lezione sensibilit insulinica 091115 [modalit compatibilit ]) resistenza - definizione e... ·...
Transcript of lezione sensibilit insulinica 091115 [modalit compatibilit ]) resistenza - definizione e... ·...
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Outline
• What is insulin resistance
• What is the relevance of insulinresistance
• How do we measure insulinresistance
• Insulin resistance and physicalexercise
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Definizione di insulino resistenzaresistenza
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The many effects of insulin
• storage of nutrientsglucose metabolismfatty acids metabolismamino acids metabolismamino acids metabolism
• paracrine effects• growth & differentiation
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The many effects of insulinMolecular basis for insulin resistance
Saltiel AR, Kahn CR. Nature 414: 799, 2001
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Race/ethnicitySexAgeing
Insulin
resistance
Obesity
resistance
Environmental factors- diet habits- habitual PA- other habits
Drugs
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EnvironmentIncreased nutrients availability
Sensingof energy balance
Insulin resistancePerseghin G. Curr Opin Lipidol, 2005
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Importanza dell’insulino resistenzaresistenza
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• Type 2 diabetes• Hypertension
Metabolic syndrome
Insulin resistance:is it important ?
• Dyslipidemia• Obesity/visceral obesity• Pro-inflammatory state• Pro-thrombotic state• Endothelial dysfunction
CVD risk factor
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Glucose
100
200
300Post-prandial
Fastingmg/dL
Natural historyof type 2 diabetes
-10 -5 0 5 10 15 20 25 300
100
200
Insulin resistanceInsulin
Years
Prediabetes ß-cell dysfunction
(%)
Bergenstal RM, International Diabetes Center
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Semplificazionedel sistema metabolico:del sistema metabolico:
il sistema glucosio insulina
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muscle
liver Glucose
brain
production
disposal
The glucoseThe glucose--insulin systeminsulin system
-
+
pancreas Insulin
tissues
degradationsecretion
+
ß-cell sensitivity
+
Insulin sensitivity
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Insulin sensitivity
-production
decrease
insulin
+
disposal
glucose glucose
increase
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Curve di sensibilità all’insulinain condizioni euglicemiche
10
12
14
1.5
2
2.5
utilizzazione totale di glucosio
produzione epatica di glucosio
mg/m
in/k
g
mg/m
in/k
g
0 200 400 600 800 100012002
4
6
8
10
20 40 60 80 100 1200
0.5
1
1.5
insulinemia periferica insulinemia portaleµU/ml µU/ml
mg/m
in/k
g
mg/m
in/k
g
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Azione dell’insulina durante un carico orale di glucosio (OGTT)
50
100
150
50
100
glu
cosio
mg
/dl
insulin
aU
/ml
0 20 40 60 80 100 120 140 1600
5
0
0
5
10
insulin
aµ
U/m
l
assorbimento
produzione
utilizzazione
flussi di glu
cosio
mg
/min
/kg
tempo (min)
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Curve di sensibilità all’insulina
2000
2500
3000u
tilizza
zio
ne
di g
luc
os
io(µ
mo
l/m
in/m
2)
normali
obesi
10 100 1000 10000 1000000
500
1000
1500
insulinemia (pmol/L)
uti
lizza
zio
ne
di g
luc
os
io(µ
mo
l/m
in/m
obesi
diabetici
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Il clamp insulinicoIl clamp insulinico
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Test standardizzato per la valutazione dell’insulino-sensibilità
utilizzazione totale di glucosio
produzione epatica di glucosio
Sollecitazione del sistema omeostatico:� insulina costante e elevata (~100 µµµµU/ml)� glucosio costante e normale (~95 mg/dl)
0 200 400 600 800 100012002
4
6
8
10
12
14
20 40 60 80 100 1200
0.5
1
1.5
2
2.5
insulinemia periferica insulinemia portale
di glucosio di glucosio
µU/ml µU/ml
mg/m
in/k
g
mg/m
in/k
g
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Sensibilità all’insulina: il clamp euglicemico iperinsulinemico
glicemia:insulinemia:
produzione glucosio(fegato) ≈≈≈≈ 0
infusione costante di insulina
infusione variabile di glucosio
glicemia:insulinemia:
utilizzazione glucosio(muscolo)
stimolata
� ad equilibrio raggiunto la velocità di infusione di glucosio esogeno (~costante) è praticamente uguale all’utilizzazione
� la velocità di infusione è l’indice di sensibilità all’insulina
costante costante
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Il clamp: procedura sperimentale
misura della glicemia
pompa insulina
pompa glucosio
algoritmo di controllo dell’infusione di glucosio
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EuEuglycemicglycemic--hyperhyperinsulinemic clampinsulinemic clamp
20
40
60
0
µµ µµU
/ml insulin
Insulin infusion
8
10
production
mm
ol/
kg
min
0
2
4
6
8
mm
ol/
l
glucose
hypoglicemia
Glucose infusion
0
0 60 120 180 240 300
Time (min)
mm
ol/
kg
min
disposal
Time (min)
0 60 120 180 240 300
mm
ol/
kg
min
SI
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110
120
130
140m
g /
dl
60
80
100
µU
/ml
Euglycemic/Hyperinsulinemic Clamp
Dextrose 20%
-30 -15 0 15 30 60 75 90 105 12070
80
90
100mg /
dl
0
20
40 µU
/ml
Glucose Insulin
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Ruolo del muscolo scheletrico nell’insulino scheletrico nell’insulino
resistenza
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Muscle Glycogen Synthesis Pathway
Glut4
Glut4glucoseHK-II
glucose
+
insulin
+
glucose - 6 - phosphate
glycogen
HK-II
GS
glucose - 1 - phosphate
UDP - glucose
glycolysis
+
+
+
Perseghin G et al, N Engl J Med 1996
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60
/kg b
ody w
t/m
inTotal Glucose Metabolism
350-400 pmol/L
Insulin Resistance & the Muscle
0
20
40
µm
ol/kg b
ody w
t/m
in
Muscle
88%Glycogen
Shulman GI et al, N Engl J Med 1990
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Effetti dell’allenamento sull’insulino resistenza sull’insulino resistenza
muscolare
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6 weeks exercise training
stair-climbing
65% VO2 max65% VO2 max
5-min warm up + 15-min sessions x 3
every other day for 6 weeks
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40
50
60
70
mu
scle
·min
]
Muscle Glycogen Synthesis: I bout
67% *62%
Perseghin G et al, N Engl J Med 1996
0
10
20
30
Before I bout
mg
/[li
ter
mu
scle
·min
Offspring type 2
Normals
Before I bout
*
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40
50
60
70
mu
scle
·min
]
Muscle Glycogen Synthesis: 6 weeks
*97%102%
Perseghin G et al, N Engl J Med 1996
0
10
20
30
Before 6 weeks
mg
/[li
ter
mu
scle
·min
Offspring type 2
Normals
*
Before 6 weeks
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Effetti acuti dell’insulino resistenza sul
metabolismo muscolare metabolismo muscolare del glucosio
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50
60
70
80
Gly
cogen
mM
II phase
insulin dependent recoveryI phase
insulin independent recovery
Effect of Acute Exercise on Muscle Glycogen
0 15 30 45 60 75 90 105 120 135 150 180 195 210 225 240 255 270 285 3000
10
20
30
40
Gly
cogen
mM
Normals Off Type 2 min
Exe
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40
50
60
70
mg
/[lit
er
·min
]
Muscle glycogen synthesis
Perseghin G et al, N Engl J Med 1996
0
10
20
30
Bas Exe Bas Exe
mg
/[lit
er
*
Off
Normali
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“Surrogati” del clamp “Surrogati” del clamp insulinico
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Insulino-sensibilità:metodi indiretti tradizionali
• Test usati (con misure di glucosio e insulina):
– Misure basali
– Iniezione endovenosa di glucosio (IVGTT)
– Carico orale di glucosio (OGTT)– Carico orale di glucosio (OGTT)
• Fondamenti del metodo:
– empirici (correlazione con il clamp)
– modelli matematici del sistema omeostatico
• I metodi indiretti sono sperimentalmente più semplici ma meno attendibili
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HOMA“HOmeostasis Model Assessment”
HOMA: metodo basato sulla semplice misura della glicemia e
insulinemia basale
glicemia basale
della glicemia e insulinemia a digiuno
Matthews et al. 1985
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Il principio di HOMA
ins
uli
ne
mia
ba
sa
le
gli
ce
mia
ba
sa
le
95
90
100
8
4
12m
g/d
l
µU
/ml
normale
ins
uli
ne
mia
ba
sa
le
gli
ce
mia
ba
sa
le
95
90
100
8
4
12
mg/d
l
µU
/ml
resistente
ins
uli
ne
mia
ba
sa
le
gli
ce
mia
ba
sa
le
95
90
100
8
4
12
mg/d
l
µU
/ml
resistente
ins
uli
ne
mia
ba
sa
le
gli
ce
mia
ba
sa
le
95
90
100
8
4
12
mg/d
l
µU
/ml
resistente
HOMA = glicemia x insulinemia basale
HOMA: indice di resistenza
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Il test di glucosio orale (OGTT)
100
insu
lin
em
ia
0
100
200
gli
cem
iam
g/d
l
0
50
100
0 60 120
insu
lin
em
iaµ
U/m
l
tempomin
Principio: stimolare il sistema omeostatico glucosio-insulina per ricavare dalle curve plasmatiche informazione sulla sensibilità con metodi empirici o modelli matematici
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50
150
250
350
0 60 120 180 240
(mg
/dl)
IVGTT
80
120
160
200
0 120 240 360 420
Meal
240
OGTT
100
140
180
0 60 120 180
Glucose
(pm
ol/l)
100
300
500
0 120 240 360 420
180
300
0 60 120 180 240
600
100
300
0 60 120 180 240
200
Insulin
Bergman RN et alAm J Physiol 1979
Caumo A et alJCEM 2000
Pacini & MariBest Practice & Res 2003
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model of ....
IVGTT, OGTT, Meal Test
Dynamic tests ± physiologic,Less invasive and cheaper than the clampbutplasma glucose and insulin are not at steady state
model of the glucose-insulin systemmodel ofß-cell
secretion
model of glucose
metabolism
glucose
insulin
....
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CONCLUSIONS
• Insulin influences many relevant metabolic pathways in many organs and tissues
• Insulin resistance is usually regarded to an impaired effectiveness on glucose metabolism
• Insulin resistance may be assessed with golden standard techniques or by means of surrogates indices
• Awareness on the use of these surrogates indices should be guaranteed