Complementary and alternative medicine for the treatment of diabetes and associated complications: A review on therapeutic role of polyphenols

Phytomedicine Plus 2 (2022) 100188
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Phytomedicine Plus
journal homepage: www.sciencedirect.com/journal/phytomedicine-plus
Complementary and alternative medicine for the treatment of diabetes and
associated complications: A review on therapeutic role of polyphenols
Preeti Sharma a, Younis Ahmad Hajam a, *, Rajesh Kumar b, Seema Rai c
a
Department of Biosciences, Division Zoology, Career Point University, Hamirpur, Himachal Pradesh, 176041 India
Department of Biosciences, Himachal Pradesh University, Shimla, Himachal Pradesh, 175001 India
c
Department of Zoology, Guru Ghasidas Vishwavidayalaya (A Central University), Bilaspur, Chhattisgarh, 495001 India
b
A R T I C L E I N F O
A B S T R A C T
Keywords:
Diabetes
Complications
Polyphenols
Pharmacological approaches
Metabolic disorders
Background: Diabetes is one of the most challenging health problems in 21st century. It is a group of endocrinemetabolic disorder characterized by high glucose level (hyperglycemia) due to insufficient insulin secretion/
action or both. It causes multi-organ failure viz hepatorenal damage, adult-onset blindness, lower-limb ampu­
tations, heart diseases and stroke, high blood pressure and nerve damage. Moreover, diabetic patients are having
higher risk of cardiovascular complications including atherosclerosis, hypertension, lipoprotein abnormalities
and cerebrovascular disease.
Study design: Considering the potencies of currently available drugs for the treatment of diabetes and
associated complications, present study was focussed to explore the role of plant bioactive components as
alternative and easily accessible therapeutic remedies.
Hypothesis/Purpose: This study the pooled status of diabetes, available treatments, attitude and traditional
herbal polyphenols regarding diabetes.
Results: This study was aimed to summarize the natural polyphenols having anti-diabetic, anti-inflammatory,
anti-apoptotic and anti-cancerous activities. Polyphenols can decrease other metabolic diseases such as insulin
resistance, hyperglycemia, hyperlipidemic, and obesity and Type-2 diabetes.
Conclusion: Polyphenols are promising alternatives that can decrease the severity of diabetes and promote
the other protective roles by decreasing the adverse effects of diabetes on other metabolic organs and their
functions.
List of Abbreviations
AD,
Alzheimer’s disease;
AGEs,
Advanced glycation end products;
Akt,
Protein kinase B;
AMPK, AMP-activated protein kinase;
AP-1,
Activator protein-1;
Aβ,
β-amyloid;
BMI,
Body mass index;
BTB,
Blood testes barrier;
CAT,
Catalase;
CDKAL1, Cdk5 regulatory associated protein 1-like;
CHD,
Coronary heart disease;
CVDs,
Cardiovascular diseases;
DM,
Diabetes mellitus;
DN,
DPP-4,
DR...…,
EC,
ECG,
ECM,
EGC,
EGCG,
EMT,
ER,
ERK,
FA,
FSH,
GADA,
GDM,
Diabetic nephropathy;
Dipeptidyl peptidase-4;
Diabetic Retinopathy;
Epicatechin;
Epicatechingallate;
Extracellular matrix;
Epigallocatechin;
Epigallocatechin-3-gallate;
Epithelial-mesenchymal trans-differentiation;
Endoplasmic reticulum;
Extracellular signal regulated kinase;
fatty acid;
Follicle stimulating hormone;
Glutamic acid decarboxylase;
Gestational diabetes mellitus;
* Corresponding author.
E-mail address: [email protected] (Y.A. Hajam).
https://doi.org/10.1016/j.phyplu.2021.100188
Available online 1 December 2021
2667-0313/© 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
P. Sharma et al.
Phytomedicine Plus 2 (2022) 100188
GFR,
Glomerular filtration rate;
GIP,
Glucose-dependent insulinotropic polypeptide;
GLP1,
Glucagon like peptide1;
GLUT4, Glucose transporter type 4;
GR,
Glutathione reductase;
GSH,
Glutathione;
GSK3β, Glycogen synthase kinase-3β;
HG,
High glucose;
HHEX, Hematopoietically-expressed homeobox protein;
HIF1α, Hypoxia-inducible factor 1α,
HLA,
Human leukocyte complex,
HNF,
Hepatocyte nuclear factor;
IA2A,
Insulinoma association protein two antibodies;
IAA,
Anti-insulin;
ICA,
islet cell antibodes;
ICAM,
Intercellular adhesion molecule;
IGE,
Insulin degrading enzyme;
IGF2BP2, Human insulin-like growth factor 2 binding proteins 2;
IGF-I,
Insulin growth factor-I;
IL,
Interleukin;
KCNJ11, Potassium Inwardly Rectifying Channel Subfamily J Member
11;
LDL,
Low-density lipoprotein;
LH,
Luteinising hormone;
LV,
Left ventricular;
MCP,
Monocyte chemotactic protein;
MHC,
Major histocompatibility complex;
MMPs, Mesangial matrix metalloproteinases;
Mtor,
Mammalian target of rapamycin;
NF-κB, Nuclear factor kappa-B;
PI3K,
Phosphoinositide 3-kinase;
p38MAPK, p38 mitogen-activated protein kinase;
PEPCK, Phosphoenolpyruvate carboxykinase;
PPARG, Peroxisome proliferator-activated receptor;
PPAR-α, Peroxisome proliferator-activated receptor-α;
PS1,
Presenilin1;
PtdIns-3 ps, Phosphatidylinositol 3-phosphate;
PTP,
Protein tyrosine phosphatise;
ROS,
Reactive oxygen species;
SGLT2, Sodium-glucose co-transporter inhibitors;
SIRT1, Sirtuin1;
SOD,
Superoxide dismutase;
T2DM, Type 2 diabetes mellitus;
T3D,
Type 3 diabetes;
TCF7L2, Transcription factor 7-like 2;
TG,
Triglycerides;
TIDM,
Type 1 diabetes mellitus;
TZDs,
Thiazolidinediones;
VEGF,
Vascular endothelial growth factor;
VLDL,
Very-low-density lipoprotein;
WHO,
World Health Organization.
2009). It has been proposed that the accelerators are associated, and
their additive effect leads to the degeneration of beta cells. It has been
reported that during apoptosis, β-cells release antigens and initiates an
autoimmune attack on the pancreatic β-cells in genetically susceptible
individuals (Wilkin et al., 2009). With time hyperglycaemia and
enhanced inflammation might lead to secondary complications such as
urological and gastrointestinal complications (Volpe et al., 2018). Dia­
betes mellitus is a group of metabolic disorders and initiates complex
interactions of genetics and environmental factors. Diabetes causes
multi-organ failure such as kidney damage, adult-onset blindness,
lower-limb amputations, heart diseases and stroke, high blood pressure
and nerve damage (Abejew et al., 2015). Chronic hyperglycaemia leads
to the impaired growth, and a person becomes susceptible to various
infectious diseases. Long-term complications include retinopathy (loss
of vision), retinopathy (kidney failure), and neuropathy (peripheral)
with the risk of amputations, foot ulcers and autonomic neuropathy with
the higher risk of sexual dysfunction, cardiovascular complications and
gastrointestinal complications. Diabetic patients have higher chances of
cardiovascular complications (atherosclerosis), hypertension, lipopro­
tein abnormalities and cerebrovascular disease (Lorenzen et al., 2012).
Today’s lifestyle changes, sedentary habits, diet changes, altered
physical activity patterns, and energy imbalance due to the intake of
high-calorie food stuffs lead to increase in body mass index (BMI).
Moreover, rapid urbanization is increasing the prevalence of metabolic
disorders, the highest increase in metabolic diseases has been reported
in urban areas changing patterns of diet and physical inactivity (Bos and
Agyemang 2013). All these alterations adversely affect overall metabolic
processes, including lipid, protein and carbohydrate metabolism etc.
These abnormal metabolic and other biochemical processes at different
levels led to various metabolic disorders such as obesity, cardiovascular
diseases (CVDs), neurodegeneration, reproductive complications, renal
failure and hormonal imbalance (Codner et al., 2012; Ormazabal et al.,
2018). In addition to this, foods and beverages are rich in fats, carbo­
hydrates and other additives, which are used as nutritional supplements,
but they are harmful (Nolan et al., 2011). For instance, in the mid-19th
century, sweeteners are used as ingredients in food, and other day-today
consumable food items contain large quantities of sugary substances and
fewer nutrients (Lozano et al., 2016).
People consuming food supplements rich in bad fats in food but
performing less physical activity increases the risk of metabolic diseases
(Bos and Agyemang, 2013). Recent studies reported that consuming
foods and beverages containing a high amount of carbohydrates in­
creases the risk of metabolic complications such as obesity, dyslipide­
mia, insulin resistance and heart disease etc. (Lozano et al., 2016). In
addition to this, consumption of a western diet (included as sugar and
saturated fat) increases the progression of metabolic diseases (Lozano
et al., 2016). In the Asian diet, rice is used as the principal source of a
diet containing 90% carbohydrates, therefore increases the higher risk
of metabolic disorders (Imam et al., 2012). Hu et al. (2012) evidenced
that the higher consumption of white rice increases the prevalence of
metabolic disorders in Asian populations.
It has been reported that rapid increase in urbanization has affected
health because it harms a healthy lifestyle (Chen et al., 2015; Gong et al.,
2012; H. Yang et al., 2017; Li et al., 2016; Miao and Wu 2016; Van et al.,
2012; Wang et al., 2018). Recent studies have reported that in devel­
oping countries like India, urbanization has been found a significant risk
factor for the progression of obesity (Goryakin et al., 2017; Ismailov and
Leatherdale 2010; Kalaria et al., 2008). Due to urbanization, the lifestyle
patterns that lead to alteration in body physiology could cause the
metabolic disorder. The consequences of obesity include cardiovascular
diseases, kidney and liver diseases and reproductive disorders (Egede
et al., 2002; McPherson et al., 2019). Therefore, an unhealthy lifestyle
and physical inactivity are a leading cause of an obesogenic environ­
ment. Overweight has become a health-related severe problem around
worldwide (McPherson et al., 2019). The prevalence of obesity
increased from 22.8% to 30.1% in one decade (2002–2012). Recent
1. Introduction
Human body is a highly complex system of hormones and neuro­
peptides that are released mainly from sweat glands, sebaceous glands,
brunner’s glands and endocrine glands (brain, endocrine cells of
pancreas, ovaries/testis, thyroid gland, parathyroid gland) adipose tis­
sue and muscle cell (Supale et al., 2012). The pancreas is a glucose
sensor to regulate the synthesis and secretion of insulin, helps to regulate
blood glucose level. It has been that apoptosis followed by necrosis leads
to the degeneration of β-cells and in the progression of diabetes mellitus
(Cnop et al., 2005). "Accelerator hypothesis", TIDM and T2DM are a
single disorder differentiated based on the degeneration of β-cells and
the accelerators that cause the loss of β-cell. These accelerators function
differently to regulate the body’s metabolic function (Wilkin et al.,
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studies have reported that globally, more than 1.9 billion adults are
overweight and 650 million are obese. Approximately 2.8 million deaths
are reported as a result of being overweight or obese (Tan and Leung
2020). According to ICMR-INDIAB study 2015, prevalence rate of
obesity and central obesity are varying from 11.8% to 31.3% and
16.9%− 36.3% respectively. In India, abdominal obesity is one of the
major risk factors for cardiovascular disease (CVDs). In addition to
obesity, these lifestyle changes, consumption of carbohydrate-rich diets,
less physical work, use of fast foods, overconsumption of alcohol,
sedentary habits, and consumption of fried item, processed foods have
increased the prevalence of diabetes mellitus. Diabetes has now become
a global health concern. It is one of the most challenging health prob­
lems in the 21st century. WHO reported that diabetes was the seventh
leading cause of death (WHO, 2006). It is a cluster of endocrinemetabolic syndrome characterised by high glucose level (hyperglyce­
mia) due to insufficient insulin secretion/action or both. Deficiency of
insulin occurs due to pancreatic β-cells dysfunction (Meng et al., 2017)
or insulin receptor becomes insensitive due to their structural changes.
Diabetes is commonly known as a “silent killer” because of its mild di­
agnostics characterised by a negligible glycemic load. This condition is
known as prediabetes, mainly found in obese patients. However, if un­
diagnosed and untreated, this prediabetic condition may result in a
permanent diabetic condition. It is a chronic metabolic disorder, resul­
ted in a persistent hyperglycaemic condition. There were 463 million
diabetic patients in 2019, and this number is estimated to rise in 2045 to
about 700 million (Thomas et al., 2019). The prevalence of diabetes
mellitus is between Nepal 3.03%, Pakistan 6.72%, Bangladesh 9.85%,
Sri Lanka 7.77%, and India 8.31% (Rizvi and Mishra 2013). Further­
more, 2.2 million deaths were caused by hyperglycaemia in 2012
reported by Ogurtsova et al. (2017). While 1.2 million deaths caused by
kidney disease in 2015 (Luyckx et al., 2018). Recently International
Diabetes Federation (IDF, 2021) reported that diabetes (due to hyper­
glycemia) is responsible for 6.7 million deaths in 2021 that is 1 death in
every 5 s occurs due to diabetes. According to the Harris et al. (1997),
diabetes mellitus is classified into four types: viz. type-1-diabetes,
type-2-diabetes, type-3-diabetes and gestational diabetes mellitus
(GDM) (American Diabetes Association 2014). The content wise data is
shown in Fig. 1. However, no treatment is available. Therefore, this
review article summarized the effect of diabetes and its associated
complication on the different body system, their functions and available
treatments to combat diabetes and its associated complications.
2. Types of diabetes mellitus
2.1. Type 1 diabetes mellitus
Type 1 diabetes mellitus is when pancreatic β-cells do not produce
sufficient insulin to metabolize the surplus glucose and control hyper­
glycaemic condition. T1DM affects 5 to 10% of people and is most
prevalent in children, therefore also known as “juvenile diabetes” or
“insulin-dependent diabetes” (Dabelea et al., 2014; Maahs et al., 2010).
Various antibodies are produced during T1DM, i.e., islet cell antibodies
(ICA). Glutamic acid decarboxylase (GADA), Insulinoma-association
protein two antibodies (IA2A), and anti-insulin (IAA) are three pri­
mary antibodies produced against the pancreas, and ICA is the first
autoantibody seen in T1DM patients. IAA antibodies were detected in
T1DM before supplementing exogenous insulin and produced against
the insulin and proinsulin. IA2A and GADA are produced by beta cells
Fig. 1. Shows the content wise prevalence of diabetes. The highest incidence of diabetes is found in western pacific (163 million) followed by south-East Asia (88
million), Europe (59 million), Middle East and North Africa (55 million), North America and Caribbean (48 million) and South and Central America (32 million).
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have been detected in 75–80% of T1DM patients. Glutamic acid decar­
boxylase (GADA) takes part in the synthesis of gamma aminobutyrate in
pancreatic cells. GAD65 is an antigenic target for T1DM. The human
leukocyte complex (HLA), particularly the DR...… and the DQ genes,
contributes significantly to the pathogenesis of TIDM (Bahendeka et al.,
2019). Genes including HLA-DQA1, HLA-DQB1, and HLA-DRB1 belongs
to the HLA family. The HLA complex helps the immune system differ­
entiate between native proteins and proteins produced by foreign
pathogens, including viruses and bacteria. Various genetic loci are
associated with TIDM such as CeCmotif, T-lymphocyte (proteins), MHC
(class II DQ-α1), MHC (class II DQβ1), HNF homeobox A, IL-2α, IL-6,
insulin, 2′ − 5′ -oligoadenylate synthetase 1, PTP (protein tyrosine phos­
phatase) and small ubiquitin-like modifier 4. Variations in these genes
present in altered chromosomes are responsible for modulation in the
synthesis of insulin. Various environmental conditions, stress and viral
infections are well recognized that implicates the etiology of TIDM
(Vermeulen et al., 2011) (Fig. 2).
modulates proglucagon gene expression and hence leads to the pro­
duction of GLP-1 (glucagon-like peptide-1) (McCarthy, 2010) (Fig. 3).
2.3. Type 3 diabetes mellitus
Type 3 diabetes (T3D) is generally a neuro-endocrine disorder that
signifies the progression of T2DM to Alzheimer’s disease (AD) (Maech­
ler et al., 2010). During the TID, various signaling pathways become
altered, such as insulin growth factor signaling, inflammatory responses,
acetylcholine esterase activity, ApoE4A allele and vascular dysregula­
tion of brain capillaries. Recent studies have established a link between
systemic dysfunction, including diabetes, and neuro-cognitive impair­
ment, including dementia, obesity, insulin resistance, diabetes, and
metabolic syndrome (Stoeckel et al., 2016). Individuals who have Alz­
heimer’s disease (AD) reveal down-regulation of insulin and neuronal
insulin receptors compared to the age-matched controls. These defective
pathways lead to gradual irregularity in the whole insulin signaling
cascade, which results in the progression of insulin resistance (Supale
et al., 2012). Stoeckel and co-authors investigated a link between
derangement of proteins, brain dysfunction, and cognitive impairment
(Stoeckel et al., 2016).
2.2. Type 2 diabetes mellitus
Type 2 diabetes mellitus, commonly known as adult-onset diabetes,
generally occurs during old age, and it comprises approximately 95% of
the diabetic population (Bhatti et al., 2017). The features of T2DM
including decreasing production of insulin and sometimes pancreatic
β-cell failure. It led to reduced transport of glucose into the liver, mus­
cles and adipocytes (Olokoba et al., 2012). The diagnosis of T2DM re­
mains unclear for many years, which results in chronic effects due to
persistent hyperglycaemia. It is a polygenic disorder that produces
because of the complex interaction among various genes and environ­
mental aspects. However, type 2 diabetes is associated with aging and
lifestyle conditions, such as sedentary habits, physical inactivity, ciga­
rette smoking, and continuous intake of alcohol significantly contributes
to the progression of T2DM severity. Type 1 diabetes and type 2 diabetes
have a genetic background; though, the genetic basis of TIDM is more
substantial compared to type 2 diabetes (T2DM). Ali et al. (2020) re­
ported that the threatened risk factors for T2DM are not area or organ
dependent but develops due to the multiple gene interactions located in
the entire genome. These genes include TCF7L2, PPARG, CDKAL1,
JAZF1, HHEX, SL30A8 and IGF2BP2. KCNJ11 encodes the islet
ATP-sensitive potassium channel (transcription factor 7-like 2) that
2.4. Gestational diabetes mellitus
Due to some irregular metabolic functions during pregnancy, glucose
level increases (hyperglycemia) and develops diabetic like conditions in
the mother, which directly affects the developing foetus known as
gestational diabetes (GDM). A hyperglycaemic condition in pregnant
women elevates the chance of adverse maternal, fetal, and neonatal
outcomes. The characteristics of gestational diabetes are carbohydrate
intolerance during pregnancy (Kharroubi and Darwish 2015). Women
suffering from gestational diabetes mellitus (GDM) are having a higher
risk for the subsequent progressions of frank diabetes. Gestational dia­
betes mellitus (GDM) could be a risk factor of neonatal mortality
because maternal hyperglycemia forces the developing foetus to secrete
more and more insulin, leading to the hyper-stimulation of foetal growth
and abnormally increased birth weight. After birth, this hyperglycaemic
might be reversed in women (Boles et al., 2017; Lorenzo et al., 2010).
Fig. 2. The diagram shows the progression of type 1 diabetes. Type 1 diabetes is a autoimmune disease produces due to the production of beta-cell specific
autoantigen production by producing different pro-inflammatory cytokines like IL-12. IL-12 production activates the Th0 CD4+ leads to the production of CTL CD8+.
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Fig. 3. The figure shows the progression of type 2 diabetes mellitus. During type 2 diabetes mellitus beta-cells of pancreases insulin in adequate quantity, however
body cells become insensitive to insulin and results in insulin resistance, activation of CDKAL1, MT1E results in ER stress and ultimately causes glucotoxcity and
lipotoxicty. Other changes such as PPARG activation leads to enhanced oxidation of free fatty acids, TCF7L2 activation leads to the production of proglucagon,
production of glucagon-like peptide-1 and increased rate of hepatic gluconeogenesis. Activation of HHEX leads to the impaired insulin secretion, JAZFA activation
leads to the apoptosis of beta-cells and defects in cell cycle.
3. Diabetes and other associated metabolic disorders
3.2. Effect of diabetes mellitus on brain
3.1. Diabesity
The hyperglycaemic condition may directly affect brain cells in both
type1 or type 2 diabetes mellitus. It decreases the pressure of oxygen in
the brain cells, which leads to a higher risk of stroke. Moreover, insulin
resistance is one of the significant causes of type 2 diabetes mellitus
because, during insulin resistance, adipocytes, muscle cells, and liver
cells do not use insulin effectively. Alzheimer’s disease (AD) pathogen­
esis is extensively understood to be driven by the production and
accumulation of the Aβ. Aβ is a protein break down by insulin, which
abnormally increases over a period in the brain. Insulin degrading
enzyme (IGE) degrades the insulin and amylin, and Aβ found in excess in
the brain of Alzheimer’s disease. Accumulation of Aβ a hallmark of AD in
the brain. The chronic diabetic condition causes impairments in cogni­
tive functions and also causes anxiety, depression, and memory
impairment and leads to the condition known as diabetic encephalop­
athy (Díaz-Gerevini et al., 2014; Dantzer and capuron 2015; Sickmann
and Waagepetersen 2015). Bathina et al. (2017) reported that neuro­
degeneration occurs in the brain hippocampus and hypothalamus re­
gion, especially in the Cornu ammonia, dentate gyrus and
paraventricular nucleus area. It has been reported that apoptosis is an
underlying potential mechanism for neuronal death, which regulates
different pathways like PI3K, Akt, mTOR. These pathways critically
contribute to the activation of the cell cycle, such as cell proliferation,
cancer, endurance and cell quiescence. Activation of PI3K pathways
phosphorylates, and it activates Akt and then translocates them into the
plasma membrane (Fulda et al., 2010). Akt signaling pathway activates
downstream events including CREB (Min et al., 2014), phosphatidyli­
nositol 3-phosphate (PtdIns-3 ps) and activating mTOR and these acti­
vated pathways affect transcription of p70 or 4EBP1 (Min et al., 2014;
Recent studies from the USA revealed that basal metabolic index in
the age group of 18% (6–11 years) and 21% (12–19) are having body
mass index of more than 95% in childhood period, and are having 45%
chances to develop type 2 diabetes. The term “Diabesity” explains the
physiological processes connection between obesity and diabetes
(T2DM). In the early 1970s, the “diabesity” term coined by Sims and
colleagues to explain how obesity and diabetes interlinked when both
metabolic dysfunctions are present in the individual (Excess body
weight is associated with the deposition of fats in visceral cavities that
increases insulin resistance, turning into type 2 diabetes. However,
many drugs are available in the market for the management or treatment
of T2DM, but the management of obesity at the clinical level is always
problematic to medical practitioners. Some surgical procedures are
used, such as bariatric surgery, which has proven the best approach for
managing obesity if untreated, may develop diabetes in many patients
(Leung et al., 2017). Assessment of body weight is not accurate for
obesity, but BMI that measures your weight about your height is general
parameters to assess obesity and its severity. WHO (World Health Or­
ganization) has kept some standards for assessing obesity, such as a
person having BMI higher than 30 is considered obesity class I. BMI
above 35 is considered Class II (indicates serious obese condition), and
BMI of more than 40 is considered class III (indicates that obesity is
severe). Patients who have type 2 diabetes and BMI above 32.5 should
go for minimally invasive bariatric weight loss and diabetes surgery or if
they suffer from any other obesity-associated comorbidity or BMI is
more than 37.5 without any comorbidity.
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Rafalski and Brunet 2011) and inhibits the p27 localizing Foxo1 in the
cytoplasm. Insulin is also essential to enhance the PI3K/Akt pathway
(Rafalski and Brunet 2011).
Moreover, this pathway is necessary to promote the proliferation and
growth of adult and neural stem cells. Therefore, this pathway may lead
to neurons apoptosis and memory impairment. It has been reported that
PI3K signaling pathway stimulates cell survival and also participates in
cell apoptosis in the CNS. Akt is, the primary protein of PKB affecting the
PI3K pathway, regulation of glucose metabolism. This protein supports
the functioning of insulin and translocated the glucose transporter type
4 (GLUT4) upto the plasma membrane, and mediates glucose uptake.
Akt also phosphorylates glycogen synthase kinase 3, which increases
glycogen synthase activity and promotes glycogen synthesis (Bathina
and Das 2018). Furthermore, Akt is also most important for the inhibi­
tion of apoptosis. It has been studied that Akt signaling pathways are
involved in the pathophysiological processes of diabetes mellitus and its
complications (Tsuchiya et al., 2014).
Reduction in consumption or deficiency of n-3 PUFAs is associated
with a higher prevalence of T2DM (Bathina and Das, 2018). Several
studies evidenced that supplementation of n-3 PUFAs can improve in­
sulin sensitivity and reduced macrophage accumulation in adipose tis­
sue. DHA administration promotes lateral segregation and alters the
composition of cholesterol-rich microdomains known as lipid rafts
which serve as membrane platforms for multiple signaling events (Rizvi
et al., 2015). DHA-dependent functions are associated with altered
protein rearrangement and co-localization membrane compartments
leading to altered downstream events, including activating
PI3k-Akt-mTOR signaling in the brain (Shaikh et al., 2009). However, it
is yet to be understood how n-3 PUFAs and other fatty acids prevent
obesity-linked inflammation, insulin resistance and mechanisms.
Cognitive dysfunction and diabetes coincidental causes pathological
changes, including alterations in anti-oxidants and elevation in inflam­
matory markers. The distribution of insulin receptors varies viz olfactory
bulb, hypothalamus, hippocampus, cerebral cortex, striatum, and cere­
bellum are present in higher density (King et al., 2016) and mediates
translocation of glucose transporter (GLUT-4), regulates memory for­
mation and other cognitive functions by activation of phosphorylated
Gsk-3β, cAMP/CREB involved in cell survival. It is known to activate
PI3K phosphorylates and activate AKT localized on the plasma mem­
brane (King et al., 2016). AKT, in turn, activates PtdIns-3 ps and mTOR
(Dan et al., 2016). Insulin is one of the essential factors that enhance
PI3K/AKT pathway (Koh and Lo 2015) (Fig. 4).
3.3. Effect of diabetes mellitus on cardiovascular diseases
Both “type 1 diabetes mellitus” and “type 2 diabetes mellitus” leads
to several cardiovascular diseases, including heart failure, arterial dis­
ease, heart muscle disease, congenital heart disease and coronary heart
disease (CHD). Sarwar et al. (2010) reported that type 2 diabetic pa­
tients are 2–4 times susceptible to cardiovascular diseases, and the
prevalence of diabetic heart disease has markedly increased over the
past period. It is considered one of the leading causes of the mortality
rate in diabetic populations (Jamnitski et al., 2013). Different implica­
tions are responsible for cardiovascular diseases, such as increased tri­
glyceride, low-density lipoprotein (LDL) and very-low-density
lipoprotein (VLDL) level. Previous studies reported that not only TG but
there are other factors responsible for the occurrence of CVDs as in 55%
of the diabetic population but they also suffering from heart disease due
to some other reasons (Kasznicki et al., 2014; Petrie et al., 2017; X.Y.
Yang et al., 2017).
It has been reported that diabetes causes alteration in the myocar­
dium structure and function, i.e., ischemic heart disease and hyperten­
sion (León et al., 2015). The alteration distinguishes diabetic
cardiomyopathy in cardiac energy metabolism, remodeling of cardiac
functions, and diastolic dysfunction (Lorenzo-Almorós et al., 2017).
Other metabolic dysfunctions such as dyslipidemia, increased free fatty
Fig. 4. Type 3 diabetes is a new type of diabetes results due to metabolic and neurocognitive impairments. Type 2 diabetes also initiates type 3 diabetes and leads to
metabolic dysfunctions, inflammation and brain dysfunction cognitive impairments and finally results in Alzheimers diseases. Moreover, type 3 diabetes leads to the
activation of ApoE4A that leads to the alteration in lipid metabolism, increased rate of apoptosis, increased glycosylation of Hb, cognitive impairments and finally
leads to the Alzheimer’s diseases.
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acids, hepatic glucose production, and insulin resistance causes diabetic
cardiomyopathy (Al-Rasheed et al., 2016,; 2017; Boudina and Abel
2010; Huo et al., 2016; Saad et al., 2017). Moreover, chronic hyper­
glycemia causes alteration in myocardial cells such as increased influx of
sugar (polyol) pathways, increased AGEs and activate PKC enzyme
(Adebiyi et al., 2016; Brunvand et al., 2017; Pappachan et al., 2013) and
ultimately leads cellular injury (Barman et al., 2015). These metabolic
complications cause ROS production, which reduces antioxidant en­
zymes such as glutathione reductase (GR) and AGEs formation (Brun­
vand et al., 2017). Decrease activities of antioxidative enzymatic
systems lead to increased oxidative stress that, in turn, leads to damage
in DNA and ultimately causes the death of cardiomyocytes.
Hyperglycaemic condition directly changes the calcium (Ca2+) ho­
meostasis and components associated, which leads to alteration in dia­
stolic pressure. During diabetes, uptake of glucose through glucose
transporter (GLUT)− 4 gets reduced, which leads to the decreased
glucose level in the myocardium in case of insulin-dependent (Picatoste
et al., 2013; Yan et al., 2017). However, uptake of fatty acid (FA) be­
comes increased that leads to the accumulation of lipid, utilization
(triglyceride TG and ceramides) in the heart, reduced free radical
scavenging ability of mitochondria and accelerates the generation of
free radical (de Jong et al., 2017; Snel et al., 2012). Furthermore, the
prolonged hyperglycaemic condition causes increased glycated circu­
latory proteins (Hristova et al., 2014). Further, it has been reported that
there is a strong relationship between elevated glycosylated hemoglobin
(HbA1c) level and cardiovascular diseases (CVDs). Jehan et al. (2016)
reported that increased HbA1c during diabetes causes severe dysfunc­
tion in left ventricular (LV) diastolic pressure. Nelson (2013) reported
diabetic chronic dyslipidaemia such as high-density lipoprotein and
high lipoprotein (Chehade et al., 2013; Dake and Sora 2016) and both
quantitative and qualitative abnormalities of lipoproteins is a significant
cause of cardiac complications and atherosclerosis (Linton et al., 2019).
Al-Rasheed et al. (2016) revealed that the prevalence of cardiovascular
diseases is higher due to increased triglycerides, total cholesterol level
and decreased level of high-density lipoproteins. Martín-Timón et al.
(2014) reported that hyperglycaemic condition increased the risk of
microvascular and macrovascular complications in diabetic patients.
Diabetic induced dyslipidaemia causes abnormal lipid accumulation in
cardiac myocytes, resulting in lipo-apoptosis and myocardial fibrosis
and contractile dysfunction.
Moreover, abnormal elevation in lipids may lead to increased pro­
duction of reactive oxygen species (ROS), oxidative degradation of
lipids, and membrane destabilization, leading to dysfunction in car­
diomyocytes through apoptosis. Gupta et al. (2013) that accumulation
of lipids causes worst myocardial insulin resistance, lipotoxicity,
increased triglyceride level, altered Ca2+ homeostasis and impairs
glucose uptake. Fatemi et al. (2014) evidenced that accumulation of
lipids in the myocardiocytes leads to the progression of DCM, mainly left
ventricular (LV) remodeling. The consequences of irregular fatty acids
availability or their uptake increase the level of intracellular long-chain
fatty acyl-CoA in cardiomyocytes (Ritterhoff and Tian, 2017). However,
cardiomyocytes have limited capacity to store lipids and excessive
/overloading of lipids results in lipotoxicity, which might be a mecha­
nism for cardiac dysfunction. Oxidation of FA increases the intracellular
long-chain fatty acyl-CoA concentration results in the production of
lipotoxic intermediates such as ceramide and diacyl-glycerol. These
lipotoxic intermediates may dysregulate the signaling pathways
affecting ATP production, insulin sensitivity and cardiomyocytes
contractility (Wende et al., 2012). Previous research reports suggested
both systolic and diastolic dysfunction in diabetic patients (Lei et al.,
2013).
patients suffer from renal failure. In diabetic patients, progressive loss of
renal function is diagnosed by increased proteinuria, and low glomer­
ular filtration barrier rate led to elevated urinary albumin defecation
(Gorriz and Martinez-Castelao, 2012). It is well known that chronic
hyperglycemia is a pro-oxidative factor that induces the overproduction
of reactive oxygen species (ROS) by the mitochondrial
electron-transport chain. Increased level of ROS causing cell membrane
loss and organ damage or failure (Sekiou et al., 2021).
Experimental and clinical observations have indicated that hyper­
glycemia may directly or indirectly contribute to the excessive produc­
tion of free radicals in the intracellular fluid (Famurewa et al., 2020).
Free radicals and oxidative stress are the major causative factors of
hepatorenal tissue damage (Ibegbulem et al., 2016). Compromised renal
functions are characterized by elevated levels of plasma creatinine, urea
and uric acid. Previous research studies reported that progression in
nephropathy could be regulated by controlling hyperglycemia (Chikezie
et al., 2015). Diabetic nephropathy (DN) resulted due to the interplay of
several distinct but interconnected high glucose- (HG-) induction and
initiation of pathways by critical factors, such as oxidative stress and
advanced glycation end-products (AGEs). These factors trigger different
abnormal signaling pathways, including inflammation, cellular prolif­
eration, and interstitial matrix expansion (Sivakumar et al., 2010).
Oxidative stress and inflammation cause the induction of each other,
resulting in a vicious circle leading to glomerular sclerosis and inter­
stitial fibrosis. Nuclear factor kappa-B (NF-κB), monocyte chemotactic
protein- (MCP-) 1, and intercellular adhesion molecule- (ICAM-) 1 are
the primary inflammatory mediators. These are attracted and activated
by MCP-1 and helped by ICAM-1 (promoted by NF-κB), circulating
monocytes invade the kidney. DN is characterized by proliferation in
glomerular mesangial cells occurs and leads to mesangial hyper­
cellularity. Glomerulosclerosis is another hallmark of DN and is char­
acterized by a gradual increase in the level of proteins of extracellular
matrix (ECM) (mostly collagen types I, III, and IV and fibronectin) and
gets inexorably accumulated in the mesangium, either by lumping
together in nodular lesions or by diffusing, invades and expands in the
interstitial space separating the glomerular loops (Dragos et al., 2020).
The excessive production and accumulation of ECM proteins mainly in
the mesangial cells, but the low activity of mesangial matrix metal­
loproteinases (MMPs) causes their excessive disposition. Moreover,
these ECM proteins also get accumulated in the glomerular interstitium,
tubular interstitium and the glomerular basement membrane and cause
more and more thickness. Alteration in the glomerulus and tubu­
lointerstitium occurs due to the epithelial-mesenchymal trans-­
differentiation (EMT). Different growth-promoting pathways associated
with DN are activated by “p38 mitogen-activated protein kinase”
(p38MAPK), “mammalian target of rapamycin” (mTOR), and phospha­
tidylinositol 3 kinase (PI3K)/Akt/glycogen synthase kinase- (GSK-) 3β
(Dragos et al., 2020). However, it has not been understood that whether
the activation of PI3K/Aktis contributing as protectively or deleteri­
ously. Endothelial dysfunction and endoplasmic reticulum (ER) stress
are associated with the pathophysiological changes occurring during the
DN (Molitch et al., 2015; Yan et al., 2015).
3.5. Effect of diabetes mellitus on eyes
Diabetic Retinopathy (DR...…) is a microvascular complication; it
primarily affects the retinal microvasculature and leads to the loss of
choriocapillaris (Ambiya et al., 2018). Moreover, this study also re­
ported that diabetic retinopathy causes Atrophy and dropout of the
choriocapillaris in the eyes (Ambiya et al., 2018). Due to the damage in
the choroid deficiency of oxygen and nutrients occurs in the outer retina
and the retinal pigment epithelium. Loss/deficiency of oxygen results in
a decrement in the cone cells. Ambiya et al. (2018) reported that
perfusion decreases in early diabetic retinopathy as studied through
Doppler fowmetry. However, there are some contradictory results
regarding the choroidal thickness (CT) with diabetes or with the
3.4. Effect of diabetes mellitus on renal system
Kidney failure is one of the most common and critical complications
that appear in diabetic patients. It was reported that 40% of diabetes
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During ovarian follicular development, corpus luteum formation, DNA
damaging, and endoplasmic reticulum (ER) stress triggers apoptosis of
granulosa cells, leading to abnormal follicular development (Robinson
et al., 2009). During the ovulatory cycle and formation of the corpus
luteum process of angiogenesis occurs for the transport and supply of
nutrients through blood vessels of theca cells into the follicular fluid.
Vascular endothelial growth factors play a significant role in developing
follicles and theca cells (Schernthaner et al., 2013). The ovary HIF1α
(hypoxia-inducible factor 1α) stimulates the vascular endothelial growth
factor (Agarwal et al., 2008; Pan et al., 2015). Zhang et al. (2017) re­
ported that the high glucose level inhibits the vascular endothelial
growth factor, and angiogenesis becomes suppressed.
In the tyrosine kinase signaling pathway, IGF-I receptors bind to
different ovarian cells like stromal cells, theca cells, granulosa and theca
cells, granulosa in the ovary. FSH secreted steroid hormone potentiated
by insulin, simultaneous exposure of insulin, and FSH increasing the
secretion of estrogen in granulosa cells (Willis et al., 1998). Insulin en­
hances folliculogenesis and the development of preovulatory follicles
(Franks et al., 1999). It promotes the maturation of follicles and sup­
presses apoptosis. High glucose level increased reactive oxygen species
involved in the HIF1α-VEGF pathway suppression, and CD31 is an
endothelial marker suppressed by hyperglycaemic condition.
Moreover, it damages ovarian cells and causes endothelial dysfunc­
tion (Y. Wu et al., 2017). Y. Wu et al. (2017) revealed that diabetes
causes DNA damage and ER stress, leading to excessive granulosa cells
apoptosis. Therefore, it causes abnormal ovarian function (suppresses
ovarian angiogenesis) by inhibiting the HIF1α-VEGF signaling pathway
(Fig. 5).
progression of DR...…; Xu et al. (2013) and Kim et al. (2013), reported
that diabetic retinopathy (DR...…) leads to the increase in thickness,
while as other studies reported that the thickness of choroid decreases
during the severe Diabetic Retinopathy (Adhi et al., 2013; Lee et al.,
2013; Querques et al., 2012; Regatieri et al., 2012; Vujosevic et al.,
2012). Xu et al. (2013) reported that the thickness of the subfoveal
choroid increases during diabetes.
Sheth et al., 2017 reported that diabetes causes choroidal thinning
and DR...… also causes muscular macular ischaemia. Subfoveal
choroidal thickness increases with age (Maruko et al., 2016; Ooto et al.,
2015). Moreover, persons of the mean age group suffering from prolif­
erative diabetic retinopathy were significantly lower than the mean age
group suffering from non-proliferative diabetic retinopathy. The chronic
diabetic condition causes significant thinning of the choroid Subfoveal
(Ambiya et al., 2018).
3.6. Effect of diabetes mellitus on female reproductive system
In mammals, ovarian follicles develop from primordial follicles,
necessary for the normal functioning of the female reproductive system.
During follicular development, granulosa cells help provide energy for
the formation of oocyte and are also essential for developing the corpus
luteum. The oocyte is surrounded by granulosa cells and covered by an
outer layer of theca cells. A Granulosa cell is also ensuing embryonic
development and also plays an essential role in corpus luteum forma­
tion. Recent studies reported that chronic hyperglycaemia harms the
development of follicles and results from infertility (Grindler and Moley
2013; Niu et al., 2014; Y. Wu et al., 2017). Recent studies revealed that
obesity and diabetes significantly accelerate the apoptosis in granulosa
cells (Wu et al., 2015). It has been reported that during diabetes,
excessive apoptosis and oxidative stress causes various complications Y.
Wu et al. (2017). The increased oxidative stress causes DNA damage,
apoptosis and suppressing maturation of oocytes (Z. Wu et al., 2017).
3.7. Effect of diabetes mellitus on male reproductive system
Abnormal glucose homeostasis has adverse effects on reproductive
functions in the male gametes. Glucose concentration varies depending
Fig. 5. This figure is showing the effect of diabetes on the male and female reproductive system. (a). β cell dysfunction and insulin resistance leads to the activation of
IGF-1, its act on leydig cells and decreases the testosterone level and finally can lead to the reduction and sperm production and infertility. Moreover, IGF-1 activation
can lead to decreases activity of sertoli cells, disrupts normal spermatogenetic process and decreases production of sperms and infertility. Decreased function of
sertoli cells affects the capacitation process of sperms. (b). During diabetes hyperglycemia leads to the production of AGE and RAGE, abnormalities in folliculo­
genesis, follicular apoptosis, early menopause and ultimately to the infertility. Insulin deficiency causes decreased production of leptin, reduced production of
gandotrophins (LH and FSH), and menstrual irregularities and finally affects fertility. Hyperinsuleminia leads to the activation of IGF-receptors and leads to the
increased production of androgens. However, administration of curcumin, genistein, EGCG and rutin can inhibits this alteration caused by diabetes.
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on the functions of different organs. Therefore, in vivo spermatogenesis
process depends upon glucose metabolic rate. Transportation of glucose
through blood testes barrier (BTB), which maintains metabolites in the
fluid of testis and plasma (Alves et al., 2013). In diabetic condition,
testicular function and spermatogenesis are affected. Various studies
revealed that type 2 diabetic patients have low testosterone level
(hypogonadism condition). The ratio is one out of four men. Low
testosterone levels can cause infertility which reduces sperm count and
erectile dysfunction. Diabetes mellitus varies HPG axis, responsible for
the ineffectiveness of diabetes-related problem (Dias et al., 2014). It has
been reported that during diabetes, gonadotrophin hormone increases
and the ratio of LH/FSH also changes. Moreover, diabetic rats showed
reduced pituitary sensitivity. Alves et al. (2013) that DM causes
alteration in sex hormones. Diabetes mellitus (DM) constitutes 51%
of sub-fertility among males (Fig. 5).
mediated incretin-like actions. Metformin may induce direct weight loss
in overweight and obese individuals as a risk for diabetes (Inzucchi
et al., 2014). However, metformin has some contradictions because its
prescription in patients with advanced stages of renal insufficiency
revealed by glomerular filtration rate (GFR). Suppose the use of met­
formin is significantly diminished GFR. I Patients should be advised to
discontinue the medication if nausea, vomiting, and dehydration
occurred due to any other cause (to prevent ketoacidosis). Metformin is
highly efficient when there is enough insulin production; however,
when diabetes reaches the state of failure of β-cells and resulting in a
type 1 phenotype, and metformin loses its efficacy. It can cause a lack of
vitamin B12 and folic acid (Fogelman et al., 2016). Non-insulin medi­
cations introduced in addition to the initial therapy lowers A1C around
0.9–1.1%. Four major drug classes were compared (sulfonylurea, DPP-4
inhibitor, GLP-1 analogue, and basal insulin) over glycaemic control and
other psychosocial, medical, and health economic outcomes (Nathan
et al., 2013).
4. Allopathy drugs used to treat diabetes mellitus
Different types of glucose-lowering (oral) drugs are available in the
market for the treatment of diabetes. First and second-line treatment
drugs are available to control diabetes mellitus. The allopathic drug
categories included: “sulfonylureas”, “biguanides”, “alpha-glucosidase
inhibitors”, “thiazolidinediones”, “SGLT2 Inhibitors”, “DPP-4 In­
hibitors” (Bader et al., 2017). Antidiabetic drugs used to manage dia­
betes are available in the market. Still, these drugs have acute side
effects such as i.e., liver toxicity, nephrotoxicity, heart diseases, hypo­
glycaemic conditions, or common side effects, i.e., stomach-related
problems and nausea (Ivemeyer et al., 2012). Allopathic drugs used as
antidiabetic are listed below:
4.3. Alpha glucosidase inhibitors
Alpha-glucosidase inhibitors delay carbohydrate absorption and
control the release of the glucose-dependent insulinotropic polypeptide
(GIP). GIP increases glucose absorption from the lower intestine. Acar­
bose, voglibose and miglitol are α-glucosidase inhibitors (Kalra 2014).
The bioavailability of acarbose and voglibose is deprived because the
intestine does not absorb these drugs. Instead of this, miglitol is a new
form of alpha-glucosidase inhibitor absorbed quickly in the small in­
testine. Miglitol suppresses the blood sugar level more efficiently more
than other inhibitors. It has been revealed that treatment of α-glucosi­
dase inhibitor given to diabetic patients has impaired glucose tolerance
and hyperglycaemic condition (Emoto et al., 2012). Additionally, pre­
vious studies reported that α-glucosidase inhibitor causes a reduction in
the risk of progression to DM and decreases in development of hyper­
tension and the risk of cardiovascular disease. Previous studies suggest
that α-glucosidase inhibitors (Acarbose, Miglitol, Voglibose) improve
the release of GLP-1. In contrast, it suppresses the release of the gluco­
se-dependent insulinotropic polypeptide (GIP) by increasing glucose
absorption from the lower small intestine. All α-glucosidase inhibitors,
acarbose and miglitol, are effective in lowering glucose level as well as
HbA1c (Chaudhury et al., 2017).
4.1. Sulfonylureas
Sulfonylureas lower glucose level. Blocking the ATP potassium
channels increases the insulin secretion in beta cells and slows down
gluconeogenesis in the liver. Sulfonylureas inhibit the breakdown of
fatty acids and decrease the allowance of insulin secretion in the liver.
Presently, it is recommended that sulfonylureas be used as a second-line
treatment to manage diabetes mellitus (type II). One of the significant
side effects of sulfonylureas is hypoglycaemia, and minor side effects are
nausea, headache, dizziness and weight gain/obesity. Sulfonylureas
treatment/medicine has contraindications because of having liver and
kidney dysfunctions in patients and pregnant women. Finally, it leads to
a low glucose level in infants. Aspirin, allopurinol, sulfonamides, and
fibrates are the drugs used to avoid the caution of hypoglycaemia,
reduce the effect of sulfonylureas (Chaudhury et al., 2017).
4.4. Thiazolidinediones
These two drugs, i.e., biguanides, Thiazolidinediones improves the
action of insulin. Other drugs of this class include rosiglitazone and
pioglitazone. TZDs are used to enhance glucose uptake in the blood cells,
liver cells and muscle cells. Action mechanisms, i.e., the deposition of
free fatty acids, reduction in inflammatory cytokines, rising adipokine
and protein hormone to the breakdown of fatty acids. However, more
health concerns than benefits, such as heart failure, are caused by
insulin-TZD combined therapy. Therefore, for first-line therapy or stepup therapy, TZDs are not preferred (Chaudhury et al., 2017).
4.2. Metformin (Biaguanide)
Biguanide and its derivatives are prescribed to manage diabetes
mellitus (Viollet et al., 2012). Metformin is the first-line treatment (oral
drug) for the management of T2DM. Metformin activates adenosine
monophosphate-activated protein kinase in the liver, causing hepatic
uptake of glucose and inhibiting gluconeogenesis through complex ef­
fects on the mitochondrial enzymes (Viollet et al., 2012). Metformin is
highly commonly prescribed due to minor side effects, lower risk of
glucose level (hypoglycaemia) and weight gain. Metformin is shown to
disturbs the progression of T2DM, reduces the risk of complications, and
decreases mortality rates by decreasing the synthesis of glucose in the
hepatic system (gluconeogenesis) and sensitizing peripheral tissues to
insulin (Viollet et al., 2012).
Additionally, it improves insulin sensitivity by activating insulin
receptor expression and enhancing tyrosine kinase activity. Recent ev­
idence also suggests that metformin lowers the level of lipids in the
plasma through a peroxisome proliferator-activated receptor (PPAR)-α
pathway and prevents cardiovascular diseases. Metformin decreases
food intake, possibly occurs by glucagon-like peptide-1 (GLP-1)-
4.5. SGLT2 inhibitors
SGLT2 or “Sodium-glucose co-transporter inhibitors” is a new class
of glucosuric agents that lowers the glucose level by blocking the
reabsorption of glucose in the kidney. SGLT2 inhibitors provide glucose
lowering by blocking the reabsorption of glucose in the proximal renal
tubule, decreases blood pressure. Some SGLT2 inhibitors drugs (cana­
gliflozin, empagliflozin, and dapagliflozin) are available in the market
with minor side effects of abdominal pain, nausea, vomiting, and
headaches. Because of their glucose-independent mechanism of action,
these drugs may be effective in advanced stages of T2DM if pancreatic
β-cell reserves are enduringly generated. These drugs sometimes cause
weight loss and a decrease in BP (blood pressure). SGLT2 inhibitors
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occasionally cause ketoacidosis. Hence, patients should stop taking
SGLT2 inhibitor and seek medical attention immediately if they feel
nausea or vomiting or even non-specific features like tiredness or
abdominal discomfort (Chaudhury et al., 2017; Riser Taylor and Harris
2013).
2011).
5.1. Catechins
Catechins belong to the flavonol family, extracted from tea, red wine
and cocoa (Cheng et al., 2015). Recent studies reported that their
different isoforms of Catechins such as epicatechin
(EC), epicatechingallate (ECG), epigallocatechin (EGC) and
epigallocatechin-3-gallate (Fig. 6). Cheng et al. (2015) reported that
catechins protect or fight against diabetes mellitus (DM) and its other
metabolic complications. In DM, EGCG inhibits hepatorenal complica­
tions by regulating the phosphoenolpyruvate enzyme that helps in
gluconeogenesis. It has been reported that catechins decrease the level
of fatty acids, triacylglycerol and cholesterol through the inhibition of
gene expressions, whereas up-regulates the expression of GLUT1 and
GLUT4 transporter and then normalizes the blood glucose level (Cao
et al., 2007; Wolfram et al., 2006). Fu et al. (2017) studied that Cate­
chins activates the erythroid-derived-2 transcription factor activated
and activated proteins that protect against oxidative stress. It has been
reported that Catechins activates the expression of SIRT1 and decreases
cardiovascular complications.
SIRT1 protein is associated directly with the RelA/p65 subunit of NFκB and deacetylates the RelA/p65 subunit, critical for NF-κB transcrip­
tional activity. Previous studies have shown that SIRT1 also deacetylates
and suppresses the transcription activity of activator protein-1 (AP-1),
leading to down-regulation of COX-2 gene expression (Zhang et al.,
2011). SIRT1 helps to improve NF-κB activation and proinflammatory
cytokines release, whereas it activates SIRT1, which inhibits the activity
of NF-κB mediated inflammatory mediators. Previous studies have
shown that the histone acetyltransferase (HAT) enzyme regulates ne­
crosis factor (NF-κB) activity and deactivated by hypoacetylation of the
RelA/p65 subunit. SIRT1 regulates the inflammatory response and
causes chronic inflammatory diseases (Singh et al., 2010). Furthermore,
the role of SIRT1 in the progression of metabolic diseases (Rajen­
drasozhan et al., 2008). SIRT1 activation by resveratrol leads to
down-regulation of NF-κB, which encodes the proinflammatory factors,
4.6. DPP-4 inhibitors
Dipeptidyl peptidase four inhibitors include sitagliptin, saxagliptin,
vildagliptin, linagliptin, and alogliptin. These drugs have used a mon­
otherapy or in combination with metformin, sulfonylurea, or TZD,
similar to other oral antidiabetic drugs. The gliptins have not been re­
ported to cause a higher incidence of hypoglycemic events compared
with controls. DPP-4 inhibitors (Dipeptidyl peptidase four inhibitors)
affect postprandial lipid levels. Vildagliptin for four weeks treatment
reduces postprandial plasma triglyceride and apolipoprotein B-48-con­
taining triglyceride-rich lipoprotein particle metabolism after a fat-rich
meal in T2DM patients who have previously not been exposed to these
medications. In diabetic patients with coronary heart disease. It has been
confirmed that treatment with sitagliptin improved coronary artery
perfusion and cardiac function. However, intake of sitagliptin or met­
formin and sitagliptin causes acute pancreatitis (Chaudhury et al.,
2017).
5. Protective role of polyphenols in diabetes mellitus
Plant-derived polyphenols comprise polyphenolic compounds pre­
sent in our diets, such as spices, fruits, cereals, or many others. More
than 8000 phenolic compounds have been identified according to their
biological function or chemical structure (Ignat et al., 2011; Lake­
y-Beitia et al., 2015). Polyphenols are excellent anti-inflammatory or
antioxidant molecules, directly proportional to the number of hydroxyl
groups present in the phenolic structure. This antioxidative property
makes them capable of polyphenols interfering in the oxidation of bio­
molecules by promptly donating protons to neutralize the free radicals
or reacting with radicals to generate stable compounds (Ajila et al.,
Fig. 6. Chemical structure of various bioactive components.
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i.e., COX-2, MMPs and iNOS (inducible nitric oxide synthase) (Chung
et al., 2010; Navik et al., 2019). These factors are inhibited by catechin
(Biswas et al., 2013). Therefore, the role of catechins in alteration of
SIRT1 and controlling the inflammatory response. It can modulate a
variety of pro-inflammatory pathways via activating SIRT1, thereby
inhibits NF-κB and AP-1 pathways. SIRT1 controls FOXO3a induce cell
cycle arrest and high SIRT1 activity endorses cell survival. Cell survival
signifying SIRT1, FOXO-dependent response cause cell death. FOXO1 is
also involved in the protection of SIRT1 against apoptosis in car­
diomyocytes. SIRT1-mediated COX-2 expression decreases oxidative
stress-induced kidney cell apoptosis (Navik et al., 2019; Teixeira et al.,
2019). The Catechins, EC, epicatechin gallate (ECG), epigallocatechin
(EGC) and epigallocatechin-3-gallate (EGCG) has been very effective for
neuronal injury during AD (Cheng et al., 2019). During stress conditions
like prediabetic conditions, lactate is one of the essential metabolic fuels
for the proper functioning of the cerebral cortex. During prediabetic
conditions, the antioxidative potential of the cortex decreases due to
elevation in oxidative reactions in lipids and proteins.
Hyperglycaemia decreases lactate accumulation in the brain cortex
by increasing lactate metabolism (increased LDH activity) (Nunes et al.,
2015). It has been reported that catechins increase the antioxidant po­
tential and reduces the peroxidative lipid damage of lipids and proteins.
Moreover, catechins up-regulate the expression of Catalase enzymes.
Recent findings evidenced that SIRT1 expression enhances antioxidant
activity and reduce oxidative stress. In addition to this, Catechins also
increase the activity of the catalase (CAT) enzyme, superoxide dismutase
(SOD) and glutathione peroxidase GSH-Px (Frei et al., 2003; Özyurt
et al., 2016; Y. Wu et al., 2017). EGCG helps to neutralize free radicals,
maintain homeostasis. Ozyurt et al., (2016) reported that EC, EGC and
EGCG inhibit carbonylation of plasma proteins (an irreversible modifi­
cation in oxidized proteins) produced by hyperglycaemic induced ROS
generation. The anti-inflammatory properties are further highlighted
since EGCG counteracts the effects of cytokines (IL-1, IL-6, TNF-α, IL-12
and IL-18) in insulin secretion (Zhang et al., 2011). Wimmer et al.,
(2015) reported that EGCG helps lower blood glucose level and in­
creases insulin secretion, thus facilitating hyperglycaemia. Such gluco­
sidase inhibitors, acarbose and miglitol, are used to inhibit α-amylase
and α-glycosidase (two intestinal enzymes that hydrolyze carbohy­
drates) to decrease the prevalence of hyperglycaemia. However, these
inhibitors cause significant side effects such as intestinal disturbances
(diarrhea, constipation, nausea, flatulence and vomiting) and Pneuma­
tosis cystoids intestinalis. Yilmazer-Musa et al., (2012) studied Cate­
chins (EC, EGC, ECG and EGCG) are potential molecules to inhibit
α-amylase activity (from human saliva) and α-glycosidase (from
Saccharomyces cerevisiae).
loss of memory, EGCG has been proved to combat the memory loss and
other neuronal damage by inhibiting cholinesterases like AChE and
CChE (Okello et al., 2004) in a dose-dependent manner ranging from
0 to 0.3 mg/ml. For the inhibition of AChE the IC50 value of EGCG
ranges from 0.03 to 0.06 mg/kg, BChE, IC50 value if 0.05 mg/ml
respectively.
Anjaneyulu et al. (2003) described that Catechin could boost the
activity of antioxidant enzymes by improving catalase activity, radical
scavenging activity and inhibit oxidative damage by enhancing the ac­
tivity of superoxide dismutase. It helps to promote the p53, p21 and
nuclear factor kappa B(NF-κB) expression, which induces the apoptosis
of vascular (smooth muscle cells) (Hofmann et al., 2004). In vivo study,
Catechin can lower the deposition of cholesterol and its oxidation
products in the wall of an artery and free radical activity, as a result,
improve circulation of blood. Yu et al. (2015) found that Catechin may
improve good cholesterol, LDL cholesterol and apolipoprotein B to
decrease the fat deposition in the blood. Furthermore, Catechin cataly­
ses the SOD activity in the liver, and inhibit the oxidation of LDL, thus
reducing the risk of cardiovascular diseases (Trnkova et al. 2011; Xiong
et al., 2020).
Moreover, Alves et al. (2015) studied that white or green tea intake
helps to decrease oxidative stress, improve total antioxidant capacity
and lipid peroxidation level. Therefore, the scavenging property of
Catechin may decrease the hydroxyl concentration and lipid-free radi­
cals to terminate the oxidation of lipids. Green tea suppresses lipid
peroxidation by utilizing its antioxidative action. By Fenton reaction,
iron and copper are metal chelating ions that exert antioxidative action,
preventing the generation of hydroxyl ions (Li et al., 2013). These
chelating ions (Cu2+, Fe2+) helps to protect DNA and to prevent DNA
alteration.
The white or green tea intake enhanced antioxidant potential and
decreased oxidative degradation of lipids in the testicular tissue (Oli­
veira et al., 2015). PFK1 (phosphofructokinase1) is a highly regulated
enzyme and key branching point involved in glycolysis. In the male
reproductive system (epididymis), the level of PFK1 was decreasing in
high blood glucose level in patients. Interestingly, the level of PFK1 is
restored by the consumption of white tea. In Catechin, B-ring is the
principal site of antioxidant activity and trihydroxy structure amplified
on B and D-rings of Catechins (like EGCG) and ability to quench free
radicals (Perron and Brumaghim 2009; Sang et al., 2002). Oxidative
stress is one of the main factors responsible for male and female infer­
tility (Wang et al., 2014). Supplementation of tea extract improves the
quality and viability of sperm through estrogen receptors in different
concentrations reported by De Amicis et al. (2012). Long-term Catechin
like EGCG is used to better the permeability of the blood-testis barrier,
which suppresses testosterone activity derived from cholesterol.
Therefore, it protects against the cell apoptosis of germ cells and
reproductive dysfunctions (Ding et al., 2017).
In addition, in the green tea treated group, testosterone level in­
creases significantly and improved histopathology of the testis (Sato
et al., 2010). Catechin attenuates acrylamide-induced testicular damage
and germ cell damage (Yassa et al., 2014). A previous study found that
Catechin restored the enzymatic activity such as glutathione S trans­
ferase and also increased the concentration of sperm in the male
reproductive system (epididymis). Catechin decreases DNA damage,
oxidative degradation of lipids and protein carbonylation (Zanchi et al.,
2015). In females, retrograde menstrual flow and abnormal growth of
cells is the leading cause of infertility. Endometriosis can cause ovarian
cysts, abdominal pain and infertility. It inhibits the extracellular
signal-regulated kinase (ERK) and generation of ROS through inhibition
of proliferated cells (Manohar et al., 2013; Matsuzaki and Darcha,
2014). EGCG was found to inhibit cell proliferation and angiogenesis,
which decrease the size of tissues that lie inside the uterus in diabetic
patients (Laschke et al., 2008; Trnková et al., 2013; Xu et al., 2009,;
2011). Intake of catechin-rich products can considerably recover the
motility and viability of sperm. It has been noted that Catechin improves
5.1.1. Anti-apoptotic activity of catechins against diabetic induced neuronal
damages
Cheng et al. (2015) studied that EGCG regulates the apoptotic
pathways by suppressing the expression of pro-apoptotic genes,
including Bcl-2 like protein 4 (Bax) and Bcl-2 associated death promoter
inducing anti-apoptotic genes, such as B-cell lymphoma 2 (Bcl-2), Bcl-2
like protein two and β-cell lymphoma-extra, and suppresses the function
of caspase-3, and hence prevents the death of neuronal cells. EGCG
stimulates the phosphatidylinositol three kinase/protein kinase b
(PI3k-Akt) signaling pathways increasing the survival rate of cells and
“waking up” cells from the conditions of aging. It has been studied that
EGCG can restore the PKC activity and elevates the liberation of a
non-amyloidogenic soluble precursor, and in turn, counteract the pro­
duction of β-amyloid plaque-like features of AD. Moreover, EGCG pro­
tects the brain from inflammation, stops the impairment in memory and
decreases oxidative stress.
Mandel et al. (2011) reported that EGCG possesses a neuroprotective
impact because of metal ion chelating property and prevents the gen­
eration of free radicals. Under in vitro conditions, it has been studied
that during AD, the cholinergic system of the brain gets affected such as
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embryo quality in fertilization and pregnancy in females.
responses and also decreases the β-amyloid plaques and decreases the
NF- κB level (Joshi et al., 2019; Navik et al., 2021; Sarubbo et al., 2018).
Current studies reported that quercetin possesses anti-inflammatory
and antidiabetic potencies by helping in the translocation of GLUT4 and
AMPK phosphorylation, hence reducing plasma glucose level (Eid et al.,
2015). Boots et al. (2008) reported that quercetin reduces the activity of
GLUT2 (glucose transporter 2) and glucoinvertase, hence decrease the
absorption of glucose in the intestines. Quercetin neutralizes the free
radicals by increasing the antioxidant defences, decreasing lipid per­
oxidation, and preventing membrane damage and cellular injury.
Rafaai et al. (2012) studied that quercetin inhibits the inflammatory
pathways and works as an antioxidant. Therefore, helps in the regen­
eration of β-cells and helps in insulin secretion. Hence, quercetin can be
used as antidiabetic therapeutic molecule due to its free radical elimi­
nation, anti-inflammatory and anti-hyperglycemic activities.
5.2. Luteolin
Luteolin is a flavone mostly present in peppers, basil, broccoli, onion
leaves and spices; it possesses various biological functions such as
antioxidant, free radical scavenging, anti-inflammatory and also inhibits
the PKC activity (Wang et al., 2011). The administration of Luteolin
doses (10 and 20 mg/kg) restores diabetic induced brain impairments
such as memory impairments and cognitive functions by exhibiting
antioxidant activity. Yu et al. (2015) reported that luteolin neutralizes
the ROS by inhibiting the ROS-mediated MAPK mechanism and sup­
pressing NADPH oxidase 4and intercellular adhesion expressions
molecule 1 (Xia et al., 2014). Protein (p22phox) is an essential compo­
nent of the NADPH-oxidase enzyme which helps to produce superoxide
anion. Vascular cell adhesion molecule 1 mediates the adhesion of WBC
cells and the development of atherosclerosis through cell signal trans­
duction. Moreover, luteolin inhibits the spreading of the plaques of AD
by inactivating the GSK3α isoform. Presenilin 1 (PS1) protein and am­
yloid precursor protein (APP) production decreases, therefore, produc­
tion of β-amyloid peptide (Sawmiller et al., 2014) (Fig. 6; Wang et al.,
2011).
It has been studied that luteolin has antidiabetic activity, Wang et al.
(2011) evidenced that administration of luteolin to diabetic rats reduces
the glucose level in blood. Luteolin (100 and 200 mg/kg) administration
increases the activities of SOD, GSH-Px and CAT (Jia et al., 2015) and
reduces the serum creatinine and blood urea nitrogen. Kim et al. (2017)
reported that luteolin increases the expression of SIRT1 and FOXO3a
and reduces ROS generation. Luteolin decreases the prevalence of dia­
betic nephropathy, mediated by the SIRT1-induced pathway because
luteolin potentially elevates the expression of SIRT1. Moreover, luteolin
increases deacetylase activity which protects the kidney from damages
caused by increased glucose level, resistance to insulin, lipid deposition
in kidneys, inflammation and oxidative stress. All these processes lead to
the progression of nephropathy (Yacoub and He, 2014). Jia et al. (2015)
studied that luteolin reduces insulin resistance by decreasing the Tumor
necrosis factor-α by influencing the function of β-cells. Yacoub and He
(2014), up-regulated expression of SIRT1 acts as antioxidative or
anti-inflammatory and regulates the biogenesis of mitochondria and
metabolic processes and hence protects the cellular injury in the renal
system (Joshi et al., 2019; Yacoub and He, 2014). Therefore, it can be
concluded that luteolin could be used as neuroprotective due to its
anti-inflammatory, antidiabetic and antioxidative, and luteolin de­
creases the production of ROS.
5.4. Genistein
Genistein is an isoflavone present in soybeans and their derivatives.
Genistein cross the BBB, due to it leads to the decline of Beta-amyloid
plaque-induced toxicity, reduces the apoptosis in neurons, and pre­
vents neuronal degeneration in AD. Wang et al. (2016) reported that the
management of 30 and 60 mg/kg doses of genistein decreases the
number of apoptotic cells due to the reduction in caspases-3 and cyto­
chrome C activity, ultimately helps in protection against AD.
Moreover, it decreases the expression of nitric oxide synthase or
nitric oxide production by inhibiting the inducible gene. This signaling
pathway decreases the pancreatic β cells toxicity. Genistein helps to upregulate the expression of beta-receptors of estrogen and Bcl-2 to protect
the pancreatic β-cells. Genistein increases the expression of anti­
oxidative enzymes, including manganese superoxide or catalase activity,
and elevates the reduced GSH/oxidized GSH. Due to the antioxidative
potency of genistein, it decreases ROS production, inflammatory cyto­
kines such as TNF-α and proinflammatory cytokines (Valsecch et al.,
2011). Genistein reduces the expression of cytokines such as TNF-α and
proinflammatory cytokines. Administration of genistein 1 mg/kg for
eight weeks elevates the SIRT1 level and down-regulates the expression
of necrosis factor (NF-κB) and interleukin1 with beta subunit (IL-1β).
This increased level of SIRT1 decreases the rate of inflammation in tis­
sues (Joshi et al., 2019; Yousef et al., 2017).
5.5. Resveratrol
Resveratrol present in peanuts, grapes, cocoa and dark chocolate. It
is a non-flavonoid polyphenol that belongs to class stilbenes, also known
as plant antibiotic. It is synthesized when a fungus infects the plants or
under environmental stress conditions. It has two isomeric forms as
trans- and cis-resveratrol. Trans isomeric form is nontoxic and is having
higher therapeutic efficacy. Li et al. (2012) reported resveratrol crosses
the blood-brain barrier and inhibits the inflammatory pathways in the
brain (Moussa et al., 2017), Al-Bishr et al., (2017) reported that
anti-inflammatory against Alzheimer’s disease (AD) in rats. Oxidative
stress and ROS generation are associated with cognitive and neurode­
generative diseases, i.e. Alzheimer’s disease, which finally leads to
memory impairment and neural injury. Due to high oxygen consump­
tion, brain cells are more susceptible to oxidative stress and reactive
oxygen species. Oxidative stress finally leads to reactive oxygen species
(ROS), and it is a major neurotoxic factor released from glial cells
included as O2 (superoxide radicals), OH (hydroxyl radicals) and H2O2
(hydrogen peroxide). O2, OH and H2O2are highly reactive and induce
DNA fragmentation, lipid peroxidation and causes cell apoptosis. So,
during oxidative stress, mitochondria injured which can produce reac­
tive oxygen species (ROS) that damages fatty acid (polyunsaturated)
membranes, proteins and increased permeability of calcium (Ca2+)
ions. ROS (reactive oxygen species) also raises Aβ peptides’ production,
and it induces oxidative stress. ROS increases Aβ production, which
5.3. Quercetin
Quercetin is commonly present in citrus fruits, beans, tea, blue­
berries, cherries and apples (Zhou et al., 2016). It can cross the
blood-brain barrier and hence protects the brain from any injury. Sab­
ogal-Guapueta et al. (2015) reported that quercetin decreases the level
of β-amyloid plaques. This study also reported that treatment of quer­
cetin (25 mg/kg) given to Alzheimer diseases and non-transgenic mice
with Alzheimer disease for three months decreases the level of plaques
(Fig. 6).
Sabogal-Guaqueta et al. (2015) quercetin enhances the GSH content
in astrocytes and neurons and prevents oxidative stress. Therefore, it can
conclude that quercetin can be used as a neuroprotective biomolecule to
treat AD.
It has been reported that a 5 mg/kg body dose of quercetin increases
the activity of AChE in mice (Tota et al., 2010). Sarubbo et al. (2018)
studied that intake of quercetin (20 mg/kg) increases the level of SIRT1
in young and elderly Sprague-Dawley rats for a period of 28. SIRT1
contributes to the regulation of memory seeing by promoting the Ach
production. Moreover, SIRT1 increases the activity of α-secretase and
modulates the NF-κB signaling, decreases the pro-inflammatory
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leads to neuronal apoptosis and increases oxidative stress. These pa­
rameters stimulate the higher risk of Alzheimer’s disease (AD). Due to
higher production of amyloid protein (Aβ) which leads to neuronal
apoptosis. Accumulation of Aβ could regulate the downstream neuro­
toxic consequences (Wang et al., 2018). ROS increases Aβ production
and induces oxidative stress, leading to neuronal apoptosis and the
progression of Alzheimer’s disease (AD). Aβ is the signs of amyloid
precursor protein (APP) by β and γ-secrets. The accumulation of Aβ
could initiate a series of downstream neurotoxic consequence s that
result in neuronal dysfunction (Reddy et al., 2017). Decreased sirtuin
levels, mainly SIRT1 expression levels, were recently linked with
elevated Aβ production and deposition in AD patients. SIRT1 may pro­
vide the modulation of APP processing, and loss of SIRT1 is closely
connected with impaired Aβ production. Though, SIRT1 overexpression
reductions of Aβ peptides (Koo et al., 2017). The activities of resveratrol
against neuroinflammation act on the target activated microglia cells
and resulted in the reduction of pro-inflammatory factors through the
modulation of signal transduction pathways (Bastianetto et al., 2015).
Yang et al. (2017) stated that resveratrol decreased the
mitophagy-mediated mitochondrial damage and attenuated the oxida­
tive stress caused by Aβ1. Neuroinflammation may also be related to the
degradation of the BBB (Annabi et al., 2012). Microvascular endothelial
cells cured with a carcinogen can signal through NF-κB, allowing the
release of MMP-9 (matrix metalloproteinase 9) and COX-2 (Annabi
et al., 2012). Resveratrol decreased secretion of matrix metal­
loproteinase (MMP-9) and expression of COX-2. It also activated the
expression of SIRT1, which regulated inflammation, hindered "NF-κB
signaling", and prevented Aβ-induced degeneration (Figure 10). Fig. 7,
Table 1, Table 2 and Table 3.
Resveratrol protects the cellular damages caused by oxidative stressmediated by reactive oxygen species, leading to damage to the proteins,
lipid, nucleic acids, and others. This antioxidative power of resveratrol
can be explained due to the electron-donating ability and increasing the
activities of antioxidative enzymes such as GSH-Px. Li et al. (2015) re­
ported that resveratrol modulates the function of glial cells by increasing
the calcium-binding protein B and Glutathione peroxidase activity.
Moreover, it has been evidenced that resveratrol acts on p38 genes and
hence inhibits the activation of caspases-3 and decreases the apoptosis in
neurons (Li et al., 2015; Ulakcsai et al., 2015). It also prevents the ag­
gregation of β-amyloid plaques in the brain and promotes
non-amyloidogenic processing of AAP (O’Brien and Wong 2011). It has
been studied that these plaques are generated due to the proteolysis of
AAP by the cleavage of β- and γ-secretase. Li et al. (2015) reported that
resveratrol promotes proteolysis through the α-secretase and therefore
inhibits the formation of Aβ. These two pathways are highly significant
by clearing the β-amyloid through autophagy and lysosomal activities
and also increase the activity of α-secretase (Vingtdeux et al., 2010).
Porquet et al. (2014) studied that resveratrol decreases the accumula­
tion of β-amyloid by activating AβPP/PS1 pathways and reducing
intracellular proteasomal activity. Moreover, it has been studied that
resveratrol at a dose of 5 mg/ml decreases the neurodegeneration in the
hippocampus, inhibits learning impairments, reduces acetylation of
PGC-1α and p53, SIRT1 (a known substrate for maintaining the meta­
bolic activities in neurons), neutralization of ROS and apoptosis.
Fig. 7. This figure shows the summarized details of protective effects of plant derived phytophenols for the prevention of diabetes and its associated complications.
During diabetes hyperglycemic condition leads to the excessive production of AGEs and AGEs activates the various down regulatory pathways such as NF-kB, in­
creases production of ROS, decreases the activity of GR due to the activation of PKC. However, treatment of Catechins, Quercetin, curcumin and isoflavones can
inhibit the activation of these inflammatory pathways, renal dysfunction, cardiovascular diseases, pancreatic degeneration and decreases the production of ROS by
normalizing the blood glucose level. Chronic hyperglycemic condition decreases the production of IGF, decreases the activity of acetyl CoA and acetylcholine and
increases production of ROS and activation of APAf and its leads to the activation of apoptic cascade such as caspases 9 activates caspases 3,6 and 7 finally leads to
the neuronal apoptosis. However, treatment of gallic acid, resveratrol and EGCG inhibits the activation of caspases 9 hence can prevents the neuronal apoptosis,
moreover treatment of quercetin, luteolin and curcumin suppresses the production of ROS by decreases the blood glucose level and hence can prevent the neuronal
apoptosis. ROS production also leads to the activation of inflammatory pathways such as NF-kB and causes the production of such as TNF-α, IL-1 and IL-1. Treatment
of resveratrol, curcumin and luteolin inhibits the activation of NF-kB. Diabetes affects the pancreas and causes the activation of IRS1 and IRS2, MAP Kinase, and SHC.
SHC activates RAS, RAS activates RAF, MEK and MAPK and finally leads to the hyperglycemia and causes hepatotoxicity. Whereas, polyphenols are able to prevent
the degeneration of pancreas and hence prevents the activation of down-regulatory cascade and finally inhibits the hyperglycaemic induced hepatotoxicity.
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Table 1
showing allopathic drugs cellular mechanism, physiologic key action and its side effects.
Class
Agents
Cellular mechanism
Physiologic key action
Side effects
Biguanides
Metformin (Glucophage; Glucophage XR;
Fortamet’; Glumetza)
Activates AMP-kinase
↓Hepatic glucose
production
↓Insulin resistance
Sulfonylureas
Tolbutamide (Orinase)
Glimepiride (Amaryl)
Glipizide (Glucotrol; Glucotrol XL)
Glyburide (Micronase, DiaBeta)
Glyburide, Micronized (GlynasePresTab)
Pioglitazone (Actos)
Rosiglitazone (Avandia)
Closes KATP channels on beta cell
plasma membranes
Stimulating the release of Insulin by
Pancreatic β-cells. Control blood
glucose level
Activates the nuclear transcription
factor PPAR
Improve sensitivity to insulin
↑Insulin secretion
GLP1-Analogs
Exenatide (Byetta)
Liraglutide (Victoza)
Albiglutide (Tenzeum)
Dulaglutide (Trelicity)
Activates GLP-1 receptors
↑Insulin secretion (glucose
dependent)
↓Glucagon secretion
(glucose dependent)
Slows gastric emptying
↑Satiety
DPP-4 Inhibitors
Alogliptin
Nesina
Sitagliptin
Onglyza
Linagliptin
Tredjenta
Inhibits DPP-4 activity, increasing
postprandial incretin (GLP-1, GIP)
concentrations
↑Insulin secretion (glucose
dependent)
↓Glucagon secretion
(glucose dependent)
α-glucosidase
Acarbose
Precose
Inhibits α-glucosidase activity
Absorption of
carbohydrates
↓Digestion
SGLT-2 inhibitor
Canagliflozin, Dapagliflozin, Empagliflozin,
ipragliflozin, dapagliflozin, luseogliflozin,
and tofogliflozin
Inhibits sodium-glucose
cotransporter
Meglitinide
Prandin and Starlix
Bromocriptine
—
Inhibits the adenosine triphosphate
dependent K+ channels in pancreatic
β-cells
To mediate and resetting of
dopaminergic and central nervous
system
↓Blood glucose level
without stimulating
insulin
Reducing renal tubular
glucose reabsorption
↑ Release of pancreatic
β-cells
↓Glucose level
Mediate the action on
glucose and lipid
metabolism
GI side effects (diarrhea,
abdominal cramping, nausea)
Kidney damage
Anxiety
Sexual health issues
Nerve damage
Vitamin B12 deficiency
Lactic acidosis (rare)
Increase cardiovascular (CV) risk
Hypoglycemia (Due to excessive
dosage)
Obesity
Hepatic failure
↑Weight
Bone fractures
↑LDL-C (rosiglitazone)
Anemia
Swelling (edema) from fluid
retention
Macular edema (in eye)
Heart attack (Myocardial
infarction)
GI side effects (nausea, vomiting,
diarrhea)
↑Heart rate
Acute pancreatitis (Inflammation)
C-cell hyperplasia/medullary
thyroid tumors in animals
Injectable
Abdominal pain
Upper respiratory infection
Weight loss
Angioedema/urticaria and other
immune-mediated dermatological
effects
Acute pancreatitis
↑Heart failure
Urinary tract infection
Sore throat
Headache
Upper respiratory infection
Gastrointestinal issues
Bloating
Nausea
Diarrhea
Flatulence
Urinary tract infection
Nausea, Increased Urination
Thiazolidinediones
(TZDs)
Inhibitors
Sarubbo et al. (2018) reported that resveratrol is having anti-aging
through the activation of SIRT1 and modulates the inflammatory path­
ways through the signaling pathways such as NF-κB.
Movahed et al. (2013) studied that resveratrol decreases the preva­
lence of hyperglycemia and improves insulin sensitivity by activating
the AMPK (activated protein kinase) pathway. Metformin (an allo­
pathic), also used to treat diabetes mellitus, also activates the AMPK. It,
in turn, activates the PI3kt-Akt pathway and subsequently increases the
rate of phosphorylation of glycogen synthase kinase-3 and pathway for
lowering the blood glucose level. However, expression of phospho­
enolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase
(G-6-Pase) decreases and reduces the process of gluconeogenesis.
Administration of 1 g/day of resveratrol has been reported very safe and
↑Insulin secretion
Weight gain
Hypoglycemia
Constipation
Heartburn
Loos of appetite
Stomach cramps
improves the insulin sensitivity connected with the activation of SIRT1
and subsequently PGC-1α deacetylation, affecting the mitochondrial
metabolism. Szkudelski and Szkudelska (2011) studied that increased
mitochondrial oxidative capacity leads to insulin resistance due to
oxidative stress, hence deacetylation of PGC-1α and subsequently leads
to the biogenesis of mitochondria, decreases oxidative stress caused by
the mitochondrial dysfunctions.
Moreover, resveratrol increases the insulin level in the blood
(Movahed et al., 2013). Szkudelski (2007) studied that the administra­
tion of resveratrol decreases the secretion of TNF-α, IL-1 and IL-6 and
down-regulates the expression of nitric oxide synthase enzyme, leads the
decreased production of nitric oxide and subsequently reduces the
chance of inflammation. Pacholec et al. (2010) reported that the
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Table 2
Diabetes associated metabolic disorders, complications, effects and cellular mechanism.
S.
No.
Complication
locations
Specific types
Parameters
Cellular mechanism
References
1.
Metabolic
Cardiovascular (atherosclerosis,
hypertension); obesity
Formation of advanced glycation end-products (AGEs),
activation of PKC, ↓glycosylated hemoglobin (HbA1c)
level
2.
Eye
complications
Visual damage, glaucoma and
blur, cataract
3.
Kidney failure
Nephropathy (kidney
dysfunction)
4.
Brain damage
Brain retardation, cognitive
impairments
↑TG
↑LDL
↑VLDL
↓GR
↑Blood glucose
↑BP
↑NF-κB
↑TGF- β
↑NF-κB
↑TGF- β
↑RAAS
↓TNF-α, IL-6
↑Inflammation
Mik et al., 2013;
Adebiyi et al., 2016; Brunvand et al.,
2017; Pappachan et al., 2013;
Lee et al., 2017
Sekiou et al., 2020;
Maruko et al., 2016; Ooto et al.,
2015;
Ambiya et al., 2018
Chikezie et al., 2015;
Wang et al., 2015; Molitch et al.,
2015
King et al., 2015;
Dantzer et al., 2015; Sickmann and
Waagepetersen, 2015
Bathina and Das, 2018
ICAM-1, COX-2, MMP9, iNOS, ↑VEGF
↓GFR, ↑ permeability, advanced glycation endproducts (AGEs), MCP-1, ICAM-1
↑Glycosylated Hb, Gsk-3β activation, ↑VDAC1
reduction in n-3 PUFAs
administration of 22.4 mg/kg of resveratrol during diabetes-induced AD
increases the activities of antioxidative enzymes, improves insulin
sensitivity and increases the working efficacy of insulin. Hou et al.
(2016) reported that resveratrol indirectly activates SIRT1, and through
AMPK pathways, activation or resveratrol might be acting via protein
enzyme interaction essential for the activation of SIRT1.
It has been evidenced that intake of curcumin decreases the preva­
lence of diabetic induced AD by improving the cognitive functions and
helps in the scavenging/neutralization of free radicals. Mathew et al.
(2011) studied that curcumin reduces the level of β-amyloid plaques.
This reduction in the plaques may be due to the regulation of phos­
phorylation of the GSK3-beta enzyme, which reduced γ-secretase and
PS1activities. Curcumin inhibits the IL-1 signaling pathway and hence
decreases the inflammation; moreover, in cultured prefrontal cortical
neurons, it has been observed that curcumin inhibits the apoptosis in
cells through the inactivation of caspases-3 (Qin et al., 2018).
5.6. Curcumin
Curcumin is a plant-derived non-flavonoid that belongs to the family
curcuminoid, which may find 3% of turmeric. It is a bioactive molecule
present in the turmeric plant known as the "Curcuma longa" plant.
Recent studies showed that curcumin has biological effects, including
antioxidant, anti-neoplastic, cardio-protective, anti-inflammatory, hep­
atoprotective, anti-rheumatic, immunomodulatory, hypoglycaemic and
antimicrobial effects. Curcumin interrupts diabetes development, im­
proves the functioning of beta cells, stops beta cell death and inhibits
insulin resistance (Pivari et al., 2019). Chougala et al. (2012) reported
that during diabetes mellitus, curcumin regulates the blood glucose
level. Curcumin improves fasting glucose level by the down-regulating
of the G-6-Pase and PECK and subsequently decreases the process of
gluconeogenesis.
Moreover, curcumin reduces the synthesis of fatty acids and tri­
glycerides level. This hypolipidemic activity of curcumin is due to the
ability to suppress the absorption of cholesterol by increasing the ac­
tivity of low-density lipoprotein receptors or increases the activity of this
enzyme to break down the cholesterol. Moreover, curcumin decreases
the level of pro-inflammatory cytokines (TNF-α and IL-1) and decreases
inflammation (Xie et al., 2012). El-Moselhy et al. (2011) reported that
curcumin improves insulin resistance by inhibiting the release of TNF-α.
It has been reported that curcuminoids decrease the lipid peroxidation
rate and subsequently increase the reduced GSH content and enhance
antioxidative enzymes’ activities. Jimenez-Flores et al. (2014) reported
that administration of 0.75% curcumin given to mice db/db
down-regulates the expression of NF- κB (a vital regulator of the in­
flammatory response) in hepatocytes. Furthermore, after the treatment
of curcumin, the expression of AMPK increases during diabetes
(Figure 11).
Due to this up-regulated expression of AMPK suppresses the hepa­
tocytes’ glucose production and, linked with SIRT1, contributes essen­
tially to lipid metabolism in hepatocytes. Hence from these studies,
curcumin contributes to the modulation of diabetic induced metabolic
disturbances by maintaining the activities of antioxidative enzymes,
decreases the level of anti-inflammatory cytokines, and reduces
neuronal damages and important hypoglycaemic activities during dia­
betes mellitus.
5.7. Gallic acid
Gallic acid belongs to hydroxybenzoic acid, commonly present in
fruits, including berries, green tea, white tea, and dark chocolate (Zhou
et al., 2016). Gallic acid possesses various therapeutic properties such as
anti-hyperlipidaemic, antioxidant, and antihyperglycemic etc. (Patel
et al., 2011). Hajipour et al. (2016) reported that gallic acid increases
antioxidative activities and manages the oxidative stress during diabetic
induced AD by reducing the production of free radicals in the brain.
Patel et al. (2011) studied that gallic acid treatment is given to the
STZ induced diabetic albino rats decreases the glucose level increases
the secretion of insulin, triglyceride and cholesterol levels. Gallic acid
decreases the free radical load, and a subsequent decrease in oxidative
stress increases the activities of antioxidative enzymes. Through the
intraperitoneal route (10 mg/kg), Gallic acid reduces insulin resistance
in diabetic patients. This reduction in insulin resistance occurs due to the
activation of the AMPK pathway and subsequent activation of SIRT1,
suggesting the role of gallic acid to treat metabolic disorders (Doan
et al., 2015). This study also reported that gallic acid stimulates the Akt
pathway and down-regulates gluconeogenic genes, including PEPCK
and glucose-6-phosphate, which plays a significant role in glycemic
control and insulin resistance.
Moreover, gallic acid treatment decreases the incidence of cardio­
myopathy by decreasing the blood pressure and contraction force and
increases the heart rate and decreases the oxidative stress in the heart by
modulation of antioxidative enzymatic activities SOD, CAT and content
of GSH. Some pharmaceutical companies recommend gallic acid as a
food supplement due to its potent antioxidant properties (Nayeem et al.,
2016). Gonzalez-Sarras et al. (2017) impact the level of ROS, redox
activity and apoptosis caused by stress. It has been studied that de­
creases hydrogen peroxide (H2O2) significantly-induced cytotoxicity by
inhibiting free radicals’ production and induces the activation of
caspases-9. In turn, it leads to the activation of caspases-3 and finally
stimulates the apoptotic pathways. Thus, it can be concluded that gallic
acid reverses the redox system, elevates the reduction potential, and
15
16
Sr. No.
Plant name
Phytoconstituents (Bioactive
components)
Parameters
Pharmacological activity
References
1.
Ficus religiosa
leucocyandin 3-O-beta-D-galactosyl
cellobioside, Leucopelargonidin-3-Oalpha-L rhamnoside
↓ROS, improved HDL level, ↓Glucose level, ↑insulin level,
modulates the inflammatory cytokine TNF-α
(Kirana et al., 2011; Kumar
et al., 2018; Tiwari et al.,
2017; Patel et al., 2012)
2.
Eugenia jambolana
Anthocyanins, glucoside, Ellagic acid,
Isoquercetin, Kaempferol, Myricetin, and
Hydrolysable tannins (1–0-galloyl
castalagin and casuarinin)
↓Activity of enzyme 3-HMG Co-A reductase in liver,
↓glycosuria and blood urea levels, ↓blood ↓cholesterol,
↓triglycerides, free fatty acids
Antidiabetic, hypolipidemic, anti-inflammatory,
analgesic, antioxidant, immunomodulatory,
estrogenic, endothelin receptor antagonist,
apoptosis inducer and cognitive enhancer
Hypolipidemic, anti-inflammatory, neuropsycho
pharmacological, and antihypertensive
3.
Momordicacharantia
Vicine, Charantin and Triterpenoids
Hypoglycemic, lipid-lowering properties,
antidiabetic
4.
Ocimum sanctum
5.
Pterocarpus marsupium
Eugenol, Ursolic acid, Carvacrol,
Linalool, Limatrol, Caryophyllene,
Rosmarinic acid, Apigenin, Isothymonin,
Orientin, Vicenin
β-sitosterol, Lupenol, Aurone glycosides,
Epicatechins, Iso-flavonoids
Stimulate the activity of hepatic glucose-6-phosphate
dehydrogenase, repair damaged β-cells, ↓α-amylase and
α-glucosidase
↓blood glucose, glycosylated hemoglobin and urea;
↑glycogen, hemoglobin and protein; ↓LDL and VLDL
Regulating glucose production through AKT and AMPK
modulation in HepG2 cells, improve insulin secretion
6.
Trigonella foenum-graecum
4-hydroxyisoleucine, Trigonelline
7.
Gymnema sylvestre
Gymnemic acid, Gymne- marerin,
Triterpenoids
8.
Allium sativum
Allicin, Allixin, Ajoene
↓Lipid peroxidation; inhibit the generation of glycationderived free radicals; ↑SOD, ↑CAT, ↑GSH
Antiobesity, antihyperlipidemic, antiinflammatory, antioxidative, antitumorigenic
and antidiabetic
Antidiabetic, anti-inflammatory, Anti-cancer and
antioxidant
Antidiabetic, anti-fertility, anti-inflammatory,
antioxidant, apoptosis inducer and
hypolipidemic
Antidiabetic, anti-inflammatory and antioxidant
Plant parts and their protective effects
Sr. No.
Plant name
1.
Urticadioica (Stinging
nettle)
Part of plant
Leaves
2.
Carthamustinctorius
(Safflower)
Flower
3.
Leaves
4.
Bauhinia forficate (Brazilian
orchid tree)
Salvia nemorosa (Sage)
5.
Ginseng sp.(Asian ginseng)
Roots, stalk, leaves and berries
6.
Cinnamomum verum
(Cinnamon)
Whole Plant
7.
Dendrobium chrysotoxum
(Golden-bow Dendrobium)
Aerial parts
8.
Zingiberzerumbet (Bitter
ginger)
Roots
Protective Effects
Urticadioica leaf improved the glucose levels in type 2 diabetic
rats, which is directly effect on pancreatic beta-cells (insulin
level maintain).
C. tinctorius can be used to treat type 1 and type 2 diabetes. It is
a rich source of flavonoids, such as quercetin and kaempferol,
which affects antioxidant and hypoglycemic conditions of
these compounds.
In the type 2 diabetic group, plasma glucose and urinary
glucose levels significantly decreased.
The aerial part of the plant significant increase in insulin
levels in diabetic rats.
Ginseng sp. significantly decreased insulin resistance and
fasting blood glucose in T2DM patients.
Cinnamon in the diet of patients with T2DM would reduce the
risk factors of diabetic associated complicaions. Cinnamon
lowered hemoglobin A1c (HbA1C).
Dendrobium chrysotoxumalleviated the increased 1 and
phosphorylated p65, IκB, and IκB kinase and decreases
inflammation.
Zingiberzerumbet roots significantly helps to reduce body
weight and the blood glucose levels.
Aerial part
Normalize the activity of creatinine kinase in liver, ↓glucose
level, ↓renal toxicity
↓Body weight, reduction in plasma proteins,
Antidiabetic, cardioprotective, antifertility, antiinflammatory, antioxidant, immunomodulatory,
and antithyroidic
P. Sharma et al.
Table 3
Showing different medicinal plants, phytoconstituents, parameters and its pharmacological activity.
(Chatterjee et al., 2012;
Baliga et al., 2013;
Sangeetha et al., 2014;
Rizvi and Mishra et al.,
2013)
(Rizvi and Mishra et al.,
2013; Keller et al., 2011)
(Khan et al., 2012;
Malapermal et al., 2017;
Mousavi et al., 2018; Mehta
et al., 2016)
(Singh et al., 2019; Hugar
and Londonkar, 2017)
(Pandey et al., 2011; Kumar
et al., 2012; Roberts, 2011)
(Rizvi and Mishra et al.,
2013; Thakur et al., 2012;
Laha and Paul, 2019)
(Bahmani et al., 2014;
Szychowski et al., 2018;
Rizvi and Mishra et al.,
2013)
References
Das et al., 2009
Salahi, 2012
Rao et al., 2010
Moradi et al., 2018
Xie et al., 2011
Yu et al., 2015
Tzeng et al., 2015
(continued on next page)
Phytomedicine Plus 2 (2022) 100188
Xie et al., 2011
P. Sharma et al.
Table 3 (continued )
17
Sr. No.
Plant name
Phytoconstituents (Bioactive
components)
Parameters
Pharmacological activity
9.
Kaempferiaparviflora
Roots
Lert-Amornpat et al., 2017
10.
Leaves
11.
Opuntiamegacantha
(culinary)
Aloe vera
12.
Trigonella foenumgraecum
Seed
13.
Bauhinia forficata
Leaf
14
15
Gymnema sylvestre
Swertiapunicea
Leaf
Whole plant
16
CombretumMicranthum
Leaves
17
Sarcopoteriumspinosum
Roots
18
Liriopespicata
Leaves
19
Caesalpiniabonducella
Seeds
20
Terminalia chebula
Seeds
Kaempferiaparviflora treatment demonstrated a significant
recovery of sexual behavior and serum testosterone levels in
diabetic rats.
Administration of the leaf extract was associated with an
increased glomerular filtration rate.
Administration of Aloe vera leaf extract inhibits renal failure in
diabetic rats.
Trigonella seeds benefits to lower blood glucose and slow
down the absorption of carbohydrates.
Bauhinia forficata leaves decreases plasma glucose and urinary
glucose levels.
The G. sylvestre crude extracts exhibits hypoglycemic effect.
S. punicea was improved hypoglycemic effect and insulin
resistance.
The aqueous extract of C. micranthum leaf has antidiabetic
property to control type 1 and type 2 diabetes mellitus.
The aqueous extract of S. spinosum root may produce
antidiabetic effect on progressive hyperglycemia in
genetically diabetic mice. The aqueous root extract of the
plant shows insulin-like actions in targets tissues.
The aqueous extract of the plant caused a marked decrease of
fasting blood sugar level and a significant improvement of
glucose tolerance and insulin resistance in streptozotocininduced type 2 diabetic mice, confirming its hypoglycemic
effects.
The aqueous and 50% ethanolic extracts of C. bonducella seed
showed antihyperglycemic and hypolipidemic activities in
streptozotocin-diabetic rats. Both the aqueous and ethanolic
extracts showed potent hypoglycemic activity in chronic type
II diabetic models. the antihyperglycemic action of the seed
extracts may be due to the blockage of glucose absorption
T. chebula is more effectively inhibited the incidence of
diabetic nephropathy. Diabetic nephropathy is mainly
associated with excess urinary albumin excretion, abnormal
renal function as represented by an abnormality in serum
creatinine.
Leaf
References
Moradi et al., 2018
Moradi et al., 2018
Kaviarasan et al., 2007
Da Cunha et al., 2010
Malik et al., 2008
Tian et al., 2010
Chika et al., 2010
Elyasiyan et al., 2017
Wen-Chi et al., 2004
Shukla et al., 2009
Ziamajidi et al., 2017
Phytomedicine Plus 2 (2022) 100188
P. Sharma et al.
Phytomedicine Plus 2 (2022) 100188
restores the antioxidant defense system (Hajipour et al., 2016;
González-Sarras et al., 2017).
4 Publication: The journal or similar periodical publication, in print
or in digital form, for which the Article is destined.
6. Summary
Clause 2 licence of rights
Diabetes mellitus is a chronic metabolic disorder caused due to
abnormal glucose metabolism. However, insulin injection controls
glucose metabolism, hypoglycaemic drugs, and insulin, which depends
on the type of diabetes. Both insulin and allopathic are associated with
various side defects such as hypoglycaemia, weight gain, diarrhea, upset
stomach, liver disease, anemia and kidney complications, respectively.
However, natural polyphenols are the best alternative remedies for the
treatment of diabetes and its associated damages in different organs
because polyphenols protect the pancreatic β-cells (improves glucose
tolerance).
Polyphenols help to protect pancreatic β-cells (improve glucose
tolerance), to inhibit α-amylase or α-glucosidase activity, lower oxida­
tive stress by activating mechanistic signaling pathway to improve
glucose level. Moreover, polyphenols also help improve glucose uptake
in adipocytes and muscle cells and manage long-term complications
associated with diabetes, i.e., nephropathy, neuropathy, retinopathy,
and cardiovascular diseases. It is cost-effective, readily available and
naturally found in the diet, which helps to control chronic and metabolic
diseases.
Fig. 6 summarized the role of phytophenols and their in the man­
agement of diabetes and its associated complications
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7. Conclusions
Diabetes is one of the most challenging health problems in the 21st
century. It is a group endocrine-metabolic disorder characterized by
high glucose level (hyperglycaemia) due to insufficient insulin secre­
tion/action or both. It causes multi-organ failure viz kidney, adult-onset
blindness, lower-limb amputations, heart diseases and stroke, high
blood pressure and nerve damage. Diabetic patients have a higher risk of
cardiovascular complications including atherosclerosis, hypertension,
lipoprotein abnormalities and cerebrovascular disease. Different allo­
pathic drugs are used for the treatment of diabetes, but they are also
associated with other complications. Therefore, use of natural poly­
phenols that have anti-diabetic, anti-inflammatory, anti-apoptotic and
anti-cancerous activities can be valuable to control diabetes mellitus.
Polyphenols can decrease other metabolic diseases such as insulin
resistance, hyperglycaemia, hyperlipidaemia, obesity and Type-2 dia­
betes. It can be concluded from this review that polyphenols having
potential to control diabetes and other associated complications
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8. Future perspective
Educational or instructional use
Considering the status of diabetes, its associated secondary compli­
cations and side effects of available allopathic medicines, plant derived
natural bioactive components are very good alternatives to minimize the
prevalence of metabolic disorders. However, various studies are re­
ported in the literature with respect to the use of plants and their
products for the treatment of metabolic disorders, but exact mechanism
of action is still lacking. Therefore, need of the day is to explore the more
and more medicinal importance of plants to minimize the use of allo­
pathic formulations.
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Acknowledgements
Authors are grateful to Department of Biosciences, Division Zoology
and Pioneer Incubator Center, Career Point University, Hamirpur,
Himachal Pradesh, India for providing necessary research facilities
under CM-startup project Scheme (Registration Numbers HP STARTUP/
2020/07/20 and HPSTARTUP/2020/12/03).
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