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Antidiabetic Phytochemicals: A
comprehensive Review on
Opportunities and Challenges in
Targeted Therapy for Herbal Drug
Development
August 2020
DOI:10.31838/ijpr/2020.SP1.242
Authors:
Pawan Prabhakar
Indian Institute of Technology Kharagpur
Mamoni Banerjee
Citations (2) References (148) Figures (2)
Abstract and Figures
The traditional system of medicine has shown much better

improvement, less side effect, and less expensive as
compared to modern synthetic drugs in the treatment of
diabetes mellitus. Medicinal plants and phytochemicals
have much importance in the present scenario in
developing countries where resources are limited. The
effectiveness and activity of a phytochemical depend upon
its binding ability with the target molecules. Identification of
the target molecule, its mechanism, and interaction with
the specific phytochemical drug, can be proved to be an
efficient therapeutic against diabetes. This review
addressed different classes of molecules and enzymes
involved in the pathogenesis of diabetes mellitus,
antidiabetic activities of different classes of
phytochemicals, its activity on antidiabetic drug targets, as
well as possibilities of herbal drug development for
diabetes in context with targeted therapy.
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ISSN 0975-2366
DOI: https://doi.org/10.31838/ijpr/2020.SP1.242
Review Article
Antidiabetic Phytochemicals: A comprehensive Review

on Opportunities and Challenges in Targeted
Therapy for Herbal Drug Development
P PRABHAKAR1*, MAMONI BANERJEE2
1,2
Bio-Research Laboratory, Rajendra Mishra School of Engineering Entrepreneurship, Indian Institute of
Technology Kharagpur, Kharagpur, India
*Corressponding Author
Email ID: pawanprabhakar1@gmail.com
Received: 16.04.20, Revised: 16.05.20, Accepted: 16.06.20
ABSTRACT
The traditional system of medicine has shown much better improvement, less side effect, and less expensive as
compared to modern synthetic drugs in the treatment of diabetes mellitus. Medicinal plants and
phytochemicals have much importance in the present scenario in developing countries where resources are
limited. The effectiveness and activity of a phytochemical depend upon its binding ability with the target
molecules. Identification of the target molecule, its mechanism, and interaction with the specific phytochemical
drug, can be proved to be an efficient therapeutic against diabetes. This review addressed different classes of
molecules and enzymes involved in the pathogenesis of diabetes mellitus, antidiabetic activities of different
classes of phytochemicals, its activity on antidiabetic drug targets, as well as possibilities of herbal drug
development for diabetes in context with targeted therapy.
Keywords: Diabetes, synthetic drugs, side effects, herbal drugs, Phytochemicals, target molecules
INTRODUCTION insulin is responsible for controlling the blood

Diabetes is a chronic condition where the body glucose level. This endocrine hormone is
fails to maintain the blood glucose level or blood produced by beta-cells of the pancreas. In
sugar due to lack in production of sufficient diabetic conditions, blood glucose level remains
insulin by the pancreas or the body is unable to high leads to a harmful effect on organs and
use the produced insulin effectively (Canivell & systems in the body. Diabetes is divided into two
Gomis, 2014). Diabetes is one of the major lethal categories- Type 1 Diabetes (T1DM) and Type 2
epidemics in India as well as in the world. Diabetes (T2DM). Type 1 diabetes is characterized
According to the International Diabetic Federation by the deficiency in the production of insulin
(South-East Asia) out of 425 million people hormone due to damage in the β-cell of the
suffering from diabetes in the world in which 82 pancreas and such condition needs daily uptake
million people are living in South East Asia and of insulin. The tissues have a deficiency of glucose
there were 72,946,400 cases of diabetes and there is an excess of glucose in the blood. In
reported in India in the year 2017 (IDF, 2019). It high blood sugar conditions, the lack of insulin
has been estimated that the worldwide diabetic leads to an accumulation of ketone bodies as the
population will increase from 425 million people body is unable to metabolize the glucose. As a
in 2017 to 629 million by 2045, while India consequence, several abnormalities and other
alone will have 98 million diabetic patients by the disorders occur like liver damage, hypertension,
end of 2030 (Cho et al., 2018; Forouhi & renal failure, coma, and in some cases death
Wareham, 2019). Thus, diabetes becomes a may occur eventually. In the low blood sugar
serious health concern after cancer and AIDS condition, the cell is unable to get glucose
worldwide (Giovannucci et al., 2010). Diabetes resulting in unconsciousness, feeling of hunger,
causes a series of metabolic disorders due to weakness, sweating, and coma. Death may occur
abnormality or defects in the secretion of insulin if the brain does not get enough glucose(Canivell
hormone. A prolonged or untreated diabetic & Gomis, 2014; IDF, 2019). Type 2 diabetes is
condition may result in severe complications of one of the major complex disorders that arise due
liver and kidney. The glucose is delivered by the to several lifestyle factors and genetics. Sedentary
blood to all the parts of the body to perform lifestyle, alcohol consumption, cigarette smoking,
necessary functions and all other physiological physical inactivity are the major lifestyle factors
activities. The food is converted into glucose by responsible for it. Such a lifestyle causes
the liver and goes into the bloodstream and overweight and obesity leads to a reduction in
1673| International Journal of Pharmaceutical Research | Jan - Jun 2020 | Supplementary Issue 1
P Prabhakar et al / Antidiabetic Phytochemicals: A comprehensive Review on Opportunities and

Challenges in Targeted Therapy for Herbal Drug Development
insulin sensitization and glucose tolerance. When Cardiovascular disease (Diabetic

beta-cells are remaining no longer to produce a Cardiomyopathy)
sufficient amount of insulin then this would cause In diabetic conditions, the heart is no more able
type 2 diabetes. Obesity and overweight also to circulate the blood throughout the body that
contribute to diabetes via many pathways such as leads to heart attack, stroke, heart failure together
increased in glucagon level, reduced adiponectin, with the accumulation of fluid in the lungs
increased leptin, increased concentration of (pulmonary edema) and legs (peripheral edema).
interleukin 6, tumor necrosis factor-alpha, Heart failure is one of the high risks of
suppresser of cytokine signaling, suppressor of a complications in diabetes due to coronary artery
retinal binding protein (Wellen & Hotamisligil, diseases. It may be due to chronic hyperglycemia
2005; Yang et al., 2005). It has been reported responsible for cardiomyopathy in patients (Miki
that among all types of diabetes, 90%-95% of et al., 2013). Disturbed or altered metabolic
patients suffer from type 2 diabetes (Randle et al., pathways result in the generation of reactive
1963). Reports also state that a large number of oxygen species (ROS) due to hyperlipidemia,
patients suffering from type 2 diabetes are hyperglycemia which results in creating oxidative
Africans, Indians, Americans, a native of stress causes contraction of the myocardial
Hawaiians, Latinos/Hispanics, which is a huge muscle and myocardiocyte fibrosis. Cellular DNA
population comprises of 300 million people damage caused by oxidative stress leads to cell
across the globe(Johnson & Olefsky, 2013). apoptosis (Fiorentino et al., 2013). Abnormalities
Diabetes mellitus causes long term complications in cellular Na+-Ca2+ ion channel, causes
that severely affect many organs in the body. decreased extrapolation and an increase in Ca2+
Such complications results into blindness, ions lead to an increase in intracellular
cardiovascular diseases, stroke, reanal failure concentration of Na+ ions which further increase
and even nerve damage (Ahmed et al., 1998). in intracellular Ca2+ concentration in cardiac cells
Thus, diabetes is really an epidemic to the world caused by diabetic hyperglycemia and it results
and considering the molecular mechanism, into abnormalities of the cardiovascular system
responsible factors, epidemiology, and available and heart failure (Liamis, 2014).
treatment in this review, we have focused on 3.2 Renal Damage (Diabetic Nephropathy)
promising area of effective therapeutics that have Adult renal failure is one of the diseases caused
already demonstrated their usefulness and their by diabetes mellitus. Abnormal physical status of
applicability for multiple target approach which the kidney such as tubular atrophy, interstitial
seems promising for novel drug development. fibrosis, increase in the glomerular basement
membrane, hypertrophy of the kidney, nodular
MATERIALS AND METHOD and diffused glomerulosclerosis cause
A progressive literature study was done using the abnormalities like systemic hypertension,
database of several reputed publishing houses, subsequent proteinuria, increase in glomeration
databases, and platforms like Scopus, NIH, rate with intraglomerular hypertension and
PubMed, Springer link, Mendeley, Google, sometimes renal function loss (Ayodele &
Google Scholar, Researchgate, and Nature Alebiosu, 2004). Hyperglycemia induced
publications. The keywords involved in the hemodynamic change that causes renal damage
research work were diabetes mellitus, synthetic and such change activates renin-angiotensin-
drugs, side-effects, antidiabetic, herbal drugs, aldosterone and endothelin system which
phytochemicals, toxicology, etc. Article published enhances the secretion of profibrotic cytokines,
in the non-English language (German, French, responsible for an increase in interglomerular
Chinese, Portuguese) were excluded as no subject and systemic pressure. Due to increased blood
matter experts were available. Proper reprint glucose, it remains diluted in fluid, exceeds its
permission was taken from the American osmotic pressure and more and more water is
Chemical Society to reproduce the figure. The filtered out results in high volume in the urine.
review consists of three research work reported, High dilution of NaCl in the urine suppresses
diabetes mellitus, antidiabetic phytochemicals, macula densa to secrete high renin leads to
and target molecule involved in the epidemiology vasoconstriction and inhibits renal functions
of diabetes. Only evidence-based research and (Tsavdaridis & Mironidou-Tzouveleki, 2011).
reviews were considered while unexplained views,
Eye Damage (Diabetic Retinopathy)
ideas, beliefs of a community were not included
In diabetic retinopathy, retinal damage becomes
in this review work.
the common factor for blindness. The
Abnormalities and disorders associated with development of soft and coarse blood capillaries
diabetes in the retina is one of the major problems

associated with diabetic retinopathy. An increase have been identified involving autoimmunity,
in blood sugar level causes blood flow change, genetic susceptibility, and environmental factors.
thickening of the basement membrane, change in Type I diabetes is genetically associated with
blood flow to the retina, and retinal vascular some variations of HLA (Human Leukocyte
permeability due to activation of protein kinase C Antigen) class II alleles such as HLA-DQA1, HLA-
enzyme. Advanced glycation Ends (AGEs) DRB1and HLA-DQB1. Such genes are involved in
produced due to activation of glycation that from the translation of proteins that distinguishes and
pericyte loss and microaneurysm causes damage identifies the body’s protein from pathogen or
to the retina (Duh et al., 2017). invader’s protein (virus and bacteria). Type 1
3.3 Neural Disorder (Diabetes Neuropathy) diabetes is an autoimmune disorder in which the
In this state of neural disorder, the blood bodies sometimes attack their organ and tissues.
capillaries supply blood to the nerves that are Hence, the immune system damages pancreatic
damaged. Diabetic neuropathy leads to complex β-cells for unknown reasons and secretion of
abnormalities such as polyneuropathy, thoraco- insulin is inhibited and symptoms of Type I
abdominal neuropathy, third nerve palsy, diabetic diabetes appears (Redondo et al., 2018).
amyotrophy, etc. Accumulation of polyols also
damages nerve fibers. In the state of Glutamic Acid Decarboxylase (GAD)
hypoglycemia, neuron mitochondrion produces Glutamic Acid Decarboxylase (GAD) is an enzyme
free radical species that damage DNA and other with a molecular weight of 65-67 KDa that works
cell membranes, inhibits the normal activity of cell as a catalyst in the conversion of glutamate to
and degeneration of nerve cells (Rolim et al., Gamma-Immunobutyric Acid (GABA) and carbon
2017). dioxide. Two isoforms of GAD are GAD65 (MW
65 KDa) and GAD67 (MW 67 KDa). It is a
Molecular Biology of Diabetes and
neurotransmitter, expressed in the insulin-
identification of therapeutic target molecules:
producing β-cells in the pancreas. GAD is the
By definition, a molecular entity or
chief candidate in auto-antigen involved in the
macromolecule whose property and function is
auto-immunity of β-cells (Ludvigsson, 2009) .
modulated by a particular drug or chemical
Menard et al (1999 ) reported that when non-
compound is known as ‘drug target’. In a
diseased condition, a drug target is crucial for obese diabetic (NOD) mouse was administered
with GAD inhibition in disease growth was
proper diagnosis and treatment. Finding a drug
observed.
target is the most important step in drug design
and discovery. An ideal drug target must have a DiaPep277
valid role in the pathophysiology of the disease, Diapep277 is a new molecular drug target that
must not express its distribution throughout the belongs to the class of heat-shock proteins made
body and must be responsive towards drug up of 24 amino acid peptides having a molecular
interaction(Schenone et al., 2013). If the target is weight of 60kDa. Heat shock proteins are the
known and valid, the process of drug family of proteins, produced by the cells, releases
development is highly facilitated by the rational during stress conditions, and other external stimuli
design of a new drug molecule with high efficacy such as wound healing, cold, tissue-regeneration,
and no adverse effect. In the case of diabetes UV light, etc (Morimoto, 1993). The human
mellitus, many drug targets have been identified variant of pep277 was administered in diabetic
but it is still a big challenge to treat diabetes with female mice inoculated with T-cells. When T-cells
high efficacy (Huggins et al., 2012). Researchers were vaccinated specifically for p277 peptide; it
have done a lot of work to improve the work of prevented pancreatic β-cells from destruction in
insulin on targeted sites and also tried to identify NOD diabetic mice for 7 months; reduction in
the lead to successfully improve the secretion of both anti-human hsp65 and antibodies was
insulin by pancreatic islet cells. Hence, in the last reported. In another experiment, the
20 years, researchers have concluded the administration of pep277 also prevented one-
following target molecules that can be modified month-old mice from hyperglycemia(Dana Elias
by natural and synthetic drugs in diabetes et al., 1991). When pep277 was administered to
mellitus(Sperling et al., 2003). the 12, 15, and 17 weeks old mice at a dose of
Therapeutic Targets for Type 1 Diabetes 50µg and after 40 days, only one of the mice was
Type 1 diabetes accounts for 5%-10% of the total died due to hyperglycemia, it was concluded that
diabetic population and can be characterized by p277 can arrest the autoimmune response (Elias
the high blood sugar level and no insulin & Cohen, 1994). In the human trial, it was
production by pancreatic β-cells. The actual cause demonstrated that diapep277 is effective in the
maintenance of c-peptide production for a short
of type I diabetes is known but certain risk factors

duration and reduces the need for insulin but transduction and cellular responses. GPR120
there is a need for long term trial and follow-up belongs to rhodopsin G protein-coupled receptor
data. Daipep277 was also proved to be efficient groups that are preferably expressed in the
in curing patients with LADA as the destruction of intestinal epithelium and adipose
β-cells takes time as compared to type I diabetes. tissue(Trzaskowski et al., 201 2). Activation and
It can be highly susceptible to the intervention in secretion of glucagon are done by GPR120 which
the autoimmune process so, favors its efficacy in is responsible for the level of insulin secretion.
LADA patients(Raz et al., 2001). Hence, GPR120 is found to be a potential
The therapeutic target for Type 2 diabetes: therapeutic target for diabetes mellitus. Besides,
Type 2 diabetes is also referred to as Non-Insulin GPR120; GPR140, and GPR119 are also suitable
Dependent Diabetes Mellitus (NIDDM) because targets in developing drug molecules. GPR is
there is no need for insulin administration significant in stimulating insulin secretion together
externally as compared to Type 1 diabetes. As with suppressing the secretion of glucagon
reported earlier, 90%-95% of the patients are (Milligan et al., 2014; Fredriksson et al., 2003).
suffering from type 2 diabetes. Type 2 diabetes
Glucose Transporter Type 4 (GLUT 4)
can be treated by a change in diet, proper
Glucose Transporter 4 or GLUT 4 is a polypeptide
medication, and exercise (Li et al., 2010).
made up of 509 amino acids in the cell
However, despite high efficacy drugs diabetes is
membrane, has an efficient role in blood glucose
still a crucial challenge and researchers are
reduction. It has a crucial role in insulin resistivity
continuously working in search of a safer and
and regulates body glucose balance. It helps in
high potential natural and synthetic derivatives on
the movement of glucose into the cells with a
many target molecules with the strong evaluation
responding mechanism associated with insulin.
of the mechanism of drug action leads to
Gene alteration or mutation in this receptor
concrete validation of a target molecule
causes Type 2 diabetes. This can be a potential
(Prabhakar & Doble, 2008).
target for the development of antidiabetic
α-glucosidase Inhibitors drugs(Huang & Czech, 2007; Thunell et al.,
α-glucosidase is one of the main active enzymes 1988).
that have a vital role in carbohydrate absorption.
Nuclear Factor Kappa Light Chain Enhancer of
α-glucosidase inhibitors are the class of enzymes Activated B-cells (NFKB)
that slows or retard the rate of d-glucose as a Nuclear Factor Kappa Light Chain Enhancer of B
byproduct of the carbohydrates metabolism. This cells (NFKB) is a polypeptide complex that has a
inhibitory action results in a postprandial significant role in cytokine production, cell signal
reduction in blood glucose levels hence reduce as well as the transcription of DNA. It has been
the chances of hyperglycemia (Lebovitz, 1997; demonstrated that NKFB has a significant role in
Kumar et al., 2011). the conduction of immune response. When the
Peroxisome Proliferator-Activated Receptor- bovine cell line is studied, it was found that when
Gamma (PPARᵧ) the plasma glucose level is high, free radical
Peroxisome Proliferator-Activated Receptor- species activation is generated which activates
Gamma (PPARᵧ) is a nuclear receptor that is NFKB. Free Fatty Acid (FFA) and pro-
expressed in adipose and fat tissues. PPARᵧ is inflammatory cytokines are also responsible for
responsible for regulating glucose metabolism the activation of NFKB. Such pathways have an
and fatty acid storage. PPARᵧ activates the genes important role in oxidative stress (ROS) induced-
that are involved in adipogenesis and lipid insulin resistance. Such stress-induced pathways
metabolism by adipose tissues (Rieusset et al., are proved to be a potential molecular target for
1999). It has been reported that complex the researchers to develop drug molecules that
formation takes place when some ligand or can inhibit the function of NFKB pathways(Benzler
agonist are attached to PPAR ᵧ that activate it and et al., 2016; Oeckinghaus & Ghosh, 2009).
bind with another transcriptional factor. It again P38 Mitogen-Activated Protein Kinase
binds to DNA motif specifically in promotor part (P38MAPK)
of the targeted gene. A drug like glitazones P38 Mitogen-Activated Protein Kinase belongs to
activates PPARᵧ which in turn activates sensitivity Mitogen-Activated Protein Kinase enzyme families
of insulin (Balasubramanyam & Mohan, 2000). that are susceptible to adverse and stressful
G-Protein coupled Receptor (GPR) conditions such as UV-irradiation, heat shock,
G-Protein coupled receptor is transmembrane cytokines, and osmotic shock. They have a
receptors that identify or detect molecules at the significant role in programmed cell death and
surface of the cells. It helps in internal signal autophagy (Segalés et al., 2016). P38MAPK

genes are activated during hyperglycemic intestinal epithelium as well as proximal renal
conditions. P38MAPK pathway is also responsible tubule (Chao, 2014). SGLT2 is mainly involved in
for several cellular mechanisms viz. cell growths, transporting 90% of glucose reabsorbed by the
apoptosis, immunity and inflammation, and other kidneys. Inhibition of SGLT2 leads to stopping the
pathways. It has been reported that activation of reabsorption of filtered glucose and thus
P38MAPK is predominant while treating insulin hyperglycemia is controlled. Glycosuria formed in
and hyperglycemia (Igarashi et al., 1999). this process coupled with SLGT2 reduction calorie
and weight. Hence, SLGT2 inhibitors can be an
Sodium-Glucose Transporter 2 (SGLT 2)
efficient drug molecule in the drug development
Sodium-Glucose Transporter is the class of
process against diabetes mellitus(Gerich and
membrane proteins that are involved in the
Bastien, 2011).
transport of many macromolecules such as amino
acids, glucose, vitamins, ions in the membrane of
Fig.1: Pathways by which commonly prescribed oral hypoglycemic agents achieve glucose
homeostasis.
("Reprinted with permission from (G R Kokil et al, inhibition of phosphorylation leads to insulin
2015, Chem Rev, 10;115 (11):4719-43.doi: resistance (Hassanin et al., 2018).
10.1021/cr5002832. Copyright©2015.
Dipeptidyl Peptidase-4 (DPP4)
American Chemical Society”)
Dipeptidyl Peptidase-4 is a protein associated with
Stress Activated Protein Kinase/c-Jun NH (2) signal transduction, apoptosis, and immune
terminal Kinase (SAPK/JNK) regulation. It involves in glucose metabolism and
Stress Activated Protein Kinase/ c-Jun NH (2) degradation of GLP-1 like incretins. GLP-1 are
terminal Kinase (SAPK/JNK) plays an essential the peptide-1 glucagon when combined with
role in the development of organs. They belong to glucose-dependent insulinotropic peptide, they
the class of Mitogen-Activated Protein Kinase and stimulate the secretion of insulin and decrease the
susceptible to heat shock, UV, cytokines, osmotic secretion of insulin and decrease the secretion of
shock. They are activated by hyperglycemia, free glucagon. Hence DPP-4 inhibitors are the class of
radical species, oxidative stress, cytokines, and drugs that can inhibit the function of incretin
most crucially apoptosis. SAPK-JNK pathway (Deacon et al., 2004; Mentlein, 1999).
performs a significant pathway and direct

Fig.2: Inhibition of Dipeptidyl Peptidase-4 (DPP4) results in the secretion of insulin together with
a decrease in glucagon level.
11β Hydroxysteroid Dehydrogenase (11β-HSD) 17β-Hydroxysteroid dehydrogenase Type 1
11β Hydroxy-Steroid Dehydrogenase (11β-HSD) It belongs to the group of alcohol oxidoreductase
is an enzyme of oxidoreductase class, responsible enzyme that has a vital function in the synthesis of
for the conversion of cortisone to cortisol. It is an estrogen estradiol. It is a potential biomarker for
NADP/NADPH dependent enzyme and hence a the identification of breast cancer and diabetes. It
much important role in liver, CNS, and adipose has been reported that increase insulin resistivity.
tissue metabolism. The conversion of cortisone to Hence, it is one of the preferred molecular targets
cortisol leads to increase blood sugar levels and for drug discovery (Nguyen & Le, 2012; Strong &
hyperglycemia. Hence, 11β Hydroxy-Steroid Study, 2002).
Dehydrogenase inhibitor can be a potential target
Solute Carrier Family 16 Member 11
in drug development for diabetes mellitus (Davani
(SLC16A11)
et al., 2004; Walker, 1999).
Rusu et al., 2017 reported a new target molecule,
Glucose Fructose-6-Phosphatase Solute Carrier Family 16 Member 11 (SLC16A11)
Amidotransferase (GFAT) which is a monocarboxylate, proton couples
Glucose Fructose-6-Phosphatase transporter, and subsequent inhibition of SLCA11
Amidotransferase (GFAT) is responsible for changes lipid and the fatty acid metabolic
controlling the glucose flux into the hexosamine mechanism that can increase the chances of Type
pathway. Synthesis of glucosamine from HBP 2 diabetes.
(Hexosamine Biosynthetic Pathway) can lead to
the movement of glucose into the cell. GFAT Role of Phytochemicals in Diabetes
catalyzes the conversion of fructose-6-phosphate Drugs available for the treatment of diabetes
into glucosamine-6-phosphate and responsible mellitus comprise many drugs like biguanides,
for glucose-induced insulin resistance by the sulfonylureas, α-glucosidase inhibitors, and
action on the hexosamine biosynthetic pathway glinides, either used alone or in the composition
(HBP), it can be a novel drug target for diabetes to get a better result. Still the side effects of drugs
mellitus(Buse, 2006; Chou, 2004). are the major challenges associated with it
(Prabhakar & Banerjee, 2020). Drugs like

chlorpropamide, tolazamide, glibenclamide, help languages based on plant medicines and

in reducing the glucose absorption from the treatment procedures. By definition, according to
intestine(Chaudhury et al., 2017). Carbohydrates the World Health Organisation (WHO), a
that are digested fastly leads to a rapid increase medicinal plant is any plant or plant part of which
in blood glucose level after a meal. Routine one or more plant organs can be used to cure
intakes of rapidly metabolized carbohydrate- diseases. The World Health Organization has
containing diets cause hyperglycemia-induced also reported that about 3.4 billion people
chronic disease. Such chronic postprandial around the globe are directly dependent on the
hyperglycemia results trigger the generation of medicinal plant which comprises 88 percent of
free radicals leading to oxidative stress affects the total world’s population. Medicinally active
protein and DNA when excessive free radicals compounds can be obtained by various extraction
interact with it. Hyperglycemia induces methods. An extraction is a method of separation
glycosylation of protein, an increase in the level of of medicinally active compounds from plants or
lipid and plasma insulin together with the risk of plants part by selective solvents through standard
cardiovascular diseases. A controlled diet is also protocols and procedures (Handa et al., 2008).
one of the very important things to treat diabetic The plant produces both primary and secondary
patients as without proper and controlled diet metabolites. Primary metabolites are produced by
drugs will not work (ADA, 2003). the plants. Metabolites are the chemical
Phytochemicals are the chemical compounds compounds synthesized by all the living
obtained from the plant by various extraction organisms by their enzyme-mediated pathways
procedures. They are considered as non-nutritive so-called metabolic pathways.
plant biomolecules having preventive properties Metabolites are divided into mainly two groups-
against disease (Altemimi et al., 2017). They are primary metabolites and secondary metabolites.
generally not required by the normal function of Primary metabolites constitute different organic
the body. It has been reported that plant compounds such as lipids, carbohydrates, and
produces these phytochemicals to protect them proteins and are regarded as basic compounds
but they can also protect human against a range formed in any metabolic pathways like
of diseases (David et al., 2011). Due to the photosynthesis, glycolysis, Krebs’s cycle, etc.
known biological activity, plant phytochemicals Primary metabolites are essential for the growth
are one of the effective methods for the treatment and development of the plants whereas
of diabetes mellitus. Formulations like pancreatic secondary metabolites are distributed to all the
tonic 180 cp, diabecon, diasulin, bitter gourd plants and have a specific function associated
powder, chakrapani, dia-care, epinsulin, diabeta, with that plant. Secondary metabolites do not
and syndrex are effective and well known have any direct role in plant growth and
remedies available in the market(Modak et al., development. They play an important role in
2007). As per the world health organization species interaction and protection in plants and
report, about 20000 medicinal plants found in 91 are highly specific to them. Secondary metabolites
countries including 12 mega biodiversities of the are colored, flavored, and aromatic compounds
world located in these countries. Many extraction having economic importance to mankind.
procedures are used from ancient days for Secondary metabolites fall into three major
collecting bioactive compounds in which categories named alkaloids, phenols, and
maceration; infusion, percolation, and decoction terpenoids (Hussain & EI-Anssary,2019; Ibrahim
are the important methods (Sasidharan et al., et al., 2012).
2011). Medicinal plants are the source of High generation of reactive oxygen species and
therapeutics from the early days with the its ineffective scavenging is one of the major roles
development of civilization on the earth. Early in diabetes mellitus. Such weak antioxidant
civilizations of Sumerian, Akkadian, Indus-valley defense systems make diabetes one of the major
were well aware of plant extract for the treatment health killers after cancer and cardiovascular
of diseases. The use of the herbal plant was in diseases(Giugliano et al., 1995) . Several
practice because more and more sophisticated remedies are available in the market for the
techniques and practices of writing text and prevention of diabetes including synthetic as well
documents were started in China, India, Egypt, as herbal drugs. The big challenges related to the
and Middle East (Sofowora et al., 2013). The time taking treatment and side effects of the
herbal drug used as in the form of tincture, available synthetic drugs. Herbal medicines have
poultices, powders, teas followed by formulations, been practiced for a very long time as compared
and with the advent of new extraction techniques to modern synthetic drugs and are always
pure compounds were identified. Several texts preferred. Plants are always recommended as a
and manuscripts have been written in many novel source of drugs. It has been reported that

about 800 plants have been identified that may phenolic acids, flavonoids, stilbenes, and lignans.
cure diabetes(Singh, 2011). A recommendation All the polyphenols have shown an
made by the World Health Organization to antihyperglycemic effect (Pandey & Rizvi, 2009) .
evaluate the traditional plants for the treatment of
Phenolic Acids
diabetes considering their efficacy, non-toxic
Phenolic acids are widely derived distributed
effect, less or no side effect (Modak et al., 2007).
polyphenols that are derived from the
While going through the enzymes and molecules
derivetization of benzoic acid with a peak
involved in the molecular mechanism of diabetes
absorbance at 280 nm C6-C1 derivative and C6-
mellitus, the majority of them are acting upon
C3 derivative cinnamic acid. Important phenolic
rapid absorption of carbohydrates that cause an
acids that are reported to be antioxidant and
increase in the level of blood glucose. Hence, one
antidiabetic include gallic acid, salicylic acid,
of the important therapeutic approaches is to
ferulic acid, caffeic acid, ellagic acid,
inhibit their carbohydrate absorption activity and
protocatechuic acid, p-coumaric acid, rosamic
keeping the postprandial plasma glucose level in
acid and elgol (Coryet et al., 2018). The
control.
antioxidant property of phenolic acid is due to the
The efficiency of phytochemicals extracted from
stabilization and delocalization of unpaired
several plants in reducing blood glucose levels
electrons of the phenolic ring (Verma & Srivastav,
has gained a scientific validation that highlights
2020). Jain et al (2010) reported that ethanolic
their role in curing diabetes. Further research is
extract of gallic acid extracted from Paspalum
essential in exploring their potential for new drug
scrobiculatum (Linn.) with a dose of 500mg/kg
formulation development and bioactive
when administered to alloxan-induced diabetic
compound from plants. It has been reported that
rats showed a decrease in plasma glucose level
the treatment of a patient having insulin-
from 181.67 ± 1.12 to 119.17±1.9 mg/dl on
dependent or non-insulin-dependent with herbal
15th day of administration. Ramesh et al, 2011
formulations has shown an effective remedy but
reported a significant reduction in the serum
many herbal formulations used today have not
glucose, triglyceride, total cholesterol, L DL-
gone under precise evaluation and cytotoxicities
cholesterol, VLDL cholesterol levels at a dose of
and their drug-to-drug interaction not have been
50mg/kg, and 100mg/kg (Patel & Goyal, 2011).
assessed. In the past few years, many
Ramkumar et al (2014) reported that
phytochemicals have been extracted, purified,
administration of gallic acid to alloxan-induced
and isolated from plants that have a remarkable
diabetic rats reduced the blood glucose level to
effect against diabetes. Some of the important
150 mg/dl at a dose of 20mg/kg. There was also
phytochemical compounds such as polyphenols,
a significant improvement in hemolysis in gallic
alkaloids, glycosides, amino acids, terpenoids,
acid administered mouse compared to
peptidoglycans, glycolipids, saponins and other
glibenclamide one and a reduction in lipid
compounds obtained from many plant sources
peroxidation. Gallic acid is also reported to be
that are reported and discussed as a potential
synergistically important in drug-herb interactions
agent for antidiabetic effect. Such phytochemicals
leads to ti improved therapeutic effect together
can improve metabolic disorders by regulating
with reduced side effects. (Oboh et al., 2016)
them and can delay complications related to
reported that acarbose, an antidiabetic drug
diabetes (Choudhury et al., 2018). Here, recent
together with gallic acid (75:25) have shown a
research reports and discussions on various
mild inhibitory effect on α-amylase and a high
classes of phytochemicals that are playing a
inhibitory effect on α-glucosidase as excessive
crucial role in the treatment of diabetes mellitus
inhibition of α-amylase could result in abnormal
are given below:
bacterial fermentation. Rena et al, 2015 reported
Polyphenols the antihyperglycemic activities of salicylic acid
Polyphenols are the secondary metabolites and anti-inflammatory effect by directly linked to
obtained from plants, primarily involved in NF-κB signaling. A recent report suggests direct
protection against UV-rays and aggression by activation of AMPK contributes to
pathogens (Aryaeian et al., 2017). Poly phenols antihyperglycemic activities of salicylic acids with
are proved to be protective against many diseases proper drug action-mechanism(Rena &
such as diabetes, cancer, osteoporosis, Sakamoto, 2014). The synergistic effect of
cardiovascular diseases, and neurodegenerative salicylic acid was observed when Figueroa-Pérez
disorders. Polyphenols are categorized based on et al ( 2015) reported the enhancement of
the number of phenol rings and structural antidiabetic property of Mentha piperba was
elements that bind these rings to each other. done using 2mM of salicylic acids leads to
Polyphenols are divided into four classes: decrease in glucose level up to 25%. Furthermore,

a concentration of 0.5 and 2 mM salicylic acid- compounds such as flavones, flavonols,

treated Mentha reduced the LDL level to 24 and anthocyanins, catechins etc. (Ayodele & Alebiosu,
27 % respectively, and increased HDL levels 2004; Sarian et al., 2017; Sarraf, 2017; Babaei,
upto18 and 37%, respectively. Chowdhury et al & Naji-Tabasi, 2019). A number of flavonoids
(2019) showed a single dose of ferulic acid of 50 have been reported which have shown anti-
mg/kg was administered to STZ-induced diabetic diabetic properties. Kaempferol, quercetin,
rat leads to significant hypoglycemic, antioxidant, naringenin, and baicalein are the flavonoids
anti-inflammatory, anti-apoptotic activities. Thus, derived from Ficus racemosa (gular) that have
ferulic acid has ability to ameliorate renal tissue shown hypoglycemic effect results in reducing
impairment and apoptosis by inhibiting ROS blood glucose level from 300 to 185 mg/dL by 1-
generation oxidative stress-induced, signaling week administration in vivo models. Streptozocin
pathway (p38, JNK, ERK 1/2) activation, induced diabetic rats were given the flavonoid
activation of NF-kB pathway and promoting extracts at a dose of 2.0 Ml/kg body weight,
autophagy as well. Matboli et al (2017) reported 1.0mL/kg body weight, 10mg/kg body weight,
the effective results of caffeic acid in the treatment and 100mg/kg body weight into seven groups
of diabetic nephropathy in STZ induced diabetic including normal control. Such an administration
rats at a dose of 40 mg/kg bodyweight for 12 also resulted in a balanced glycogen level in the
weeks. Significant improvement was observed in liver (Keshari et al., 2016). Wu et al (2013) and
albumin excretion, reduction in renal mesangial Rukmini et al (2004) reported Glabrin flavonoid
matrix extension together with high vacuolation, from Glycyrrhiza glabra that showed a reduction
and reappearance of autophagosomes that lead in glucose level, SOD (Super Oxide
to conceptualize that caffeic acid is efficient in Dismutase)activity of kidney and liver. In addition
modulating autophagy pathway via inhibition of to this, the reduction in FBG (Fast Blood Glucose)
autophagy regulatory miRNAs hence proved to be and MDA (Malondialdehyde) was also observed
protective against diabetic nephrotoxicity. The which was high in diabetic cases. In SOD activity,
Transmission Electron Microscope (TEM) analysis superoxide dismutase enzyme catalyzes the
has shown the presence of rare autophagic dimutation of superoxides (O2-) radical into either
vacuoles in the tubular cells of the control and or oxygen molecules or peroxides (H2O2). In
diabetic rats. There was an increased autophagy oxygen metabolism, superoxide is produced
level observed in rat groups treated with caffeic which is regulated by several metabolic pathways
acid and prophylactic caffeic acid. Subsequent to reduce its toxic effect. Cell damage occurs
increase autophagosomes and when a superoxide molecule is not disintegrated
autophagolysosomes together with autophagic by these pathways. Enzymes like catalases are
was observed in proximal tubular cells. In tubule, responsible for the metabolism of harmful
double membrane vacuoles consist of peroxides produced during metabolic processes.
degenerating cytoplasmic organelles, electron- Hence, SOD has an important role in superoxide
dense material, and mitochondria with loss of metabolism in all living cells and tissues having
visible crista. Adedara et al (2019) reported interaction with oxygen molecules. Tsuda et al
neuroprotective, prevention in oxidative stress; (2006) demonstrated that when anthocyanins a
control acetylcholinesterase activity leads to an flavonoid when treated with human adipocyte
improvement in pancreatic, cerebral and cells shown a change in gene expression for
cerebellar structure when streptozotocin-induced adipocytokine secreted from adipocytes.
type 1 diabetic rat was treated with protocatechuic Adipocyte dysfunction causes the irregular
acid at a dose of 50mg/kg. The structurally and secretion of adipocytokine that is responsible for
functionally normal pancreatic sections are obesity as well as a reduction in insulin sensitivity.
observed from control as well as the (Sarian et al ( 2017) reported the extraction of
protocatechuic acid group. Pathological lesions flavonoids in a large quantity from Tetracera
were identified in untreated diabetic rats that indica Merr. and Tetracera scadens (L.). Isolation
showed infiltration of the acini by inflammatory of T.indica leaves yield isoscutellarein and
cells. hypolectin, kaempferol, and quercetin
respectively. The -glucosidase inhibitory activity
Flavonoids
was done and an IC50 test indicated the sample
Flavonoids are one of the important secondary
concentration needed to inhibit the activity of the
metabolites which come under polyphenols,
α-glucosidase enzyme by linear regression
widely distributed in the plant kingdom. They
analysis. Again, the inhibitory action of dipeptidyl
have remarkable antioxidant, anticancerous, anti-
peptidase IV enzyme was tested, responsible for
Alzheimer, and antidiabetic properties. Such
insulin secretion and blood glucose level. It has
compounds are classified into several phenolic
been revealed that quercetin and isoquercetin

have shown high IC50 value of 21.75±8.81 and lower hepatic gluconeogenesis in diabetic rats
22.33±1.52 µg/ml followed by hypolaetin and (Jayaraman et al., 2018). Gao et al (2007)
kaempferol at 34.89±7.44 and 45. 93±8.6 reported chebulin, chebulinic acid, and
µg/ml whereas wogonin, techtochysirin, 8-hyrdo- chebulagic acid were isolated from the Terminalia
7-methoxyflavone, norwogenin and acetate chebula using 70% methanol as solvent and
showed the least activity which was less shown inhibiting activity against α-glucosidase. It
than100µg/ml. Li et al (2015) reported grape has been reported that these three compounds
seed having proanthocyanindin flavonoids have showed intestinal maltase inhibitory activity with
significant role in reducing reducing FBG, HbA1C IC50 of 670µm, 30µm, 97µm respectively. While
serum insulin, and systolic blood pressure. Such two phenolics compound, 3-O-galloylepicatechin,
flavonoids are also helpful in improving kidney and 3-O-galloycatechin was isolated from the
functions. Falvonoids like Galbridin, luteolin, Bergenia ciliate using 50% aqueous methanol
eurycarpin A, licochalconetin, glabrone, 4’-7 and demonstrated significant inhibitory action
Dihydroxyflavone, formonetin, glabrol, against α-glucosidase activity (Bhandari et al.,
licoflavone, A-C liquiritigenin and glabrol were 2008). Minaiyan et al (2014) reported that fruits
isolated from species Glycyrrhiza, family of Prunnus varicata contain phenolic compound
Fabacae. A significant activity was reported pruning that has the potential to inhibit the activity
against alpha-glycosidase (upto 95%) at a against α-glucosidase activity. Geetha et al
concentration of 5 µg/mL (Z. Guo et al., 2015). (1994) isolated a phenolic derivative
Granados et al (2015) reported that isolation of leucodelphinidin from the bark of Ficus
flavonoids such as 5,7,4’-trihydroxy-3-5’- benghalensis and a dose of 200 mg/kg was
Dimethoxyflavone from Jatropha gossypifolia highly effective on alloxan induced diabetic rats
from the family Euphorbiacae shown as and was found to be hypoglycemic. In other
significant increase in glucose uptaking in C2C12 experiment, Manickam et al (1997) reported that
myotubes. There was also a reduction in under marsupin and pterostilbene phenolic compound
the curve of glucose tolerance, which was found from heartwood; Pterocarpus marsupium
to be 32 percent. Chakravarthy et al (1981) significantly helpful in reducing the blood
reported an important flavonoid epicatechin pressure level of hyperglycemic rats. Yang et al (
isolated from the bark of Indian medicinal plant 2017) reported that total flavonoid extract of
Pterocarpus marsupium Roxb. A dose of 30mg/kg Oxytropis falcata Bunge results in lowering of
was significantly effective in protection against blood glucose level. (Hui et al., 2015) reported
alloxan induced diabetic albino rats. that the dried root of Radix puerariae contains
Another flavonoid epigallocatechin gallate isoflavone that has hypoglycemic effect and help
isolated from Camellia sinensis of family in lipid peroxide reduction. Huang et al (2018)
Theaceae has been significantly effective in reported antidiabetic activity of four flavonoids-
protecting β-cells from streptozotocin-induced apigenin, maackiain; leachianone A and
diabetic rats(Gomes et al., 1995). Mezei et al leachianone B isolated from Sophora davidi
(2003) reported that soy contains flavonoids like (French.) and invitro and invivo models suggested
High Isoflavone (HIS) that activates PPARᵧ that Sophora davidi (French.) promoted GLUT4
(Peroxisome Proliferator-Activated Receptor- expression and activated AMPK (Adenosine
gamma) that is responsible for transcription of Monophosphate-activated Protein Kinase)
many genes involved in lipid metabolism and phosphorylation in insulin target tissues of KKAy
insulin sensitization results in a significant mice, leads to ameliorate insulin resistance in
hypolipidemic and lowering blood glucose level. type 2 diabetes mellitus. Simultaneously,
In another research report, flavonoid, hesperetin activation of PPARᵞ and inhibiting activity of ACC
has shown lower glucose level and an (Acetyl-CoA carboxylase) was also observed.
improvement in glucokinase activity results in
Table 1: Antidiabetic flavonoids and their therapeutic effect
S.No Plant Name Phytochemicals Therapeutic Effects Part Used References
1. Ficus Kaempferol, Singnifying diabetic Stem bark (Keshari et al.,
racemosa quercetin, action, reduced 2016)
naringenin, blood glucose level,
baiclain restored body weight
2. Glycyrrhiza Glabrin Reduction in FBG root and (Wu et al., 2013)
glabra (Fast Blood Glucose) stolon
and MDA
(Melanodialdehyde),

SOD (Super Oxide

Dismutase) activity of
kidney and liver,
Reduction in glucose
level
3. Tetracera isocutellarein and inhibits the activity of leaves (Sarian et al.,
indica Merr. hypolaetin, alpha-glucosidase 2017)
and Tetracera kaemferol and enzyme
scadens (L) quercetin
4. Grape seed proanthocyanindin reducing FBG, seed (Y. Li et al.,
HbA1C serum 2015)
insulin, systolic blood
pressure and kideney
functions
5. Glycyrrhiza Glabridin, luteolin, inhibit the activity of root and (Z. Guo et al.,
eurycarpin A, alpha-glucosidase stolon 2015)
licochalaconetin, enzyme
glabrone, 4’-7’
dihydrooxyflavone,
formonetin,
glabrol,
licoflavone, A-C
liquiritigenin and
glabrol
6. Jatropha 5,7,4’-trihydroxy-3- increase in glucose Leaves (Granados et al.,
gossypifolia 5’- upataking in C2C12 2015)
dimethoxyflavone myotubes
7. Pterocarpus epicatechin Reduction in glucose Bark (Chakravarthy et
marsupium level al., 1981)
Roxb
8. Camellia epigallocatechin protecting beta-cells Leaves (Gomes et al.,
sinensis (L.) gallate from streptozotocin 1995)
Kuntze induced diabetic rats
9. Soybeans High Isoflavone in lipid metabolism Seed (Mezei et al.,
(HIS) and insulin 2003)
sensitization
10. Prunus Prunin inhibits the activity of stem (Minaiyan et al.,
varicata alpha-glucosidase 2014)
11. Garcinia kola kolaviron Reduction in glucose seed (Iwu et al., 1990)
level
12. Ficus Leucodelphinidin antihypoglycemic bark (Geetha et al.,
benghalensis 1994)
13. Pterocarpus marsupsin and Reduction in glucose Heartwood (Manickam et al.,
marsupium pterostilbene level 1997)
14. Oxytropis Total flavonoid Reduction in glucose Bunge (Yang et al.,
falcata level 2017)
15. Radix Total flavonoid antihypoglycemic root (Hui et al., 2015)
puerariae
Stilbenes sorghum (Sorghum bicolor) and Pinus and Picea

Stilbenes are polyphenols having 1, 2- species (Hammerbacher et al., 2011) . Zhang et al
Diphenylethylene nucleus, have a C6–C2–C6 (2019) isolated and identified one
carbon skeleton. They are produced by plants in paeonilactiflorol and 14 other stilbenes
response to any stress conditions (Huang et al., compound from Peony Seeds and reported their
2018; Panel et al., 2014). Stilbenes compound antidiabetic properties. They showed inhibitory
occur in many plant species including pean activities on PTP1B and α-glucosidase, superior to
(Arachis hypogaea), grape wine (Vitis vinifera), the monoterpenes glycosides. Compounds like

stilbenes tetramers and trimers have highly and tannin are among alkaloids compounds
inhibiting properties against PTB1B with IC50 widely used by the people (Kim et al., 2011). A
values of 27.23 and 27.81 Μm respectively and number of alkaloids have been extracted that are
α-glucosidase with IC50 values of 13.57 and focused to show the significant hypoglycemic
14.39 μM respectively together with this two properties. Tiong et al ( 2013) reported that four
Trans-dimers were also reported to be DPPIV alkaloids- Four alkaloids-vindoline I, vindolidine
inhibiting activity (55.35% and 61.26%, 500 μM). II, vindolicine III and vindolinine IV were
Takizawa et al (2015) reported that resveratrol is extracted, isolated and purified from the leaves of
one of the highly investigated stilbenes that was Catharanthus roseus (L.) G.Don and MTT Assay
found too high potent in activating PPAR α due to for cytotoxicity evaluation, ORAC Assay for
the presence of 40-hydroxyl groups having a antioxidant activity, and DPPH Assay for cell
critical role in direct activation of PPARα. scavenging activity were performed and vindoline
I, vindolidine II, vindolicine III have no cytotoxic
Lignans activity towards pancreatic β-TC6 cells at a
Lignans are the polyphenols made up of C6-C3 concentration 25µg/ml. The compound
carbon units of n-propylbenzene skeleton. They vindolidine II, vindolicine III, and vindolinine IV
are cinnamic derived units. Entrolactone and have high inhibition activity towards protein
Entradiole Secoisolariciresinaol (SDG) tyrosine phosphatase-1B (PTP-1B) proved to them
Diglucosided Secoisolariciresinaol (SDG) are the to be antidiabetic compounds. In another
major lignans isolate from Linum usitatissimum experiment, Agrawal et al (2013) reported that
(flaxseed) was reported to show antioxidant and alkaloids isolated from the roots of Aerva lanata
active in controlling the generation of free Juss. and methanol extract was given at a dose of
radicals in diabetes mellitus (Maghsoudi, 2016). 10 and 20 mg/kg to streptozotocin-nicotinamide
Xu et al (2008) reported that the ethanol induced diabetic rats and a reduction in serum
extraction of total lignan from Fructus arctii which glucose level (>180±8mg/dl) was observed.
was given to alloxan-induced diabetic mice and Herbs like Berberis thunbergii, Berberis vulgaris,
rats at a dose of 2.0, 1.0, 0.5 gm /kg body Berberis patiolari and Berberis aquafolium
weight and 1.38, 0.69, 0.35 gm/kg bodyweight contain important alkaloid berberine that has
for 10 days. There was a notable reduction in the potential antihyperglycemic activity because it
blood glucose level, cholesterol, total cholesterol, inhibits the activity of α-glucosidase leads to a
and triglycerides while using glibenclamide as decrease in transport of glucose through intestinal
standard drugs. While Xu et al ( 2014) reported epithelium (Pan et al., 2003). The wild variety of
total lignin extract from Fructus arctii which Tinospora cordifolia has been recognized as the
showed invitro α-glucosidase inhibitory activity potential source of berberine as reported by(Singh
and promotes better hypoglycemic activity than et al., 2003). There was a significant reduction in
the standard drug nateglinide, together with the the level of HbA1C, total cholesterol, and
release of Glucagon-Like Peptide (GLP-1) and triglyceride and increased the secretion of insulin
Glucose-dependent-Insulinotropic-Polypeptide in diabetic mice when they were treated with
(GIP) in the GK (Goto-Kakizaki) mice. The berberine at a dose of 150mg and 350 mg/kg
histopathological study of pancreatic islets cells for 12 weeks consecutively Dong et al ( 2016).
revealed that there were irregularities in structure Whereas in another experiment Lan et al, 2015
and volume and number reduction was observed reported that when a dose of 500mg was given
compared to normal GK (Goto-Kakizaki) mice post-meal for 12 weeks to patients suffering from
cells. Shrunken unusual cellular changes such as diabetes mellitus, there is a reduction in Fast
coarse chromatin, mild hyperchromasia, and Blood Glucose (FBG) level, HbA1C level and post
pyknosis were the characteristics of abnormal prandial blood glucose together with significant
islets cells. Later on, treatment with Nateglinide change in lipid profile (Lan et al., 2015; Dong et
with total lignans was able to regenerate the al., 2016). Down-regulating the function of
structure to the normal control cells. glucose-6-phosphate and phosphoenolpyruvate
Alkaloids carboxykinase was observed when treated with
Alkaloids are the lower molecular weight berberine in diabetic mice (Jiang et al., 2015).
nitrogenous compound derived from amino acids Berberine is considered to be a high potential
like tryptophan, lysine, tyrosine etc. They are a alkaloid drug having the capacity to treat cardiac
structurally diverse group of over 12, 000 cyclic dysfunction, nephropathy and endothelial
nitrogen-containing compounds which are found dysfunction complications observed in diabetic
in about 20% of plant species (Kennedy and mouse (Chang et al., 2016; Tao et al.,
Wightman, 2011) Alkaloids are very popular and 2017).Constantino et al, 2003, reported the
widely used in the daily life to stay alert; caffeine isolation of three alkaloids, 5-β-

hydroxyskitanthine, boschinakine and tacomine maltase as well as sucrose(Li et al., 2016).

from Tecoma stans (L.) Juss. ex Kunth has shown Cryptoleipine an indoloquinolone alkaloid
a significant effect on the glucose uptake rate in isolated from Cryptolepis sanguinolenta helps
mice adipocytes as compared haemoglycemic lower glucose when administered orally to
mice whereas the other two alkaloids have shown diabetic rats (Gaikwad et al., 2014). Jambosine,
no activity up to 100µm (Costantino et al., 2003). an important alkaloid which inhibits the diastatic
Isolation of casuarine-6-α-glucoside from the conservation of starch was isolated from Syzygium
bark of Syzygium malaccense family Myrtaceae cumini (L.) Skeels also is known as Eugenia
has shown inhibiting activity against α- jambolana (Swami et al., 2012). Zhou & Zhou
glucosidase(B. Gaikwad, Krishna Mohan, & Rani, (2012) reported that trigonelline an alkaloid
2014). A new type of nortropone isolated from Trigonella foenum-graecum L.
polyhydroxylated alkaloids of a calystegine which fenugreek acts on β-cell generation, increases
was isolated from the fruit of Morus alba L, family insulin secretion promotes activities of enzymes
Moraceae, and the structure was found to be related to glucose metabolism. López et al (2004)
similar to the structure of 3-O-D- reported that quinolizidine alkaloid isolated from
glucopyranosylcalystegine and have antidiabetic the Lupinus species has a significant role in the
property by reducing glycosidase activity treatment of Type II diabetes. Leaves of Murray
(Bourebaba et al., 2016) . Seeds of Nigella koenigii contains carbazole alkaloid that reduces
gladilifera family Ranunculaceae have three elevated fasting blood glucose, low-density
norditerpenoid alkaloids, nigelladines-A-C and a lipoprotein, triglycerides and increases high
parrolyquinadine alkaloid, nigellaquinomine density lipoprotein at a dose of 50 and
isolated by Chen et al, 2014 and it was proved to 100mg/kg (Dinesh kumar et al., 2010).(Asthana
be potent PTT1B inhibitory activity and cytotoxic to & Sharrna, 1990) reported that isolation of
A431 cell line at a concentration of 100µm swerchirin alkaloid from the bark of S. chirayita is
(Chenet al., 2014). An increase in glucose significant in the stimulation of insulin as well as
consumption, glycogen content, and hexokinase its enhancement in its action. Alkaloids like
activity was observed when nigelladines A-C was piperumbellactum-A to C was isolated from
exposed to L6 myotubes that improved Piperumbellactum and a moderate inhibition of
metabolism (Zheng et al., 2020). Liu et al (2007) α-glucosidase was observed with IC 50 value 98.07
provided the information that the seeds of Nigella ±0.44, 43.80 ±0.56 and 29.64 ±0.46
glandulifera have shown strong α-glycosidase respectivey as reported by Tabopda et al (2008).
inhibitory activity. SZ-A, an alkaloid found in Gao et al (2008) reported the isolation of two
Ramulus mori and total alkaloids are fifty percent major alkaloid ascinol and vasicine by assay
by weight and another alkaloid, 1- guided fractionantion from Justicia adhatoda. L.
deoxynojirimycin is thirty or more by weight in and showed a potential high sucrose inhibitory
total alkaloid has found to be a strong α- activity with an IC50 value of 125 and 250 µm
glycosidase inhibitory activity and such treatment respectively.
with SZ-A had a potential significant inhibitor of
Table 2: MTT Assay of β-TC6 cell [Tiong et al (2013)]
Cytotoxicity(IC50) Vindolidine Vindoline Vindolicine Vindolinine
µG/mL 76.7±8.1 82.1±9.8 68.0±10.4 20.5±3.6
µM 180.1±19.0 180.1±21.5 73.5±11.3 57.6±10.7
Table 3: Antidiabetic alkaloids and their therapeutic effect
S.No Plant Name Phytochemicals Therapeutic Part of References
Effect the Plant
1. Catharanthus Vindolidine , Lowering blood Leaves (Tiong et al.,
roseseous Vindoline glucose level 2013)
Vindolicine,
Vindolinine
2. Aerva lanata Juss. canthin-6-one Reduction of Root (Agrawal et
serum glucose al., 2013)
level
3. Berberis thunbergi Berberine Inhibition of α- Root, (Pan et al.,
glucosidase stem- 2003)
activity bark

5. Berberis patiolaris Berberine Inhibition of α- Root, (Pan et al.,

glucosidase stem- 2003)
activity bark
6. Berberis Berberine Inhibition of α- Root, (Pan et al.,
aquafolium glucosidase stem- 2003)
activity bark
7. Tinospora Berberine Inhibition of α- Root and (Singh et al.,
cordifolia glucosidase stem 2003)
activity
8. Morus alba L. calystegine Inhibition of the Fruit (Bourebaba
α-glucosidase et al., 2016)
activity
9. Nigella gladilifera nigelladines-A-C PTT1B inhibitory Seed (Liu et al.,
parrolyquinadine activity and 2007)
cytotoxic to A431
cell line
10. Ramulus Mori SZ-A α-glycosidase Root and (M. Li et al.,
1- inhibitory activity stem 2016)
deoxynojirimycin
13. Cryptolepis cryptoleipine helpful in Root (J. Luo et al.,
sanguinolenta lowering glucose 1998)
14. Lupinus arcticus quinolizidine Stimulate insulin (López et al.,
secretion 2004)
15. Murraya koenigii carbazole reduces elevated Leaves (Dineshkumar
fasting blood et al., 2010)
glucose, low-
density
lipoprotein,
triglycerides and
increases high-
density lipoprotein
16. Swertia chirayita swerchirin inhibition of α- Bark (Kar et al.,
glucosidase 2003)
activity
Terpenoids number of biological processes like glucose

Terpenes are the largest class of phytochemicals absorption, glucose uptake and insulin secretion
produced by a number of floral families. (Alqahtani et al., 2013). Terpenoids like
Terpenes are oxidized or reduced to a specific cycloartane, dammarane and protostane having
chemical compound known as Terpenoids. a significant role in reducing blood glucose level,
Terpenes are synthesized by polymerization of were isolated from Astragalus membranaceus,
their monomer known as isoperene having Gynostemma pentaphyllum, Panax
formula (C5H8). Terpenes have a basic formula quinquefolium, Panax notoginseng as reported by
(C5H8)n where n is the number of repeating units Alqahtani et al (2013). Lai et al (2012) reported
and consists of dreivatives like polyterpenes, the isolation of terpenoid 2-3-seco-2-O-
tertraterpenes, triterpenes, sesterpenes, (29)lapene-2,3 dioic acid from the twigs and leaf
diterpenes, monoterpenes, hemiterpenes(Putta et of Fagus hayate, family fagacae that acts as an
al., 2016). Li et al, 2013 reported that a large inhibitor of α-glucosidase of Bacillus
number of terpenoids like oleanolic acid, ursolic stearothermophillus bacterial species with a
acid acid, botulin, glycyrrhizin, glycyrrhetinic acid, cytotoxic IC50 of 62.1µm. While Uddin et al
betulinic acid, and lupeol were extracted from a (2012) demonstrated that triperpene
number of plant species like Glycyrrhiza sp., dammarane, pistagrenine acid isolated from
Centella asiatica, Camellia sinensis, crataegus sp. Pistia stratiotes family anarcadacae showed a
and olea europaea. Such phytochemicals fall significant inhibition of α-glycosidase activity.
under sub-category of triterpenoids and they have Twelve triterpenoids saponins were isolated from
a significant role in treating diabetic vascular the plant Aralia chinensis and their antidiabetic
abnormalities, neuropathy, retinopathy via a effect was demonstrated by inhibition of lipid

peroxidation in rat liver as well as the evaluation fibres by 7gm/day as reported by Botnia Dietary
of its inhibitory effect was done by haemoglobin- (Ylönen et al., 2003).
δ-gluconolactone(δ-glue) assay, N-acetyl-glycyl-
Polysaccharides
lysine methyl ester-ribose assay and bovine-serum
Polysaccharides are the complex macromolecules
albumin assay (BSA) glucose assay(Xi et al.,
and long polymer chain of monosaccharides that
2010). Terpenes like astragalosides isolated from
are linked by glycosidic bonds. Plant cellulose,
Astragalus radix which can alter the bond
starch, glycogen are major classes of
formation between reducing sugars and amino
polysaccharides. They have the general formula
acids hence reducing Advanced Glycation End
Cx (H20)y composed of long-chain units of
Products (AGES) like carboxyl methyl lysine results
monosaccharides (CH2O)n , where n is the
in inhibiting protein-glycation process(Motomura
number of repeating units. Glucose, fructose,
et al., 2009). In another experiment Kuang et al
galactose, mannose, arabinose, rhamnose, and
(2011) reported that euscaphic acid and p-
xylose are important monosaccharides (Zong et
counaroylursolic acid were isolated from the root
al., 2012). Kumar Bhateja & Singh, (2014)
of Sanguisorba tenufolia family Rosaceace
reported an antidiabetic property of aqueous
showed inhibitory effect on α-glucosidase activity
extract of Acacia tortilis gum exudates.
with IC50 value of 0.67 and 0.62 Mm. Guo et al
Aconintans A, B, C, and D, the four glycans were
(2015) reported some new terpenoids like 3-O-
isolated from the roots of Aconitum carmichaeli,
olean-11,13 [18]-diene 23, 28-dioic acid was
family Ranunculacae showed an antihperglycemic
isolated from and Anoectochilus elwesii plant that
activity in alloxan-induced diabetic mice (Gray &
acts on insulin resistant human HepG2 cells leads
Flatt, 1997). Six glycan molecules named
to a reduction in glucose uptake activity
saccharans A, B, C, D, E, and F were extracted
Triterpenoids isolated from Agrimonia pilosa
from the stalk of Saccharum Officinarum, family
Ladeb showed a significant sensitization of insulin
Poaceae exhibited a prominent reduction in the
through activating PPAR ᵧ and downstream
blood glucose level in alloxan-induced
controlled genes. Curcuma longa, family
hyperglycemic mice(Hikino et al., 1985).
zinzberaccae was used to isolate a tricyclic
Polysaccharide isolated from corn silk was found
diterpenoids, tetraterpenoids from the leaves
to be hypoglycemic and hypolipidemic in
which showed antidiabetic activity and oxidative
streptozotocin-induced hyperglycemic mice. Such
stress(Motomura et al., 2009).
polysaccharides were also effective in reducing
Fibres blood glucose levels, total glycogen, and serum
Fibres are the complex food derived from plants total cholesterol in diabetic mice (Zhao et al.,
that cannot be broken into simpler parts by 2012).
digestive enzymes. Fibre improves intestinal
Glycosides
digestive efficiency, cholesterol reduction, and an
Glycosides are the macromolecules and acetal
increase in microbial mass. Chemically, dietary
derivatives forms when a monosaccharide reacts
fibre is a complex carbohydrate and lignin group
with alcohol. The bond results due to such linkage
of vegetable origin that supports laxation and
known as a glycosidic bond. Previous research
decrease fasting blood glucose level. The diet
work has been proven that glycosides have high
contains a high amount of mono, disaccharides,
potential in curing diabetes mellitus. Vennekens et
and fat increases higher chances of diabetes as
al, 2017 reported a new type of glycosides,
compared to diet having high fibre content
stevioside and rebandioside A which was isolated
(Gittelsohn et al., 1998). (Chau et al ( 2003)
from Stevia rebanundiana showed decrease in
reported that dietary fibre which is water-soluble
plasma glucose level in the hyperglycemic wild rat
as well as alcohol soluble obtained from the peel
by improvement in the secretion of glucose-
of Citrus sinesis, family Rutaceae showed a
induced insulin by TRPM5 (Transient Receptor
reduction in glucose diffusion and inhibition of α-
Potential cation channel subfamily M member 5)
amylase. McKeown et al (2002) reported that
channel(Philippaert et al., 2017). Liu & Li (2016)
intake of dietary fibre with daily diet maintains the
reported that new phenolic glycosides- 4-acyl-2,
BMI (Body Mass Index), total cholesterol, WHR
6-dimethoxyphenol glucoside (6), and
(Waist-to-Hip Ratio) and fasting insulin level. He
lipariglycoside K-O (1-5) was isolated from
also concluded that an increase in insulin
Liparis odorta was identified as an inhibitor of
sensitivity reduces the chances of diabetes. It may PTP1B (Protein Tyrosine Phosphatase 1B) and α-
due to the intake of whole-grain cereals and
glucosidase. Vitexin, 3-O-β-D rutinoside, and
dietary fibres. There is a reduction in fasting
isovitexin were glycosides isolated from the leaves
insulin level by 2.9 % by the intake of dietary
of Microcos pinaculata, family tilicae, and were

observed to exhibit inhibitory activity against α- considered for testing phytochemical activities.
glucosidase (Chen et al., 2013). These enzymes are well known for their role in
Besides these organic compounds, inorganic increasing blood glucose levels and insulin
compounds have also a vital role in the treatment resistivity. There must be ongoing necessities to
of diabetes mellitus. Such inorganic compounds find more effective drugs that have multiple
are highly efficient in intervening in the targets with much fewer side effects as the single-
mechanism of diabetes mellitus and inhibiting the target drug has shown limited therapeutic effects.
enzymatic activity associated with it. High As phytochemicals have very much side effects
manganese content leaves of Medicago sativa, with the promise of better therapeutic activities
family Fabaceae was found to be highly effective there is a need for continuous focus on the
in IDDM (Insulin Dependent Diabetes Mellitus) determination of their activities and mechanism of
patients and it has also been reported that action on available multiple targets.
manganese is an important factor in
phosphorylation of insulin receptor (Luo et al., CONCLUSION
1998). Sulfur-containing the amino acid, S-allyl Medicinal plants and phytochemicals have much
cysteine sulphoxide, allicin obtained from Allium importance in the present scenario in developing
sativum is highly efficient in reducing blood countries where resources are limited. So far in
glucose level in diabetic mice (Yatsunami et al., this review, it has been demonstrated that
2003). phytochemicals are highly efficient in the
treatment of diabetes mellitus by acting on their
DISCUSSION specific targets. Regular uptake of herbal
Diabetes mellitus is recognized as the most medicines containing these phytochemicals can
common chronic metabolic disorder causes high be beneficial in reducing blood glucose levels and
morbidity and mortality. There is no such concrete other complications. Such complications are
and an efficient method is developed so far to promoted by the majority of enzymes and
cure it. Unhealthy lifestyle, unbalanced BMI (Body molecules. Hence, there is a need for some
Mass Index), less physical work, consumption of additional pathway or multi-targeted approach
high calorific value diet, smoking, alcoholism, that can be used to overcome the risk of renal,
some genetic and environmental factor are the eye, cardiovascular complexities. Phytochemicals
main causes of diabetes. From decades strategies have therapeutic potential to bind with the specific
are made to lower the glucose level and the drug target but their activities have been determined on
was designed to stimulate the secretion of insulin a limited number of enzymes and molecules.
as well as insulin controlled glucose uptake by the Identifying the potential multidrug target is crucial
tissues. But they are facing the problem of side to drug development and identification of
effects and serious complications. This review phytochemicals mechanism towards multi-target
reveals that several molecules are involved in the molecules can be a matter of huge research and
molecular mechanism of diabetes. Inhibition or provide a landmark in achieving efficient
affecting their activity may result in lowering therapeutic against diabetes without causing any
blood glucose levels or reduce the complexities side effects.
associated with diabetes. Synthetics drugs can
Conflict of research interests: The authors
reduce such complexities but they are facing the
declare no conflict of interest.
problems of lethal adverse effects. Hence, due to
side effects patients stops taking these medicines. Authors: All research done by the authors
Herbal drugs containing antidiabetic
Financial support: No
phytochemicals are much efficient in the
treatment of diabetes mellitus. It has been Conflict of interest: none
successfully demonstrated that synthetic drugs
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P P abha a e a An d abe Ph o hem a A omp ehen e Re ew on Oppo un e and

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Citations (2) References (148)
... Carbohydrates, proteins, and lipids are

considered primary metabolites, necessary for the
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Antidiabetic Phytochemicals: A comprehensive Review

INTRODUCTION insulin is responsible for controlling the blood

P Prabhakar et al / Antidiabetic Phytochemicals: A comprehensive Review on Opportunities and

insulin sensitization and glucose tolerance. When Cardiovascular disease (Diabetic

P Prabhakar et al / Antidiabetic Phytochemicals: A comprehensive Review on Opportunities and

P Prabhakar et al / Antidiabetic Phytochemicals: A comprehensive Review on Opportunities and

P Prabhakar et al / Antidiabetic Phytochemicals: A comprehensive Review on Opportunities and

P Prabhakar et al / Antidiabetic Phytochemicals: A comprehensive Review on Opportunities and

P Prabhakar et al / Antidiabetic Phytochemicals: A comprehensive Review on Opportunities and

chlorpropamide, tolazamide, glibenclamide, help languages based on plant medicines and

P Prabhakar et al / Antidiabetic Phytochemicals: A comprehensive Review on Opportunities and

P Prabhakar et al / Antidiabetic Phytochemicals: A comprehensive Review on Opportunities and

a concentration of 0.5 and 2 mM salicylic acid- compounds such as flavones, flavonols,

P Prabhakar et al / Antidiabetic Phytochemicals: A comprehensive Review on Opportunities and

P Prabhakar et al / Antidiabetic Phytochemicals: A comprehensive Review on Opportunities and

SOD (Super Oxide

Stilbenes sorghum (Sorghum bicolor) and Pinus and Picea

P Prabhakar et al / Antidiabetic Phytochemicals: A comprehensive Review on Opportunities and

P Prabhakar et al / Antidiabetic Phytochemicals: A comprehensive Review on Opportunities and

hydroxyskitanthine, boschinakine and tacomine maltase as well as sucrose(Li et al., 2016).

P Prabhakar et al / Antidiabetic Phytochemicals: A comprehensive Review on Opportunities and

5. Berberis patiolaris Berberine Inhibition of α- Root, (Pan et al.,

Terpenoids number of biological processes like glucose

P Prabhakar et al / Antidiabetic Phytochemicals: A comprehensive Review on Opportunities and

P Prabhakar et al / Antidiabetic Phytochemicals: A comprehensive Review on Opportunities and

P Prabhakar et al / Antidiabetic Phytochemicals: A comprehensive Review on Opportunities and

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Citations (2) References (148)

... Carbohydrates, proteins, and lipids are

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