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

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!