Critical ReviewsTM in Eukaryotic Gene Expression, 31(3):65–80 (2021)

Role of Heavy Metals in Diabetes: Mechanisms and

Treatment Strategies
Anam Javaid, Iqra Akbar, Hamna Javed, Ujala Khan, Hira Iftikhar, Duaa Zahra, Fatima Rashid,
& Usman Ali Ashfaq*
Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
*Address all correspondence to: Usman Ali Ashfaq, Department of Bioinformatics and Biotechnology, Government College University, Faisalabad,
Pakistan; Tel.: +92-03314728790, E-mail: usmancemb@gmail.com

ABSTRACT: Toxic metals affecting metabolic pathways have a broad range in the ecosystem from both natural and
anthropogenic sources. Because of constant contamination from waste and untreated chemical effluents, their emissions
have risen significantly over the last few decades, quickly gaining attention due to their crucial role in the development
of several metabolic disorders, notably diabetes mellitus. Cadmium and arsenic not only spread widely in our atmosphere
but are also linked to a wide range of health hazards. These are primarily accumulated in the liver, kidney, and pancreas
once they reach the human body, where they have deleterious effects on the metabolism of glucose and its association
with other metabolic pathways, particularly glycolysis, glycogenesis, and gluconeogenesis, by altering and impairing the
specific activity of major enzymes. Impairment of hepatic glucose homeostasis plays a crucial role in diabetes mellitus
pathogenesis. Impaired liver and kidney functions, as well as decreased pancreatic and muscle function, also contribute
significantly to elevated levels of blood glucose. Heavy metals have the potential to cause changes in the conformation
in these enzymes. They also impair hormonal balance by destroying the pancreas and adrenal glands. Such metals often
facilitate the development of reactive oxygen species and inhibit antioxidant defense mechanisms, with multiple organs
subsequently damaged. This review briefly discusses the involvement of heavy metals in metabolic disorders such as
diabetes mellitus, the enzymes involved in this pathway, and glucose homeostasis.

KEY WORDS: metabolic disorder, diabetes, reactive oxygen species, antioxidant defense

I. INTRODUCTION diabetes has increased by about 49% in America.2

Metabolic syndrome has become a major health
concern due to its increasing worldwide prevalence
and its affiliation with lethal and serious conditions
like cardiovascular diseases, diabetes, and stroke.
These syndromes, also known as insulin resistance
syndrome or syndrome X, narrate the incidence of
serious conditions that increase the risk for heart
and many other disorders.1 Diabetes mellitus is be-
coming a serious threat to human health, spreading
throughout the world, and is creating a significant
deleterious effect on human health. The effect of un-
constrained industrialization has rendered much of
the human population vulnerable to disease-causing
or -intensifying agents.2 Diabetes mellitus is a severe
health issue caused by a reduction in the metabolism
of carbohydrates, proteins, and fats due to insulin
resistance or unstable insulin secretion.3 According
to a study (1991–2000) by the Centers for Disease
Control and Prevention (CDC), the prevalence of
According to recent studies, the global prevalence of
diabetes mellitus increased up to 8.5% in 2014 and
is estimated to increase from 422 to 642 million by
2040.4,5 In the past decade, prevalence has increased
rapidly due to factors which include average age,
hereditary influence, unhealthy diet, and sedentary
lifestyle.6,7 Therefore, more research is required to
evaluate and avoid potential agents that may cause
hyperglycemia or diabetes metabolic disorder (dia-
betes mellitus), identified as fasting hyperglycemia,
insufficient insulin secretion, or insensitivity to the
insulin receptor.2
In particular, type 2 diabetes mellitus (T2DM)
combines risk factors with genetic susceptibility,
obesity, high calorie intake, lack of physical activ-
ity, and high blood pressure.8 Oxidative stress is
caused by heavy metals, eventually increasing the
impairment of islet cell succession.9,10 Various stud-
ies suggest that reactive oxygen species contribute
significantly to the destruction of pancreatic β cells,

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66 Javaid et al.
as β cells exhibit high expression of metal transport-
ers and a low-level antioxidant system.2,8 This weak
defense system makes β cells extremely sensitive to
heavy metals and their effects, resulting in the dys-
function, destruction, or even death of pancreatic
β cells.2 Due to the destruction of β cell islets, the
autoimmune influence of humoral, cellular, and de-
structive immune regulation can arise. Reduced in-
sulin secretion or insulin resistance may lead to type
2 diabetes.2,8 For example, exposure to environmen-
tal pollution can cause pathogenesis and elevation
of Diabetes mellitus, such as gestational diabetes
mellitus (GDM). GDM can occur during pregnancy
due to exposure to heavy metals.11 Accumulation of
mercury (Hg) and lead (Pb) induces oxidative stress
and causes dysfunction, apoptosis, death of β cells
and degeneration of proteins, lipid peroxidation, and
damage nucleic acid.12–15
In recent years, there has been a tremendous rise
in the concentration of trace elements in the envi-
ronment, and they are studied as an essential factor
in the environment’s appropriate functioning. Some
molecules are important for biological activity, such
as chromium, nickel, vanadium, selenium, silicon,
molybdenum, iron, and arsenic. An impairment in
functions from optimal to suboptimal may result
due to deficient intake of essential elements which
ultimately cause different diseases. Plants play an
important role in the transfer of trace elements to
humans from the soil. Diabetes is a mixed metabolic
disease related to altered protein, carbohydrate, and
lipid metabolism.16
The Genome Project has shown that thousands
of genes encode Zinc- (Zn) binding proteins and that
different metabolic processes are dependent on the
availability of Zn. Disturbance in the Zn balance
was found to be linked with metabolic disorders
such as diabetes mellitus.17 Deficient or surplus es-
sential micronutrients and trace toxic metals may
lead to serious health hazards for humans. Some
heavy metals are toxic in trace amounts, like mer-
cury, lead, and cadmium (Cd).18
Nanotechnology is expected to make a signifi-
cant breakthrough by developing more target-spe-
cific drugs for the treatment of metabolic disorders
such as diabetes and cancer. Conventional biomed-
ical processes have limitations, but biologically
synthesized nanoparticles with advanced physical,
chemical, and biological characteristics work as
targeted drug delivery systems.19 Ethnobotanical
research has found medicinal plants an important
factor in the treatment of hypoglycemic and hyper-
glycemic disorders. Various studies show that more
than 1,200 plants are used worldwide to treat dia-
betes mellitus. These include Asparagus racemosus,
Butea monosperma, Catharanthus roseus, Coccinia
indica, Gymnema sylvestre, Syzygium cumini, and
Momordica charantia. They are used both by tribal
societies for the prevention of diabetes and in ad-
vanced medicine.20
II. EPIDEMIOLOGY
Over the past three decades, the number of people
with diabetes mellitus has quadrupled and the ninth
leading cause of death is diabetes mellitus. Around
1 in 11 people aged 20–79 years around the world
suffer from diabetes mellitus, 90% of whom have
type 2 diabetes mellitus. Asia is a significant part of
the rapidly evolving global T2DM epidemic, with
China and India among the top two epicenters.21 It
has been estimated that in 2010 diabetes mellitus
and its complications caused 3.96 million deaths
of adults aged 20–79 (6.8% of global mortality).22
In an IDF study, this number increased to 5 million
deaths, which correspond to one death every six sec-
onds due to exposure to cadmium, arsenic, and so
on.23
Overall, from 1980 to 2014, the number of
people living with diabetes mellitus quadrupled. In
developed countries, the number of adults with di-
abetes mellitus is expected to rise by 20% and in
developing countries by 69% between 2010 and
2030.24 In China, it has been estimated that more
than 113.9 million people, or about 11.6% of the
adult population, had diabetes mellitus in 2010, and
that 493.4 million adults (about 50.1% of the total
population) had pre–diabetes mellitus. Less than
one-third of diabetes mellitus patients had been di-
agnosed; only one-fourth had been treated, and of
those treated only 39.7% had blood levels of HbA1c
greater 7.0%.25
A national study in India found that in 2011 62
million people suffered from diabetes mellitus and
Critical ReviewsTM in Eukaryotic Gene Expression
Role of Heavy Metals in Diabetes67

77 million from pre–diabetes mellitus due to drink-
ing arsenic-contaminated water.26 The IDF expects
India to have 69.2 million diabetes mellitus patients
in 2015, with an expected rise to 123.5 million by
2040.23 In 2015, the United States had the third-high-
est number of patients with diabetes mellitus23 and
in 2008 half of adults aged 65 or older had pre–dia-
betes mellitus.27
Arsenic, a metalloid, has been attracting par-
ticular attention due to its association with diabetes
for more than two decades since the publication of a
cross-sectional study in Southwest Taiwan in 1994.28
Since then, evidence of diabetes-related effects of
arsenic even below the 10-ppb limit for drinking
water at exposure levels of the World Health Orga-
nization has increased. Nonetheless, debate on the
associations of arsenic and diabetes continues due
to limited-quality evaluation of the relationship of
arsenic and diabetes and relatively limited prospec-
tive evidence.29,30
Evidence of the association of other heavy
metals with diabetes mellitus is still controver-
sial. A handful of studies and conflicting data are
available on mercury and cadmium.29 This issue
has been documented in an international journal
establishing a cross-sectional combination of uri-
nary nickel exposure with diabetes prevalence in
a representative sample of adults aged 50 to 70
from Beijing and Shanghai.31 An American study
of T2DM established the relationship between
heavy metal exposure and country-level diabetes
mortality. According to a national survey carried
out in 1999, the prevalence of T2DM in Pakistan
was 11 million due to heavy metal–contaminated
drinking water. According to a national popula-
tion survey performed in 2018, about 16.98 mil-
lion people in Pakistan have diabetes. Pakistan’s
DM prevalence of almost 9% is almost twice the
global prevalence.32 In the 5th edition of the At-
las, the International Diabetes Federation (IDF)
reported a prevalence of 6.8% in Pakistani citizens
aged 20–79,33 but healthcare professionals found
this unrealistic. Opposing prevalence results range
from 7.2% to 19.21% in different regions of the
country (Table 1).34 To investigate the relationship
between arsenic exposure and risk factors for DM
development, 150 participants were recruited from
Faisalabad, 50 of which were nondiabetic and 100
were diabetic.32
III. HEAVY METALS AND DIABETES MELLITUS
Heavy metals are naturally existing metallic ele-
ments that possess high atomic weights and den-
sities almost five times greater than water.35 One
hundred milligrams of a macrometal like magne-
sium are required in the daily diet while less than
100 ppm of macronutrients like manganese, cop-
per, nickel, zinc, and iron are required.36,37 These
metals are essential in different physiological and
bochemical processes in the body.38,39 Various stud-
ies suggest that instability in the amount of these
metals causes serious adverse effects on health as
in the case of pancreatic islets, which lead to the
development of diabetes.2 However, some heavy
metals possess high toxicity, like cadmium, nickel

TABLE 1: Adults aged 20–70 years with diabetes, current and projected, according to 2019 IDF report
Region Percentage 2019 2030 projected 2045 projected
(million) (millions)
World 51% (increase) 463 578 700
Europe 15% (increase) 59 66 68
Western Pacific 31% (increase) 163 197 212
Southeast Asia 74% (increase) 88 115 153
Middle East and North Africa 97% (increase) 55 76 108
Sub-Saharan Africa 143% (increase) 19 29 47
North America 33% (increase) 48 56 63
South and Central America 55% (increase) 32 40 49

Volume 31, Issue 3, 2021

68 Javaid et al.

(Ni), mercury, arsenic, and lead have an adverse
effect on human health (Table 2).1 Some toxic
metals have been identified in T2DM patients as
affecting glucose uptake and glucose regulation.46
Several studies have been done to measure the ex-
tent of heavy metals in diabetic patients relative to
nondiabetic controls. The results show that varying
concentrations of certain heavy metals contribute
to the progression of diabetes mellitus.2 Exposure
to toxic metals like Pb, Ni, Cd, and Hg resulting
from unregulated pollution and industrialization
contribute to glucose uptake disruption and other
complications. Exposure to humans occurs through
different routes but, except for arsenic, no data as of
yet associate heavy metals and T2D.47
A. Zinc
Zinc is a physiologically significant trace element
in biological systems. Because it is not involved in
redox reactions, many biomolecules require it for
preventing the side effects of redox chemistry.48
Zinc occurs in ionic stable form +2 and is involved
in many cell and biochemical processes; it is used
as a cofactor by almost 300 enzymes for catalytic
functions.49,50 Zinc imbalance results in dermal,
gastrointestinal, neurological, and immunological
abnormalities, diabetes mellitus, and increased ox-
idative stress.51 Zinc accumulation and regulation of
insulin excretion in islet pancreatic β cells are con-
trolled by key protein Zinc transporter (ZnT-8).52 In
many recent genome-wide studies, the genetic his-
tory of diabetes mellitus has been analyzed through
SNP genotyping that has resulted in the identification
of some nonidentical SNPs in the gene of Zn trans-
porter (SLC30A8), rs13266634, which is mostly re-
sponsible for T2D.53 The function of pancreatic islet
β cells is critically controlled by Zn, which plays a
role in the inhibition of diabetes through antioxidant
activity. A low level of Zn may unfavorably affect
insulin secretion and production by islet cells. How-
ever, a mutation in the Zinc transporter gene may
result in T2DM.46
In experimental studies on zinc-deficient rats,
it has been observed that there is a significant de-
crease in pancreatic zinc and serum and an increase
in glucose sensitivity. One study showed that the
zinc additive given to several rodent models of type
1 and type 2 diabetes is effective in ameliorating
diabetes.40,54
B. Cadmium
Cadmium is a well-known soft, silver-white, noto-
riously toxic heavy metal that is naturally present
in air, water, and soil and widely distributed in the
Earth’s crust with an approximate concentration of
0.1 mg/kg.2 It is frequently used in industry (for the

TABLE 2: Heavy metal effects on study models for diabetes

Heavy metal Study model Effect Result Ref.
Zinc Zn-deficient rat Mutation in ZnT-8 protein Zn and serum level down; glucose 40
intolerance up
Cadmium Human Necrosis and degeneration Serum insulin level down; glucose 41
of Pancreatic β cells level up
Rat adipocyte Downregulation of Impaired glucose tolerance; 42
GLUT4 protein GLUT4 expression down
Mercury Mouse HIT-TI5 Affect pancreatic β cells P13K-activation up; Akt pathway 43
cell and pancreatic through ROS production activation via oxidative stress
β cells pathway up
Human Increased blood glucose In children: 0.34 µg/L; in women: 44
(blood sample) level 1.02 µg/L
Nickel Rat Impaired enzyme related Hyperglycemia up; iNOS and 45
to DNA repair cGMP up; plasma glucose level up

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Role of Heavy Metals in Diabetes69
production of alloy, pigments, and batteries); how-
ever, due to environmental concerns its use is less
in developing countries. The US daily intake of
cadmium is almost 0.4 µg/kg/day, which is half the
EPA’s reference dose.55,56 However, because there
is no significant use for cadmium in physiological,
biochemical, and biological systems, its accumula-
tion in the body causes diseases like itai-itai.57,58
Exposure to 0.84-mg/kg of Cd in model or-
ganisms significantly increases blood glucose con-
centration.59 Also, there is a significant increase in
glucose and a decrease in serum concentration in ex-
perimental subjects as compared to control subjects
after exposure.41 However, the exact mechanism and
effect of cadmium on insulin secretion, production,
utilization, and regulation of blood glucose are un-
clear, as only a few reports have been written on the
association of cadmium and diabetes until now.2
Experimental studies identified Cadmium’s in-
volvement in the down-regulation of glucose trans-
porter-4 (GLUT4) and the increase in disruption
of pancreatic β cells in diabetes.2 Cadmium expo-
sure’s association with diabetes has been identified
in rat adipocytes. Reduced GLUT4 protein and
mRNA expression and lower glucose tolerance in
rats have been observed.42 Other reports show that
the accumulation of Cadmium metal is involved
in certain dysfunctions like cell degeneration or
necrosis and weak degranulation in pancreatic β
cells.60,61 So, Cd exposure might be the cause of
diabetic symptoms by inducing degradation of
islet β cells and oxidative stress.2 Cadmium may
adversely control glucose transporter 4 transfor-
mation through thyroxine and higher levels for the
destruction of glands like cells of the pancreas in
diabetes (Fig. 1).46
C. Mercury
Mercury is a heavy metal that exists in organic, in-
organic, and elemental forms with varying levels of
toxicity. Its cationic oxidation is +1 and +2.62,63 Mer-
cury has become a major health concern because
of its exposure to humans through environmental
pollution, food contaminants, industrial and agricul-
tural operations, and dental care.64,65 Most important,
several reports have identified that the consumption
Volume 31, Issue 3, 2021
FIG. 1: Schematic pathway of toxic metals’ effect on in-
tracellular signaling and their role in induced islet β cell
dysfunction
of fish is a major source of mercury intake: methyl
mercury enters fish and shellfish, and ultimately hu-
mans through the food chain.66
One report found that the estimated daily
dosage of 1,100 μm/kg mercury causes a signifi-
cant deleterious effect in nonhuman mammals.67
Another showed that the hair of a diseased per-
son (such as a diabetic) contains almost 2.08 to
36.5 ppm of mercury, which is much higher than
that of a healthy person.68 The organic and inor-
ganic forms of mercury cause damage to renal
cells, nerve cells, pancreatic islets, and many
others.69–71 An experimental study on the primary
cell culture of rat pancreatic islets cells showed
that mercuric chloride exposure causes significant
adverse effects on insulin secretion and calcium
homeostasis.72,73
Mercury exposure is highly associated with the
induction of oxidative stress as the biomarker (8-hy-
droxy-2-deoxyguanosine) responsible for oxidative
damage is significantly increased in the urine sam-
ple of people that are exposed to mercury-contami-
nated areas.74 Another recent experimental study in
mice shows a small dose of mercury-induced P13K
activation or Akt pathway which is triggered by ox-
idative stress that leads to dysfunction of pancreatic
β cells in model organisms and cell culture.43 This
proves that the viability of mercury is an important
environmental risk factor for diabetes.2
70 Javaid et al.
D. Nickel
Nickel is a ferromagnetic element found in combi-
nation with other elements in soil and meteorites.
Exposure in humans is through drinking water, air,
and contaminated food.75 Nickel strongly affects the
kidney, but a recent report showed the association of
Ni with T2DM as the presence of 0.89 ng/ml of Ni in
the blood of diabetic patients, which is much higher
relative to controls.76 Nickel is associated with the
production of reactive oxygen species leading to
the impairment of DNA repair enzymes.77 Some
studies have shown that the ROS pathway induces
glucose degradation and increases iNOS (inducible
nitric oxide synthase) and cGMP (cyclic guanosine
monophosphate), causing hypoglycemia via nickel
exposure.45 However, other studies have shown that
nickel-chloride intercepts hypoglycemia, a preven-
tive effect caused by the enhanced Cu-Zn superoxide
dismutase process.78 There is still controversy about
the association of Ni with diabetes and research on
the etiology of Nickel’s role is ongoing.2
E. Chromium
Chromium is a naturally occurring heavy metal
that is present in the Earth’s crust with a stable
oxidation state from chromium II and chromium
IV.79 It is widely used in industry, chrome plating,
leather tanning, and in dyes and paints. Chromium
is an industrial contaminant in many systems and is
highly toxic, surpassing the WHO limit of 50 µg Cr
per liter of drinking water.80 The biological activity
of chromium is determined through its oxidation
state; a trivalent form of chromium is highly im-
portant in biological processes such as optimal glu-
cose uptake.81 Chromium helps maintain glucose
levels by activating the insulin-signaling pathway
and up-regulating GLUT4 protein.82 Cr deficiency
may thus leads to an increase in blood glucose,
which if sustained may result in a metabolic disor-
der like diabetes progression.83 Cr additives given
to patients with diabetes caused decreased blood
glucose.84 The imbalance of physiologically signif-
icant metals impairs glucose tolerance and causes
many complications that will subsequently lead to
diabetes.46
IV. MECHANISMS
Some metals, like iron, zinc, and manganese, are
crucial biological components that carry out vital
functions. But the accumulation of some metals in
the body like arsenic, cadmium, lead, and mercury
is highly toxic. These toxic agents have accumu-
lated considerably in drinking water probably due to
their use in industrial, medical, and agricultural pro-
cesses.9 Elevated levels of heavy metals are linked
to diabetes mellitus but the mechanism of this link-
age is still under discussion. Proposed mechanisms
are discussed next.
Experimental studies of blood samples have
shown that diabetic patients have low levels of Zn,
Mn, and Cr but elevated levels of Cd and iron (Fe).
There is a lot of evidence linking metal ion imbal-
ance to diabetes because of its adverse effects on
pancreatic tissues.85 Among these heavy metals, ar-
senic is considered to be involved in the glycolysis
(Fig. 2).86 In arsenolysis, arsenic (As) can inhibit
the production of ATP during the glycolysis cycle
through the replacement of anionic phosphate with
arsenate.87
Arsenic has strong -SH affinities. As a result, it
allows the molecules and receptors of insulin to form
covalent disulfide bridge, and also subsequently
degraded their functions.88 Arsenic can release im-
paired insulin due to the production of reactive
free oxygen species in cells. Uncoupled protein-2
(UCP2) serves as a switch control for the release
of negative insulin and induces leakage of protons
through the inner mitochondrial membrane.89 The
superoxide-UCP2 pathway has been suggested to
FIG. 2: Role of cadmium and arsenic in diabetes mellitus
and their coupling in different pathways
Critical ReviewsTM in Eukaryotic Gene Expression
Role of Heavy Metals in Diabetes71

impede the secretion of insulin from pancreatic β
cells. Metals like arsenic have a potentially high
ability to generate superoxide. An increase in the
concentration of superoxide in β cells leads to a de-
crease in insulin secretion.90 Cadmium can inhibit
the glycolysis cycle through reduced activity of
phosphofructokinase in the liver and muscles.91
Similarly, the quantity of toxic metals like zinc
is comparatively elevated in the pancreas, with
DNA, RNA, and has been found to be involved
in the synthesis of protein. Cadmium has enough
potential to replace Zinc due to similar chemical
properties.92 Cadmium competes for several binding
sites with Zn+2 ions. It can also replace zinc trans-
porters (ZnTs) in various kinds of cells including β
cells, where the elevated amount of Zn+2 is used for
cell transportation.93 Cadmium has a high affinity to
these zinc transporters and affects islet β cells.94
Heavy metals like Cd, Ni, As, and Hg disrupt
intracellular signaling and cause islet β cell dys-
function due to oxidative stress. Exposure leads to
deregulation of insulin-responsive glucose trans-
porter (GLUT-4) expression and activity.95 Toxic
heavy metals interact with different biological pro-
teins, altering their kinetics and thus their function.
Thus, they directly damage pancreatic β cells by
producing ROS, which is the leading cause of oxy-
gen level imbalance (Fig. 3).46
Heavy metals interfere with the insulin gene
by producing ROS, which decreases its activity-en-
hancing ability and mRNA regulation in pancreatic
β cells, thus impairing insulin production. Because
heavy metals have long been suspected to produce
genotoxicity.10,46 The role of essential metals in bi-
ological systems is evident. They regulate redox
systems, bind to enzymes as cofactors, and maintain
the structural integrity of proteins.96 Because some
heavy metals have the same physiochemical prop-
erties as essential metals, they mimic the action of
essential metals and compete with them for enzy-
matic binding as cofactors, causing tissue damage.46
Heavy metals may contribute to diabetes and obesity

FIG. 3: Role of Arsenic in diabetes mellitus pathogenesis. Arsenic binds and renders nonfunctional insulin and insulin
receptor bridge (disulfide); arsenic impairs GLUT translocation by decreasing Akt’s phosphorylation. Arsenic acts as
a competent of phosphate ion (Pi) and interacts with adenosine-diphosphate to produce adenosine-diphosphate arse-
nate (ADPA) that is then applied to production of glucose-6-arsenate. Metals such as As induce greater imbalance in
systematic manifestation of reactive oxygen, causing production of unhealthy cytokines like TNF-α and IL-6, which
reduce regulation of PPAR-γ. These two agents have a leading role in insulin resistance development. PIP3, phosphati-
dylinositol (3,4,5)-trisphosphate; TNF-α, tumor necrosis factor-alpha; GLUT, glucose transporter; IL-6, interleukin-6;
NF-κB, nuclear factor kappa B; PI3k, phosphoinositide 3-kinase; IRS, insulin receptor substrate; PPAR-γ, peroxisome
proliferator-activated gamma receptor; PIP2, phosphatidylinositol 4,5-bisphosphate.

Volume 31, Issue 3, 2021

72 Javaid et al.
by altering the weight of an individual. One study
showed much higher blood cadmium levels in obese
diabetic patients than in nondiabetic controls.97
V. RELATIONSHIP OF HEAVY METAL
EXPOSURE TO GESTATIONAL DM DURING
PREGNANCY
Gestational diabetes is considered a common prob-
lem during pregnancy. This impaired glucose toler-
ance leads to hypoglycemia of varying severity at
the onset of pregnancy.98 One study showed that
intrauterine maternal diabetes has a significant im-
pact on the health of mother and child in later life.99
Epidemiological studies suggest that the increas-
ing prevalence of GDM is due to lifestyle factors
and environmental exposure to chemicals during
pregnancy.100 Certain processes increase the risk of
GDM, including oxidative stress, impaired glucose
homeostasis, PPAR-γ inhibition, and up-regulation
of inflammatory markers.101 The main sources of
exposure are mining and other industries, contam-
inated food, and heavy metal ingredients in prod-
ucts.102 The relationship of various toxic metals like
Cd, As, and Pb with GDM has been elucidated (Fig.
4).11
Diagnosis of GDM is done in the second tri-
mester via venous blood samples in EDTA tubes
for assay. After aliquoting, the sample is frozen at
−80°C and then centrifuged at 3,000 rpm for almost
5 min. Further analysis of the concentration of toxic
metals is through electrothermal atomic absorp-
tion spectrometry.103 After 24–18 weeks, glucose
FIG. 4: Confounding factors and exposure to heavy
metal during pregnancy
concentration is measured, and GDM is tested ac-
cording to Carpenter and Coustan criteria through
an oral glucose tolerance test.104 Experimental stud-
ies have shown that 75% of women have high Cd
concentrations in their blood and that some have a
higher concentration of Pb. Cadmium is highly toxic
and is the leading cause of GDM, with women hav-
ing high Cd concentrations at greater risk.101 Some
epidemiological studies associate Cd with T2DM,
and it is evident that T2DM individuals, both men
and women, have high Cd concentration in their
urine.101
Type 2 diabetes and GDM might share a common
pathogenic mechanism and occur due to environmen-
tal factors, family history, and life style, among oth-
ers.105 Although they share several common insulin
deregulation pathways like oxidative stress, they are
not directly analogous as their association varies with
different studies. Another reported method through
which heavy metals increase the risk of diabetes is
endocrine disruption.102 Humans are susceptible to
exposure to multiple toxic metals on a daily basis,
so it is rather difficult to find the exact mechanism
through which each heavy metal causes diabetes.
VI. DIAGNOSIS
In many studies, it is evident that there is a high con-
centration of heavy metals in the blood and urine
of diabetic patients. Many epidemiological studies
have shown that a significant amount of cadmium
in blood and arsenic in urine is mainly associated
with the high risk of diabetes mellitus.85,106 Some
researchers have found that a high mercury (Hg)
concentration correlates with GDM,11 as observed
in women who consume high amounts of fish and
shellfish.107,108 The mechanism of impaired insulin
secretion may be the high concentration of Fe, Cu,
and Ni and the low concentration of Zn, Cr, and Mn
in diabetic patients.85
Biological samples such as venous blood, urine,
and hair are used to detect the presence of heavy
metals and their relationship with diabetes. One
diagnostic method is to collect 3–5 ml of venous
blood in metal-free vacutainer blood collection
tubes, spray the tubes with 1.5 mg of EDTA solution,
and store them at −20°C  for further examination.
Critical ReviewsTM in Eukaryotic Gene Expression
Role of Heavy Metals in Diabetes73
Urine samples must be collected in decontaminated
100 ml of polyethylene and acid-washed (HNO3)
containers and held at 4°C. Inductively coupled gas
chromatography and mass spectrometry are used for
analysis of toxins or heavy metals present in urine.109
Metals detected by inductively coupled mass
spectrometry in urine include aluminum, titanium,
vanadium, manganese, chromium, iron, cobalt,
nickel, copper, zinc, arsenic, barium, tin, molybde-
num, and strontium. Electrothermal atomic absorp-
tion spectrometry is used to detect Pb, Cd, and Mn.101
Concentrations of some toxic/heavy metals are mea-
sured through spectrophotometry (atomic absorp-
tion) after digestion of acid aided by microwave
wavelengths. Clear conventional wet acid digestion
methods and comparison are used to check the ef-
fectiveness of heavy metals in biological samples.110
Exposure to cadmium through smoking is a more
critical health issue than exposure through products.
Smokers may intake twice as much cadmium in their
daily routine as nonsmokers. Cigarette smoke con-
tains approximately 1–2 μg of cadmium and almost
40% to 60% is inhaled by the lungs. Cigarette smok-
ers inhale almost 1–3 μg of cadmium from every
pack of cigarettes they smoke.110 Several techniques
have been developed for early detection of elevated
levels of disease in patients affected by diabetes
mellitus type 1 or type 2, including molecular im-
aging, biomedical imaging, and nanotechnology.111
VII. TREATMENT
A. Nano-Based Treatment
Nanotechnology is the repairing, monitoring, and
checking of human biological systems at the na-
noscale using various engineered materials. A min-
ute amount of insulin and blood glucose fluctuation
is rapidly measured in various ways, as discussed
next.
A multiwalled carbon nanotube–based micro-
physiometer detects insulin levels periodically by
measuring the electron transfer when a molecule of
insulin oxidizes in the presence of glucose. The cur-
rent in the sensor rises when more insulin molecules
are produced in the cell and vice versa. Nanotech-
nology-based glucose sensors provide more surface
Volume 31, Issue 3, 2021
area and speed up the catalytic activity of glucose
detection electrodes for molecules of glucose-bind-
ing proteins, oxidases, and some others.111,112
Nanoparticles are also being examined as
transporters of insulin in a nanodrug delivery sys-
tem. Using polymers such as dextran, chitosan,
and polylactide-co-glycolic acid, insulin-loaded
nanoparticles have been developed.113 Polymeric
nanoparticles have shown significant therapeutic
potential for diabetes treatment in replacing daily
subcutaneous injections. Insulin undergoes degrada-
tion when administrated orally, so it is encapsulated
in matrix-like polymeric nanoparticles to protect
it from gastric enzymes. Insulin-loaded polymeric
nanoparticles prepared using biodegradable poly-
mer improve the absorption of insulin from the gas-
trointestinal tract.114
Heavy metal accumulation in the human body
due to contaminated water can be alleviated by
nanoparticles. Most drinking water is contaminated
with arsenic and is highly dangerous to human
health. Huge populations in the US and Bangla-
desh have been exposed to arsenic-contaminated
water. Iron nanoparticles effectively decontaminate
drinking water of arsenic.115 The efficiency of iron
oxide nanoparticles can be enhanced by changing
the functional group on the particle surface.116 Sil-
ica-coated magnetite nanoparticles are also used
for the removal of cadmium, copper, manganese,
nickel, and lead.117
B. Plant-Based Treatment
Research shows that a plant-based diet significantly
reduces the risk of diabetes type 2 as compared to an
animal-based diet.118 Studies show a vegetarian diet
reduces diabetes risk by almost 50% compared with
a diet containing meat, because the former lowers
body weight, which helps prevent diabetes.119 Ap-
proximately 1,200 medicinal plants are used for di-
abetes mellitus treatment. Clinically, 109 have a full
mode of action and 450 have antidiabetic properties.
Against hyperglycemia, some plant-derived com-
pounds like peptidoglycans, hypoglycans, steroids,
terpenoids, polysaccharides, glycopeptides, ste-
roids, guanidine, and alkaloids have demonstrated
bioactivity. Aloe barbadensis, commonly known as
74 Javaid et al.
aloe, has a wide range of oral applications for the
management of T2DM and hyperlipidemia.120
Crude and active natural products of some
Asian medicinal plants are considered most effec-
tive against diabetes: Allium cepa, Ficus begalene-
sis, Pterocarpus marsupium, Tinospora cardifolia,
Eugenia jambolana, Ocium sanctumsyn, Murraya
koenigii, Allium sativa, Momordica charantia, and
Trigonella foenum-graecum. The approved drug
metformin, obtained from medicinal plants (e.g.,
Galega officinalis), is useful for the prevention of
diabetes (non-insulin-dependent).
Cadmium accumulation in the human body is
associated with many lethal diseases along with di-
abetes. Cadmium damages the body by activating
oxidative stress.121 Flavanols, flavonoids, and antho-
cyanins are obtained through plants that exhibit in-
hibitory and protective activity against Cd toxicity.
Flavonoids are protective via their promotion of the
antioxidative activity of enzymes and hormone re-
lease, which inhibits Cd accumulation by chelating
and impeding inflammation and cell death.122
Chelation therapy is one of the best treatments
for heavy metal poisoning.123 It works by combin-
ing antioxidants with chelating agents.124 Some
phyto-antioxidants like flavonoids and phenolic
compounds are obtained from edible plants.125 They
provide protection against heavy metal poisoning.126
Curcumin is a potentially active compound that
has received attention as a therapeutic agent against
diabetes.127 Obtained from turmeric, it acts as a che-
lating agent against many heavy metals like nickel,
lead, and cadmium,128 reducing heavy metal toxicity
and effectively reducing glycemia and hyperlipid-
emia  in experimental models.129,130 Various experi-
mental studies have reported the effect of Curcumin
on diabetic animal models and on some clinical
T2DM patients to treat complications.131 Garlic
juice also exhibits protection and inhibiting activity
against toxicity of cadmium and lead.132
VIII. ENVIRONMENTAL EFFECTS
According to epidemiological studies, T2DM is
thought to occur due to environmental, biologi-
cal, and behavioral risk factors.133 Healthy habits
are limited in the absence of a culture supporting
them, and behavioral and educational interventions
in this nonenabling environment can be remarkably
ineffective. Evidence from the literature indicates
that socioeconomic, demographic, and behavioral
variables are important prognosticators of T2DM
at individual levels.134 Environmental variables are
hypothesized to increase or restrict behavioral, psy-
chosocial, and physical stressors to increase risk
factors for T2DM. These are the environmental be-
haviors and kind of stress that cause the T2DM.135
In physiological systems, long-time manifes-
tation of various adverse environmental factors
may lead to “allostatic load” or to biological wear
and tear.136 Stress causes excessive release of sub-
stances such as cytokines, which accelerate the
expansion/progression of long-lasting disorders
like cardiovascular disease and T2DM.137 Exces-
sive processed food consumption also negatively
affects sleep and body weight; sleep disorders and
obesity are leading causes of T2DM, thus metab-
olism as well as body weight might be affected,
increasing T2DM risk.138
It has been documented that air pollution affects
epithelial actions, induces eruption and reduction
of insulin, and is correlated with a high danger of
hypertension among other conditions. Also, blood
lipid level is adversely affected by atmospheric and
noise pollution, affecting blood pressure and T2DM
risk.139,140 Socioeconomic, and other correlated vari-
ables may also elevate the environmental impact
on diabetes mellitus (primarily type 2) risk. For
example, lower-income individuals might be more
affected by unhygienic environmental conditions.
Environmental conditions and changes will even-
tually shape the determinants and progression of
T2DM throughout life.138
Contaminants other than atmospheric pollutants
have been shown to affect insulin resistance and thus
diabetes mellitus. Recent research has determined a
correlation between arsenic level in urine and inci-
dence of T2DM in the united states, which has been
shown to reduce to medium level of arsenic. Such
research authenticates that data previously collected
after exposure to high levels of arsenic in drinking
water correlate with an increased danger of T2DM.
These data were collected from countries like Tai-
wan, Bangladesh, and Mexico.141
Critical ReviewsTM in Eukaryotic Gene Expression
Role of Heavy Metals in Diabetes75
TABLE 3: Permissible heavy metal limit in drinking water
Serial no. Standard Arsenic
1 WHO 10
2 European Union (EU) 10
3 EPA 10
IX. PREVENTION OF HEAVY METAL
EXPOSURE
Heavy metals’ intensity in the air is increasing
day by day as their deposition from ores and sub-
sequent processing allows their spread into the
atmosphere (Table 3). Because they are not bi-
ologically degradable, they accumulate in food
chain waste and thus chain into the environment.
Pollution from heavy metals poses significant
threats to human health. Several physical and
chemical solutions have been proposed but they
possess shortcomings like high cost and care and
their modification and disturbance of soil. There-
fore, an efficient elimination method with fewer
complications is needed.145 Remediation by plants
is a comparatively better solution for heavy metal
contamination. Most phytic and soil-associated
bacteria carry out phytoremediation to lessen the
harmful impacts of heavy/toxic metal on the en-
vironment. This is a relatively new technology
and seems to have gained considerable public
acceptance as cost-effective, innovative, reliable,
and environmentally friendly, particularly if so-
lar-driven. It works for metals like cadmium
which is found extensively in soil and is a major
cause of diabetes. Metal hyperassemblies are be-
ing built for plant-based remediation and mining.64
Specific molecular methods have been used to bet-
ter understand plant uptake of metals, changeover,
appropriation, and acceptance. From an economic
perspective, phytoremediation can cost as little as
5% of the cost of standard clean-up methods.146
X. CONCLUSION
It has been shown that heavy metal exposure con-
tributes to the development of several metabolic
disorders causing changes in glucose and lipid ho-
meostasis. However, the available data include
Volume 31, Issue 3, 2021
Lead Cadmium Ref.
10 3.0 142
10 5.0 143
15 5.0 144
conflicting results. Nonetheless, the prevalence of
metabolic disorders involving impaired glucose
metabolism is significant. Metals such as cadmium
and arsenic are found extensively in the atmosphere.
Further research is needed on various aspects of the
relationship of chronic arsenic and cadmium toxic-
ity and diabetes mellitus.
XI. FUTURE PERSPECTIVES
Because of the conclusive nature of the reported cor-
relations and because of elongated exposure to heavy
metals, large prospective cohort studies are urgently
needed. We suggest that future prospective studies
or nested case-control work address major gaps in
the current literature. Examination of clustered case
controls will reveal all cases and controls based on
both baseline and follow-up physical and clinical
biochemical measures. In short, there is consensus
that prospective large-scale, high-quality studies
of well-characterized populations are immediately
needed for further investigation of heavy metal ex-
posure as a risk factor in progression of diabetes
mellitus.
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