabetic rat
model. An HPLC analysis used to find out phytoconstituents,
which showed that quercetin, gallic acid, vanillic acid, p-
coumaric acid, m-coumaric acid, and cinnamic acid were
present. A blood glucose and lipids level reduction showed
its antidiabetic and antiobesity activities. Histopathological
evaluations were also done to prove its efficacy as improve-
ment in hepatocyte and pancreatic β-cells islets architecture
were observed. Its safety was established up to the dose of
2000 mg/kg [65].
There are several herbal drug formulations that are cur-
rently available in the market for the treatment of diabetes,
like Epinsulin, which is marketed by the Swastik formula-
tions, having epicatechin, a benzopyran as main phyto-
chemical, which is associated with increased insulin release
and increase in the metabolism of glucose and lipids. Pan-
creatic Tonic is an Ayurvedic herbal mixture of traditional
Indian Ayurvedic herbs, for the treatment of diabetes as well
as a dietary supplement [66].
Khan et al. stated antidiabetic potential of aqueous leaf
extract of Moringa oleifera and estimated whole flavonoid
and phenolic content from the plant and concluded that as
antidiabetics, the plant portion such as leaves, seeds, and
pods have been methodically proved in the present study.
The learning also suggested that a small amount of extract
significantly shows higher anti-diabetic potential than previ-
ously reported in Ayurved Pharmacopoeia [67]. Liang et al.
estimated antihyperglycemic and antihyperlipidemic actions
in aqueous extract of Hericium erinacues in diabetes-induced
rats along with the considerable decline of serum glucose
level [68]. Maiti et al. stated anti-diabetic impact on aqueous
seed extract of T. indica into diabetes-induced mice, in a
period reliant manner. Injections of streptozotocin resulted in
diabetes, following seven and fourteen days supplementation
of aqueous seed extract of T. Indica, about to be huge lessen-
ing in the level of blood glucose [69].
Other herbal formulations, such as Diasulin, Diamed,
Coagent db, etc., are the polyherbal formulation of Annona
squamosa and Nigella sativa having an effect on plasma
insulin, blood glucose, and tissue lipid profile. Glycosmis
pentaphylla, Tridax procumbens, and Mangifera indica are
evaluated as polyherbal formulation in the ratio of 2:2:1 and
evaluated against streptozotocin + nicotinamide induced dia-
betes mellitus in rats found to have significant antidiabetic
activity [70]. Kathakakhadiradi kashyam (KKS) is an in-
digenous polyherbal Ayurvedic formulation for diabetes
treatment along with dryness of mouth, polyuria, fatigue,
polydipsia, and constipation. The mechanism proposed for
the same is inhibition of starch to glucose conversion, inhibi-
tion in renal glucose reabsorption, stimulation of insulin se-
cretion etc.[71].
3.3. Antidiabetic Properties of Semi-synthetics Inspired
from Natural Products
Wang et al. synthesized and assessed a set of novel thia-
zolidinedione derivatives potential anti-diabetic agents.
Imidazolidinedione was synthesized and validated on an
alloxan model, indicating good antidiabetic activities [72].
Moravej et al. isolated chemical compounds and evaluated
for effectiveness in walnut hydrosol (WH) for type 1 diabetic
patient. Flavonoids and phenolic acids were found to be two
key categories of phenols which exist in walnut leaves and
concluded that WH might be effective for the treatment of
diabetes, however, it might be associated with side effects
[73].
Leila M. et al. reviewed anti-diabetic chemical sub-
stances isolated from conventional medicinal plants and de-
scribed natural bioactive substance from plants with anti-
diabetic potentials and their pharmacological properties, such
as oleanolic acid and ursolic acid, tormentic acid, gymnemic
acid in terpenoids, swerchirin, kola flavanone, quercetin leu-
cocyanidin, (-)-epicatechin, bellidifolin in flavonoids [74].
Grover et al. studied the potency of forty-five plants, which
are further mentioned in the Indian conventional system of
medicine and have shown clinical anti-diabetic action [75].
Pamunuwa et al. identified the antidiabetic properties of
Scoparia dulcis, also its anti-inflammatory and antioxidant
activities in relation to diabetes and its entanglements. They
have been shown through logical investigations with regard
to their antidiabetic impact and bioactive constituents. The
essential component activities of antidiabetic action of the
herbs are through α glucoside interruption. Scoparic acid A,
Scoparic acid D, Apigenin, Luteolin, Coixol, and Glutinol,
these compounds were found responsible antidiabetic for
action via α glucoside interruption (Fig. 4) [76].
A Review on Natural Products and Herbs Current Diabetes Reviews, 2021, Vol. 17, No. 2 193
On the other hand, metformin-3-hydroxy flavone, charac-
terized through different spectroscopic techniques and its
properties against diabetes, was assessed in a high-fat diet
(HFD) for type 2 diabetes. The molecule was assessed by
glucose tolerance test, QUICK I, and was found effectively
comparable to metformin, a standard medication [77].
Brahmachari et al. stated andrographolide, a molecule of
antidiabetic promise in Fig. (5A); it is di-terpenoid lactone
and a significant central compound of Andrographis panicu-
late. It was further observed to be a key therapeutic com-
pound. Furthermore, its semi-synthetic derivatives in con-
trolling diabetic complications were found to give a contri-
bution to the antidiabetic drug discovery process [78].
Hayes et al. have proposed CADD (Computer-aided drug
discovery) on inhibitors of glycogen phosphorylase, and also
explored all seven dissimilar binding sites that have been
discovered till date and found the most potent and promising
compounds effective against diabetes to be imino sugars,
analogs of glucose, flavonoids, PT, and indirubins [79]. Lu-
thra et al. reported another class of oxindoles like a potent α
glucosidase antagonists [80]. Dev et al. worked on glucose
4-transporter obtained from nature. Inside the perspective,
they analyzed that aqueous extract of Cynodon dactylon
shows the presence of luteolin, and apigenin (Fig. 3) by us-
ing MS, HPLC. These compounds were further docked with
GLU-270 of the GLUT-4 receptor in-silico. An interaction of
luteolin and apigenin to Glu 270 of GLUT4 receptor showed
docking score −4.23 kcal/mol, -6 kcal/mol respectively,
which was further found to be more analogous with mole-
cules of genistein with the score -5.19 kcal/mol [81]. Sharma
et al. isolated six compounds from the Sweet Broom weed of
S. dulcis and identified potent insulin secretagogue activity
from the Nepalese region, the compounds I to VI were found
active for insulin secretagogue action on islets of mice and β-
cell line of MIN 6 pancreas. Also, compounds I and II were
established as potent and mild active, correspondingly.
Compound I (Coxicol), shown in Fig. (4), further evaluated
the secretory activity of insulin on MIN-6 cells. The elabo-
rated study further supported the use of S.dulcis as a power-
ful agent for diabetes [82]. Colín-Lozano et al. synthesized
five 3-4-(aryl methoxy) phenylpropanoic acids, shown in
Fig. (5B), these compounds were further checked for their
in-vitro action against a series of targets of protein, which
were further identified as prime basics for diabetes. Docking
studies were further performed to elucidate the pharmacol-
ogical mechanism of action and to check the binding effect
of most active compounds on the targets [83].
Prabha et al. isolated phytochemical investigation of the
stem bark of Myristica fatua and the identification of a novel
compound 1,3-tridecanoylbenzoic acid. The compound
showed modest antagonistic action of α-amylase and signifi-
cant action on α glucosidase. The molecular docking studies
confirmed the efficient binding of the novel compound, as
shown in Fig. (5C) [84].
Li et al. suggested that natural products are an important
source for drug discovery based on multiple- targets. This
showed the advantage and viability of searching multi-
compound–multi-target drugs (MTs) via natural products
and provides a novel viewpoint about functional group en-
largemen t of MTs [85]. Wu et al. linked pathological condi-
tions of type 2 diabetes and Alzheimer's through designing,
synthesizing, and biological evaluation of novel pyrimidi-
nones as potential PDE9 inhibitors. Rosiglitazone was found
to be PPARγ agonists and PDE9 inhibitors [86]. Pàmies
have identified natural compounds as antidiabetic agents
using CADD methods with the following studies [87].
1) The expansion of docking-based QSAR(3D) models for
PPARγ for its agonistic action.
2) The knowledge of structure and design of novel PPARγ
agonists with an elevated affinity of binding and less
transactivation action.
3) Estimation of agonistic action of PPARγ by an effective
broadcast of natural products.
4) Estimation of several extracts with the antid iabetic ef-
fect.
5) Estimation of new dipeptidyl peptidase IV inhibitors ob-
tained from natural origin: virtual screen ing and activity
assays.
6) Natural extracts have been estimated as potential anti-
diabetic agents w ith DPP-IV inhibitory effect.
Yasmin et al. have outlined the adjustments of chemicals
around TZDs, in recent years, to get potent antidiabetic com-
pounds, they also summarized the following points within a
framework [88]. The replacement of a benzyl ring from
naphthalene, benzothiophene, and quinoline was not
observed as effective as its prototype. Most of the molecules
were believed as less linker based. They were further found
to be less effective than the TZDs.
Abbas et al. reviewed α glucosidase enzyme inhibitory
action of natural products and examined new encouraging
antagonists of α glucosidase, which was further identified in
in-vitro and in-vivo. They also performed an exhaustive
OH
OCOOH
H
Scoparic acid A
OH
HO
HOOC
Scoparic acid D
O
N
H
O
O
O
Coixol
H3C
OH
H
H
H
Glutinol
Fig. (4). Different natural products i.e. Scoparic acid, Scoparic acid D, Coixol, and Gluten.
194 Current Diabetes Reviews, 2021, Vol. 17, No. 2 Patle et al.
study on these enzyme inhibitors [89]. Jain et al. synthesized
structurally modified novel glycogen synthase kinase-3β
inhibitors to overcome insulin resistance in type 2 diabetes
mellitus and to overcome associated health problems with
reducing morbidity, mortality and economic costs of diabetes
[90]. The syntheses of proposed six hydantoin analogs were
performed based on docking results by two approaches,
Knoevenagel condensation, and Steglich Esterification reac-
tion. Mishra et al. performed an in vitro study on amylase
and glycosidase enzyme (located in the intestine) and identi-
fied them as mostly responsible for the rising postprandial
level of glucose in the body. Furthermore, they demonstrated
the effectiveness of the methanolic extract of S. dulcis to
check the level of glucose. The hypoglycemic activity ob-
tained in-vivo for a methanolic extract of S. dulcis, per-
formed on streptozotocin-induced diabetes, showed a huge
decreased level of blood glucose [91].
3.4. Antidiabetic Properties of Vegetables, Fruit and
Spices
Different plants, as a whole, have also been used as an-
tidiabetic drug-like Wattakaka volubilis (L.f.) Stapf belongs
to Asclepiadaceae. This plant is locally known as Perun-
kurinjan having a fleshy and very large climber and its leaf
powder is orally used as antidiabetic with cow’s milk.
Whereas its root extract has been reported for antihypergly-
cemic and neuroprotective effects [92].
Another plant, Abrus precatorius L., belongs to Fabaceae
is a climber and known as Wild Liquorice. Its local name is
Kundumani and in India, its leaves are used for polyherbal
formulations along with Gymnema sylvestre, Andrographis
paniculata, and Syzygium cumini. This polyherbal mixture is
used as powder and taken orally with cow’s milk [93].
Fenugreek is another common antidiabetic and antioxi-
dant herbal drug. Its’ biological name is Trigonella foenum
graecum and is commonly found in India where it used as
spices. Its seeds have 4-hydroxyleucine, which is proposed
to increase insulin release in the response of glucose. It also
improves glucose metabolism and decreases hepatic and
renal glucose-6-phosphatase and fructose –1, 6-
biphosphatase activity. This plant also shows antioxidant
activity [94].
Tinospora cordifolia is known as Guduchi which belongs
to Menispermaceae. Its root extracts are orally used in the
reduction of blood and urine glucose as well as lipids thus,
can be used as an Ayurvedic medicine for treating diabetes
mellitus [95].
Allium cepa, which is onion, is used as a common ingre-
dient of vegetable preparation and is found to have anti-
hyperglycemic activity in diabetic rabbits. It also has anti-
oxidant and hypolipidaemic activity. Its sulfur ingredient S-
methyl cysteine sulphoxide has been proposed to be the key
for controlling the blood glucose level as well as lipids.
Other common Indian spices, like Allium sativum which is
known as garlic is also reported for antidiabetic effect via its
main phytoconstituents allicin [96].
Bitter gourd locally known as Kaattu pagar-kai (Momor-
dica charantia) is well known for its’ antidiabetic and anti-
hyperglycemic action. It’s used as a vegetable in India while
its fruit extracts, as well as a whole plant, showed a hypogly-
cemic effect. It is proposed to have polypeptide p, and
charantin is known for its hypoglycemic effect. Its powder is
marketed by garry and sun for hypoglycemic activity along
with astringent, stomachic, anthelmintic antihaemorrhoidal,
emmenagogue, blood purifier, and hepatic stimulant proper-
ties [97].
Fig. (5). (A) Andrographolide, (B) 3-4-(aryl methoxy) phenyl propanoic acid derivatives, (C) 1,3-tridecanoylbenzoic acid.
OH
O
OAr
N
3
2
1
Ar=
O
HOOC
1,3-tridecanoylbenzoic acid
OH
O
O
OH
OH
Andrographolide
A)
B)
C)
A Review on Natural Products and Herbs Current Diabetes Reviews, 2021, Vol. 17, No. 2 195
CONCLUSION
As the learning of the heterogeneity of diabetes mellitus
increases, there is a necessity to search for more efficacious
agents along with fewer side effects. Difficulties are the real
reason for morbidity and mortality in diabetes mellitus. Tra-
ditional natural remedies and herbs, used at present, have not
undergone experienced cautions scientific appraisal and few
of them can possibly cause severe toxic actions and severe
drug to drug interaction. Subsequently, worldwidethere is a
high demand to develop novel antidiabetic agents from natu-
ral products and herbs for the treatment of diabetes and to
evade its’ serious complications. Orderly research and de-
velopment in the form of drug discovery systems are impor-
tant to elucidate the pharmacological activities of natural
products to treat diabetes mellitus.
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
None.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
Authors are gratefully acknowledging the contribution of
Dr. Vivek Gupta (Associate Professor) at LPU for editing the
manuscript.
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