REV.CHIM.(Bucharest) 69No. 9 2018 http:www.revistadechimie.ro 2515Oxidative Stress in Diabetes [602691]

REV.CHIM.(Bucharest) ♦69♦No. 9 ♦2018 http://www.revistadechimie.ro 2515Oxidative Stress in Diabetes
A model of complex thinking applied in medicine
ANCA PANTEA STOIAN1, GRIGORINA MITROFAN2*, FLORIAN COLCEAG3, ANDRA IULIA SUCEVEANU4, RAZVAN HAINAROSIE5,6,
SILVIU PITURU5, CAMELIA CRISTINA DIACONU5,7, DANIEL TIMOFTE9, CORNELIA NITIPIR5, CATALINA POIANA5,8,
CRISTIAN SERAFINCEANU1,2
1 Carol Davila University of Medicine and Pharmacy, Department of Diabetes and Nutrition, 5-7 Ion Movila Str., 051577,
Bucharest, Romania
2 Prof. Dr Nicolae Paulescu National Institute of Diabetes, Nutrition and Metabolic Diseases, 5-7 Ion Movila Str., 051577, Buchar est,
Romania
3 Human Knowledge Research and Development Institute, Bucharest, Romania
4 Ovidius University, Faculty of Medicine, 1 Universitatii Str., 900470, Constanta, Romania
5 Carol Davila University of Medicine and Pharmacy, 37 Dionisie Lupu Str., 020021, Bucharest, Romania
6 Prof. Dr D. Hociota Institute of Phonoaudiology and Functional ENT Surgery, 21st Mihail Cioranu Str., 050751, Bucharest, Romania
7 Internal Medicine Clinic, Floreasca Clinical Emergency Hospital , 8 Floreasca Av., 014461, Bucharest, Romania
8 C.I. Parhon National Institute of Endocrinology, 34 – 38 Aviatorilor Av., 011863, Bucharest, Romania
9 Department of Surgical Sciences, Grigore T Popa University of Medicine and Pharmacy, 16 Universitatii Str.,700115, Iasi,
Romania
Since their first mention, almost 60 years ago, there were a plethora of articles about oxidative stress and
antioxidants, published in a wide range of journals (biochemistry, cell physiology, molecular biology or
environmental biology). Also, in the last decade the definition of oxidative stress (OS) undergone different
changes, and currently OS is seen as a disruption of redox signalling and control. This review aims to offer
the perspective of Complexity Theory on antioxidants framework, and diabetes disease is taken as an
example.
Keywords: oxidative stress, antioxidants, complexity theory, algebraic fractals
Currently, most of the scientific literature considers that
OS produces adverse effects through the imbalancebetween the production of ROS (reactive oxygen species)
and the biological neutralising capacity of the body (i.e.
enzymes) [1-3,6-10]. At a macroscopic level, obesity (i.e.insulin resistance) and a sedentary lifestyle are well-known
risk factors for type 2 diabetes, but at a molecular level,
oxidative stress is regarded as the primary contributor tothe pathogenic process [7,22-23]. As a consequence, in
the progression of cardiovascular or renal disease (diabetes
complications), OS is also taken as the primary pathogenicmechanism [1]. Although there are studies that show the
benefit of antioxidant treatment in chronic pathology,
particularly in diabetes and its complications, there is not ageneral consensus among medical practitioners [2]. This
review brings the attention on how our thinking models
influence the way we judge pathogenic mechanisms andconsiders the importance of looking at a phenomenon from
multiple points of view.
Experimental part
Materials and methods
We made a literature review by searching in the
MEDLINE database for the most representative articles
published since 1980. The searched terms used were
oxidative stress and diabetes antioxidants . We selected
29 articles published in specialised journals excluding those
that were not directly related to the topic. Also, Complexity
Theory in the understanding of the latest mathematicalsigns of progress made by Colceag was considered.
Upgrading our thinking models
Currently, one of the latest perspectives in biological
research is based on the system’s dynamics and Complex
* email: mitrofan.grigorina@gmail.com; Phone:+40766646399 All the authors have contributed equally to this paper.Systems Theory. The network concept is increasingly usedfor analysing complex systems, such as living organisms
[3]. Fractal varieties and algebraic fractals theory representone of the main alternatives to understanding how to
characterise a phenomenon, without losing its complexity
[4]. Informational feedback is an object with severalproperties: 1) every two nodes generate the third one, 2)
functionality is associated to each node, 3) each node bears
a semantic content. Extended research in this field wasdone by Colceag [5]. Based on informational feedback,
the process of oxidative stress can be characterised if
several questions are answered:
1. What is it understood through oxidative stress?
2. Which are the properties of reactive oxygen species?
3. Do these properties maintain if the complexity of the
system is changed? (i.e.
in vivo versus in vitro )
4. How do the effects of oxidative stress express in the
body?
5. How can oxidative stress be quantified and
characterised?
6. Which are the strategies of the organisation when
dealing with reactive oxygen species and oxidative stress?
Most of the papers published so far focus solely on one
of these questions, but an integrative perspective is neededto avoid one of the most common thinking biases, such as
forced generalisation.
What is it understood through oxidative stress?
The reactive oxygen species, as well as reactive nitrogen
species (RNS), have multiple sources of generation: asbyproducts of normal cellular respiration given by the new
cooperation between mitochondria and cellular
membrane networks, deliberate production by immunecells killing pathogens or random products of non-

http://www.revistadechimie.ro REV.CHIM.(Bucharest) ♦69♦No. 9 ♦2018 2516enzymatic and enzymatic processes. To compensate for
this potentially harmful species, several mechanisms that
neutralise these effects have been developed, such asscavenging enzymes, non-enzymatic antioxidants (free
radical scavengers), compartmentalisation, repair of
damaged components and metal sequestration [6].
A generic definition of an anti-oxidant is given as a
structure that can neutralise/inhibits oxidation of other
molecules. The following equation summarises thisdynamics:
X• +Y→X+•Y ,
(1)
where X• is the harmful free radical, which becomes X
(non-radical) and Y is the scavenger, which becomes a
more stable radical. Also, the by-products lose their adverse
effect because X is metabolised, while •Y is excreted. It isworth mentioning that this explanation is valid only when
speaking about antioxidants from a chemical point of view.
In the beginning, oxidative stress was defined solely as
a disturbance of the equilibrium between increased free
radicals production and reduced antioxidant capacity of
the organism [7]. This was a quantitative approach,implying that different biological systems respond in a
similar way to the lack of equilibrium. In the last decade, it
was proposed an alternative definition for OS, as a
disruption of redox signalling and control [8], shifting to a
qualitative model. Thus, OS can cause pathway-specific
toxicity related to processes such as uncontrolled fibroticprocess, inappropriate apoptosis, immune dysfunction,
altered membrane permeability and barrier functions [9].
In other words, this new concept opens the possibility thatOS could emerge without an overall imbalance of pro-
oxidative and anti-oxidative factors [9]. This property
suggests that there may be semantic properties associatedwith chemical structures because some of the ROS effects
are linked more with signalling, while the others are
connected more with negative given impacts by oxidative
stress.
It should also be noted that the effects are dose
mediated, known as hormetic effect [10]. Hormetic
behaviour plays a significant role in the dynamics of redox
biology because it encompasses both physiological andpathological roles ROS/NOS. Overproduction of ROS leads
to oxidative stress, a process that profoundly impacts cell
structures including proteins, lipids or DNA. On the otherhand, beneficial effects occur at low/moderate
concentrations and play a role in physiological pathways
in cellular responses to infectious agents or induction ofmitogenic response [11]. The most intriguing behaviour is
that various ROS-mediated processes have a protective
effect against ROS-induced oxidative stress and re-establish or maintain
redox balance [12]. This fact opens
up the idea that there may be a chemical, behavioural
vocabulary of ROS/NOS family that generates differenteffects depending on the various contexts.
Shifting the definition of oxidative stress from the view
of a global imbalance of pro-oxidants and antioxidants toone that addresses disruption of specific redox signalling
and control pathways would stimulate the development
of therapeutic strategies, targeting a particular circuit ofredox and eventually would contribute to disease
prevention.
In the same time, different definitions of OS were
adapted concerning a specific scientific field such as
dietary oxidative stress, physiological oxidative stress,
photo-oxidative stress, radiation-induced oxidative stress,oxidative stress status, reductive stress, nitrosative stress
[8]. Although there are many types of reactive species, in
this paper will be considered mostly reactive oxygen
species.
Which are the molecules that can be regarded as
antioxidants?
Keeping in mind that oxidative stress represents a
disruption in a specific oxidative pathway, at a cellular level,
one can speak of either direct and indirect oxidative stressor antioxidants.
From a chemical point of view, the underlying properties
of partially reduced species are given by molecular orbitaloxygen structures [6]. Highly reactive molecular species
with unpaired electron persist only for very short duration
10
-9-10-12 s, and then they collide with another molecule,
donate the electron and achieve stability. Molecular oxygen
is itself a radical, and by adding one electron forms
superoxide anion radical (O2•-), is considered the primary
ROS. The secondary ROS results from reactivity of
superoxide with other molecules either directly or through
enzyme or metal catalysed processes [6]. The chemicalreactions of generating free radicals are presented in the
formulas below (2):
(2) Free radicals generations
O
2+e- ⇒O2•-
O2•- +2H+ + e- ⇒H2O2H2O2+ H+ + e- ⇒HO•+OH-
HO•+ e− ⇒H2O
Hydrogen peroxide has a limited ability to cause tissue
damage, depending on the interaction with transition metal
ions, when it forms hydroxyl radical, which is the mostpotent of all oxygen radicals. When speaking about free
radicals, Fenton reaction (3) and Haber-Weiss reaction (4)
are the always mentioned as the main sources of hydroxyl
radical. Although Fenton reactions are specific to
in vitro
reactions, in vivo their significance is not clear [13].
(3) Fenton reaction
Fe+2+H2O2⇒ Fe+3+ HO•+OH-
Fe+3+ O2•-⇔Fe+2+O2
(4) Haber-Weiss reaction
O2•- + H2O2⇔ HO•+ OH-+O2
The main properties of reactive oxygen species are
summarized in table1.
From a cellular signalling point of view, a closer look is
needed when speaking about anti-oxidants and pro-oxidants molecules. There are molecules able to induce
gene expression of components known to play a role in
scavenging free radicals or interfere with signallingpathways. For example, the synthesis of a group of
antioxidant enzymes is regulated via antioxidant response
element (ARE) and transcription factor NfR2 [14]. Anotherexample is represented by
α-tocopherol, which prevents
phosphorylation of P47 and assembly of the active oxidase,
and subsequently inhibits NADPH oxidase in macrophagesand the oxygen burst [15]. On the other hand, in the
mitochondrial complex III, the electron flow is blocked by
antimycin A, which doesn’t have any reactive oxygengroups, but induces superoxide and hydrogen peroxide
release [16], therefore can antimycin A be regarded as
pro-oxidant?
By giving these examples, we support the idea of some
authors [9, 17] that the definition and properties of
antioxidants or pro-oxidants should be regarded more than

REV.CHIM.(Bucharest) ♦69♦No. 9 ♦2018 http://www.revistadechimie.ro 2517description associated with the imbalance between
reactive oxygen species production [18].
Do these properties maintain if the complexity of the
system is changed? (i.e. in vivo versus in vitro)
Due to extensive research made in this field from food
science, the associations between oxidative stress anddiet generated the concept of
dietary oxidative stress and
it was regarded as a substance in food that significantly
decreases the adverse effects of reactive species, such as
reactive oxygen species, reactive nitrogen species, on
normal physiological function in humans [8]. So far, a wide
range of molecules was named as antioxidants includingvitamin E, vitamin C, carotenoids, polyphenols, lycopene
and other micronutrients such as selenium [11].
When taken as a supplement, usually an antioxidant
follows the route of intestine, plasma and either liver or
directly to the target tissues, but it has been noticed that
through methylation or glucuronidation the antioxidantproperties are lost, and the molecules may still have effects
at a cellular level, in a similar way as the initial antioxidant
[17]. This observation may lead to the previous hypothesisthat some antioxidant’s effects are exerted considering
semantic functionalities of chemical structures.
In the same time, molecules proved to have antioxidant
properties
in vivo might have additional features in vivo and
their first functionality changes. For example, retinol, which
is an antioxidant in vitro initiates the process of vision
together with rhodopsin, due to isomerisation of the
pigment and not due to its antioxidant properties, but in
some studies, it was classified as an antioxidant [19].Melatonin also has antioxidant properties in vitro , but
through G protein-coupled receptors takes place its primary
function of generating circadian rhythm [20, 21].
Their bioavailability represents another issue regarding
oral supplements, and it is well known that dietary
antioxidants are bioavailable but in a decreased quantityper portion.
How do the effects of oxidative stress express in the body?
An increased quantity of free radicals or modified signal
transductions has been associated with almost all of the
chronic diseases [6]. In clinical research two approachesare considered: either if there are specific nutritional
interventions able to prevent a particular disease or,
nutritional interventions able to alleviate progression,symptoms or complications of the diseases. In the same
time, the diseases break into two groups: (i) the first
involves the so-called
mitochondrial oxidative stress
conditions (cancer and diabetes) and (ii) the second group
involves the so-called inflammatory, oxidative conditions
(atherosclerosis, chronic inflammation, and ischemia and
reperfusion injury [6, 22].
In the case of diabetes, there are several structural
transformations given by hyperglycemia: protein oxidationand lipid oxidation are the most recognised. Free radicals
induce damage to sulfhydryl groups and proteins are no
longer recognised as self, leading to cross-reactions andautoimmune diseases.
Also, peroxidation of plasmatic lipids produces abnormal
LDL which are not identified by liver’s LDL receptors andsubsequently, macrophage scavenger receptors take
Fig. 1. Primary prevention of diabetes
can be made through education about
healthy lifestyle, while secondary
prevention can be realised through
approaches that limit the impact of
hyperglycemiaTable 1
OXYGEN TOXICITY AND REACTIVE
SPECIES (ADAPTED AFTER DAL ET.
Al., 2016)

http://www.revistadechimie.ro REV.CHIM.(Bucharest) ♦69♦No. 9 ♦2018 2518modified LDLs, forming engorged lipid macrophages
(LEM), and infiltrate under blood vessel endothelium.
Another mechanism of lipid peroxidation involves loss
of membrane functions and integrity. A chain reaction
between polyunsaturated fatty acids and ROS affects
membrane lipids, which leads to increased permeability,increased calcium influx and subsequent mitochondrial
damage. The dynamics can be described as follows:
A). Initiation by OH• attack of polyunsaturated lipids,
extracting one proton, B) free radical chain reaction with
O2, C) Lipid peroxyl radical propagates and degrades lipidic
structures
D) Lipid soluble antioxidants such as vitamin Estop the
chain reaction.
The dynamics of free radical interaction in lipid
peroxidation follows the logic of laticeal automata
described by Colceag [5]. A so-called defect appears in an
initial structure, which is transmitted to the surroundedstructures to get to an equilibrium state, inducing
conformational changes of the initial structure.
Figure 1 presents the dynamic of the pathogenic process
in diabetic disease and how to tackle the illness through
primary and secondary prevention.
How could oxidative stress be quantified and
characterised?
There are many lines of evidence that are suggesting
that oxidative reactions play a role in the progression of
age-related pathologies (in the field of healthy ageing) and
significant disease processes including cardiovasculardisease, diabetes, cancer and neurodegenerative diseases
[6].
Although extensive research on oxidative damage was
achieved, there is no consensus for routine clinical
assessment of oxidative stress. The main burden is that
most of the assays do not assess the balance of pro-
oxidants and antioxidants, but instead focus on either
oxidants and oxidation products or antioxidants andantioxidant systems. For example, disease-oriented
research goes for the pro-oxidant side, while nutrition
research in more often focused on the antioxidants side.
Several methods have been described previously in order
to assess oxidative stress: HPLC and CG-MS for
antioxidants (ascorbate,
α-tocopherol, glutathione,
carotenoids, polyphenols), d-ROMs and ESR for oxidants
(superoxide anion, H2O2), immunoassays, HPLC, LC-MS/
MS GC-MS for oxidation products (isoprostanes, proteincarbonyls), mRNA expression, immunoassay, enzyme
activity (catalase, SODI-2, GPx1,2, Trx 1,2, Prx1,2)[9].
However, the large number of antioxidant systems limitsthe utility of antioxidant assays for assessment of oxidative
stress under clinical conditions.
Some authors describe the balance of GSH/GSSH
antioxidant system as an essential alternative for
assessment [9]. GSH has a central role as an antioxidant,
maintaining thiol/disulfide redox state proteins, and it alsosupports the redox state of ascorbate and indirectly vitamin
E. On the other hand, GSSG is reduced back by GSSG
reductase, which is ubiquitously distributed in tissues.Therefore, there is a direct link between their respective
tissular concentration and plasma concentration, providing
useful indications about oxidative stress. More than this,analysing the interaction between GSH/GSSH with Cys/
CySS in healthy individuals, the investigators obtained that
there is a lack of equilibrium between the two systems,suggesting that the concept of a single balance between
pro-oxidant and antioxidant system is a simple approach
of oxidative stress [9]. Recognition of the existence ofmultiple, discrete redox signalling pathways suggests that
a more suitable definition for oxidative stress is a condition
that disrupts redox signalling control.
Due to the difficulty in assessing cellular redox processes
(reactive species are present at very low concentrations
in cells, and it is difficult to measure them directly), there islimited evidence of specificity in redox signal transduction
mechanisms, although most studies have an underlying
assumption of uniqueness. The main burden is representedby the difference of experimental conditions
in vivo
compared with in vitro . To study a redox pathway, three
critical components are needed: a redox-signal generator,a redox signal sensor and a redox signal. If the sensors
could have an increased sensitivity in discriminating
between hydrogen peroxide and superoxide these circuitscould exist within the same physical space and transmit
biological information independently [9]. Therefore, the
description of
oxidative stress should be considered if the
molecular details of the imbalance are known.
Which are the strategies of the body when dealing with
reactive oxygen species and oxidative stress?
As mentioned above, there are many strategies by which
the body tries to cope with an increased flow of freeradicals; some of them are short or medium term reactions,
while others can be considered as long-term defence
mechanisms.
In the physiopathological chain of T2D, insulin resistance
(IR) is seen as the primary factor involved in hyperglycemic
state, and the central dogma considers IR a high risk tothe body and should be counteracted at any cost, but
recently insulin resistance is seen as a
physiological
defence against metabolic stress [23][24]. Although most
of the therapeutic strategies are focused on lowering
glucose concentration and HbA1c, it is questionable
whether if this approach is the most beneficial. For
example, the ACCORD trial showed that aggressive
glycemic control compared with standard treatmentincreased all cause of mortality including death from
cardiovascular causes [25]. Also, a meta-analysis of
UKPDS, ADVANCE, ACCORD and VADT showed that astrategy based on intensive versus standard glycemic
approaches were associated with only a 15% reduction in
myocardial infarction [26].
These contradictory results could be at least partially
explained if IR is accepted as a mechanism for myocardial
protection against glucolipotoxicity. In healthy people thereis an inverse relationship between glucose and free fatty
acids level (FFA), whereas, in low controlled T2D patients,
both circulating glucose and free fatty acids are elevatedsimultaneously, leading to an exposure of the myocardium
to nutrient overload and glucolipotoxicity [27]. Therefore,
treating T2D patients with exogenous insulin increased lipidcontent in the myocardial tissue by 80% [ 28-29], and more
than this, even in healthy subjects, short-term
hyperinsulinemia and hyperglycemia led to increase inmyocardial lipid accumulation [30]. This situation was
described as
insulin-mediated metabolic stress [31], and
various authors established mitochondrial oxidative stress(i.e. superoxide stress) as a predecessor of insulin
resistance [32-34].
Conclusions
In this paper, we showed that the assessment of a
phenomenon using a complex logic leads to a betterunderstanding of pathogenic processes, which may avoid
oversimplification or overgeneralization.

REV.CHIM.(Bucharest) ♦69♦No. 9 ♦2018 http://www.revistadechimie.ro 2519Also, the research made in the field of oxidative stress
will have a meaningful impact in understanding the
signalling pathways that generate chronic diseases (i.e.diabetes), with an enormous contribution in both primary
and secondary prevention.
Acknowledgements: This research was not supported from any
funding source.
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Manuscript received: 20.02.2018