Download ATP - Réanimation médicale

CHU de GRENOBLE
Direction Scientifique
Nutrition Humaine
et Sécurité des Aliments
E-0221
Université J. Fourier
Bioénergétique Fondamentale et Appliquée
Xavier Leverve
Glucose
et lactate chez
le patient agressé:
le meilleur et le pire!
Grenoble, DESC de Réanimation Médicale, 31 mai 2006
The steady state of the “milieu intérieur” results
from the metabolism of every cell
glucose
lactate …..
best compromize between various organ or cell priorities
and/or benefits ?
Lipid storage is more efficient…
but glucose oxidation is more powerful!
storage
(Kcal)
glucose :
lipids :
Daily consumption
(Kcal/J)
680
glucose : 700 (175g)
(brain)
(80%)
100 000
lipids :
proteins
860 (100g)
25 000
proteins : 240 (50g)
To store 1g of glycogen
We must store 2.5 g of water !
1g of glucose = 4 Kcal
1g of lipids = 9 Kcal
Acidosis Alkalosis +
ATP/ADP
-
NAD NADH
lactate
pyruvate
acylcarnitine
insuline
glucagon
+
glucose
acylCoA
AcetylCoA
NADH
CoA
NAD
pyruvate pyruvate
acetylCoA
CO2
Krebs’
cycle
dehydrogenase
CO2
cytosol
mitochondrion
-
Regulation of glycolysis
Glucose
ATP
Glucose
HK
HK
G-6P
G-6P
ADP
pH
ATP
ADP
ATP
H+
ADP
pyruvate
pyruvate
lactate
Pedersen, Brdiczka, Wallimann
glucose
glycogen
Plasma
membrane
glucose 6-phosphate
ADP
Acidosis
Alcalosis +
ATP
+
ADP
1
NAD
ATP
H+
NADH
alanine
4
pyruvate
3
NADH + O2
ADP
2
ATP
NAD + H2O
CO2
lactate
H+
lactate
Fatty acids
Leucine Ketone bodies
Reperfusion
with glucose
and
lactate
as the
main energyEssential
and non-essential
fuels
for
energy
production.
Note that
glucose, providing
lactate and pyruvate provide both substrates for the citrate
synthase reaction : acetyl-CoA and oxaloacetate.
glucose
palmitic acid
standard protein
180
256
2257.4
O2 consumed (l /g)
0.747
2.013
1.045
CO2 produced (l /g)
0.747
1.4
0.864
H2 O produced (g/g)
0.6
1.125
0.427
RQ
1.00
0.70
0.83
energy potential (kcal/g)
3.87
9.69
4.704
5.19
4.81
4.50
5.19
6.92
5.44
mol/mol
38
129
450
kcal/mol
456
1548
5400
yield
0.65
0.62
0.51
molar mass (g)
energy equivalent
O2 (kcal/l )
CO2 (kcal/l )
synthesized ATP
In normal heart
• fatty acids contribute to 50% of energy
expenditure,
• ß-hydroxybutyrate 20%
• glucose 10%
In presence of high concentration of glucose and
insulin
• GLUT-4 is translocated,
• Glucose transport and metabolism is activated
=> large increase in glucose extraction
Korvald, Am J Physiol, 2000
Myocardium metabolism in normoxic and
hypoxic condition
150
Other
100
CHO
FAT
50
0
Normoxia
Hypoxia
Hochachka et al, PNAS 2001
Metabolic modulation of acute MI
the ECLA glucose-insulin-potassium trial
• RCT in 29 hospitals from 6 Latin American countries
• 407 patients with acute MI, admitted within 24 hrs of symptoms onset
• Randomized (2:1) into 2 therapeutic groups
1. GIK high dose: 25% glucose + 50 UI insulin/L
+ 80 mmol KCl/L, 1.5 ml.kg-1.h-1 (~ 25 g.h-1
versus standard therapy
2. GIK low dose:
10% glucose + 20 UI insulin/L
+ 40 mmol KCl/L
versus standard therapy
Metabolic modulation of acute MI decreases
mortality, One-year survival curves for reperfused
patients
Diaz R et al, Circulation 1998; 98: 2227
34% in RR, Log-rank test, p< 0.046
Tight control of blood glucose in ICU
Insulin Treatment
Conventional Intensive
P
(N = 783)
(N = 765)
8.0%
4.6%
0.005*
5-days mortality rate
1.8%
1.7%
0.9
ICU deaths among 451 long-stayers
20.2%
10.6%
0.005
In-hospital deaths (N = 1548)
10.9%
7.2%
0.01
In-hospital deaths among 451 long-stayers 26.3%
16.8%
0.01
ICU deaths (N = 1548)
* after correction for multiple interim analyses, adjusted P = 0.036
Van den Berghe G et al. N Engl J Med. 2001; 345: 1359-1367
Xue-Liang Du, PNAS, 2000, 97, 12222–12226
ATP
ROS
ROS
ROS
Complex I
Complex III
n1H+
n2H+
nH+
Complex IV
n3H+
Cyt c
Intermembrane
space
Cyt c1
Cyt c
Cyt c
Cyt a
Cyt bk
FeS
FMN
FeS
Q
FeS
II
Cyt bT
2e-
2e-
matrix
Succinate
NADH + H+
NAD+
Cyt a3
FADH2
Fumarate
n2H+
1/2 O2 + 2H+
H2O
ADP
ATP
nH+
n1H+
n3H+
ADP
Sho-ichi Yamagishi, DIABETES, 2001, 50
Sho-ichi Yamagishi, DIABETES, 2001, 50
HMEC-1, propidium iodide
20
48H
72H
15
*
*
10
5
0
Glucose
(5.5mM)
Mannitol
(25mM)
Glucose
(30mM)
CsA 1µM
+Glucose 30mM
MET 100µM
+Glucose 30mM
NAC 10mM
+Glucose 30mM
Detaille et al, Diabetes, 2005
HUVEC
D-glucose
(5.5 mM)
L-glucose
(25 mM)
D-glucose
(30 mM)
Cytochrome c
compartmentation
CsA 1µM +
D-glucose 30 mM
MET 100µM +
D-glucose 30 mM
Detaille et al,
Diabetes, 2005
glucose
glycogen
Plasma
membrane
glucose 6-phosphate
ADP
Acidosis Alcalosis +
ATP
ADP +
1
NAD
ATP
H+
NADH
alanine
4
pyruvate
3
NADH + O2
ADP
2
ATP
NAD + H2O
CO2
lactate
H+
lactate
O2
CO 2
Pyruvate
ADP
+
Pi
FFA
Ca2+
Ca 2+
G-6-P
ATP
SR
Ca2+
G-6-P
Pyruvate
Ca2+
3 Na+
2 K+
GLUCOSE
LDH
Lactate
Glycogen
Glucose
ß-oxydation
O2
glucose
glucose
6 ADP
ADP
6 ATP
lactate
lactate
H2O
Lactate
ATP
adrenaline
Glucose
noradrenaline
Lactate
glucagon
Protection by Lactate
of Cerebral
Functions during
Hypoglycemia
Autonomic
Symptom
Score
GH
pH
cortisol
Maran et al, Lancet, 1994 343: 17-20
Lactate effect on counterregulation to hypoglycaemia
Symptoms scores during
the hypoglycaemic clamp
studies with Na-lactate (*)
or saline infusion (*) in
normal
volunteers (A, C) and
diabetic patients (B, D). A
and B show
autonomic symptoms, and
C and D show
neuroglycopenic
symptoms
Maran et al, Diabetologia (2000) 43: 733±741
Lactate administration attenuates cognitive deficits following traumatic
brain injury
Injured rats with lactate
performed significantly better
in MWM task than injured
rats with saline (p < 0.05):
lactate infusion attenuated the
cognitive deficits
Rice et al, Brain research, 2002 928: 156-7
lactate
glucose
2-deoxyglucose
glucose
A
40
Recovery, (% slices)
glucose or lactate, nmol/slice
Normoxia Hypoxia Normoxia
0
B
60
40
B
100
80
60
40
20
A
0
0
0
20
40
Time, min
60
80
Schurr et al, Brain Res 1997
glucose
glucose 6-phosphate
ATP
ADP
ADP
ATP
pyruvate ATP
CO2
Oxygen
H2O
lactate
Normal condition
glucose
X
ADP
ATP
glucose
glucose 6-phosphate
CO2
ATP
CO2
H2O
ADP
ADP
ATP
X
pyruvate ATP
X
glucose, 6-phosphate
X
ATP
ADP
pyruvate
Oxygen
H2O
lactate
ROS
Reaction after oxygen restoration post
hypoxia
Oxygen
lactate
Reaction during hypoxia
% Postabsorptive Endogenous Glucose Production
Liver
Liver
Renal
Glycogenolysis Gluconeogenesis Gluconeogenesis
Renal balance
75
25
0
Renal balance +
Deuterated glucose
50
30
20
EGP before and after removal of the liver during liver transplantation
Joseph SE et al. Diabetes 2000;49:450-456
n = 5, EGP calculation
during 6,6[2H2]glucose infusion
54 %
36 %
Glucose-lactate recycling in the kidney
•
•
•
Lactate production from glucose and lactate consumption occurred
at a high rate, demonstrating a lactate recycling between renal cortex
and medulla in the intact kidney.
Lactate production from glucose correlated with glomerular
filtration rate (p<0.001), urine flow rate (p<0.01) and sodium
reabsorption (p<0.05).
Inhibition of Na+ reabsorption or prevention of filtration (the 'non'filtering kidney') decreased lactate production by 39% and 50%
respectively.
It is concluded that glycolysis is required for medullary Na+ transport,
and that some different transport function(s) require lactate
oxidation.
Bartlett et al, Biochem J. 1984, 219:73-8
Central Role of lactate in Sertoli cell–germ cell
metabolic cooperation.
Boussouar & Benhamed, TRENDS in Endocrinology and Metabolism, 2004, 15, 345-350
• pCO2
Determinants of
+
[H ]
– pCO2 + H2O -> H2CO3 -> H+ + HCO3-
• ATOT
– ATOT -> A- + AH
– albumin (80%), phosphate (20%)
• SID (strong ion difference)
– Na+ + K+ Ca++ + Mg++ - Cl- - L-
Electrical Neutrality
Na+
K+
Mg++ Ca++
H+
lactate
alb-
PO4- CO2
SO4- -, OH -, others
Cl-
- Lactate is a strong anion
- It is metabolized
Hence, when infused as sodium salt, sodium
remains after lactate metabolism.
Therefore sodium-lactate is alkalinizing
Effect of hypertonic infusion (lactate versus NaCl)
on acid base status
Mustafa & Leverve, Shock, 2001
Effect of hypertonic infusion (lactate versus NaCl)
on hemodynamic
0,8
D CI
Moy. des cellules
0,7
0,6
0,5
La cta te
0,4
Na
0,3
0,2
0,1
0
DCI-1
DCI-2
0
0
-10
-20 0
-30 0
La cta te
-40 0
Na
-50 0
-60 0
D SVRI
-70 0
-80 0
Moy. des cellules
Moy. des cellules
-10 0
-20
La cta te
-30
Na
-40
D PVRI
-50
-60
DSVRI-1
DSVRI-2
DPVRI-1
DPVRI-2
Mustafa & Leverve 2003
Glucose and lactate: both are useful and
complementary, high glucose has deleterious effects!
glucose
lactate …..
The major therapeutic challenge in the ICU: assessing and
understanding the metabolic hierarchy between functions and organs!