Доклад с 15 Межрегиональной научно-практической конференции "Искусственное питание и инфузионная терапия больных в медицине критических состояний" 21-22 мая 2015 г

1. Insulin resistance and
intensive insulin therapy
Peter B. Soeters
Maastricht University Medical Center
St Petersburg
Russia

2. Who stayed in this little house in Zaandam in 1697?

5. 7 g Nitrogen/day lost in urine
43 g Protein/day lost from the body
170 g of wet Muscle mass/ day lost from the body
Provides not more than 20-25 g of glucose
Not more than 5-8% of energy requirement
Remaining energy (92-95%) covered by fat oxidation

7. 14 g Nitrogen/day lost in urine
87 g Protein/day lost from the body
340 g of wet Muscle mass/ day lost from the body
Not more than 40-50 g of glucose
Not more than 10-12% of energy requirement
88-90% of energy requirement covered by oxidation of fat

8. ??
!!!
!!!

9. Limitation of glucose oxidation
• The body limits glucose oxidation in starvation and
stress starvation.
• This limits protein degradation because amino acids
need to be degraded to produce glucose
• This promotes survival because when more glucose
would be oxidized more protein would have to be
degraded which would shorten survival
• In evolution periods of (stress) starvation regularly
occurred and genes have survived that could code
for inhibition of glucose oxidation
• How does the body do this?

10. What do the following situations have in common?

11. Immune cells,
biomass, NADPH
Biomass,
immune cells
Biomass,
immune cells
Cori-cycle
Glucose metabolism in inflammatory states, growth,
rapid cell proliferation and starvation (see previous slide)
Glucose Glucose-6-phosphate
glycolysis
Glycogen
Cytosol
PyruvateLactate
Gluconeogenesisin
liverandkidney
Mitochondrion
Fatty acids
Biomass,
immune cells
CitrateOxaloacetate
Acetyl CoA
TCA-cycle =
Krebs-cycle
Energy!!

12. Effects of intravenous glucose on
endogenous glucose production in
healthy subjectsEGP(mg.kg.min)
0
1
2
3
1 2 4 4 + INS
Before glucose
During glucose
* * P < 0.05
*
*
*
Glucose delivery
Mg.kg-1.min-1
Wolfe RR et al, Metabolism 1979; 28: 210

13. Effects of enteral carbohydrate on
glucose flow (Ra) and endogenous
production (EGP) in critically ill patients
# P < 0.05
mol.kg.min
0
10
20
30
40
28% CHO 53% CHO 75% CHO
Glucose Ra EGP
#
# #
Schwarz JM, Am.
J. Clin. Nutr
2000; 72: 940

14. Immune cells,
biomass, NADPH
Biomass,
immune cells
Biomass,
immune cells
Cori-cycle
Glucose metabolism in inflammatory states, growth, rapid
cell proliferation and starvation (see previous slide)
Glucose Glucose-6-phosphate
glycolysis
Glycogen
Cytosol
PyruvateLactate
Gluconeogenesisin
liverandkidney
Mitochondrion
Fatty acids
Biomass,
immune cells
CitrateOxaloacetate
Acetyl CoA
TCA-cycle =
Krebs-cycle
Energy!!

15. What do they have in common?
• Sparing glucose
• Utilizing glucose for purposes that can only be served
by glucose:
• Tissue synthesis, immune response, redox regulation
• How to do this?
• Increased glucose/lactate/alanine/glucose cycling
• No full glucose oxidation (can be done by fat)
• No glycogen synthesis (is less relevant)
• What is an additional survival effect?
• Protein sparing !!!! (protein is in starvation the most
important glucose precursor)

16. Mohammad MA, Sunehag AL, Chacko SK, Pontius AS, Maningat PD,
Haymond MW. Mechanisms to conserve glucose in lactating women during
a 42-h fast. American Journal of Physiology - Endocrinology And
Metabolism. 2009 October 1, 2009;297(4):E879-E88.
Lactation leads to insulin
resistance!

17. Pinto, J., et al. (2014). "Following healthy pregnancy by NMR metabolomics of
plasma and correlation to urine." Journal of Proteome Research.

18. Upregulation PPP in
estivation (starvation in
summer)
Ramnanan CJ, Storey KB. Glucose-6-phosphate dehydrogenase regulation
during hypometabolism. Biochemical and Biophysical Research
Communications 2006;339:7-16.

19. Upregulation PPP in oxidative
stress in yeast
Ralser, M., et al. (2009). "Metabolic reconfiguration precedes
transcriptional regulation in the antioxidant response." Nat
Biotech 27(7): 604-605.

20. Grant, C. (2008). "Metabolic reconfiguration is a regulated
response to oxidative stress." Journal of Biology 7(1): 1.

21. No oxidation
Levine AJ, Puzio-Kuter AM. The control of the metabolic switch in cancers by
oncogenes and tumor suppressor genes. Science. 2010 Dec 3;330(6009):1340-4.
Anaplerosis

22. Kahn BB, McGraw TE. Rosiglitazone, PPARgamma, and type 2
diabetes. N Engl J Med 2010;363(27): 2667-2669.
Benefit (?) and Harm of oral antidiabetics

23. Bodmer M, Meier C, Krahenbuhl S, Jick SS, Meier CR. Long-
term metformin use is associated with decreased risk of
breast cancer. Diabetes Care 2010;33(6): 1304-1308.
Benefit (?) and Harm of oral antidiabetics

24. Euglycemic clamp studies in septic
patients and volunteers, no caloric intake
Expe-
riment
Insulinemia
mIU/ml
Glycemia
mmol/L
Glucose infusion
mg/kgBW/min
Glucose oxidation
mg/kgBW/min
Glc. non-oxid.
disposal
mg/kg/BW/min
Volun-
teers
250 5 mmol 11 3.4 7.6
Sepsis 250 5 mmol 3.6 2.8 0.4
Volun-
teers
1250 5 mmol 17.2 4.5 11.6
Sepsis 1250 5 mmol 6.4 3.7 2.3
Rusavy, Z., et al. (2004). "Influence of insulin on glucose metabolism and energy
expenditure in septic patients." Critical Care 8(4): R213 - R220.

25. Euglycemic clamp studies in septic patients at two
plasma levels of Glucose and Insulin.
Glucose infusion
Rusavy Z, Macdonald IA, Sramek V, Lacigova S, Tesinsky P, Novak I. Glycemia
Influences on Glucose Metabolism in Sepsis During Hyperinsulinemic Clamp.
Expe-
riment
Insulinemia
mIU/ml
Glycemia
mmol/L
Glucose infusion
mg/kgBW/min
Glucose oxidation
mg/kgBW/min
Glc. non-oxid.
disposal
mg/kg/BW/min
1 250 5 mmol 3.8 2.6 0.7
2 250 10 mmol 7.9 4.2 3.5
3 1250 5 mmol 7.0 3.6 2.9

26. Agwunobi AO, Reid C, Maycock P, Little RA, Carlson GL. Insulin Resistance and
Substrate Utilization in Human Endotoxemia. Journal of Clinical Endocrinology &
Metabolism 2000;85:3770-8.
Glucose storage = Glycogen synthesis
Pentose phosphate
pathway
Anaplerosis/Cataplerosis
Fatty acid synthesis
Endotoxin
Control

27. Glucose concentrations > 4-6
mmol drive glucose uptake
Protein Km
2
(mM)
Major sites of expression Proposed function
Facilitative glucose transporters (GLUT)
GLUT 1 3-7 Ubiquitous distribution in tissues
and culture cells
Basal glucose uptake; transport
across blood tissue barriers
GLUT 2 17 Liver, islets, kidney, small intestine High capacity low affinity transport
GLUT 3 1.4 Brain and nerve cells Neuronal transport
GLUT 4 6.6 Muscle, fat, heart Insulin-regulated transport in muscle
and fat
GLUT 5 Intestine, kidney, testis Transport of fructose
GLUT 6 unknown Spleen, leukocytes, brain

28. Authors Study design Glucose dosage/
Nutrition
Glucose level target Outcome
Van den Berghe
e.a. 20011
1258 patients
PRCT ICU on mech.
vent. predominantly
card.surg. patients
200-300g/d CHO i.v. EN
and PN starting on
admission
IIT: 4.4-6.1 mmol
C: Insulin when gluc
>10-11.1 mmol
Effects attributable to ICU stay > 5 d:
IIT: Mortality: 4.6%; C: 8% (S); LOS ICU:
shorter and less infection (S)
Van den Berghe
e.a. 200667
1200 patients
PRCT ICU medical 255-340 g CHO/d EN
and PN starting on
admission
IIT: 4.4-6.1 mmol
C: Insulin when gluc
>12 mmol
No effect on total mortality
IIT: less renal failure, shorter mech. vent.,
shorter LOS ICU (S)
De Azevedo e.a.
201071
337 patients
PRCT critical illness Low CHO:33% Cal of EN
IIT: 45% CHO Cal of EN
Total Cal not indicated
33% Cal CHO: Insulin
when gluc >10 mmol
45% Cal CHO IIT: gluc
6.7-10 mmol
Low CHO: Insulin 2 IU/day; IIT 52 IU/d.
Low CHO hypoglycemia. 3.5% of pat.; IIT:
16%.: related to neurological signs and
mortality. Overall mortality and morbidity
(NS)
Finfer e.a. 20093
6104 patients
PRCT ICU patients
expected > 3d ICU
109-129 g CHO/d
EN and PN
IIT: 4.5-6 mmol
C: 10 mmol or less
Mortality IIT: 27.5%; C: 24.9. OR 1.14 (S)
Gluc <2.2 mmol IIT 6.8% C: 0.5% (p
<0.001)
LOS ICU,mech. vent., renal replacement
(NS)
Studies Tight Glucose Control
Low CHO intake and ITT bad results
Deprivation of CHO for anabolic actions?!

29. Intensive Insulin therapy
• In critically ill patients glucose levels of approximately
10 mmol should be aimed for/allowed
• Levels between 4 and 6 mmol and limited glucose in
the diet increase the risk of hypoglycemia and
decrease host response (synthesis tissue, immune cells,
redoxregulation)
• With 50% of energy requirements covered by glucose
the risk of hypoglycemia is diminished and host
response is promoted.
• Oral antidiabetic drugs may interfere with the
beneficial effects of insulin resistance (insulin!?)

30. Beans et al
Expert Reviews
Mol Medicine
2003 Vol. 5 March
Stages of wound
healing:
Trauma/Damage/Disease
Clotting
Early inflammation
Late inflammation:
Growth biomass/cells
Remodeling/strengthening

31. Inflammation
• Immune cells perform local work
• Clot, remove debris, prepare
• Rebuild
• Immune cells steer metabolism
• Steer the periphery (predominantly muscle) in
conjunction with the liver to deliver an adequate mix of
building stones (glucose, glutamine, proline, alanine,
glycine far more than in muscle protein; essential amino
acids, other non-essential acids)
• Fat provides energy
• The way metabolism is steered causes insulin
resistance
• Inflammation and insulin resistance are inextricably
connected and are beneficial adaptive mechanisms