Oxidative toxicity in diabetes and Alzheimer’s disease: mechanisms behind ROS/ RNS generation
Ahmad et al. Journal of Biomedical Science
Oxidative toxicity in diabetes and Alzheimer's disease: mechanisms behind ROS/ RNS generation
Waqar Ahmad 0
Bushra Ijaz 2
Khadija Shabbiri 0
Fayyaz Ahmed 2
Sidra Rehman 1
0 School of Biological Sciences, University of Queensland , Brisbane 4072 , Australia
1 COMSATS Institute of Information Technology Abbottabad , Abbottabad 22010 , Pakistan
2 Centre of Excellence in Molecular Biology, University of the Punjab, Thokar Niaz Baig , Lahore 54000 , Pakistan
Reactive oxidative species (ROS) toxicity remains an undisputed cause and link between Alzheimer's disease (AD) and Type-2 Diabetes Mellitus (T2DM). Patients with both AD and T2DM have damaged, oxidized DNA, RNA, protein and lipid products that can be used as possible disease progression markers. Although the oxidative stress has been anticipated as a main cause in promoting both AD and T2DM, multiple pathways could be involved in ROS production. The focus of this review is to summarize the mechanisms involved in ROS production and their possible association with AD and T2DM pathogenesis and progression. We have also highlighted the role of current treatments that can be linked with reduced oxidative stress and damage in AD and T2DM.
Alzheimer's disease; Type-2 diabetes mellitus; Oxidative stress; ROS production; Antioxidant treatments; Anti-diabetic drugs
A set of chemical processes through which living bodies
sustain their lives called as metabolism. This includes
digestion of food, transport into the body cells and excretion of
waste materials through well-conserved intermediary
metabolism. The metabolic pathways are the bio-chemical
processes involving DNA replication, transcription and
translation by enzyme catalysed reaction through which
food or other chemicals from the body transformed into
different chemicals and produce energy for various life
]. In the living organism’s body cells and tissues
are always gone through the assembly, and disassembly
processes in a regular manner involving several metabolic
pathways. Disturbs in metabolic process by any external or
internal factors may result in metabolic disorder followed
by many types of life-threatening diseases. The
understanding of the cellular and molecular mechanism for incurable
diseases like Alzheimer’s disease (AD) and Type-2 Diabetes
Mellitus (T2DM) has been progressing rapidly, which also
enhances the therapeutic approaches [
It has been noteworthy that the advancement in
diagnostic and therapeutic approaches improved the disease
management. However, pathophysiology of many diseases is still
under way. AD and T2DM, the two-utmost communal
overwhelming diseases caused by neurological and insulin
function disorder, have become a major public health
concern worldwide [
], and needed to be address effectively.
A large-scale clinico-epidemiological data indicates that
both T2DM and AD are most common age-associated
diseases around the globe. People with T2DM are prone to risk
of AD. The first strong evidence regarding the correlation
between AD and T2DM was reported in Rotterdam cohort
]. A number of clinical, epidemiological,
biological, molecular and genetic data supports a
pathophysiological link between T2DM and AD, including
obesity, impaired glucose, cholesterol metabolism, and
]. Presence of these symptoms altogether
known as metabolic syndrome (MetS) and could signify a
pathological connection between impaired metabolism and
several neurological disorders [
increased blood glucose is a major cause of T2DM, which is
associated with injury of insulin-producing pancreatic
βcells or by insulin sensitivity in adipose or muscle tissues
]. Both T2DM and AD induce disease severity based
on same path-physiological mechanisms, including
mitochondrial damage and formation of advanced glycation
products (AGEs). Both mitochondrial damage and AGEs
are influenced by induced oxidative stress, which not only
impair mtDNA and RNA but also affect protein and lipids
]. Several studies found induced levels of DNA,
RNA, protein and lipid oxidative products in T2DM and
AD like 8-hydroxyguanosine, 8-hydroxydeoxyguanosine,
protein carbonyls and nitrotyrosine; and lipid peroxidation
markers, for example, 4-hydroxynonenal, F2-isoprostanes,
and malondialdehyde [
Oxidative stress has been proposed to play a
significant role in T2DM and AD progression. The present
review highlights the complex mechanism involved in the
production of reactive oxygen species (ROS), induced
oxidative stress, and their impact on T2DM and AD
progression. Moreover, we also highlight the possible
treatments to cope with the bad effects of oxidative
stress in T2DM and AD.
ROS production and oxidative damage
ROS in living organisms was first described in 1954 [
]. In 1969, theory of oxygen toxicity was expressed in
aerobic organisms after the discovery of superoxide dismutase
(SOD) by McCord and Fridovich. ROS production can be
associated with age-related diseases, their developmental
processes and cell singling pathways [
radicals have very short lifespan and react rapidly with other
]. Presence of transition metals, especially Fe
and Cu can help to clarify and explain oxidative damage to
living cells [
]. Important oxidants in the living organism
includes ROS, reactive nitrogen species (RNS) and
sulphurcentred radicals. Although not all of them are radicals but
in many cases, these non-radicals can produce radical
species by reacting cellular compounds and damaging them by
]. The ROS can be classified into two groups;
radicals and non-radicals. The radicals contain superoxide
(O.2−), alkoxyl (RO.), peroxyl (ROO.), hydroxyl (OH.),
hydroperoxyl (HO.2) and nitric oxide (NO.). The non-radicals
include hydrogen peroxide (H2O2), organic peroxides
(ROOH), aldehydes (HCOR), hydrochlorous acid (HOCL),
peroxynitrite (ONOOH/ ONOO−), ozone (O3) and singlet
oxygen (1O2) [
ROS and RNS can be generated through exogenous and
endogenous sources [
]. Exogenous sources may include
UV radiations (direct oxidation of cellular components)
], ultrasound, drugs (like narcotics, anaesthetizes,
adreamicine, nitroglycerine and belomycinem) , food
(containing oxidants such as transition metals, aldehydes,
fatty acids and peroxides) [
], γ- radiations [
xenobiotics and toxic chemicals (alcohol, phosphine,
mustard gas) [
]. The endogenous sources may include
neutrophils, cytokines and other components of white
blood cells [
], direct ROS producing enzymes such as
NO synthase, indirect ROS producing enzymes such as the
xanthin oxidase, mitochondrial, metals and side effects of
various diseases [
]. These molecules ultimately target
the macromolecules like proteins, lipids and nucleotides
that result in genome instability and impaired organ
]. These molecules are critical for neuronal
and pancreatic beta cell stability and functions [
ROS readily attacks and generates a variety of variety DNA
lesions. These lesions could result in DNA base
transversions (e.g. G:C to T:A) [
]. More than 200 clinical
disorders have been associated with early initiation of ROS.
These disorders may include T2DM, AD, cardiovascular
damage, inflammation, intestinal tract disease, eye diseases,
brain degenerative impairments, aging, hemochromatosis,
thalassemia, and Wilson disease [
In living organisms, Oxidants and antioxidants play a
significant role in regulating free radical balance within
the body produced during active metabolism. A
disturbed endogenous antioxidant system favors shift
towards more pro-oxidants production called as “oxidative
stress.” If it shifts towards more production of
antioxidants or reducing power termed as “reductive stress”
25, 30, 47–49
]. As induced oxidative stress impairs
natural defense by unbalancing the oxidants and de-oxidant
ratio, balancing oxidative stress is an emerging therapy
in various diseases. Figure 1 explains the detailed
mechanism involved in the ROS generation in mitochondria.
ROS as cellular defence
ROS generally maintains the normal physiological
functions and cellular defense of the body. Many living
organisms survive below a specific homeostatic set point [
Although ROS production is beneficial for cellular
mechanism, their excessive quantities are always toxic and lead
to oxidative damage of many biological functions [
To reduce its toxicity, mammalian cells have evolved
defense mechanisms, including different DNA base
excisions and strand repair enzymes [
]. In this way,
living organisms have not only adapted themselves to
develop self-protective mechanisms for ROS but also able
to use it constructively [
]. Intracellular low level of
ROS may act as signaling molecules in many physiological
processes, including redox homeostasis and cellular signal
transduction . The divergent effects of ROS on many
cellular processes suggest that ROS is not merely
detrimental by-products, but also generated purposefully to
mediate a variety of signaling pathways.
Oxidative stress in T2DM
DM is a metabolic disorder categorized into two main
groups: Type I (Insulin dependent) that is due to
immune-mediated beta-cells destruction and lead to
insulin deficiency, and Type 2 (Non-Insulin dependent) that is
due to insulin secretion defects and resulted in insulin
]. Prolonged period of high blood-glucose
levels generally linked to both macro and micro vascular
complications like CVDs, strokes, peripheral vascular
diseases, neuropathy, retinopathy and nephropathy [
In addition to elevated blood-glucose levels, other factors
include high-cholesterol level (hyperlipidemia) and
oxidative stress leading to high risk of complications [
According to epidemiological studies, diabetic mortalities
can be explained by an increase in vascular diseases that
could be a cause of oxidative damage [
research reported that apo-lipoprotein component of LDL
instead of lipid alone could be a cause of oxidative damage
in DM [
Production of free radicals and their high levels in
diabetic patients could be non-enzymatic (i.e. glycated
proteins, glucose oxidation and increased lipid peroxidation)
or enzymatic (over/under-expressed levels of enzymes like
catalase (CAT), superoxide dismutase (SOD) and
glutathione peroxidise (GSH–Px)). These abnormalities may lead
to damage of enzymes, cellular machinery and increased
insulin resistance due to oxidative stress [
studies have provided a clear evidence that the main
source of ROS/ RNS production in T2DM is mitochondria
]. Abnormal mitochondrial functions and excessive
ROS/RNS production play a primary role in onset T2DM
and its complications. These studies also support the
possibility for mitochondrial-targeted antioxidant’s therapy of
T2DM complications .
During cellular metabolism, insulin reacts with it
receptors that lead to activation of Akt and translocation
of GLUT4 to cell membrane. Impaired oxidative
phosphorylation, reduced NADH oxidoreductase and citrate
synthase activities resulted in insulin resistance [
This insulin resistance could be the result from either
impaired fatty acid acetyl-CoA oxidation or from
subsequent accumulation of intracellular lipid and
diacylglycerol with consequent activation of protein kinase C and
ROS production. This impaired fatty acid oxidation
resulted in activation of serine kinases followed by
phosphorylation of insulin receptor substrates and interfering
insulin signal transduction .
Multiple studies have observed the presence of oxidative
markers like F2-isoprostane and nitrotyrosine in urine,
plasma and tissue levels of diabetic patients [
and NOS production in DM can be promoted by both
enzymatic and non-enzymatic sources. Main enzymatic
sources may be endothelial and vascular smooth muscle
cells, NADPH oxidase, xanthine oxidase, cyclooxygenase
and uncoupled NOS whereas, non-enzymatic sources
include mitochondrial respiratory chain, AGES, glucose
autoxidation process and activated polyol pathway .
ROS production has become a fundamental part in the
T2DM pathogenesis and severity [
]. During the normal
glucose oxidation process, the final product is NADH and
pyruvate. NADH can reduce pyruvate to lactate or
donates its reducing equivalents to electron transport
chain. On the other hand, in mitochondrial pyruvate
enters into Krebs’s cycle, get oxidised and produce CO2,
H2O, NADH and FADH2 [
]. In glucose autoxidation,
glucose forms radical and converted to reactive
ketoaldehydes and superoxide, consequently, produced hydroxyl
radical in presence of transition metals via H2O2 [
Superoxide can also form peroxynitrite radicals by
reacting with nitric oxide [
]. Hyperglycemia induced
superoxide formation in the mitochondrial electron
transport chain by driving the inner mitochondrial membrane
potential upward through the generation of excessive
electron donors in the Krebs’s cycle [
]. This situation
resulted in hyperpolarization of mitochondrial membrane
potential and increase in ATP/ADP ratio followed by an
inhibition of complex-III and electron accumulation at
coenzyme Q. Consequently; this situation accelerates free
radical formation by partial reduction of O2 and reduces
ATP synthesis [
Superoxide presence decreases
glyceraldehyde-3phosphate dehydrogenase (GAPDH) activity by 66% and
resulted in PARP activation and NAD+ depletion [
hyperglycemia, glucose conversion to the polyalcohol
sorbitol and fructose via the polyol pathway reduces NAD
+ to NADH. Sorbitol oxidation through NAD+ escort to
increased cytosolic NADH: NAD+ ratio and inhibit the
GAPDH activity, and consequently, increased production
of triose phosphate [
]. Increased triose phosphate
induced formation of methylglyoxal and diacylglycerol
(DAG), PKC and PARP activation [
also increases hexosamine pathway flux because of
increased bio-availability of nutrients and enhances
fructose-6-phosphate levels by inhibiting GAPDH by ROS
]. The outcome of the hexosamine pathway is
UDP-N-acetyl glucosamine that triggers many
transcription factors and pathways, and lead to microvascular
complications of T2DM [
Overproduction of superoxidase radicals is countered
by superoxide dismutase’s (SODs) and by uncoupling
proteins (UCPs). In hyperglycemia, over expression of
UCPs reduce mitochondrial hyperpolarization and ROS
formation, and block the glucose induced cell death.
Superoxide radical generation was enhanced in patients
with diabetic endothelial cells that promote oxidative
stress toxicity [
]. A study by Nishikawa et al.
observed the excessive generation of pyruvate via
accelerated glycolysis and production of superoxides radicals at
the Complex-II level under hyperglycemia [
Although glucose is least reactive reducing sugar, it may
lead to Amadori product through Schiff base formation
by reacting free amino acids. These Aamdori products
accumulate on proteins and start the production of
] that in turn increase ROS production
through binding to RAGE (receptors of AGEs) and
resulted in the NF-kB induction and NADPH oxidase
]. NADPH oxidase is major source of
O2−. Levels of NADPH and O2− were increased in vascular
specimens in diabetic patients [
] and . Binding
of AGEs to their receptor RAGE enhanced cytokines
and adhesion molecule’s production [
binding also has an abnormal effect on matrix
metalloproteinases (MMPs) and transforming growth factor (TGF)
]. Hyperglycemia also promotes ROS generation
by lipid peroxidation of low-density lipoprotein (LDL)
]. Peroxyl radicals produce hydroperoxides by
removing one hydrogen from lipids and propagate
further . ROS production also induces cellular
stresssensitive pathways like NF-kB, JNK/ SAPK, P38 MAPK
that leads to cellular damage, and late complications in
]. Figure 2 summarizes the mechanism
involved in progression of T2DM under high oxidative
Oxidative stress in AD
Clinically AD is characterized by sinister onset, slowly
progressive and sporadic disorder, with episodic
memory; instrumental signs include aphasia, apraxia, and
agnosia, together with general cognitive symptoms, such as
impaired judgment, decision-making, and orientation
]. There are two opinions about the onset of aging.
One view is that, it is genetically programmed
developmental processes, like the cell senescence, the
neuroendocrine and immunological changes. Another opinion
presents that, it is caused by accumulation of somatic
mutations and oxidative stress randomly at any time
]. The crucial events occur during aging progression
or their onsets are telomere erosion, oxidative stress and
cell senescence. Aged cell phenotype showed futile ROS
regulation on mitochondrial super-complexes that
causes ROS signalling changes [
]. The neuronal cells
are highly sensitive and susceptible to oxidative stress as
a result of its high intake of oxygen, lipid content and
scantiness of antioxidant enzymes as compared to
normal other body tissues [
]. It has been shown that
with the passage of time and advance age, ratios of ROS
production and antioxidant activities (superoxide
dismutase and catalase or glutathione peroxidase enzymes)
are disturbed and oxidative damage of macromolecules
and their product’s build-up in the brain [
One of the hallmarks of AD is the accumulation of
amyloid beta (Aβ) peptide mostly in mitochondria and it
has been shown that Aβ peptide itself can generate ROS
in the presence of metal ions such as Fe2+ and Cu2+
]. In mouse models and autopsy analysis of AD
patients, mitochondrial dysfunction leads to increased ROS
or increased ROS production lead to mitochondrial
dysfunction, which in turn enhances Aβ peptide
aggregation. Importantly, these elevated markers for oxidative
stress precede Aβ deposition and neurofibrillary tangles,
suggesting that oxidative stress is an early event involved
in AD pathogenesis. Abnormal production of proteins
and mtDNA mutation may be due to defective or
deficient base excision repair (BER) enzymes and its
associated pathways [
Several hypotheses described oxidative stress as a main
culprit in AD pathophysiology [
]. The nervous
system is rich source of unsaturated fatty acids and iron.
Both these high lipid and iron contents become the
targets for oxidative damage in nervous system. In AD
pathology, decline in synaptic activities, defects and low
energy metabolism with comparatively increased amount
of ROS, reduced antioxidants enzymes levels like Cu/
Zn-SOD, glutathione (GSH) and catalase in frontal and
temporal cortex, and presence of Aβ and NFTs together
lead to mitochondrial dysfunctions and neuronal cell
death. There are many mechanisms responsible for
oxidative stress, like sugar modifications, peroxidation of
lipids, oxidation of protein DNA/RNA and production
of free radicals by Aβ itself. These molecules are critical
for neuronal stability and functions [
]. In AD
patients, the free-radical production is intimately
associated with unique sources of AD pathology. The Aβ
(formed by proteolysis of a transmembrane glycoprotein
Aβ precursor protein (β-APP)) component of senile
plaques is main source of free radical production once it
formed outside the neurons via metal-catalysed
oxidation of APP [
]. Metals, especially iron plays a
significant role in free radical production in AD.
Increased iron contents have been found in Aβ and NFTs
deposits that catalyses hydrogen peroxide (H2O2) and
form hydroxyl radicals by Fenton reaction. Aβ is also
able to boost up the metal ions (such as iron, aluminium
and copper) capacity to generate free radicals. Aβ has
been shown to produce (H2O2) and releasing
thiobabituric acid reactive substances (TBARS) mainly associated
with hydroxyl radicals (OH) via metal ion reduction. Aβ
also induce neurodegeneration by targeting microglial
NADPH oxidase however, mechanism behind this
destruction is poorly understood [
AGEs that are present in the senile plaques also produce
free radicals by chemical oxidation and degradation, by
binding to their receptors (RAGE) or interacting with
microglia that surrounds the senile plaques. It results in
respiratory blast and production of superoxides and NO
]. The membranes from the brain are composed of
proteins and phospholipids. Presence of aluminium in NFTs
stimulates iron-induced lipid peroxidation of oxidisable
polyunsaturated fatty acids (PUFAs) that contain weak
double bond hydrogen atoms. These PUFAs (like
arachidonic acid, docosahexaenoic acid) resulted in multiple
aldehydes like acrolein and 4-hydroxy-2-nonenal (HNE). HNE
accumulation was shown in NFTs may cause tau
phosphorylation, damage or kill primary hippocampus neurons, gene
induction, crosslinking of cytoskeletal proteins, cytotoxicity
and inhibition of cyclins D1 and D2. HNE also disrupts the
binding of histones to DNA and increases chances of DNA
oxidation in AD brain . F2-isoprostanes a lipid reliable
peroxidation marker is also produced from non-enzymatic
peroxidation of arachidonic acid [
The oxidation of amino acids like lysine, arginine,
proline and histidine via peroxynitrite generates protein
carbonyls and nitrile that were increased in AD [
Increased levels of protein carbonyls may decrease ATP
availability in synaptic terminals and disrupt the
cytoskeletal protein assembly . The protein oxidation
via nitric oxide produce ONOO radical and
nitrotyrosine that are important non-invasive marker for
protein oxidation in AD [
]. The other protein’s
oxidation such as ubiquitin, methionine and cysteine is
associated with NFTs and the number of tangles has
inverse relation with soluble proteins. .
The oxidation of DNA and RNA especially mtDNA in
AD results in hydroxylated base’s products, DNA-protein
crosslinking, strand breakage and impairment of DNA
repair system. The levels of 8OHdG were high in AD when
compared to the age-matched controls [
oxidation is a primary target in AD as RNA is less secure
than DNA due to single stranded and specific proteins like
histones. The non-coding RNAs are also involved in
synapsis, neuronal specification and differentiation, and
regulation of dendritic spine development. So their damage due
to oxidative stress contributes in development of
neurodegenerative diseases specially AD [
]. Nunamara et
al., extensively reviewed the RNA oxidation in
neurodegenerative diseases and discussed the biological significance
and cellular mechanism against RNA oxidation [
As mitochondria are concerned with a regulatory role in
cells through apoptosis, their dysfunction due to oxidative
stress may lead a disruption of cellular functions [
]. Apoptosis activates caspases via proteins like BAD,
BOX and results in morphological and biochemical
changes leading to cell death whereas anti-apoptotic
protein BCL-2 over expression may reduce Aβ-induced
toxicity in AD via inhibiting p38, MAPK and NFkB
proapoptotic activation [
]. Aβ presence also
decreased the mitochondrial respiratory chain complexes
activity, while the activity of ATP synthase α-chain reduced
with accumulation of NFTs [
129, 138, 139
]. Figure 3
highlighted the important pathways involved in damage
created by oxidative stress in AD.
The effect of oxidative stress on both T2DM and AD
remained to define. Intervention to excessive ROS
production through scavenging free radicals and increasing
antioxidant defence mechanisms are extensively
anticipated as anti-aging therapy and also managing AD and
T2DM. However, positive and conclusive results have not
been achieved even with the association of
supplementation and pharmacological or natural compounds. It is
possible that few antioxidants may become useless or even
harmful sooner or later. Supporting evidence has been
obtained from the previous research, which indicates the
significant role of oxidative stress in the development of
neuronal injury in the diabetic brain and the beneficial
effects of antioxidants. We must take into account, that
research studies also reported on the failure of antioxidant’s
therapies for T2DM. In contrast, the ongoing large clinical
trials will also shed additional light on the clinical merit of
antioxidant supplementation [
]. These studies
suggest that the clearly linking products i.e. deregulated ROS
production and oxidative stress in both disorders may lead
to common therapy.
The multi-factorial and inexorable phenomenon of disease
complexity of both T2DM and AD leads to gradual
reduction of resistance towards oxidative stress, and metabolic
disorders that are the major hallmarks of both illnesses.
Genetic studies have improved our understanding of
pathways that lead to both disorders that highlighting possible
interventional targets. Association between AD and
T2DM suggests that drug givens to AD patients would be
more effective as given to DM [
6, 114, 141, 142
Therefore, targeting T2DM might be more constructive for
treating AD. It is also suggested that drugs which used to
treat T2DM may affect AD progression ether directly in
the brain, provided they pass the blood-brain barrier or
indirectly, by modification of systemic blood-glucose
concentrations, insulin, inflammatory markers and AGEs.
Hence, recent research mostly focuses on treating AD
through anti-diabetic drugs that have a direct effect on the
brain tissue since brain insulin resistance is often
associated with AD . Preclinical and postmortem
neuropathological studies have identified significant effect of
normal insulin signaling in proper functioning through
the brain. These findings have given way for investigating
novel therapeutic agents for common AD and T2DM
Epidemiological research data has substantiated a strong
linkage between T2DM and AD whereas the exact
mechanism behind this enhanced risk yet to be discovered.
Both AD and T2DM have a high incidence rate at
advanced age. Several recent researches reported communal
pathological causes between T2DM and AD and
therefore, common preventive and therapeutic agents might be
effective for both types of disease. The oxidative stress has
a transitional part in the AD development. More research
is requisite for explore explosive rate in T2DM in the
younger generation. Unfortunately, observations made for
T2DM and AD drugs seemed to be working in vertebrate
and invertebrate models of T2DM, but appears to fail
during clinical trials except intranasal insulin therapy.
Considering present review, enzyme inhibition is also answering
and promising strategy against both types of disease.
However, its role in patho-physiology and therapeutics is still
needed to explore fully. In conclusion, shared
pathogenesis and curative agents make possible to manage life style
pattern and use of new therapeutic agents.
A better understanding of oxidative stress production
and coping in the AD and T2DM might offer some
novel targets for therapy. It is further to point out
that whether oxidative stress is the eventual basis of
pathogenesis; anti-oxidant therapy gets the reward for
ultimate treatment. The strategy should be designed
in aims of specifically targeting free radical
production and oxidative stress that limit its production and
progression in the body but how is it possible?
Natural products, which are extensively studied to
control different diseases by hindering or suppressing
ROS production, might be a good choice. Further
work is required for better understanding the role of
oxidative stress in AD and T2DM progression hence
new techniques are compulsory against these
substances. Poor knowledge of basic mechanisms
involved in aging process, which might interfere to
prevent or delay age-related pathologies, like T2DM,
cardiovascular disorders, neurodegenerative disorders,
and cancer. More investigations are clearly needed to
clarify the discrepancy in the role of ROS and
antioxidant enzymes in aging process and age-related
diseases and to understand the precise role of free
radicals play in that processes.
AD: Alzheimer’s disease; AGEs: Advanced glycation end products; Aβ:
Betaamyloid; BBB: Blood brain barrier; DAG: Diacylglycerol; GAPDH:
Glyceraldehyde-3phosphate dehydrogenase; GSH: Glutathione peroxidise; GSK3: Glycogen synthase
kinase3; H2O2: hydrogen peroxide; HNE: 4-hydroxy-2-nonenal; KGDHC:
αKetoglutarate dehydrogenase complex; LDL: Low-density lipoprotein; LMWA: Low
molecular weight antioxidants; MAO: Monoamine oxidases; MetS: Metabolic
syndrome; MMPs: Matrix metalloproteinases; MPO: Myeloperoxidase;
NADH: Nicotinamide dinucleotide; OMM: Outer mitochondrial membrane;
RET: Reverse electron transfer; RNS: Reactive nitrogen species; ROS: Reactive
oxygen species; SOD: Superoxide dismutase; T2DM: Type-2 diabetes mellitus;
TZDs: Thiazolidinediones; α –GDH: α-glycerophosphate
Availability of data and materials
WA, BI, KS, FA, and SR wrote the different parts of the manuscript. WA and
KS draw the pictures included in this manuscript. WA and BI edited the
manuscript. All authors read and approved the final manuscript.
Waqar Ahmad is working as Research Officer while Khadija Shabbiri is
post-doctoral Research fellow at School of Biological Sciences, University of
Queensland, Australia. Bushra Ijaz is Assistant professor at CEMB, University of
the Punjab, Lahore, Sidra Rehman is Assistant professor at COMSATS; while
Fayyaz Ahmed is PhD a student.
Ethics approval and consent to participate
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before and not submitted to any other journal.
The authors have no competing interests.
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