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Université J. Fourier

CHU de GRENOBLE. Direction Scientifique Nutrition Humaine et Sécurité des Aliments. Université J. Fourier. E-0221 Bioénergétique Fondamentale et Appliquée. Xavier Leverve. Glucose et lactate chez le patient agressé: le meilleur et le pire!.

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Université J. Fourier

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  1. CHU de GRENOBLE Direction Scientifique Nutrition Humaine et Sécurité des Aliments Université J. Fourier E-0221 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

  2. 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 ?

  3. Lipid storage is more efficient… but glucose oxidation is more powerful! storage (Kcal) Daily consumption (Kcal/J) glucose : lipids : proteins 680 100 000 25 000 glucose : (brain) lipids : proteins : 700 (175g) (80%) 860 (100g) 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

  4. - - acylcarnitine glucose + + insuline - glucagon Acidosis - Alkalosis + ATP/ADP acylCoA ß-oxidation NADH NAD NADH AcetylCoA CO2 CoA NAD Krebs’ cycle acetylCoA pyruvate pyruvate lactate pyruvate dehydrogenase CO2 mitochondrion cytosol

  5. Regulation of glycolysis G-6P Glucose Glucose ATP HK HK ADP G-6P H + pyruvate lactate pH ATP ADP ATP ADP pyruvate Pedersen, Brdiczka, Wallimann

  6. + + 1 4 3 2 glucose glycogen Plasma membrane glucose 6-phosphate ADP Acidosis Alcalosis NAD ATP ADP ATP H+ H+ NADH lactate pyruvate lactate alanine NADH + O2 ADP ATP NAD + H2O CO2

  7. Fatty acids Leucine 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. Reperfusion with glucose and lactate as the main energy-providing

  8. e n e r g y e q u i v a l e n t g l u c o s e p a l m i t i c a c i d s t a n d a r d p r o t e i n m o l a r m a s s ( g ) 1 8 0 2 5 6 2 2 5 7 . 4 O c o n s u m e d ( l / g ) 0 . 7 4 7 2 . 0 1 3 1 . 0 4 5 2 C O p r o d u c e d ( l / g ) 0 . 7 4 7 1 . 4 0 . 8 6 4 2 H O p r o d u c e d ( g / g ) 0 . 6 1 . 1 2 5 0 . 4 2 7 2 R Q 1 . 0 0 0 . 7 0 0 . 8 3 e n e r g y p o t e n t i a l ( k c a l / g ) 3 . 8 7 9 . 6 9 4 . 7 0 4 O ( k c a l / l ) 2 5 . 1 9 4 . 8 1 4 . 5 0 C O ( k c a l / l ) 2 5 . 1 9 6 . 9 2 5 . 4 4 s y n t h e s i z e d A T P m o l / m o l 3 8 1 2 9 4 5 0 k c a l / m o l 4 5 6 1 5 4 8 5 4 0 0 y i e l d 0 . 6 5 0 . 6 2 0 . 5 1

  9. 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

  10. Korvald, Am J Physiol, 2000

  11. Myocardium metabolism in normoxic and hypoxic condition 150 Other 100 CHO FAT 50 0 Normoxia Hypoxia Hochachka et al, PNAS 2001

  12. 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-1versus standard therapy2. GIK low dose: 10% glucose + 20 UI insulin/L+ 40 mmol KCl/Lversus 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

  13. 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 Tight control of blood glucose in ICU Insulin Treatment Conventional Intensive P (N = 783) (N = 765) * after correction for multiple interim analyses, adjusted P = 0.036 Van den Berghe G et al. N Engl J Med. 2001; 345: 1359-1367

  14. Xue-Liang Du, PNAS, 2000, 97, 12222–12226

  15. ATP ROS ROS ROS nH+ n2H+ Complex I Complex III Complex IV n1H+ n3H+ Intermembrane space Cyt c Cyt c Cyt c Cyt c1 Cyt a Cyt bk FeS FMN FeS Q Cyt a3 Cyt bT FeS II 2e- 2e- matrix Fumarate Succinate NADH + H+ FADH2 ADP ATP n2H+ 1/2 O2 + 2H+ H2O NAD+ nH+ ADP n3H+ n1H+

  16. Sho-ichi Yamagishi, DIABETES, 2001, 50

  17. Sho-ichi Yamagishi, DIABETES, 2001, 50

  18. 20 48H 72H 15 * * % of Dead Cells 10 5 0 Glucose (5.5mM) Mannitol (25mM) Glucose (30mM) CsA 1µM +Glucose 30mM MET 100µM +Glucose 30mM NAC 10mM +Glucose 30mM HMEC-1, propidium iodide Detaille et al, Diabetes, 2005

  19. HMEC-1 HUVEC Cytochrome c compartmentation D-glucose (5.5 mM) L-glucose (25 mM) D-glucose (30 mM) CsA 1µM + D-glucose 30 mM MET 100µM + D-glucose 30 mM Detaille et al, Diabetes, 2005

  20. + + 1 4 3 2 glucose glycogen Plasma membrane glucose 6-phosphate ADP - Acidosis Alcalosis NAD ATP ADP ATP H+ H+ NADH lactate pyruvate lactate alanine NADH + O2 ADP ATP NAD + H2O CO2

  21. O C O 2 2 + 2 C a + 2 + C a 3 N a + 2 K G L U C O S E Pyruvate ADP + Pi FFA Ca2+ G-6-P Glycogen ATP Ca2+ SR G-6-P ATP ADP + Pi LDH Lactate Pyruvate - - 6 P G

  22. Glucose Lactate O2 glucose glucose 6 ADP ADP ß-oxydation 6 ATP ATP lactate lactate H2O

  23. adrenaline Protection by Lactate of Cerebral Functions during Hypoglycemia Glucose noradrenaline Autonomic Symptom Score glucagon Lactate GH pH cortisol Maran et al, Lancet, 1994 343: 17-20

  24. 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

  25. 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

  26. Normoxia Hypoxia Normoxia lactate glucose 2-deoxyglucose A glucose 40 B 100 0 80 B glucose or lactate, nmol/slice 60 Recovery, (% slices) 60 40 A 20 40 0 0 0 20 40 60 80 Schurr et al, Brain Res 1997 Time, min

  27. Normal condition Reaction after oxygen restoration post hypoxia Reaction during hypoxia

  28. EGP before and after removal of the liver during liver transplantation Joseph SE et al. Diabetes 2000;49:450-456 % Postabsorptive Endogenous Glucose Production Liver Liver Renal Glycogenolysis Gluconeogenesis Gluconeogenesis Renal balance 75 25 0 Renal balance + Deuterated glucose 50 30 20 n = 5, EGP calculation during 6,6[2H2]glucose infusion 54 % 36 %

  29. 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

  30. Central Role of lactate in Sertoli cell–germ cell metabolic cooperation. Boussouar & Benhamed, TRENDS in Endocrinology and Metabolism, 2004, 15, 345-350

  31. 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-

  32. Mg++ Ca++ Cl- K+ Na+ CO2 H+ alb- Electrical Neutrality lactate PO4- - SO4- -, OH -, others

  33. - Lactate is a strong anion - It is metabolized Hence, when infused as sodium salt, sodium remains after lactate metabolism. Therefore sodium-lactate is alkalinizing

  34. Effect of hypertonic infusion (lactate versus NaCl) on acid base status Mustafa & Leverve, Shock, 2001

  35. Effect of hypertonic infusion (lactate versus NaCl) on hemodynamic D CI D PVRI D SVRI Mustafa & Leverve 2003

  36. 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!

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