PLoS Computational Biology,
Год журнала:
2023,
Номер
19(11), С. e1011617 - e1011617
Опубликована: Ноя. 9, 2023
The
islets
of
Langerhans
are
critical
endocrine
micro-organs
that
secrete
hormones
regulating
energy
metabolism
in
animals.
Insulin
and
glucagon,
secreted
by
beta
alpha
cells,
respectively,
responsible
for
metabolic
switching
between
fat
glucose
utilization.
Dysfunction
their
secretion
and/or
counter-regulatory
influence
leads
to
diabetes.
Debate
the
field
centers
on
cytoarchitecture
islets,
as
signaling
governs
hormonal
depends
structural
functional
factors,
including
electrical
connectivity,
innervation,
vascularization,
physical
proximity.
Much
effort
has
therefore
been
devoted
elucidating
which
architectural
features
significant
function
how
derangements
these
correlated
or
causative
dysfunction,
especially
using
quantitative
network
science
graph
theory
characterizations.
Here,
we
ask
if
there
non-local
islet
cytoarchitecture,
going
beyond
standard
statistics,
relevant
function.
An
example
is
ring
structures,
cycles,
α
δ
cells
surrounding
β
cell
clusters
opposite,
cells.
These
could
appear
two-dimensional
section
images
a
sphere
consisting
one
type
surrounds
cluster
another
type.
To
address
issues,
developed
two
independent
computational
approaches,
geometric
topological,
such
For
latter,
introduce
an
application
topological
data
analysis
determine
locations
biologically
significant.
We
show
both
applied
large
collection
sections,
complete
agreement
context
developmental
diabetes-related
changes
characteristics.
approach
can
be
three-dimensional
imaging
well.
Biochemical Journal,
Год журнала:
2023,
Номер
480(11), С. 773 - 789
Опубликована: Июнь 7, 2023
Glucose-regulated
insulin
secretion
becomes
defective
in
all
forms
of
diabetes.
The
signaling
mechanisms
through
which
the
sugar
acts
on
ensemble
beta
cells
within
islet
remain
a
vigorous
area
research
after
more
than
60
years.
Here,
we
focus
firstly
role
that
privileged
oxidative
metabolism
glucose
plays
detection,
discussing
importance
'disallowing'
cell
expression
genes
including
Lactate
dehydrogenase
(Ldha)
and
lactate
transporter
Mct1/Slc16a1
to
restrict
other
metabolic
fates
for
glucose.
We
next
explore
regulation
mitochondrial
by
Ca2+
its
possible
sustaining
towards
secretion.
Finally,
discuss
depth
structure
dynamics
cell,
their
potential
therapeutic
targeting
incretin
hormones
or
direct
regulators
fusion.
This
review,
2023
Sir
Philip
Randle
Lecture
GAR
will
give
at
Islet
Study
Group
meeting
Vancouver,
Canada
June
2023,
honor
foundational,
sometimes
under-appreciated,
contributions
made
Professor
his
colleagues
our
understanding
Diabetes
is
caused
by
the
inability
of
electrically
coupled,
functionally
heterogeneous
β-cells
within
pancreatic
islet
to
provide
adequate
insulin
secretion.
Functional
networks
have
been
used
represent
synchronized
oscillatory
[Ca2+]
dynamics
and
study
β-cell
subpopulations,
which
play
an
important
role
in
driving
function.
The
mechanism
highly
subpopulations
drive
function
unclear.
We
experimental
computational
techniques
investigate
relationship
between
functional
networks,
structural
(gap
junction)
intrinsic
slow
fast
oscillating
islets.
Highly
network
were
differentiated
dynamics,
including
metabolic
activity
KATP
channel
conductance,
more
than
coupling.
Consistent
with
this,
predictive
high
synchronization
as
compared
levels
Finally,
dysfunction
gap
junctions,
can
occur
diabetes,
decreases
efficiency
clustering
network.
These
results
indicate
that
rather
structure
connections
but
junctions
are
still
essential
for
overall
efficiency.
findings
deepen
our
interpretation
formation
dynamic
tissues
such
islet.
Physical review. E,
Год журнала:
2023,
Номер
108(5)
Опубликована: Ноя. 22, 2023
Pancreatic
beta
cells
are
coupled
excitable
oscillators
that
synchronize
their
activity
via
different
communication
pathways.
Their
oscillatory
manifests
itself
on
multiple
timescales
and
consists
of
bursting
electrical
activity,
subsequent
oscillations
in
the
intracellular
${\mathrm{Ca}}^{2+}$,
as
well
metabolism
exocytosis.
The
coordination
intricate
multicellular
level
plays
a
key
role
regulation
physiological
pulsatile
insulin
secretion
is
incompletely
understood.
In
this
paper,
we
investigate
theoretically
principles
give
rise
to
synchronized
cell
populations
by
building
up
phenomenological
model
incorporates
basic
features
dynamics.
Specifically,
composed
slow
fast
units
reflect
metabolic
processes
respectively.
Using
realistic
description
intercellular
interactions,
study
how
combination
coupling
generates
collective
rhythmicity
shapes
functional
networks.
It
turns
out
while
solely
can
responses,
addition
interactions
further
enhances
coordination,
spatial
range
increases
number
connections
networks,
ensures
better
consistency
with
experimental
findings.
Moreover,
our
computational
results
provide
additional
insights
into
relationship
between
heterogeneity,
profiles,
connectivity,
supplementing
thereby
recent
endocrine
Molecular Metabolism,
Год журнала:
2024,
Номер
85, С. 101947 - 101947
Опубликована: Апрель 26, 2024
Type
2
diabetes
(T2D)
is
characterised
by
the
loss
of
first-phase
insulin
secretion.
We
studied
mice
with
β-cell
selective
glucagon
receptor
(Gcgrfl/fl
X
Ins-1Cre),
to
investigate
role
intra-islet
signalling
on
pan-islet
calcium
activity
and
Metabolic
profiling
was
conducted
Gcgrβ-cell−/−
littermate
controls.
Crossing
GCaMP6f
(STOP
flox)
animals
further
allowed
for
specific
expression
a
fluorescent
indicator.
These
islets
were
functionally
imaged
in
vitro
vivo.
Wild-type
transplanted
expressing
β-cells
into
anterior
eye
chamber
placed
high
fat
diet.
Part
cohort
received
analogue
(GCG-analogue)
40
days
control
group
fed
achieve
weight
matching.
Calcium
imaging
performed
regularly
during
development
hyperglycaemia
response
GCG-analogue
treatment.
exhibited
higher
glucose
levels
following
intraperitoneal
challenge
(control
12.7
mmol/L
±
0.6
vs.
15.4
0.0
at
15
min,
p
=
0.002);
fasting
glycaemia
not
different
In
vitro,
showed
profound
[Ca2+]I
waves
which
only
partially
rescued
Diet
induced
obesity
also
resulted
co-ordinated
islets.
This
reversed
treatment,
independently
weight-loss
(n
8).
data
provide
novel
evidence
GCGR
sustaining
synchronised
support
possible
therapeutic
glucagonergic
agents
restore
secretory
capacity
lost
T2D.
PLoS Computational Biology,
Год журнала:
2024,
Номер
20(5), С. e1012130 - e1012130
Опубликована: Май 13, 2024
Within
the
islets
of
Langerhans,
beta
cells
orchestrate
synchronized
insulin
secretion,
a
pivotal
aspect
metabolic
homeostasis.
Despite
inherent
heterogeneity
and
multimodal
activity
individual
cells,
intercellular
coupling
acts
as
homogenizing
force,
enabling
coordinated
responses
through
propagation
waves.
Disruptions
in
this
coordination
are
implicated
irregular
hallmark
diabetes.
Recently,
innovative
approaches,
such
integrating
multicellular
calcium
imaging
with
network
analysis,
have
emerged
for
quantitative
assessment
cellular
islets.
However,
different
groups
use
distinct
experimental
preparations,
microscopic
techniques,
apply
methods
to
process
measured
signals
various
derive
functional
connectivity
patterns.
This
makes
comparisons
between
findings
their
integration
into
bigger
picture
difficult
has
led
disputes
interpretations.
To
address
these
issues,
we
present
here
systematic
analysis
how
approaches
influence
representation
islet
activity.
Our
show
that
choice
used
construct
networks
is
not
crucial,
although
care
needed
when
combining
data
from
Conversely,
conclusions
drawn
can
be
heavily
affected
by
pre-processing
time
series,
type
oscillatory
component
signals,
preparation.
tutorial-like
investigation
aims
resolve
interpretational
reconcile
conflicting
views,
advance
implications,
encourage
researchers
adopt
analysis.
As
conclude,
outline
challenges
future
research,
emphasizing
broader
applicability
our
other
tissues
exhibiting
complex
dynamics.
Frontiers in Cell and Developmental Biology,
Год журнала:
2024,
Номер
12
Опубликована: Июль 9, 2024
Pancreatic
regeneration
is
a
complex
process
observed
in
both
normal
and
pathological
conditions.
The
aim
of
this
review
to
provide
comprehensive
understanding
the
emergence
functionally
active
population
insulin-secreting
β-cells
adult
pancreas.
renewal
governed
by
multifaceted
interaction
between
cellular
sources
genetic
epigenetic
factors.
Understanding
development
heterogeneity
β-cell
populations
crucial
for
functional
regeneration.
mass
pancreatic
increases
situations
such
as
pregnancy
obesity.
However,
specific
markers
mature
postnatal
progenitors
capable
increasing
self-reproduction
these
conditions
remain
be
elucidated.
capacity
regenerate
through
various
pathways,
including
proliferation
pre-existing
β-cells,
neogenesis,
differentiation
from
progenitor
cells,
transdifferentiation
non-β-cells
into
reveals
molecular
mechanisms
identifying
inducers
cell
renewal.
This
provides
an
opportunity
identify
regeneration,
which
could
have
clinical
applications
treating
pathologies,
vitro
cell-based
technologies,
deepen
our
different
physiological
Frontiers in Endocrinology,
Год журнала:
2024,
Номер
14
Опубликована: Янв. 16, 2024
Tight
control
of
beta
cell
stimulus-secretion
coupling
is
crucial
for
maintaining
homeostasis
energy-rich
nutrients.
While
glucose
serves
as
a
primary
regulator
this
process,
incretins
augment
function,
partly
by
enhancing
cytosolic
[Ca
2+
]
dynamics.
However,
the
details
how
precisely
they
affect
recruitment
during
activation,
their
active
time,
and
functional
connectivity
plateau
activity,
influence
deactivation
remain
to
be
described.
Performing
multicellular
Ca
imaging
in
acute
mouse
pancreas
tissue
slices
enabled
us
systematically
assess
effects
GLP-1
receptor
agonist
exendin-4
(Ex-4)
simultaneously
many
coupled
cells
with
high
resolution.
In
otherwise
substimulatory
glucose,
Ex-4
was
able
recruit
approximately
quarter
into
an
state.
Costimulation
stimulatory
shortened
activation
delays
accelerated
More
specifically,
time
increased
faster,
required
reach
half-maximal
effectively
halved
presence
Ex-4.
Moreover,
regularity
IC
oscillations
increased,
especially
first
part
response.
contrast,
subsequent
addition
already
did
not
significantly
enhance
activity.
Network
analyses
further
confirmed
activity
Ex-4,
hub
roles
remaining
rather
stable
both
experiments
Interestingly,
demonstrated
biphasic
effect
on
deactivation,
slightly
prolonging
at
physiological
concentrations
shortening
supraphysiological
concentrations.
sum,
costimulation
increases
indicating
that
may,
important
extent,
explained
enhanced
signals.
During
previous
incretin
stimulation
does
critically
prolong
cellular
which
corroborates
low
risk
hypoglycemia.
Cellular and Molecular Life Sciences,
Год журнала:
2023,
Номер
80(6)
Опубликована: Июнь 1, 2023
Abstract
Recent
studies
reported
that
pancreatic
β-cells
are
heterogeneous
in
terms
of
their
transcriptional
profiles
and
abilities
for
insulin
secretion.
Sub-populations
have
been
identified
based
on
the
functionality
expression
specific
surface
markers.
Under
diabetes
condition,
β-cell
identity
is
altered
leading
to
different
sub-populations.
Furthermore,
cell–cell
contact
between
other
endocrine
cells
within
islet
play
an
important
role
regulating
This
highlights
significance
generating
a
cell
product
derived
from
stem
containing
along
with
major
treating
patients
diabetes,
instead
transplanting
purified
population
β-cells.
Another
key
question
how
close
heterogeneity
cells?
In
this
review,
we
summarize
adult
pancreas
those
generated
cells.
addition,
highlight
health
disease
conditions
can
be
used
design
cell-derived
therapy.