Diabetes II - Diabetes II β β Learning Objectives

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Unformatted text preview: Diabetes II β β Learning Objectives • Define
IR
and
pancrea-c
beta
cell
dysfunc-on
 • Describe
the
stages
of
diabetes
progression

 • Discuss
the
molecular
mechanisms
by
which
 hyperglycemia
can
contribute
to
diabetes
related
 pathologies:
 ‐ Glutathione
(GSH)
deple-on

 ‐ Advanced
Glyca-on
End‐products
(AGEs)

 ‐ Protein
Kinase
C
(PKC)
ac-va-on

 T2DM: Represents the “tip of the iceberg” of long existing disturbances with deleterious effects on the vascular system, tissues and organs Atherosclerosis
 Re-nopathy
 Neuropathy
 Nephropathy
 Matthaei, S. et al. Endocr Rev 2000;21:585-618 Obesity dramatically increases risk for T2DM •  The
risk
of
diabetes
is
93
and
42
-mes
higher
at
a
 BMI
>
35
in
women
and
men
respec-vely.
 93 Risk
of
Diabetes
 Insulin resistance (IR) and β-cell dysfunction are underlying causes of T2DM Genetic susceptibility, obesity, Western lifestyle Insulin resistance β IR β-cell dysfunction Type 2 diabetes Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl. 3):3–13. IR occurs when the body fails to respond to the insulin it already produces • IR
contributes
to
hyperglycemia
 and
dyslipidemia

 • Increases
in
gluconeogenesis
 and
lipolysis
 • Reduc-ons
in
glucose
uptake
 • People
who
are
IR
may
have
the
 ability
to
overcome
the
 resistance
by
producing
more
 insulin
 • If
the
body
cannot
produce
 sufficient
amounts,
blood
 glucose
increases
and
T2
 diabetes
ensues.
 β-cell dysfunction is the reduced ability to secrete insulin in response to hyperglycemia β β β β • May
be
a
consequence
 of
IR
but
also
occurs
in
 insulin
sensi-ve
people
 • When
β‐cells
are
unable
 to
maintain
increased
 insulin
secre-on
in
IR
 individuals,
impaired
 glucose
tolerance
and
T2
 diabetes
ensues

 DeFronzo RA, et al. Diabetes Care 1992; 15:318–354. Fasting Blood Glucose, mg/dL Five stages of diabetes progression Stage
1:

Compensa-on
 • Insulin
secre-on
increases
 to
maintain
normal
glucose
 in
the
face
of
IR
resul-ng
 from
obesity
and
gene-c
 predisposi-on.

See
 increase
in
β‐cell
mass
 (mostly
number).
 Diabetes 53:S16-S21, 2004 Fasting Blood Glucose, mg/dL Five stages of diabetes progression Diabetes 53:S16-S21, 2004 Stage
2:
Adapta-on
(Stable)
 • B‐cells
fail
to
compensate
 completely

 • Stable
because
individuals
 can
evade
progression
to
 stage
3
for
years
 ‐ ~
11%
of
untreated
 individuals
with
IGT
 progress
to
diabetes
 • See
loss
of
glucose
 s-mulated
insulin
secre-on
 but
cAMP
route
remains
intact
 (ie,
Incre-n
sensi-ve)
 • Beta
cell
hypertrophy
which
 may
be
a
glucose‐driven
 growth
response
stopping
 short
of
replica-on
 Five stages of diabetes progression Fasting Blood Glucose, mg/dL Stage
3:
Decompensa-on
 (Unstable)
 • Progress
quickly
to
Stage
4
 at
a
cri-cal
point
when
B‐ cells
mass
becomes
 inadequate
and/or
IR
 increases.

As
a
result
 glucose
levels
rise
quickly.

 • Changes
in
caloric
intake
 and
exercise
allow
people
to
 move
in
and
out
of
stage
3.
 • Typically
no
overt
 symptoms
(polyuria,
weight
 loss)
 Diabetes 53:S16-S21, 2004 Fasting Blood Glucose, mg/dL Five stages of diabetes progression Diabetes 53:S16-S21, 2004 Stage
4:
Decompensa-on
 (Stable)
 • Individuals
typically
have
 enough
insulin
to
remain
in
 this
stage
without
progression
 to
ketosis
 • 
In
most
cases
this
stage
lasts
 a
life-me
for
people
with
T2D
 (people
with
T1D
progress
 rapidly
to
stage
5)

 • B
cell
mass
is
now
clearly
 reduced
(~
50%
of
non‐ diabe-c
control
subjects).
 • Capacity
for
insulin
secre-on
 is
considerably
less
 • Individuals
with
treated
T2D
 can
move
to
stage
1
or
2.
 Fasting Blood Glucose, mg/dL Five stages of diabetes progression Stage
5:
Severe
 Decompensa-on
 • Severe
loss
of
B‐cells
leads
 to
ketosis
and
individuals
 are
truly
dependent
on
 insulin
for
survival.


 • Typically
found
only
with
 T1D

 Diabetes 53:S16-S21, 2004 Complications of Diabetes •  Microvascular
disease
leading
to
blindness,
renal
 failure
and
nerve
damage
 –  Re-nopathy,
Nephropathy,
Neuropathy
 •  Macrovascular
disease
 –  Accelerated
atherosclerosis
leading
to
increased
risk
of
 myocardial
infarc-on,
stroke
and
limb
amputa-on.
 •  Molecular
mechanisms
of
glucose‐mediated
vascular
 damage
are
linked
to
increases
in
oxida-ve
stress
 and
inflamma-on
 Increased sorbitol-aldose reductase pathway flux depletes glutathione (GSH) • In
hyperglycemic
 environment,
unused
 glucose
is
converted
to
 sorbitol

via
aldose
 reductase
with
 concommitant
decrease
 in
NADPH
 • Deple-on
of
NADPH
 results
in
a
reduc-on
in
 the
reduced
form
of
 glutathione
(GSH),
a
 major
an-oxidant
 • This
results
in
 oxida-ve
stress
 Nature
2001:414:813‐820
 AGEs arising from hyperglycemia contribute to diabetes related pathologies Advanced
glyca-on
end‐products
(AGEs)
are
a
 heterogenous
group
of
sugar
derived
substances
 produced
by
nonenzyma-c
glyca-on
and
 oxida-on
of
sugars
with
free
amino
groups
on
 proteins,
lipids
and
nucleic
acids
 AGEs
are
found
in
increased
amounts
in
diabe-c
 re-nal
vessels,
renal
glomeruli
and
vascular
 -ssues
and
contribute
to
cardiovascular
disease,
 re-nopathy
and
nephropathy

 Formation of Advanced Glycation Endproducts (AGEs) Aldehyde of glucose (H-C=O) Amino Group (NH2) OH-C=N O=C=NH AGEs contribute to endothelial cell dysfunction and arterial stiffening Nature
2001:414:813‐820
 Endothelial Dysfunction autooxida(on NF‐KB
 AGE‐crosslinking
with
 collagen
results
in
 arterial
s-ffening
with
 loss
of
elas-city
of
large
 vessels
‐>
HTN

 Arterial stiffness is reversed in animal models by administration of anti-AGE drugs called AGE breakers Modification of plasma proteins by AGE precursors creates ligands that bind to AGE receptors, inducing changes in gene expression in endothelial cells Endothelial Dysfunction autooxida(on NF‐KB
 AGE‐crosslinking
with
 collagen
results
in
 arterial
s-ffening
with
 loss
of
elas-city
of
large
 vessels
‐>
HTN

 Reduc-on
in
NO
 Oxida-ve
Stress
 Chemokines/Cytokines
 Nature
2001:414:813‐820
 AGE plasma proteins can also be taken up by other cells (mesangial cells and macrophages) and induce the production of growth factors and cytokines Nature
2001:414:813‐820
 AGEs contribute to the structural changes of diabetic nephropathy (thickened glomerular basement membrane and mesangial expansion) First
Layer:
Endothelium:
Excludes
blood
and
 large
plasma
proteins
 2nd
layer:
Basement
 Membrane
 Major
barrier
to
 macromolecules
 Third
Layer:
epithelial
cells
of
Bowman’s
capsule
 A
thickened
glomerular
basement
 membrane,
is
accompanied
by
 accumula-on
of
AGEs
leading
to
 glomerulosclerosis
and
malfunc-on
 (leakage
of
protein
into
urine)
 Aminoguanidine,
an
inhibitor
of
AGE
forma-on,
is
shown
to
prevent
diabe-c
 nephropathy
in
diabe-c
animals.

 AGEs are linked to damage of the small blood vessels in the eye and vision problems (Retinopathy) • The
re-nal
blood
vessels
serve
the
inner
layers
of
 the
re-na
by
providing
nutrients
and
oxygen
 • An
excessive
amount
of
glucose
in
the
blood
may
 cause
damage
to
these
blood
vessels.

 • Within
the
eye
the
damaged
vessels
leak
blood
 and
fluid
into
the
surrounding
-ssues,
causing
 vision
problems.
 • AGEs
are
found
in
re-nal
vessels
of
diabe-c
 pa-ents
and
correlate
with
re-nopathy
severity
 Re-na
‐
the
thin
layer
of
cells
at
the
 back
of
the
eyeball
where
light
is
 converted
into
neural
signals
sent
to
 the
brain
 Aminoguanidine,
an
inhibitor
of
AGE
forma-on,
is
 shown
to
prevent
diabe-c
re-nopathy
in
diabe-c
 animals.

 (Bulge
in

 artery
wall)
 Increased activation of PKC leading to a number of pathogenic consequences ET
=
endothelin
 eNOS
=
endothelial
NO
synthase
 plasminogen
ac-vator
inhibitor‐1
(PAI‐1)
 VEGF=vascular
endothelial
growth
factor
 Nature
2001:414:813‐820
 ...
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This note was uploaded on 01/28/2012 for the course NS 441 taught by Professor Caudill during the Fall '11 term at Cornell University (Engineering School).

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