Fructose/ 1,6 bisphosphate loading for marathon runners?
Whilst the benefits of carbohydrate loading in marathon runners,
which is intended to increase glycogen stores, are equivocal fructose
loading might enhance performance significantly by increasing the capacity
for ATP resynthesis by anaerobic means and potentially limit the risks of
over-hydration addressed in this paper. The capacity of the liver for
metabolising lactate and other metabolites may, however, be the ultimate
determinant of performance in marathion runners.
Unlike glucose fructose does not require insulin to enter muscle or
liver cells. Neither does fructose stimulate the release of insulin, as
glucose does, certainly in aerobic conditions. Fructose also enhances
the rate of lipolysis in adipose tissues and the availability of free
fatty acids for the synthesis of acetyl coenzyme A and of glycerol for
entry into the Embden-Meyhoff pathway in anaerobic tissues (1,2). Insulin,
which is released by glucose, does the reverse in adequately perfused and
oxygenated tissues.
Fructose competes unsuccessfully with glucose for hexokinase, the
enzyme catalysing the formation of fructose-6-phosphate from both glucose
and from fructose. The relative rates of reactions in aerobic conditions
are 20/1. Fructose may, however, also enter the Embden-Meyhoff pathway by
being catalysed by fructokinase an enzyme that does not catalyse glucose
reactions but is not present in muscle. In by-passing the
phosphofructokinase step fructose bypasses the fructokinase pathway and
escapes the negative feedback controls hypoxia, a fall in pH and a fall in
[ATP]/[AMP] exerts upon the rate and direction of metabolism within the
glyocolytic pathway (3). Indeed this pathway evades all of the negative
feed back controls exerted upon glucose metabolism as the severity of
anaerobiosis increases.
To circumvent the inhibitory controls in anaerobiosis glucose may be
converted to fructose by activating the polyol pathway. The first enzyme
in the polyol pathway, aldose reductase, reduces glucose to sorbitol,
which is then converted to fructose by sorbitol dehydrogenase [if as is
likely it also exists in man]. Thus fructose may be the preferred
substrate by muscle in marathon runners the glucose being used for
reductive biosynthesis, if necessary, and more importantly to provide
substrate for the brain.
An intravenous infusion of fructose has a half-life of 18 minutes,
half that of glucose. Its metabolic pathways bypass the pentose phosphate
shunt, its synthesis of the NADPH and hence reductive biosynthesis of
fatty acids in adipocytes, cholesterol and the steroid hormones in the
liver, and other important products of reductive biosynthesis including
cytochrome P450, reduced glutathione, nitric oxide and tetrahydrofolate
all of which use ATP.
In anaerobiosis in exercising muscle phosphofructokinase is inhibited
initially by the fall in pH induced by the accompanying unreversed ATP
hydrolysis and later by the fall in [ATP] and rise in [AMP]. Concurrently
fructose-6-phosphatase is upregulated so that F-6-phosphate accumulates.
Gluconeogenesis is thus stimulated promoting a rise in blood glucose from
synthesis in the liver from the lactate, glycerol and amino acids.
Glycogenolysis may also be inhibited further preserving the glucose
generated by gluconeogenesis for consumption by the brain. Thus in
anaerobiosis of exercising muscle fatty acids become the preferred
substrate for muscle and the glucose entering the blood is preserved for
uptake and utilisation by the glial cells interposed between capillaries
and neurons. The glial cells traffic nutrient from capillaries to neurons.
Glial cells do not require insulin for their glucose uptake from
blood even in normoxic conditions. In a sense, therefore, glucose behaves
like fructose in glial cells presumably with the same purpose, increasing
the rate of substrate utlisation for ATP resynthesis. In the normal course
of events ATP resynthesis in glial cells occurs by anaerobic means. The
lactate generated by glial cells is, however, used as substrate by
adjacent and oxygenated neurons. As with lactate generated by exercising
muscle which is converted into glucose in the liver (Cori cycle)the
neurons may rely upon an adequately oxygenated and normal functioning
liver to complete their metabolic functions if also supported by anaerobic
rather than aerobic means. These circumstances may exist in some patients
with isolated head injuries or strokes.
It should be emphasised that for anaerobic metabolism to be an
efficient generator of ATP in exercising muscle any lactate, and probably
NAD, glutamate and NH4, needs to be washed into the systemic circulation
so that they can be metabolised in the liver. The lactate is converted to
glucose in the liver (Cori cycle), the NAD to NADH by the conversion of
glutamate into alpha ketoglutarate in the Krebs cycle [this may occur
primarily within the brain] and the NH4 into amino acids in the liver for
synthesis, additional fuel for the Krebs cycle or convesion into urea and
excretion in urine. The kidneys may also dispose of the NH4.
In glial cells glutamate and NH4 is converted into glutamine and
transported to the oxygenated neurons. The lactate enters the Krebs cycle
by being converted into pyruvate. The glutamine is converted back into
glutamate which is either released into the synaptic clefts and taken up
again by glial cells or used to form NADH from NAD and alpha ketoglutarate
which is consumed in the Krebs cycle. The disposal of lactate and NH4 and
replenishment of NADH are necessary for the ATP resynthesis by anaerobic
means not be inhibited to their accumulation in accordance with the law of
mass action. In the cases of regional intracerebral anaerobiosis, as may
occur with isolated head injuries and strokes, an adequately oxygenated
liver [and to a lesser degree kidneys] becomes essential if anaerobic
metabolism is to generate the ATP needed for the brain to survive.
An intravenous administration of fructose has the potential to
increase ATP resynthesis in both anaerobic tissues without interfering
with gluconeogenesis or with fatty acid utilisation by muscle. Fructose,
but not glucose if phosphofructokinase is inhibited, is metabolised to
form fructose 1,6 bisphoglycerate an intermediate metabolite within the
Embden-Meyhoff pathway. If it, instead of fructose, were to be
administered intravenously two moles of ATP would be preserved increasing
from 2 to 4 moles the net yield of ATP generated from one mole of glucose
(or for that matter fructose) in the Emden-Meyerhoff pathway. [There
would, however, be a need to replenish the NADH from NAD for the
conversion of pyruvate to lactate, a reaction that could take place in
adequately oxygenated liver if it is impaired within the glycolytic
pathway in anaerobiosis as would seem. [This may occur in the Embden-
Meyhoff pathway but befoire the synthesis of fructose 1,6 bisphoglycerate
and can be suppressed in oxidative stress, notably that induced by
cytokines].
If phosphofructokinase is inhibited and glucose is made to pass
throught the pentose phosphate shunt the phosphofructokinase step is
bypassed in glycolysis preserving one mole ATP normally used in the
metabolism of glucose. The net yield of ATP from glucose in anaerobic
metabolism may, therefore, be increased from 2 to 3 moles, but this
increase is probably off-set by the ATP consumed in the reducitve
biosynthetic pathways. In other words enough ATP may be resynthesised in
anaerobioisis from glucose alone for reductive biosynthesis to proceed and
for the basic metabolic needs for cell survival to be met.
Glycolytic turnover and hence yield of ATP by anaerobic means may
increase by four or even as much as eight times in hypoxic conditions.
This may be the product of increased extraction of nutrient from each unit
of flowing capillary blood, and increased rate of capillary blood flow and
of the 10% increase in metabolic rate that occurs with each degree of rise
in regional temperature that occurs with exercise, an increase in
metabolic activity or inflammation [the Q10 effect]. Thus the net yield of
ATP in anerobiosis, regardless of whether glucose of fructose is the
substrate, is much greater than commonly supposed. It may even be as high
as 16 moles or 24 moles for each mole of substrate utilised. As the yield
from aerobic metaolism may also be increased from 38 moles by these
influences the net yield from anaerobic metabolism in any given set of
circumstances remains much lower than that from aerobic metabolism. It is,
however, sufficient to meet the needs of highly metabolically active
physicological processes such as wound healing.
Honey has been applied to wounds for millenia. Its reduces the risk
of infection and enhances wound healing in burns, ulcers, and other
cutaneous wounds (4). As Willmore, Hunt and others have shown wounds
replenish their ATP by anaerobic means even in hyperoxic conditions. As
honey contains large amounts of fructose, fructose could be one of its
active ingredients. This deduction is consistent with frutose being the
preferred carbohydrate substrate in anaerobic metabolism and suggests that
the supplementary supplies of fructose in honey may promote wound healing
by enhancing the yield of ATP from anaerobic metabolism. In which case
spermatazoa might depend upon the high concentations of fructose in semen
and ova upon the high concentrations of fructose in follicular fluid to
survive and thrive in the hostile microaerophilic environments of the
vagina, oviduct (i.e. Fallopian tube)and uterus.
Fructose-1,6-bisphosphate, the intermediary product of fructose in
the Emden-Meyerhoff pathway, has a neuroprotective effect when
administered intravenously immediately before or after inducing
hypothermic circulatory arrest in a porcine model (5). Animals treated
with it have significantly better postoperative behavioral scores. The
administration of the fructose-1,6-bisphosphate was also associated with
lower intracranial pressures and lower venous creatine kinase isoenzyme MB
measured during rewarming (P =.01 and P =.001, respectively). Among the
treated animals, brain glucose, pyruvate and lactate levels tended to be
higher, brain glycerol levels tended to be lower, and the histopathologic
score of the brain was significantly lower (P =.04). This raises the
possibility that fructose loading and especially fructose 1,6-bisphosphate
loading might enhance the performance of marathon runners. But, apart from
oral fructose causing gastrointestinal upsets, there may be a risk.
Fructose may cause a metabolic acidosis when administered to patients
in shock (2). This is not surprising for hepatic metabolism is likely to
be impaired in shock and with it the ability to metabolise lactate and NH4
and to replenish NADH. [Hence perhaps the rise in CSF glutamine and NH4 in
liver failure]. As the gastric intramucosal pH, which falls in severe
exercise, may correlate closely with hepatic venous lactates this could
be an indication of an inadequacy of hepatic oxygenation (6). Fructose
loading might, therefore, be dangerous in the many marathon runners who
develop a gastric intramucosal acidosis.
On the other hand catalytic quantities of fructose (<_10 of="of" total="total" carbohydrate="carbohydrate" flux="flux" enhance="enhance" liver="liver" glucose="glucose" uptake="uptake" in="in" a="a" dose="dose" dependent="dependent" manner.="manner." the="the" primary="primary" fate="fate" is="is" glycogen="glycogen" synthesispossibly="synthesispossibly" because="because" fructose="fructose" may="may" inhibit="inhibit" glyogenolysis7.="glyogenolysis7." ability="ability" to="to" augment="augment" not="not" impaired="impaired" by="by" presence="presence" marked="marked" insulin="insulin" resistance="resistance" such="such" as="as" type="type" _2="_2" diabetes="diabetes" or="or" infection.="infection." this="this" surprising="surprising" since="since" upon="upon" insulin.="insulin." potent="potent" acute="acute" regulator="regulator" and="and" synthesis.="synthesis." furthermore="furthermore" inclusion="inclusion" catalytic="catalytic" quantities="quantities" meal="meal" improves="improves" tolerance.="tolerance." fructose-16-diphosphate="fructose-16-diphosphate" administration="administration" also="also" attenuates="attenuates" post-ischemic="post-ischemic" ventricular="ventricular" dysfunction="dysfunction" _8in="_8in" addition="addition" having="having" neuroprotective="neuroprotective" effect="effect" porcine="porcine" model="model" circulatory="circulatory" arrest5.="arrest5." but="but" these="these" observations="observations" appear="appear" have="have" been="been" made="made" circumstances="circumstances" which="which" adequately="adequately" oxygenated="oxygenated" those="those" shock="shock" it="it" has="has" inadequately="inadequately" oxygenated.="oxygenated." p="p"/> In the absence of inhibitory controls might an intravenous infusion
of fructose and especially of fructose-1,6-bisphosphate, which has the
potential to double the capacity for ATP resynthesis in anaerobiosis,
induce a lactic acidosis? Only if the adequacy of hepatic tissue
oxygenation is impaired or if there is preexisting hepatic disease which
compromises the ability to metabolise lactate and NH4 and replenish NADH?
The co-existing presence of renal disease can be expected to increase the
risk
There may indeed be the potential to enhance performance in marathon
runners with fructose loading by either or intravenous means. If
accompanied by bicarbionate loading to off-set the degree of any gastric
intramucosal acidosis that develops in anaerobiosis the potential to
enhance performance could be much greater. Phosphate loading to
accommmodate the increased rate of ATP resynthesis might be an additional
benefit. It is needed to prevent complications from the development of the
hypophosphataemia induced by the increase in rate of resynthesis
apparently occurring with the commensement of feeding in burned patients
and possibly malnourished children (9,10).
If it enhances performance in marathon runners fructose or fructose-
1,6-bisphosphate loading might be of partcular benefit to patients by
limiting the degree of irreversible cellular damage induced by, for
example, head injuries, strokes, and acute coronary artery occlusions.
Maintining the adequacy of hepatic tissue oxygenation and function is
likely to be an especially important determinant of benefit in these
circumstances. There will, however, be no benefit if tissue perfusion in
the region in question, be it muscle , brain or heart, and nutrient
transport to remainder of the body including the liver is not maintained.
These potentail benefits might, however, be off-set by an widening of the
intercapiiary distances that might be induced by overhydration.
1. Biochemistry, 5th edition, Berg JM, Tymoczko JL, Stryer L Edds, WH
Freeman and Company, New York, 1995.
2. Salway JG. Metabolism at a glance. Blackwell Scientific, Oxford, 1999.
3. Chung SS, Ho EC, Lam KS, Chung SK. Contribution of polyol pathway to
diabetes-induced oxidative stress. J Am Soc Nephrol. 2003 Aug;14 Suppl
3:S233-6.
4. Lusby PE, Coombes A, Wilkinson JM. Honey: a potent agent for wound
healing? J Wound Ostomy Continence Nurs. 2002 Nov;29(6):295-300
5. Romsi P, Kaakinen T, Kiviluoma K, Vainionpaa V, Hirvonen J, Pokela M,
Ohtonen P, Biancari F, Nuutinen M, Juvonen T. Fructose-1,6-bisphosphate
for improved outcome after hypothermic circulatory arrest in pigs. J
Thorac Cardiovasc Surg. 2003 Mar;125(3):686-98. Review
6.Landow L, Phillips DA, Heard SO, Prevost D, Vandersalm TJ, Fink MP.
Gastric tonometry and venous oximetry in cardiac surgery patients. Crit
Care Med. 1991 Oct;19(10):1226-33.
7. McGuinness OP, Cherrington AD. Effects of fructose on hepatic glucose
metabolism. Curr Opin Clin Nutr Metab Care. 2003 Jul;6(4):441-8
8. Woo YJ, Cohen JE, Taylor MD, Berry MF, Grand T, Burdick JW, Sweeney HL.
Fructose-1,6-diphosphate administration attenuates post-ischemic
ventricular dysfunction. Heart Surg Forum. 2003;6 Supp 1:S36
9. Hyperphosphataemia, hypophosphataemia and risk of organ dysfunctions
and failuresRichard G Fiddian-Green
bmj.com/cgi/eletters/326/7385/382#29805, 20 Feb 2003
10. Hypophosphataemia and the feeding of malnourished children Richard G
Fiddian-Green bmj.com/cgi/eletters/326/7381/146#29382, 3 Feb 2003
Rapid Response:
Fructose/ 1,6 bisphosphate loading for marathon runners?
Whilst the benefits of carbohydrate loading in marathon runners,
which is intended to increase glycogen stores, are equivocal fructose
loading might enhance performance significantly by increasing the capacity
for ATP resynthesis by anaerobic means and potentially limit the risks of
over-hydration addressed in this paper. The capacity of the liver for
metabolising lactate and other metabolites may, however, be the ultimate
determinant of performance in marathion runners.
Unlike glucose fructose does not require insulin to enter muscle or
liver cells. Neither does fructose stimulate the release of insulin, as
glucose does, certainly in aerobic conditions. Fructose also enhances
the rate of lipolysis in adipose tissues and the availability of free
fatty acids for the synthesis of acetyl coenzyme A and of glycerol for
entry into the Embden-Meyhoff pathway in anaerobic tissues (1,2). Insulin,
which is released by glucose, does the reverse in adequately perfused and
oxygenated tissues.
Fructose competes unsuccessfully with glucose for hexokinase, the
enzyme catalysing the formation of fructose-6-phosphate from both glucose
and from fructose. The relative rates of reactions in aerobic conditions
are 20/1. Fructose may, however, also enter the Embden-Meyhoff pathway by
being catalysed by fructokinase an enzyme that does not catalyse glucose
reactions but is not present in muscle. In by-passing the
phosphofructokinase step fructose bypasses the fructokinase pathway and
escapes the negative feedback controls hypoxia, a fall in pH and a fall in
[ATP]/[AMP] exerts upon the rate and direction of metabolism within the
glyocolytic pathway (3). Indeed this pathway evades all of the negative
feed back controls exerted upon glucose metabolism as the severity of
anaerobiosis increases.
To circumvent the inhibitory controls in anaerobiosis glucose may be
converted to fructose by activating the polyol pathway. The first enzyme
in the polyol pathway, aldose reductase, reduces glucose to sorbitol,
which is then converted to fructose by sorbitol dehydrogenase [if as is
likely it also exists in man]. Thus fructose may be the preferred
substrate by muscle in marathon runners the glucose being used for
reductive biosynthesis, if necessary, and more importantly to provide
substrate for the brain.
An intravenous infusion of fructose has a half-life of 18 minutes,
half that of glucose. Its metabolic pathways bypass the pentose phosphate
shunt, its synthesis of the NADPH and hence reductive biosynthesis of
fatty acids in adipocytes, cholesterol and the steroid hormones in the
liver, and other important products of reductive biosynthesis including
cytochrome P450, reduced glutathione, nitric oxide and tetrahydrofolate
all of which use ATP.
In anaerobiosis in exercising muscle phosphofructokinase is inhibited
initially by the fall in pH induced by the accompanying unreversed ATP
hydrolysis and later by the fall in [ATP] and rise in [AMP]. Concurrently
fructose-6-phosphatase is upregulated so that F-6-phosphate accumulates.
Gluconeogenesis is thus stimulated promoting a rise in blood glucose from
synthesis in the liver from the lactate, glycerol and amino acids.
Glycogenolysis may also be inhibited further preserving the glucose
generated by gluconeogenesis for consumption by the brain. Thus in
anaerobiosis of exercising muscle fatty acids become the preferred
substrate for muscle and the glucose entering the blood is preserved for
uptake and utilisation by the glial cells interposed between capillaries
and neurons. The glial cells traffic nutrient from capillaries to neurons.
Glial cells do not require insulin for their glucose uptake from
blood even in normoxic conditions. In a sense, therefore, glucose behaves
like fructose in glial cells presumably with the same purpose, increasing
the rate of substrate utlisation for ATP resynthesis. In the normal course
of events ATP resynthesis in glial cells occurs by anaerobic means. The
lactate generated by glial cells is, however, used as substrate by
adjacent and oxygenated neurons. As with lactate generated by exercising
muscle which is converted into glucose in the liver (Cori cycle)the
neurons may rely upon an adequately oxygenated and normal functioning
liver to complete their metabolic functions if also supported by anaerobic
rather than aerobic means. These circumstances may exist in some patients
with isolated head injuries or strokes.
It should be emphasised that for anaerobic metabolism to be an
efficient generator of ATP in exercising muscle any lactate, and probably
NAD, glutamate and NH4, needs to be washed into the systemic circulation
so that they can be metabolised in the liver. The lactate is converted to
glucose in the liver (Cori cycle), the NAD to NADH by the conversion of
glutamate into alpha ketoglutarate in the Krebs cycle [this may occur
primarily within the brain] and the NH4 into amino acids in the liver for
synthesis, additional fuel for the Krebs cycle or convesion into urea and
excretion in urine. The kidneys may also dispose of the NH4.
In glial cells glutamate and NH4 is converted into glutamine and
transported to the oxygenated neurons. The lactate enters the Krebs cycle
by being converted into pyruvate. The glutamine is converted back into
glutamate which is either released into the synaptic clefts and taken up
again by glial cells or used to form NADH from NAD and alpha ketoglutarate
which is consumed in the Krebs cycle. The disposal of lactate and NH4 and
replenishment of NADH are necessary for the ATP resynthesis by anaerobic
means not be inhibited to their accumulation in accordance with the law of
mass action. In the cases of regional intracerebral anaerobiosis, as may
occur with isolated head injuries and strokes, an adequately oxygenated
liver [and to a lesser degree kidneys] becomes essential if anaerobic
metabolism is to generate the ATP needed for the brain to survive.
An intravenous administration of fructose has the potential to
increase ATP resynthesis in both anaerobic tissues without interfering
with gluconeogenesis or with fatty acid utilisation by muscle. Fructose,
but not glucose if phosphofructokinase is inhibited, is metabolised to
form fructose 1,6 bisphoglycerate an intermediate metabolite within the
Embden-Meyhoff pathway. If it, instead of fructose, were to be
administered intravenously two moles of ATP would be preserved increasing
from 2 to 4 moles the net yield of ATP generated from one mole of glucose
(or for that matter fructose) in the Emden-Meyerhoff pathway. [There
would, however, be a need to replenish the NADH from NAD for the
conversion of pyruvate to lactate, a reaction that could take place in
adequately oxygenated liver if it is impaired within the glycolytic
pathway in anaerobiosis as would seem. [This may occur in the Embden-
Meyhoff pathway but befoire the synthesis of fructose 1,6 bisphoglycerate
and can be suppressed in oxidative stress, notably that induced by
cytokines].
If phosphofructokinase is inhibited and glucose is made to pass
throught the pentose phosphate shunt the phosphofructokinase step is
bypassed in glycolysis preserving one mole ATP normally used in the
metabolism of glucose. The net yield of ATP from glucose in anaerobic
metabolism may, therefore, be increased from 2 to 3 moles, but this
increase is probably off-set by the ATP consumed in the reducitve
biosynthetic pathways. In other words enough ATP may be resynthesised in
anaerobioisis from glucose alone for reductive biosynthesis to proceed and
for the basic metabolic needs for cell survival to be met.
Glycolytic turnover and hence yield of ATP by anaerobic means may
increase by four or even as much as eight times in hypoxic conditions.
This may be the product of increased extraction of nutrient from each unit
of flowing capillary blood, and increased rate of capillary blood flow and
of the 10% increase in metabolic rate that occurs with each degree of rise
in regional temperature that occurs with exercise, an increase in
metabolic activity or inflammation [the Q10 effect]. Thus the net yield of
ATP in anerobiosis, regardless of whether glucose of fructose is the
substrate, is much greater than commonly supposed. It may even be as high
as 16 moles or 24 moles for each mole of substrate utilised. As the yield
from aerobic metaolism may also be increased from 38 moles by these
influences the net yield from anaerobic metabolism in any given set of
circumstances remains much lower than that from aerobic metabolism. It is,
however, sufficient to meet the needs of highly metabolically active
physicological processes such as wound healing.
Honey has been applied to wounds for millenia. Its reduces the risk
of infection and enhances wound healing in burns, ulcers, and other
cutaneous wounds (4). As Willmore, Hunt and others have shown wounds
replenish their ATP by anaerobic means even in hyperoxic conditions. As
honey contains large amounts of fructose, fructose could be one of its
active ingredients. This deduction is consistent with frutose being the
preferred carbohydrate substrate in anaerobic metabolism and suggests that
the supplementary supplies of fructose in honey may promote wound healing
by enhancing the yield of ATP from anaerobic metabolism. In which case
spermatazoa might depend upon the high concentations of fructose in semen
and ova upon the high concentrations of fructose in follicular fluid to
survive and thrive in the hostile microaerophilic environments of the
vagina, oviduct (i.e. Fallopian tube)and uterus.
Fructose-1,6-bisphosphate, the intermediary product of fructose in
the Emden-Meyerhoff pathway, has a neuroprotective effect when
administered intravenously immediately before or after inducing
hypothermic circulatory arrest in a porcine model (5). Animals treated
with it have significantly better postoperative behavioral scores. The
administration of the fructose-1,6-bisphosphate was also associated with
lower intracranial pressures and lower venous creatine kinase isoenzyme MB
measured during rewarming (P =.01 and P =.001, respectively). Among the
treated animals, brain glucose, pyruvate and lactate levels tended to be
higher, brain glycerol levels tended to be lower, and the histopathologic
score of the brain was significantly lower (P =.04). This raises the
possibility that fructose loading and especially fructose 1,6-bisphosphate
loading might enhance the performance of marathon runners. But, apart from
oral fructose causing gastrointestinal upsets, there may be a risk.
Fructose may cause a metabolic acidosis when administered to patients
in shock (2). This is not surprising for hepatic metabolism is likely to
be impaired in shock and with it the ability to metabolise lactate and NH4
and to replenish NADH. [Hence perhaps the rise in CSF glutamine and NH4 in
liver failure]. As the gastric intramucosal pH, which falls in severe
exercise, may correlate closely with hepatic venous lactates this could
be an indication of an inadequacy of hepatic oxygenation (6). Fructose
loading might, therefore, be dangerous in the many marathon runners who
develop a gastric intramucosal acidosis.
On the other hand catalytic quantities of fructose (<_10 of="of" total="total" carbohydrate="carbohydrate" flux="flux" enhance="enhance" liver="liver" glucose="glucose" uptake="uptake" in="in" a="a" dose="dose" dependent="dependent" manner.="manner." the="the" primary="primary" fate="fate" is="is" glycogen="glycogen" synthesispossibly="synthesispossibly" because="because" fructose="fructose" may="may" inhibit="inhibit" glyogenolysis7.="glyogenolysis7." ability="ability" to="to" augment="augment" not="not" impaired="impaired" by="by" presence="presence" marked="marked" insulin="insulin" resistance="resistance" such="such" as="as" type="type" _2="_2" diabetes="diabetes" or="or" infection.="infection." this="this" surprising="surprising" since="since" upon="upon" insulin.="insulin." potent="potent" acute="acute" regulator="regulator" and="and" synthesis.="synthesis." furthermore="furthermore" inclusion="inclusion" catalytic="catalytic" quantities="quantities" meal="meal" improves="improves" tolerance.="tolerance." fructose-16-diphosphate="fructose-16-diphosphate" administration="administration" also="also" attenuates="attenuates" post-ischemic="post-ischemic" ventricular="ventricular" dysfunction="dysfunction" _8in="_8in" addition="addition" having="having" neuroprotective="neuroprotective" effect="effect" porcine="porcine" model="model" circulatory="circulatory" arrest5.="arrest5." but="but" these="these" observations="observations" appear="appear" have="have" been="been" made="made" circumstances="circumstances" which="which" adequately="adequately" oxygenated="oxygenated" those="those" shock="shock" it="it" has="has" inadequately="inadequately" oxygenated.="oxygenated." p="p"/> In the absence of inhibitory controls might an intravenous infusion
of fructose and especially of fructose-1,6-bisphosphate, which has the
potential to double the capacity for ATP resynthesis in anaerobiosis,
induce a lactic acidosis? Only if the adequacy of hepatic tissue
oxygenation is impaired or if there is preexisting hepatic disease which
compromises the ability to metabolise lactate and NH4 and replenish NADH?
The co-existing presence of renal disease can be expected to increase the
risk
There may indeed be the potential to enhance performance in marathon
runners with fructose loading by either or intravenous means. If
accompanied by bicarbionate loading to off-set the degree of any gastric
intramucosal acidosis that develops in anaerobiosis the potential to
enhance performance could be much greater. Phosphate loading to
accommmodate the increased rate of ATP resynthesis might be an additional
benefit. It is needed to prevent complications from the development of the
hypophosphataemia induced by the increase in rate of resynthesis
apparently occurring with the commensement of feeding in burned patients
and possibly malnourished children (9,10).
If it enhances performance in marathon runners fructose or fructose-
1,6-bisphosphate loading might be of partcular benefit to patients by
limiting the degree of irreversible cellular damage induced by, for
example, head injuries, strokes, and acute coronary artery occlusions.
Maintining the adequacy of hepatic tissue oxygenation and function is
likely to be an especially important determinant of benefit in these
circumstances. There will, however, be no benefit if tissue perfusion in
the region in question, be it muscle , brain or heart, and nutrient
transport to remainder of the body including the liver is not maintained.
These potentail benefits might, however, be off-set by an widening of the
intercapiiary distances that might be induced by overhydration.
1. Biochemistry, 5th edition, Berg JM, Tymoczko JL, Stryer L Edds, WH
Freeman and Company, New York, 1995.
2. Salway JG. Metabolism at a glance. Blackwell Scientific, Oxford, 1999.
3. Chung SS, Ho EC, Lam KS, Chung SK. Contribution of polyol pathway to
diabetes-induced oxidative stress. J Am Soc Nephrol. 2003 Aug;14 Suppl
3:S233-6.
4. Lusby PE, Coombes A, Wilkinson JM. Honey: a potent agent for wound
healing? J Wound Ostomy Continence Nurs. 2002 Nov;29(6):295-300
5. Romsi P, Kaakinen T, Kiviluoma K, Vainionpaa V, Hirvonen J, Pokela M,
Ohtonen P, Biancari F, Nuutinen M, Juvonen T. Fructose-1,6-bisphosphate
for improved outcome after hypothermic circulatory arrest in pigs. J
Thorac Cardiovasc Surg. 2003 Mar;125(3):686-98. Review
6.Landow L, Phillips DA, Heard SO, Prevost D, Vandersalm TJ, Fink MP.
Gastric tonometry and venous oximetry in cardiac surgery patients. Crit
Care Med. 1991 Oct;19(10):1226-33.
7. McGuinness OP, Cherrington AD. Effects of fructose on hepatic glucose
metabolism. Curr Opin Clin Nutr Metab Care. 2003 Jul;6(4):441-8
8. Woo YJ, Cohen JE, Taylor MD, Berry MF, Grand T, Burdick JW, Sweeney HL.
Fructose-1,6-diphosphate administration attenuates post-ischemic
ventricular dysfunction.
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Competing interests:
None declared
Competing interests: No competing interests