Lactate kinetics deep dive

1. Tracer-determined lactate kinetics: problems
of quantification and interpretation
• Why use a lactate tracer?
• Choice of label: 2H/3H vs. 13C/14C
• Problems of quantification and interpretation
– Difficult to quantify whole-body Ra
– Difficult to differentiate between pyruvate and
lactate kinetics

2. The classical perspective: lactate as (is) a
‘dead end’ metabolite
C
C
C
O
H
H H
H
O-
OH
Pyruvate Lactate
C
C
C
O
H
H H
H
O-
O
LDH

3. A modern alternative:
Brooks’ ‘lactate shuttle’ hypothesis
“The lactate shuttle hypothesis holds that lactate
plays a key role in the distribution of carbohydrate
potential energy that occurs among various tissue
and cellular compartments such as between:
cytosol and mitochondria, muscle and blood,
blood and muscle, active and inactive muscles,
white and red muscles, blood and heart, arterial
blood and liver, liver and other tissues such as the
exercising muscle, intestine and portal blood,
portal blood and liver, zones of the liver, and skin
and blood.”
Brooks, MSSE 32:790, 2000

4. Lactate Ra varies depending on site of tracer
infusion and site of blood sampling
Katz et al. Biochem. J. 194:513, 1981

5. General circulatory model for substrate that
first appears intracellularly (e.g., lactate)
Wolfe, p. 170
Sampling at point
a = A-V mode
Enrichment is
lower, therefore
Ra is higher
L* = infusion of tracer
Sampling at point
b = V-A mode
Enrichment is
higher, therefore
Ra is lower
Lower bound:
precise estimate
of Ra into
plasma (pool 1)
Upper bound:
variable
underestimate
of whole body
Ra

6. Lactate Ra, or lactate/pyruvate Ra?
From Sahlin, AJP 252:E439, 1987

7. Rapid and extensive equilibration between
lactate and pyruvate in anesthetized dogs
From Wolfe et al. AJP 254: E532, 1988

8. Rapid and extensive equilibration between
pyruvate and lactate in human blood
From Romijn et al. AJP 266: E334, 1994

9. Equilibration is extensive, but not complete,
and may vary with physiological state
From Henderson et al. JAP 2004 Feb 27 [Epub ahead of print]

10. Steady-state compartmental model of tissue
lactate/pyruvate metabolism
From Chinkes et al. AJP 267:E174, 1994

11. Lactate/pyruvate metabolism in resting
skeletal muscle of anesthetized dogs
From Chinkes et al. AJP 267:E174, 1994

12. Lactate/pyruvate metabolism in gut of
anesthetized dogs
From Chinkes et al. AJP 267:E174, 1994

13. “…quantifying lactate kinetics per se is a difficult
problem. The rate of tracer uptake across a
tissue will always be high, even though there
may be a net output of lactate occurring in that
tissue. The implication of this fact on the
interpretation of whole body turnover studies is
uncertain at this time, and it may well turn out
that this is too difficult a problem to solve. At the
tissue level, considerable work is still needed to
describe appropriately the various interactions
that occur.”
From Wolfe, p. 312