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ß-Cell-specific pyruvate dehydrogenase deficiency impairs glucose-stimulated insulin secretion.
[pyruvate dehydrogenase deficiency]
Glucose-stimulated
insulin
secretion
(
GSIS
)
by
β-cells
requires
the
generation
of
ATP
from
oxidation
of
pyruvate
as
well
as
generation
of
coupling
factors
involving
three
different
pyruvate
cycling
shuttles
.
The
roles
of
several
key
enzymes
involved
in
pyruvate
cycling
in
β-cells
have
been
documented
using
isolated
islets
and
β-cell
clonal
lines
.
To
investigate
the
role
of
the
pyruvate
dehydrogenase
(
PDH
)
complex
(
PDC
)
in
GSIS
,
a
murine
model
of
β-cell-
specific
PDH
deficiency
(
β-
PDHKO
)
was
created
.
Pancreatic
insulin
content
was
decreased
in
1
-
day
-old
β-
PDHKO
male
pups
and
adult
male
mice
.
The
plasma
insulin
levels
were
decreased
and
blood
glucose
levels
increased
in
β-
PDHKO
male
mice
from
neonatal
life
onward
.
GSIS
was
reduced
in
isolated
islets
from
β-
PDHKO
male
mice
with
about
50
%
reduction
in
PDC
activity
.
Impairment
in
a
glucose
tolerance
test
and
in
vivo
insulin
secretion
during
hyperglycemic
clamp
was
evident
in
β-
PDHKO
adults
.
No
change
in
the
number
or
size
of
islets
was
found
in
pancreata
from
4
-
wk-old
β-
PDHKO
male
mice
.
However
,
an
increase
in
the
mean
size
of
individual
β-cells
in
islets
of
these
mice
was
observed
.
These
findings
show
a
key
role
of
PDC
in
GSIS
by
pyruvate
oxidation
.
This
β-
PDHKO
mouse
model
represents
the
first
mouse
model
in
which
a
mitochondrial
oxidative
enzyme
deletion
by
gene
knockout
has
been
employed
to
demonstrate
an
altered
GSIS
by
β-cells
.