Alloxan-induced diabetes, a common model for evaluating the glycemic-control potential of therapeutic compounds and plants extracts in experimental studies

Abstract

Glycemic homeostasis refers to glucose balance or control within circulation in living organisms. It is normally and largely compromised in diabetes. The compromise when exacerbated, leads to several complications including retinopathy, nephropathy and neuropathy which are collectively known as diabetic complications and are the principal actors in co-morbidity and eventual mortality often associated with diabetes. The ability of therapeutic compounds including medicinal plants to restore glycemic balance or homeostasis in hyperglycemic condition is an index of their antidiabetic function and relevance. Alloxan and streptozotocin are the most popular diabetogenic agents used for assessing the antidiabetic or hypoglycemic capacity of test compounds. Notably, alloxan is far less expensive and more readily available than streptozotocin. On this ground, one will logically expect a preference for use of alloxan in experimental diabetes studies. Surprisingly, a sub meta-analysis of randomly selected studies conducted within the last one and half decade revealed otherwise. This observation necessitated the review of alloxan as a diabetogenic agent in animal studies.

Full text

Review
Alloxan-induced
diabetes,
a
common
model
for
evaluating
the
glycemic-control
potential
of
therapeutic
compounds
and
plants
extracts
in
experimental
studies
Osasenaga
Macdonald
Ighodaro
a,b,
*,
Abiola
Mohammed
Adeosun
a,b
,
Oluseyi
Adeboye
Akinloye
b
a
Department
of
Biochemistry,
Faculty
of
Sciences,
Lead
City
University,
Ibadan,
Nigeria
b
Department
of
Biochemistry,
College
of
Biosciences,
Federal
University
of
Agriculture,
Abeokuta
(FUNAAB),
Abeokuta,
Nigeria
1.
Introduction
Alloxan
which
is
chemically
known
as
5,5-dihydroxyl
pyrimi-
dine-2,4,6-trione
is
an
organic
compound,
a
urea
derivative,
a
carcinogen
and
cytotoxic
glucose
analog
[1].
The
compound
has
the
molecular
formulae,
C
4
H
2
N
2
O
4
and
a
relative
molecu-
lar
mass
of
142.06.
Alloxan
is
one
of
the
common
diabetogenic
agents
often
used
to
assess
the
antidiabetic
potential
of
both
pure
compounds
and
plant
extracts
in
studies
involving
diabetes.
Among
the
known
diabetogenic
agents
which
include
dithizone,
monosodium
glutamate,
gold
thioglucose,
high
fructose
load,
high
glucose
load
and
anti-insulin
serum;
alloxan
and
streptozotocin
(STZ)
are
the
most
widely
used
in
diabetes
studies.
The
current
average
cost
of
one
gram
of
m
e
d
i
c
i
n
a
5
3
(
2
0
1
7
)
3
6
5
–
3
7
4
*
Corresponding
author
at:
Department
of
Biochemistry,
Lead
City
University,
Ibadan,
Nigeria.
E-mail
addresses:
Ighodaro.macdonald@lcu.edu.ng,
macigho@gmail.com
(O.M.
Ighodaro).
a
r
t
i
c
l
e
i
n
f
o
Article
history:
Received
14
September
2017
Accepted
8
February
2018
Available
online
27
February
2018
Keywords:
Alloxan
Diabetes
mellitus
Diabetogenic
agent
Streptozotocin
Animals
a
b
s
t
r
a
c
t
Glycemic
homeostasis
refers
to
glucose
balance
or
control
within
circulation
in
living
organisms.
It
is
normally
and
largely
compromised
in
diabetes.
The
compromise
when
exacerbated,
leads
to
several
complications
including
retinopathy,
nephropathy
and
neu-
ropathy
which
are
collectively
known
as
diabetic
complications
and
are
the
principal
actors
in
co-morbidity
and
eventual
mortality
often
associated
with
diabetes.
The
ability
of
therapeutic
compounds
including
medicinal
plants
to
restore
glycemic
balance
or
homeo-
stasis
in
hyperglycemic
condition
is
an
index
of
their
antidiabetic
function
and
relevance.
Alloxan
and
streptozotocin
are
the
most
popular
diabetogenic
agents
used
for
assessing
the
antidiabetic
or
hypoglycemic
capacity
of
test
compounds.
Notably,
alloxan
is
far
less
expensive
and
more
readily
available
than
streptozotocin.
On
this
ground,
one
will
logically
expect
a
preference
for
use
of
alloxan
in
experimental
diabetes
studies.
Surprisingly,
a
sub
meta-analysis
of
randomly
selected
studies
conducted
within
the
last
one
and
half
decade
revealed
otherwise.
This
observation
necessitated
the
review
of
alloxan
as
a
diabetogenic
agent
in
animal
studies.
©
2018
The
Lithuanian
University
of
Health
Sciences.
Production
and
hosting
by
Elsevier
Sp.
z
o.o.
This
is
an
open
access
article
under
the
CC
BY-NC-ND
license
(http://creative-
commons.org/licenses/by-nc-nd/4.0/).
Available
online
at
www.sciencedirect.com
ScienceDirect
journal
homepage:
http://www.elsevier.com/locate/medici
https://doi.org/10.1016/j.medici.2018.02.001
1010-660X/©
2018
The
Lithuanian
University
of
Health
Sciences.
Production
and
hosting
by
Elsevier
Sp.
z
o.o.
This
is
an
open
access
article
under
the
CC
BY-NC-ND
license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

alloxan
and
STZ
are
respectively
1.5
and
200
US
dollars
respectively.
Due
to
relative
affordability
and
availability,
one
will
logically
expect
that
alloxan
will
be
more
used
compared
to
STZ
[2].
However,
a
literature
survey
and
sub
meta-analysis
that
we
carried
out
on
the
use
of
both
compounds
in
experimental
diabetes
studies
conducted
within
the
last
one
and
half
decade
(2000–2016)
suggested
otherwise
(Table
1).
Analysis
of
the
data
obtained
showed
that
30.3%
of
the
studies
used
alloxan
while
57.9%
made
used
of
STZ
as
a
diabetogenic
agent,
and
others
which
used
glucose,
fructose
and
genetic
diabetic
mice
constituted
the
remaining
11.8%
(Table
1).
2.
Alloxan-induced
diabetes
Alloxan-induced
diabetes
is
a
form
of
insulin-dependent
diabetes
mellitus
that
occurs
as
a
result
of
alloxan
adminis-
tration
or
injection
to
animals
[78,79].
It
has
been
successfully
induced
in
a
variety
of
animal
species;
rabbits,
mice,
rats,
monkeys,
cats
and
dogs
[80,81].
Alloxan
has
been
administered
in
single
or
multiple
doses,
through
different
routes
(intraper-
itoneal,
intravenous
and
subcutaneous);
with
single
intraperi-
toneal
administration
apparently
the
most
employed
mode.
The
dosage
of
the
drug
also
varies
across
studies,
ranging
between
90
and
200
mg/kg
of
body
weight
(BW),
with
150
mg/
kg
BW
being
the
most
frequently
used
dosage.
Animal
species,
route
of
administration
and
nutritional
status
have
been
considered
to
play
a
role
in
determining
the
dose
of
alloxan
appropriate
for
induction
of
diabetes
[2].
However,
single
intraperitoneal
administration
of
the
drug
at
170–200
mg/kg
BW
appears
to
be
most
effective
[2].
Alloxan
was
first
isolated
by
Brugnatelli
in
1818
and
initially
described
by
Frederick
Wohler
and
Justin
Liebig
in
1838
[83].
Alloxan
causes
diabetes
by
a
mechanism
which
basically
involves
partial
degradation
of
the
beta
(b)
cells
of
pancreatic
islets
and
subsequent
compromise
in
the
quality
and
quantity
of
insulin
produced
by
these
cells.
Its
use
as
a
diabetogenic
drug
in
experimental
animals
was
first
reported
by
Dunn
and
McLetchie
in
their
study
in
which
they
successfully
induced
diabetes
in
experimental
rabbits
[78].
Thereafter,
several
authors
have
used
alloxan-induced
diabetes
model
as
a
‘‘study
tool’’
to
elucidate
the
pathophysiology
of
the
disease
and
much
more
as
a
‘‘search
engine’’
for
antidiabetic
compounds
with
better
therapeutic
characteristics.
The
model
employs
two
distinct
pathological
effects
which
include
selective
inhibition
of
glucose-stimulated
insulin
secretion,
and
induced
formation
of
reactive
oxygen
species
(ROS)
which
promotes
selective
necrosis
of
beta
cells
of
the
pancreas.
Both
effects
collectively
result
in
a
pathophysiologi-
cal
state
of
insulin-dependent
diabetes
or
type
1-like
diabetes
mellitus
in
cells
[78,84].
The
former
is
associated
with
specific
inhibition
of
a
pancreatic
glucose
sensor
enzyme,
glucokinase
by
alloxan
whereas
the
latter
is
rather
connected
with
the
redox
cycling
ability
of
alloxan
which
results
in
ROS
genera-
tion.
More
importantly,
both
effects
have
been
linked
to
the
chemical
properties
of
alloxan
as
well
as
its
structure.
2.1.
Chemical
features
of
alloxan
and
their
contribution
to
its
diabetogenicity
The
diabetogenicity
of
alloxan
is
underlined
by
its
selective
cellular
uptake
by
beta
cells
of
the
pancreas
and
consequent
Table
1
–
Randomly
selected
experimental
diabetic
studies
conducted
within
the
last
two
decades
(1995–2016).
Authors
Diabetogenic
agent
used
Authors
Diabetogenic
agent
used
Authors
Diabetogenic
agent
used
Kameswararao
et
al.
[3]
Alloxan
Yadav
et
al.
[28]
Fructose
Ighodaro
et
al.
[53]
Alloxan
Pari
and
Saravanan
[4]
Alloxan
Al-Azzawie
and
Alhamdani
[29]
Alloxan
Nyomaan
et
al.
[54]
STZ
Eidi
et
al.
[5]
STZ
Verspoh
et
al.
[30]
Glucose
Petchi
et
al.
[55]
STZ
Maiti
et
al.
[6]
STZ
Jaiswal
et
al.
[31]
STZ
Akaladi
et
al.
[56]
STZ
Gupta
et
al.
[7]
STZ
Sunil
et
al.
[32]
STZ
Olatunji
et
al.
[57]
Fructose
Bagri
et
al.
[8]
STZ
Jelodar
et
al.
[33]
Alloxan
Daud
et
al.
[58]
STZ
Tabuchi
et
al.
[9]
STZ
Ighodaro
et
al.
[34]
STZ
Cao
et
al.
[59]
STZ
Ragavan
and
Krishnakumari
[10]
Alloxan
Asgary
et
al.
[35]
Alloxan
Saravanan
et
al.
[60]
STZ
Dewanjee
et
al.
[11]
Alloxan
Kumar
et
al.
[36]
Alloxan
Hakkim
et
al.
[61]
Alloxan
Yang
et
al.
[12]
Alloxan
Venkatesh
et
al.
[37]
Alloxan
Lee
et
al.
[62]
STZ
Jala
et
al.
[13]
Fructose
Paril
et
al.
[38]
Alloxan
Poudyal
et
al.
[63]
CHO/High
fat
Jemai
et
al.
[14]
Alloxan
Shanmugasundaram
et
al.
[39]
Alloxan
Dzeufiet
et
al.
[64]
STZ
Sridhar
et
al.
[15]
STZ
Nugroho
et
al.
[40]
Fructose
Anathan
et
al.
[65]
Alloxan
Pandit
et
al.
[16]
STZ
Jelastin
et
al.
[41]
Alloxan
Miura
et
al.
[66]
KK
mice
Papato
et
al.
[17]
STZ
Satheesh
and
Paril
[42]
Alloxan
Oliveira
et
al.
[67]
STZ
Zhang
and
Tan
[18]
STZ
Wainstein
et
al.
[43]
STZ
Singh
et
al.
[68]
STZ
Sarkhail
et
al.
[19]
STZ
Moon
[44]
STZ
Bnouham
et
al.
[69]
STZ
Habibuddin
et
al.
[20]
STZ
Chung
et
al.
[45]
STZ
Surana
et
al.
[70]
Alloxan
Liu
et
al.
[21]
STZ
Ahangarpour
et
al.
[46]
Fructose
Anwar
et
al.
[71]
STZ
Abdelmoaty
et
al.
[22]
STZ
Prince
et
al.
[47]
Alloxan
Ju
et
al.
[72]
STZ
Oku
et
al.
[23]
STZ
Abedinzade
et
al.
[48]
STZ
Gandhi
et
al.
[73]
STZ
Orhan
et
al.
[24]
STZ
Kook
et
al.
[49]
STZ
Shirwaikar
et
al.
[74]
STZ
Ezquer
et
al.
[25]
STZ
Kumar
et
al.
[50]
STZ
Chen
et
al.
[75]
STZ
Zhao
et
al.
[26]
STZ
Shajeela
et
al.
[51]
Alloxan
Djomeni
et
al.
[76]
STZ
Singh
et
al.
[27]
STZ
Sowmia
and
Kokilavani
[52]
Alloxan
Veerapur
et
al.
[77]
STZ
STZ,
streptozotocin.
m
e
d
i
c
i
n
a
5
3
(
2
0
1
7
)
3
6
5
–
3
7
4366

accumulation
in
these
cells
[85].
The
chemical
properties
of
alloxan
and
how
they
contribute
to
its
toxicity
or
diabeto-
genicity
are
shown
below.
2.1.1.
Alloxan
shares
semblance
with
glucose
in
molecular
shape
and
hydrophilicity
Alloxan
shares
huge
structural
(molecular
shape)
similarity
with
glucose
[86].
It
is
a
b-cell
toxic
glucose
analog
with
hydrophilic
characteristic
(with
a
partition
coefficient
of
1.8)
and
exists
as
alloxan
monohydrate
in
aqueous
solutions
[1].
Glucose
is
a
hydrophilic
molecule
and
hence,
incapable
of
crossing
the
lipid
bilayer
of
the
plasma
membrane
on
its
own
into
the
cytosol.
Rather
it
is
transported
via
a
facilitated
diffusion
transport
mechanism
involving
a
transport
protein
known
as
glucose
transporter
2
(GLUT2)
which
is
located
in
plasma
membranes
of
cells.
In
the
same
manner,
due
to
structural
similarity
of
alloxan
to
glucose,
its
movement
across
the
plasma
membrane
into
the
cytosol
of
the
beta
cells
is
also
carried
out
by
GLUT2
[1,87].
Interestingly,
alloxan
does
not
in
any
way
inhibit
the
activity
of
GLUT2
and
this
attribute
significantly
enhances
its
uptake
by
beta
cells,
resulting
in
its
selective
bio-accumulation
and
toxicity
in
these
cells
[88,89].
This
view
is
substantiated
by
the
fact
that
alloxan
has
been
reported
to
be
non-toxic
to
insulin-producing
cells
which
lack
or
are
deficient
in
the
GLUT
2.
Secondly,
N-substitution
with
the
alkyl
group
in
alloxan
produces
alloxan
derivatives
with
lipophilic
characteristic
and
these
compounds
have
been
noted
to
easily
transit
the
lipid
bilayer
of
the
plasma
membrane
without
the
assistance
of
glucose
transporter
2,
GLUT2
[90].
Consequently,
they
can
permeate
all
cell
types
including
those
which
do
not
express
GLUT2
and
cause
systemic
toxicity
rather
than
diabetogenicity
[91].
It
is
important
to
note
that
the
mechanism
of
glucose
uptake
in
humans
is
contrastingly
different
from
that
of
animals
(rodents)
and
this
probably
accounts
for
why
alloxan,
even
at
high
concentrations
are
non-toxic
to
humans.
2.1.2.
Alloxan
is
a
weak
acid
Alloxan
is
a
weak
acid,
a
barbituric
acid
derivative
(5-
ketobarbituric
acid)
and
hence,
readily
attacks
thiol
reagents
or
the
sulfhydryl
group
(–SH)
present
in
proteins.
The
selective
inhibition
of
glucose-stimulated
insulin
secretion
has
been
described
as
the
major
pathological
effect
of
alloxan
[1,85]
and
is
directly
linked
with
the
ability
of
alloxan
to
oxidized
or
attack
the
thiol
group
present
in
glucokinase,
a
glucose
phosphorylating
enzyme
which
plays
a
key
role
as
glucose
sensor
in
the
pancreas
and
liver.
2.1.3.
The
chemical
structure
of
alloxan
has
a
5-carbonyl
group
The
chemical
structure
of
alloxan
(Fig.
1)
has
a
5-carbonyl
group
which
is
hyper
reactive
with
thiol
groups,
and
this
is
indicative
of
a
structure-function
relationship
in
alloxan
toxicity
or
diabetogenicity.
Glucokinase
has
two
thiol
groups
(–SH)
in
its
binding
site
which
makes
it
exceptionally
susceptible
to
oxidation
by
alloxan
[92].
The
binding
of
alloxan
to
glucokinase
results
in
the
formation
of
a
disulphide
bond
and
consequent
inactivation
of
the
enzyme.
This
phenome-
non
occurs
as
fast
as
within
the
first
minute
of
exposure
of
the
enzyme
to
alloxan
and
accounts
for
the
selective
inhibition
of
glucose-stimulated
insulin
secretion
usually
observed
within
minutes
of
alloxan
injection
[86].
Although,
alloxan
can
inhibit
the
activities
of
several
other
functionally
important
thiol-
enzymes
such
as
phosphofructokinase
[93],
aconitase
[92],
hexokinase
[94]
and
Ca
2+
/calmodulin-dependent
protein
kinase
[95]
but
glucokinase
is
the
most
susceptible
thiol
enzyme
to
alloxan
attack
in
the
beta
cells
[96,97].
The
inhibitory
action
of
alloxan
on
glucokinase
hinders
glucose
oxidation,
and
by
extension
the
formation
of
adenosine
triphosphate
(ATP)
In
turn,
lack
of
ATP
suppresses
the
signal
generating
metabolic
flux
necessary
for
glucose-stimulated
insulin
secretion
[98].
The
same
mechanism
may
likely
be
responsible
for
the
inhibitory
action
of
alloxan
on
insulin
biosynthesis
[99].
2.1.4.
Alloxan
is
a
very
unstable
compound
In
addition,
alloxan
is
a
very
unstable
compound,
a
property
that
enables
it
to
readily
undergo
redox
cycling.
In
the
presence
of
intracellular
thiols
especially
glutathione
(GSH),
alloxan
undergoes
a
persisting
continuous
cyclic
reaction
to
generate
reactive
oxygen
species
(ROS)
such
as
superoxide
radical
anion
(O
2

)
and
hydroxyl
radical
(

OH)
via
the
auto-
oxidation
of
its
reduction
product,
dialuric
acid.
The
process
involves
the
reduction
of
alloxan
to
dialuric
acid
and
re-
oxidization
of
dialuric
acid
to
alloxan
[100].
Re-oxidation
of
alloxan
to
dialuric
acid
causes
a
release
of
alloxan
radical
that
in
the
presence
of
oxygen
generates
O
2

(Fig.
2).
O
2

is
usually
dismutated
to
a
relatively
harmless
hydrogen
peroxide
(H
2
O
2
)
by
superoxide
dismutase
(SOD),
an
antioxidant
enzyme
present
in
virtually
in
all
tissues
(Fig.
2).
Catalase,
another
antioxidant
enzyme
is
required
to
prevent
the
accumulation
of
H
2
O
2
and
its
consequent
conversion
to
hydroxyl
radical,
by
quick
degradation
of
the
compound
to
water
and
molecular
oxygen.
However,
catalase
activity
is
very
low
in
the
pancreas
[101]
and
as
a
result
H
2
O
2
accumulates,
leading
to
its
conversion
to
highly
reactive
hydroxyl
radical
through
Fenton
reaction
(Fig.
2).
Hydroxyl
radical
is
apparently
the
most
dangerous
radical
in
the
cell
and
considered
to
be
the
principally
culprit
in
beta
cell
toxicity
and
alloxan
diabeto-
genicity.
Damage
of
pancreatic
beta
cells
by
ROS
has
been
linked
to
fragmentation
of
DNA
of
these
cells,
leading
to
the
stimulation
of
poly
ADP-ribose
polymerase
1,
an
enzyme
that
plays
an
important
role
in
DNA
repair
process
[102].
Naturally,
compounds
with
sulfhydryl
group
(GSH,
cysteine
and
dithiothreitol)
should
protect
glucokinase
against
alloxan
inhibition
by
a
reductive
process,
but
they
have
to
continu-
ously
maintain
the
reduction
product,
dialuric
acid
in
its
reduced
form
in
order
to
effectively
protect
the
enzyme
Fig.
1
–
Chemical
structure
of
alloxan.
m
e
d
i
c
i
n
a
5
3
(
2
0
1
7
)
3
6
5
–
3
7
4
367

[92,103].
Unfortunately,
this
is
not
the
case,
as
the
thiols
are
often
exhausted
by
the
persisting
continuous
cyclic
reaction
of
alloxan.
Winterbourn
and
Munday
[104]
informed
that
the
amount
of
reduced
GSH
available
in
a
cell
for
redox
cycling
diminishes
gradually
and
thus
fosters
a
lower
pro-oxidative
ratio
between
alloxan
and
GSH,
rather
than
a
higher
antioxidative
ratio.
This
explains
why
co
administration
of
thiols
such
as
GSH
or
cysteine
with
alloxan
tends
to
ameliorate
the
toxic
and
diabetogenic
effects
of
alloxan
as
reported
by
a
number
of
other
studies
[105–107].
2.2.
Alloxan-induced
diabetes
is
characterized
by
multiphasic
blood
glucose
response
Alloxan
induces
a
multiphasic
blood
glucose
response
when
injected
into
to
experimental
animals
as
noted
in
our
recent
study
in
which
we
examined
the
time
course
effects
of
alloxan
in
Wistar
rats.
Within
36
h
post
alloxan
administration,
several
phases
of
glucose
response
were
observed
in
the
animals
administered
170
and
200
mg/kg
BW
alloxan
(Fig.
3).
The
observation
is
similar
to
previous
reports
on
blood
glucose
behavior
or
response
to
alloxan
[1,2,85,108].
Some
of
these
authors
also
noted
that
changes
in
blood
glucose
concentra-
tion
are
accompanied
by
corresponding
inverse
changes
in
the
plasma
insulin
concentration.
Lenzen
[1]
postulated
that
blood
glucose
multiphasic
response
to
alloxan
injection
begins
in
the
first
few
minutes
with
a
transient
hypoglycemic
phase
that
lasts
maximally
for
30
min.
This
event
has
been
adduced
to
a
transient
hyper-
insulinemia
that
is
probably
due
to
a
momentary
increase
in
ATP
level
resulting
from
the
temporary
effects
of
alloxan
inhibition
of
glucokinase.
The
second
phase
that
usually
takes
place
1
h
post
alloxan
administration
is
characterized
by
upsurge
in
blood
glucose
concentration
and
concomitant
decrease
in
plasma
insulin
concentration.
This
is
the
first
hyperglycemic
effect
of
alloxan
and
it
lasts
for
a
period
of
2–4
h.
In
our
study,
alloxan
induced
diabetic
hyperglycemia
(blood
glucose
≥200
mg/dL
or
11.1
mmol/
L)
in
rats
1
h
post
its
administration.
Previous
authors
have
also
noted
the
immediate
diabetogenicity
of
alloxan
following
its
administration
to
experimental
animals.
Lenzen
[1]
in
his
study
titled
‘‘Alloxan
and
streptozotocin
diabetes’’
informed
that
notable
hyperglycemia
commenced
in
experimental
rats
1
h
after
alloxan
injection.
Similar
reports
that
alloxan
administra-
tion
to
rats
causes
immediate
hyperglycemia
which
reaches
its
peak
within
two
or
three
hours'
had
been
earlier
communicated
by
Goldner
and
Gomori
[80].
Inhibition
of
insulin
secretion
from
the
pancreatic
beta
cells
due
to
ROS
attack
accounts
for
this
phase
of
alloxan
diabetogenicity
[109].
According
to
Szkudelski
[85],
alloxan
is
a
hydrophilic
and
unstable
substance
with
a
half-
life
of
1.5
min
at
neutral
pH
and
37
8C.
This
implies
that
the
time
for
alloxan
degradation
(metabolism)
is
sufficiently
short
enough
to
allow
it
to
reach
the
pancreas
very
fast
and
in
deleterious
amount.
This
also
explains
and
buttresses
the
1
h
post
hyperglycemic
effect
of
alloxan.
As
alloxan
uptake
by
the
insulin-secreting
beta
cells
of
the
pancreas
reaches
its
maximum,
its
toxicity
via
ROS
increases,
leading
to
induced
rupture
of
the
secretory
granules
and
cell
membrane
of
the
beta
cells
[1,85,97,110,111].
The
attendant
effect
of
this
burst
up
is
flooding
of
the
circulation
with
insulin,
a
pathophysiological
condition
that
results
in
a
severe
transitional
hypoglycemic
phase
which
is
observable
a
couple
of
hours
after
alloxan
injection.
The
hypoglycemic
phase
in
alloxan
diabetogenicity
has
also
been
associated
with
the
ability
of
alloxan
to
cause
significant
influx
of
free
Ca
2+
into
the
cytosol
of
pancreatic
islet
beta
cells,
thereby
compromising
the
intracellular
calcium
homeostasis
[112].
The
process
involves
the
depolarization
of
the
pancreatic
beta
cells,
which
facil-
itates
further
calcium
entry
into
pancreatic
cells
via
voltage
dependent
calcium
channels.
High
intracellular
level
of
Ca
2+
has
been
noted
to
contribute
significantly
to
super
high
level
of
insulin
release
[85].
Fig.
2
–
Formation
of
ROS
through
redox
cycling
of
alloxan.
m
e
d
i
c
i
n
a
5
3
(
2
0
1
7
)
3
6
5
–
3
7
4368

Hypoglycemia
is
characteristic
of
experimental
diabetes
and
the
phase
has
been
noted
to
last
for
at
least
3
h
or
more
[1,113,114]
and
is
largely
responsible
for
the
mortality
associated
with
alloxan-induced
diabetes.
This
view
is
consistent
with
the
opinion
of
Goldner
and
Gomori
[80],
who
hinted
that
alloxan-induced
hyperglycemia
in
rats
is
followed
by
a
severe
and
fatal
hypoglycemia,
which
after
a
duration
of
several
hours
yields
to
a
final
hyperglycemia,
last
phase
of
alloxan
induced
diabetes.
The
last
phase
of
the
blood
glucose
response
to
alloxan
administration
is
touted
to
be
a
permanent
diabetic
hypergly-
cemic
phase
that
takes
place
between
24
and
48
h
after
alloxan
administration.
Supposedly,
there
is
complete
degranulation
and
loss
of
structural
integrity
of
the
beta
cells
during
this
phase
[1,113].
The
incidence
in
this
phase
indicates
that
other
cell
types
of
the
pancreas
are
spared
of
alloxan
toxicity,
substantiating
the
theory
of
selective
uptake
of
alloxan
by
the
insulin-producing
cells
(pancreatic
beta
cells)
[115,116].
2.3.
Protective
effects
of
glucose
against
alloxan
toxicity
and
diabetogenicity
It
is
a
popular
postulation
that
blood
glucose
protects
the
pancreatic
islet
beta
cells
against
the
toxicity
and
diabeto-
genicity
of
alloxan
[98].
There
are
a
couple
of
reasons
to
believe
that
this
is
possible.
Principally,
the
mechanism
by
which
alloxan
elicits
its
toxicity
and
diabetogenicity
provides
that
possibility.
As
already
stated,
the
toxic
and
diabetogenic
effects
of
alloxan
are
underlined
by
its
selective
inhibition
of
glucose-stimulated
insulin
secretion
via
inactivation
of
gluco-
kinase
and
selective
necrosis
of
the
beta
cells
via
induced
ROS.
These
two
processes
are
sequel
to
alloxan
uptake
by
beta
cells
and
subsequent
accumulation
in
these
cells.
Alloxan
uptake
by
beta
cells
is
facilitated
by
GLUT2.
Since
both
glucose
and
alloxan
due
to
similarity
in
molecular
shape
competes
for
the
same
transport
protein,
it
therefore
implies
that
high
level
of
glucose
in
circulation
will
automatically
lower
the
chance
of
alloxan
binding
to
GLUT2.
Even
at
a
relatively
equal
concentration
of
both
molecules,
GLUT2
has
a
stronger
affinity
for
glucose
than
alloxan
and
thus
favors
the
binding
of
glucose
compared
with
alloxan
[90,116–118].
This
effect
will
consequently
minimize
alloxan
uptake
and
invariably
affects
its
ability
to
induce
diabetes.
It
has
also
been
suggested
that
glucose
through
the
pentose
phosphate
pathway
has
the
ability
to
supply
reduced
nicotinamide
adenine
dinucleotide
phosphate
(NADPH)
and
reduced
nico-
tinamide
adenine
dinucleotide
(NADH)
which
are
capable
of
recycling
GSH,
i.e.
keeps
it
in
its
reduced
form
[1].
This
in
itself
will
effectively
attenuate
the
ability
of
alloxan
to
generate
reactive
radicals
through
redox
cycling.
More
so,
high
level
of
blood
glucose
will
protect
glucokinase
and
prevent
its
exposure
to
alloxan
attack.
This
happens
in
such
a
way
that
once
glucokinase
is
bound
by
glucose,
the
sulfhydryl
groups
in
its
glucose-binding
site
is
no
more
available
for
alloxan
attack
[98].
The
protection
offered
by
glucose
explains
why
fed
animals
are
less
sensitive
to
alloxan
induced
diabetes
compared
with
fasted
animals
with
relatively
lower
blood
glucose
level
[119].
In
the
same
manner,
animals
fed
on
fat
diet
have
been
observed
to
be
more
susceptible
to
alloxan
diabetogenicity
relative
to
those
fed
on
high
carbohydrate
and
protein
prior
to
alloxan
injection.
2.4.
Limitations
of
alloxan-induced
diabetes
The
effectiveness
of
alloxan
for
induction
of
experimental
diabetes
has
been
queried
by
a
number
of
investigators.
This
is
rightly
so
as
noticeable
limitations
have
been
associated
with
the
use
of
alloxan
as
a
diabetogenic
agent.
Jain
and
Arya
[120]
highlighted
several
anomalies
and
inconsistencies
in
alloxan-
induced
diabetes
model,
and
we
are
of
the
opinion
that
the
concerns
raised
by
these
authors
should
be
given
some
level
of
consideration
and
attention.
Instability
and
auto-reversibility
of
alloxan-induced
hyper-
glycemia
is
particularly
of
utmost
concern.
Alloxan
when
administered
causes
multiphasic
glucose
response
character-
ized
by
inconsistent
increase
and
decrease
in
blood
glucose
Fig.
3
–
Time
course
effect
of
alloxan
on
blood
glucose
level
of
rat.
m
e
d
i
c
i
n
a
5
3
(
2
0
1
7
)
3
6
5
–
3
7
4
369

concentration
[1,2,108].
In
other
words,
the
hyperglycemia
induced
by
alloxan
is
not
sufficiently
stable
for
proper
evaluation
of
the
antidiabetic
or
hypoglycemic
potential
of
test
compounds.
Even
in
few
cases
where
apparent
stability
is
achieved,
the
duration
of
such
stable
hyperglycemia
is
on
the
average
less
than
a
month
and
this
period
is
not
adequate
for
proper
evaluation
of
a
test
drug.
This
often
leads
to
illusive
conclusion
on
the
antidiabetic
relevance
of
the
test
compound.
According
to
Misra
and
Aiman
[108],
a
wide
range
of
fluctuations
in
the
blood
glucose
level
and
auto
reversal
from
confirmed
diabetic
hyperglycemia
to
the
non-diabetic
range
is
a
major
setback
as
regards
alloxan-induced
diabetes
model.
Another
problem
with
alloxan
is
that
its
diabetogenic
and
toxic
effects
on
animals
vary
widely,
even
among
those
belonging
to
the
same
species.
Such
inconsistent
effect
makes
the
drug
an
unreliable
model
for
affirming
the
antidiabetic
potency
of
test
compounds,
a
view
shared
by
previous
authors
[108,120].
Moreover,
alloxan
does
not
exactly
induce
the
human
type
2
diabetes
mellitus
[121]
which
accounts
for
about
90–95%
of
all
diabetic
cases.
In
support
of
this,
Jain
and
Arya
[120]
drew
our
attention
to
a
couple
of
test
compounds
reported
to
have
exhibited
notable
antidiabetic
activities
against
alloxan-
induced
diabetes
but
were
found
to
be
ineffective
against
human
diabetes.
Alloxan
has
been
noted
to
stimulate
a
type
1
form
of
diabetes
when
used
in
animals.
This
form
of
diabetes
is
often
associated
with
high
level
of
ketoacidosis
that
arguably
is
partly
responsible
for
the
high
animal
mortality
rate
(30–60%)
[120]
usually
observed
with
use
of
alloxan
as
a
diabetogenic
agent.
Besides,
the
mechanism
of
alloxan
diabetogenicity
encloses
a
chronic
measure
of
toxicity
involving
free
radical
generation,
particularly
(

OH).
No
doubt,
this
play
a
bigger
role
in
the
mortality
of
experimental
animals
exposed
to
alloxan.
Mortality
from
diabetes
has
been
adduced
to
either
initial
hypoglycemic
shock
or
emergence
of
diabetic
complications
or
direct
kidney
tubular
cell
toxicity
[85].
The
practice
of
placing
alloxan-treated
animals
on
5–10%
glucose
solution
in
a
bid
to
prevent
hypoglycemic
shock
is
often
observed
but
this
intervention
appears
not
to
be
significantly
helpful,
and
thus
the
problem
of
mortality
persists.
High
mortality
rate
is
a
major
drawback
in
the
use
of
alloxan
diabetic
model.
First,
it
increases
the
financial
burden
of
the
study
as
several
animals
more
than
required
have
to
be
used
in
attempt
to
carry
the
study
to
a
meaningful
end.
Secondly,
it
does
not
allow
for
proper
evaluation
of
the
antidiabetic
potential
of
the
investigated
compound
or
test
drug.
2.5.
Comparing
alloxan
with
streptozotocin
as
diabetogenic
agents
STZ
has
notable
advantages
over
alloxan
as
chemical
agents
for
induction
of
experimental
diabetes,
thus,
is
often
preferred
to
the
latter
(alloxan).
For
instance,
STZ
has
longer
half-life
(15
min
against
1.5
min
of
alloxan)
[122].
This
makes
it
more
stable
in
solution
before
and
after
injection
into
animals.
STZ-
induced
hyperglycemia
is
relatively
more
stable
and
for
a
longer
duration
(as
much
as
three
months
compared
to
alloxan-induced
hyperglycemia
that
can
only
be
sustained
for
less
than
a
month).
Moreover,
the
mechanism
of
STZ
diabetogenicity
is
less
associated
with
cellular
toxicity,
hence,
lesser
animal
mortality.
Alloxan
on
the
contrary,
induces
diabetes
by
a
mechanism
characterized
by
incidences
of
ketosis,
ROS
toxicity,
and
high
mortality
rate
which
is
particularly
a
major
setback
in
experimental
diabetes
studies
[85].
One
reason
for
this
is
that
STZ
is
more
selective
to
islet
beta
cells
than
alloxan
which
causes
severe
damage
to
other
cell
types
which
express
GLUT2
(systemic
toxicity).
More
so,
STZ-induce
diabetes
is
associated
with
well
characterized
diabetic
complications
unlike
alloxan-induced
diabetes
[1].
In
addition,
compared
to
alloxan,
STZ
diabeto-
genicity
is
not
severely
interfered
with
by
blood
glucose
level.
Overall,
STZ
diabetogenicity
is
more
effective
and
with
lesser
variation
with
animal
species.
2.6.
Suggestions
to
improve
the
use
of
alloxan
as
a
diabetogenic
drug
1.
Alloxan
is
very
unstable,
and
with
a
half-life
of
about
1.5
min,
it
could
easily
disintegrate
when
left
to
stand
in
aqueous
solutions.
Therefore,
when
used
as
a
diabetogenic
agent,
it
should
be
freshly
prepared.
In
a
case
where
the
animals
to
be
injected
are
quite
many,
it
is
advisable
that
the
appropriate
amount
of
alloxan
for
a
specific
number
of
animals
(i.e.
5)
is
measured
in
replicates
for
different
batches
of
animals.
This
means
that
alloxan
for
a
batch
of
animals
(n
=
5)
is
dissolved
in
freshly
prepared
0.9%
saline
just
before
the
commencement
of
administration.
This
practice
improves
alloxan
diabetogenicity.
On
the
contrary,
when
all
the
animals
in
a
large
group
is
injected
from
the
same
alloxan
preparation,
there
is
a
possibility
that
the
last
set
of
animals
administered
the
drug
may
not
receive
sufficient
amount
of
the
active
drug
due
to
disintegration.
According
to
Lenzen
and
Munday
[123],
alloxan
when
left
to
stand
in
aqueous
solutions
is
readily
converted
to
non-
diabetogenic
alloxanic
acid
due
to
spontaneous
decompo-
sition.
2.
Poor
diabetogenicity
and
easy
auto-reversal
of
alloxan-
induced
hyperglycemia
is
very
common
with
intraperito-
neal
doses
of
150
mg/kg
and
below
[85,124].
In
the
use
of
alloxan,
higher
dose
between
170
and
200
mg/kg
BW
have
been
noted
to
be
more
effective.
3.
Very
young
animals
have
been
observed
to
be
highly
resistant
or
less
susceptible
to
the
diabetogenic
effect
of
alloxan
[120,125].
Older
animals
should
be
preferably
used
in
diabetic
studies
involving
the
use
of
alloxan.
Antioxidant
defense
system
has
been
reported
to
decrease
with
age;
this
may
be
responsible
for
this
difference
in
age–dependent
response
to
alloxan.
4.
Fed
animals
due
to
the
effect
of
blood
glucose
are
less
susceptible
to
alloxan
toxicity
and
diabetogenicity
[84,85].
Animals
should
therefore
be
fasted
for
at
least
12
h
prior
to
alloxan
injection.
Fasted
animals
have
relatively
low
blood
glucose
level.
This
physiological
condition
enhances
allox-
an
uptake
by
the
islet
beta
cells
and
consequently
improve
alloxan
diabetogenicity.
5.
Exogenous
GSH
has
been
reported
to
protect
well
against
alloxan
toxicity
which
is
often
connected
with
animal
mortality
[1].
Probably,
co-administration
of
very
low
m
e
d
i
c
i
n
a
5
3
(
2
0
1
7
)
3
6
5
–
3
7
4370

concentration
of
GSH
and
higher
dose
of
alloxan
(170–
200
mg/kg)
should
be
considered
for
improved
diabetogeni-
city
of
alloxan.
6.
The
route
and
speed
of
administration
have
been
reported
to
affect
the
diabetogenicity
of
alloxan,
with
fast
or
rapid
intravenous
administration
preferred
to
slow
intravenous
and
intraperitoneal
(I.P.)
administration.
But
higher
rate
of
mortality
have
also
been
associated
with
rapid
intravenous
injection
[108].
In
alloxan
diabetes
studies,
intraperitoneal
injection
is
commonly
used.
Perhaps,
increasing
the
speed
of
intraperitoneal
administration
may
improve
alloxan
diabetogenicity.
Conflict
of
interest
The
authors
state
no
conflict
of
interest.
r
e
f
e
r
e
n
c
e
s
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