Université J. Fourier Xavier Leverve Grenoble, DESC de Réanimation Médicale, 31 mai 2006 CHU de...

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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!