Université J. FourierUniversité J. Fourier
Xavier LeverveXavier Leverve
Grenoble, DESC de Réanimation Médicale, 31 mai 2006
CHU de GRENOBLE
Direction Scientifique Nutrition Humaine
et Sécurité des Aliments E-0221 Bioénergétique Fondamentale et Bioénergétique Fondamentale et AppliquéeAppliquée
Glucoseet lactate chez le patient agressé: le meilleur et le pire!
glucoselactate …..
The steady state of the “milieu intérieur” results from the metabolism of every cell
best compromize between various organ or cell priorities and/or benefits ?
storage(Kcal)storage(Kcal)
glucose :
lipids :
proteins
680
100 000
25 000
Daily consumption(Kcal/J)
Daily consumption(Kcal/J)
glucose :(brain)
lipids :
proteins :
700 (175g)(80%)
860 (100g)
240 (50g)
To store 1g of glycogenWe must store 2.5 g of water !
1g of glucose = 4 Kcal1g of lipids = 9 Kcal
Lipid storage is more efficient… but glucose oxidation is more powerful!Lipid storage is more efficient… but glucose oxidation is more powerful!
lactate pyruvate pyruvate dehydrogenase
Krebs’cycle
ß-oxidation
ß-oxidation
NAD NADH
acetylCoA
-
pyruvate
glucose
acylCoA
cytosol mitochondrion
AcetylCoA
CoACO2
CO2
acylcarnitine
insulineglucagon
NADH
NAD
+-+
Acidosis - Alkalosis + ATP/ADP
-
ADP
ATP
H+
Pedersen, Brdiczka, Wallimann
Regulation of glycolysis
pyruvatepyruvate
lactate
Glucose
HK
G-6P ADP
ATP
HK
GlucoseG-6P
pH
ATPADP
glucose
glucose 6-phosphatePlasmamembrane
lactate
H+
NAD
pyruvatealanine
CO2
Acidosis
Alcalosis+ATPADP ATP
ADP
glycogen
NADH
3
1
4
NAD + H2O
NADH + O2
2ATP
ADP
H+
lactate
+
Reperfusion with glucose and lactate as the main energy-providing
LeucineFatty acids
Ketone bodies
Essential and non-essential fuels for energy production. Note that glucose, lactate and pyruvate provide both substrates for the citrate
synthase reaction : acetyl-CoA and oxaloacetate.
glucose palmitic acid standard proteinmolar mass (g)
180 256 2257.4O2 consumed (l/g) 0.747 2.013 1.045CO2 produced (l/g) 0.747 1.4 0.864H2O 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
energy equivalent O2 (kcal/l) 5.19 4.81 4.50CO2 (kcal/l) 5.19 6.92 5.44
synthesized ATP
mol/mol 38 129 450
kcal/mol 456 1548 5400
yield 0.65 0.62 0.51
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
0
50
100
150
Normoxia Hypoxia
Other
CHO
FAT
Hochachka et al, PNAS 2001
Metabolic modulation of acute MIthe 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 groups1. 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 therapy2. 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 patientsDiaz R et al, Circulation 1998; 98: 2227
34% in RR, Log-rank test, p< 0.046
Tight control of blood glucose in ICU
Conventional Intensive P
(N = 783) (N = 765)
ICU deaths (N = 1548) 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
Insulin Treatment
* 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
matrix
Intermembranespace
Complex I n1H+
FeS
FeS
FMN
2e-
NADH + H+
NAD+
Complex III
Cyt c1
Cyt bk
Cyt bT
FeS
Cyt c Cyt c
Cyt c
Q
n2H+
Complex IV n3H+
Cyt a
Cyt a3
2e-
1/2 O2 + 2H+
H2O
Succinate Fumarate
ROS ROS
n1H+
n2H+
n3H+
II
ADP ATP
nH+
nH+
ATP
ADP
FADH2
ROS
Sho-ichi Yamagishi, DIABETES, 2001, 50
Sho-ichi Yamagishi, DIABETES, 2001, 50
20
% of Dead Cells
Glucose(5.5mM)
Mannitol(25mM)
Glucose(30mM)
MET 100µM+Glucose 30mM
CsA 1µM+Glucose 30mM
NAC 10mM +Glucose 30mM
0
5
10
15
48H
72H
*
*
HMEC-1, propidium iodide
Detaille et al, Diabetes, 2005
D-glucose (5.5 mM)
D-glucose (30 mM)
L-glucose (25 mM)
CsA 1µM +D-glucose 30 mM
MET 100µM +D-glucose 30 mM
HUVECHMEC-1
Cytochrome ccompartmentation
Detaille et al, Diabetes, 2005
glucose
glucose 6-phosphatePlasmamembrane
lactate
H+
NAD
pyruvatealanine
CO2
Acidosis
Alcalosis +ATPADP ATP
ADP
glycogen
NADH
3
1
4
NAD + H2O
NADH + O2
2ATP
ADP
H+
lactate
+
-
FFA
Ca2+
G-6-P
O 2 CO 2
2 K+3 Na+
GLUCOSE
Ca2+
Pyruvate LactateLDHATP
G-6-P
PyruvateADP+Pi
ATP
SR
ADP + PiG-6-P
Ca2+
Ca2+
Glycogen
glucose
lactate
ADP
ATPATP
LactateLactate
GlucoseGlucose
glucose
lactate
6 ADP
6 ATP
H2O
ß-ox
ydat
ion
O2O2
Protection by Lactate of Cerebral
Functions during Hypoglycemia
Maran et al, Lancet, 1994 343: 17-20
Glucose
Lactate
pH
adrenaline
noradrenaline
GH
glucagon
cortisol
AutonomicSymptomScore
Symptoms scores during the hypoglycaemic clampstudies with Na-lactate (*) or saline infusion (*) in normalvolunteers (A, C) and diabetic patients (B, D). A and B showautonomic symptoms, and C and D show neuroglycopenic symptoms
Lactate effect on counterregulation to hypoglycaemia
Maran et al, Diabetologia (2000) 43: 733±741
Lactate administration attenuates cognitive deficits following traumatic brain injury
Rice et al, Brain research, 2002 928: 156-7
Injured rats with lactate performed
significantly better in MWM task than injured rats with saline (p < 0.05): lactate infusion
attenuated the cognitive deficits
gluc
ose
or la
ctat
e, n
mol
/sli
ceNormoxia Hypoxia Normoxia
A
B
A
B
Rec
over
y, (
% s
lice
s)
0
20
60
40
100
80
Time, min0 8020 60
lactateglucose2-deoxyglucoseglucose
Schurr et al, Brain Res 1997
0
40
0
40
60
40
glucose glucose 6-phosphate
ATP ADP
pyruvateCO2
ATPADP
ATP
H2O Oxygen
lactate
glucose glucose 6-phosphate
ATP ADPpyruvateCO2
ATP
ADPATP
H2OX
XOxygen
lactate
glucose glucose, 6-phosphate
ATP ADP
pyruvateCO2
ATP
ADP
H2O
XX
Oxygen
lactate
ROS
Reaction after oxygen restoration post hypoxia
Reaction during hypoxia
Normal condition
% 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;49:450-456n = 5, EGP calculation during 6,6[2H2]glucose infusion
36 %
54 %
• 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
Glucose-lactate recycling in the kidney
Central Role of lactate in Sertoli cell–germ cell metabolic cooperation.
Boussouar & Benhamed, TRENDS in Endocrinology and Metabolism, 2004, 15, 345-350
Determinants of [H+]• pCO2
– pCO2 + H2O -> H2CO3 -> H+ + HCO3
-
• ATOT
– ATOT -> A- + AH
– albumin (80%), phosphate (20%)
• SID (strong ion difference)– Na+ + K+ Ca++ + Mg++ - Cl- - L-
Na+ K+Mg++ Ca++
H+
Cl-
alb- CO2
lactate
SO4- -, OH -, others
PO4- -
Electrical Neutrality
- Lactate is a strong anion- It is metabolized
Hence, when infused as sodium salt, sodium remains after lactate
metabolism.
Therefore sodium-lactate is alkalinizing
Mustafa & Leverve, Shock, 2001
Effect of hypertonic infusion (lactate versus NaCl) on acid base status
0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
DCI-1 DCI-2
Na
Lactate
-800
-700
-600
-500
-400
-300
-200
-100
0
DSVRI-1 DSVRI-2
Na
Lactate
-60
-50
-40
-30
-20
-10
0
DPVRI-1 DPVRI-2
Na
Lactate
Mustafa & Leverve 2003
Effect of hypertonic infusion (lactate versus NaCl) on hemodynamic
CI
SVRI PVRI
glucoselactate …..
Glucose and lactate: both are useful and complementary, high glucose has deleterious effects!
The major therapeutic challenge in the ICU: assessing and understanding the metabolic hierarchy between functions and organs!
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