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Researched and Composed by By Jacob Wilson and Gabriel "Venom" Wilson
Abstract
Galen who lived from 129 - 216 AD has been regarded as a father of
exercise physiology. He suggested that “it does not seem that all
movement is exercise, but only when it is vigorous. But since vigor is
relative, the same movement might be exercise for one and not for
another. The criterion of vigorousness is change of respiration; those
movements, which do not alter the respiration, are not called exercise.
But if anyone is compelled by any movement to breathe more or less or
faster, that movement becomes exercise for him.” 2000 years latter, it
is recognized that this transient increase in minute ventilation
reflects the need to supply oxygen to meet the higher energetic
requirements of exercise. While at rest, and especially during meal
absorption the physiological environment is one which favors the
biosynthesis of molecules such as proteins, carbohydrates, and lipids.
Exercise is characterized by an altered state which favors the
catabolism of stored nutrients to supply the working musculature with
adequate substrates for ATP formation. Both rest and recovery are
primarily under the control of the parasympathetic nervous system, and
storage hormones such as insulin. While exercise is mediated by the
sympathoadrenal system, which, from a chemical standpoint can be
characterized by the catecholamines: epinephrine and norepinephrine.
Other hormones involved include growth hormone, cortisol, thyroid
hormone, aldosterone, and glucagon. Therefore the purpose of this
paper, was to review each of the hormones discussed and clearly relay
their role in nutrient (carbohydrate, lipid, and protein) utilization
during exercise.
Epinephrine and Norepinephrine’s Roles in Nutrient Utilization during
Exercise
Epinephrine (E) and Norepinephrine (NE) are classified as
catecholamines. Catecholamines
fall under the class of amine hormones, or hormones derived from amino
acids. E and NE are derivatives of the amino acid tyrosine. Further, E
and NE fall under a subgroup of chemical messengers known as counter
regulatory hormones. Insulin is said to regulate glucose by promoting
its uptake into tissues. The overall effect is hypoglycemia, or lowered
blood glucose levels. Counter regulatory hormones promote the release
of glucose from muscle, as well as the hepatic system (liver) and are
therefore counter the regulatory role of insulin. In short, E and NE act
to increase catabolism and release of stored nutrients during exercise,
while antagonizing (opposing) hormones which promote storage and
synthesis of biological molecules (i.e. anabolism).
Catecholeamines are part of the sympathoadrenal (SA) system.
Physiologically it is known as the fight or flight system, while
anatomically it is referred to as the thoracolumbar system. It is
comprised of sympathetic nerves which arise out of the thoracic (chest
region of spinal cord) and lumbar (lower back region of spinal cord)
regions of the body; the adrenal medulla (the core of the adrenal
gland); and executive control centers located in the central nervous
system, such as the hypothalamus and brain stem. The sympathetic nerves
are characterized by direct synapses (connections) with their effecter
tissues, and therefore can elicit a response within milliseconds. This
is therefore the neurological control of the system. However, the SA
system also has a hormonal component, in that the adrenal medulla
secretes catecholamines directly into the blood stream. When E and NE
are released by neurons directly to the target tissue they are referred
to as neurotransmitters. When released into the blood stream by the
adrenal gland, they are referred to as hormones. If secreted by neurons
into the blood stream, they are referred to as neurohormones.
Catecholamines exert their effects by binding to beta 1-3
adrenergic receptors, and to alpha 1 and 2 receptors (See Wilson, 2004
Exercise Endocrinology Principles and
Catecholamines). A receptor can be thought of as a receiving
station, which accepts the message carried by said hormone. In general,
beta receptors are stimulatory, while alpha receptors are inhibitory
(emphasis on generally as this is not always the case) (Wilson,
2004). For example, beta receptor stimulation initiates lipolysis (the
break down of fats), while alpha receptor stimulation, inhibits
lipolysis (Richterova, 2004, Stich, 2002, Riviere, 1989). This provides
an important mechanism of differential effects. A tissue with primarily
alpha receptors may experience inhibition, while a tissue with primarily
beta receptors may experience stimulatory effects (Mauriege et al.,
1987). Further, it has been proposed that obese individuals have a
higher concentration of alpha receptors than lean individuals. In this
context Stich et al. (2000) investigated the effect of administering an
alpha antagonist ( a chemical which blocks the ability of catecholamines
to bind to alpha receptors ) to obese and lean people during exercise.
Lean and obese participants were tested with and without the
antagonists. It was found that the obese had a 6 fold greater increase
in lipolysis (fat breakdown or catabolism ) than the lean individuals.
This suggests that they were experiencing more inhibition of lipolysis
from alpha receptors than lean individuals. However, as will be
discussed further, exercise as well as diet can actually cause
significant changes in receptor concentrations. Further, the nervous
system has direct alpha and beta influence, meaning it can selectively
target one aspect over another.
E and NE bind to receptors located on the membrane or outer
portion of a cell. The binding triggers a secondary messenger to carry
out the message into the cell. This is known as transduction, or the
path which connects a hormone to its effecter mechanism within a cell.
One of the primary ways E and NE work is through the cyclic adenosine
monophosphate (cAMP) secondary messenger system. Said hormones activate
cAMP, which then activate a protein kinase. A protein kinase is an
enzyme which adds a phosphate group to a protein, which has the effect
of activating or changing the effects of that protein. For example, when
epinephrine binds to beta 2 receptors on muscle, it activates cAMP,
which activates cAMP dependent protein kinase, which activates glycogen
phosphorylase ( Richter et al. 1981b, 1982). Glycogen phosphorylase is
responsible for the break down of glycogen (the body’s stored form of
carbohydrates) into glucose so that it can be used to form ATP. Studies
indicate that when the adrenal gland is removed that glycogenolysis is
lower in contracting muscles than when the adrenal gland is in tact
(Richter et al. 1981a; Sonne et al. 1985). However, both Arnall et al.
(1986) and Winder et al. (1987) found that rats who were administered
epinephrine, experienced the same amount of glycogenolysis even with
their adrenal glands removed, supporting its role in the process.
Catecholamines Effect on Fat Mobilization
Fatty acids are oxidized or used to form ATP through a process known as
beta oxidation. The first step to beta oxidation is the catabolism of a
triglyceride. A triglyceride is comprised of a glycerol backbone and
three fatty acids. The enzyme responsible for catalyzing this reaction
is known as hormone sensitive lipase (HSL). This has implications for
dieting. For example, Martins-Afferri et al. (2004) found that a low
carbohydrate diet reduced whole body lipolytic activity compared to a
balanced diet in rats. When studying the underlying biochemical
mechanisms, it was found that adipocytes had a 40 % reduced lipolytic
response to epinephrine and norephinephrine, compared to the balanced
diet group. Much of this is attributed to hormone sensitive lipase.
For example, in the balanced diet group catecholeamines stimulated a 50
% increase in HSL translocation ( its expression and activity in the
cell). However, the low carbohydrate group only showed a 20-25 %
increase in HSL activity, strongly suggesting HSL’s role in fat
metabolism, and its correlation to lowered lipolytic activity in
nutrient deficient diets. Once fatty acids are cleaved off of the
glycerol molecule, they must enter the mitochondria for further
catabolism. Transfer of fatty acids into the mitochondria is carried out
by the rate limiting enzyme carnitine transferase. Once inside they can
be utilized for energy (oxidized).
Fatty acids can come from circulating fatty acids and lipoproteins,
intramuscular stored lipid droplets (storage depot of triglycerides),
and adipose tissue. Fatty acids are released from adipose tissue, after
they have been broken down by hormone sensitive lipase. Lipoproteins are
large molecules comprised of proteins and lipids. They are too large to
enter either adipose or muscle tissue. In order to escort the fat into
the tissue, a rate limiting enzyme which lies on the capillary lining
layer called endothelium cleaves or breaks fatty acids off of the
lipoprotein (Eckel, 1989, Zechner, 1997). It then enters the tissue
through a ‘fatty acid transport protein;’ or if the fatty acid is small
enough it can diffuse into the cell. The enzyme that catalyzes this
process is known as lipoprotein lipase (LPL). The greater the
expression of LPL, the greater the tissues ability will be to take up
and either store, or oxidize fat.
Catecholamines increase the rate of fat break down by
acting on beta receptors in adipose and muscle tissue. Beta 1-3 are
acted on in adipose, while beta 2 are found in the musculature (See
Wilson, 2004
Exercise Endocrinology Principles and
Catecholamines). However, alpha receptors inhibit lipolysis.
Therefore the relative distribution of alpha and beta receptors on
certain regions of the body, will in large part determine where a
participant primarily stores fat, and how easily they metabolize it from
a region. In general however, the net whole body effect of E and NE is
increased lypolysis in adipose tissue and muscular tissue. Further, it
powerfully reroutes lipids in the blood stream towards muscle tissue for
oxidation, while inhibiting its uptake in fat tissue (Deshaies, 1993,
Eckel, 1996, Friedman, 1986. Pedersen, 1999).
Lipoprotein lipase is enhanced in skeletal muscle by a cAMP transduction
mechanism (Deshaies, 1993, Eckel, 1996, Friedman, 1986. Pedersen, 1999)
however it is inhibited in adipose tissue, causing the rerouting effect
discussed previously (Ball et. al, 1987). Ball et al. (1987) found that
the inhibition in adipose was due catecholamine’s ability to both
enhance degredation of LPL as well as decrease its synthesis. Further,
Eckel et al. (1996) found a significant increase in muscular LPL and LPL
mRNA concentration in the vastus lateralis (outer quad sweep ) after
administration of catecholeamines.
Catecholamines Effect on Glucose Utilization
Catecholamine’s counter regulatory actions on glucose are initiated by
an increase in NE during systemic hypoglycemia( low blood glucose
levels); however, to stimulate a full epinephrine response an additional
sharp decline in the livers glycogen stores must occur (Donovan et al.,
1991). For example Donovan et al. (1991) investigated the effects of
insulin induced hypoglycemia and liver depletion on NE and E secretion.
It was found that both E and NE rose significantly from resting levels
in the hypoglycemia and lowered liver glycogen condition. In a second
condition, a glucose infusion maintained normal liver glycogen stores.
It was found that NE rose as before, but that the rise in E was 40 %
less than the liver depleted condition. This is significant because at
low levels Epinephrine can powerfully stimulate lipolysis (Romijn,
1993). However, Galster et al. (1981) demonstrated that epinephrine’s
effect on the liver, in terms of counter regulation (I.E. stimulating
the liver to increase glucose output) requires double its concentration
in the blood plasma than to stimulate lipolysis. This suggests that
catecholamine’s counter regulatory actions are secondary to its
lipolytic effects. Though this is the case, its hyperglycemic actions
increase during high intensity exercise, when its secretion is
maximized, and glucose is rapidly being depleted by the working
musculature. Its effects are elicited through the following mechanisms:
hepatic and muscular glycogenolysis (Richter et al. 1981b, 1982);
hepatic gluconeogenesis ( Chu et al, 1996, 1997a, 1997b); auxiliary
(supplementary) actions on other counter regulatory hormones; and
suppression of the regulatory hormone insulin ( Lee, 1997).
Glycogenolysis is the process by which glycogen is broken down into
molecules of glucose, and is mediated by the enzyme glycogen
phosphorylase. This process acts in the liver to increase hepatic
glucose release, and therefore, promotes hyperglycemia. In the liver,
catecholamines glycogenolytic effects are unique, in that they act on
both beta (Steiner et al, 1985) and alpha(Kmiec et. al, 1990)
adrenergic receptors. Beta A-R’s activate a cAMP-dependent protein
kinase (explained earlier), which subsequently phosphorylates (adds a
phosphate group) the enzyme phosphorylase, effectively activating it,
and thus, increasing glycogenolysis. While alpha receptors utilize
calcium to stimulate glycogenolysis (Althaus-Salzmann et al. 1980).
Calcium can act as a secondary messenger on numerous occasions—for
instance, calcium release in a muscle for the initiation of muscular
contractions, can also cause other stimulatory effects such as
activation of GLUT-4 receptors during exercise (Wilson, 2003, Wilson and
Venom; 2004), which carries glucose into the muscle. In muscles,
epinephrine stimulates glycogenolysis by binding to beta receptors.
Gluconeogenesis is the formation of glucose from
non-glucose molecules such as lactate, pyruvate, and amino acids. This
process occurs plentifully in the liver, and helps to preserve stable
blood glucose levels. Catecholamines have both direct and indirect
effects on gluconeogensis. They directly stimulate gluconeogensis
through activating gluconeogenic enzymes (Kessar, 1990). They indirectly
stimulate this process through up regulation of other counter regulatory
hormones such as glucagon. They also help provide the raw precursors for
gluconeogensis through stimulation of the production of lactic acid,
pyruvate, and glycerol. Glycolysis is the first stage for the
utilization of ATP formation, when glucose is the substrate. The end
products of glycolysis are either pyruvate, or lactic acid (see Wilson
and Venom 2004
Energetic Transference Occurring in the
Biosphere Part II for more information). By stimulating
glycolysis, E and NE increase the release of gluconeogenic precursors,
if they diffuse out of the musculature and into the blood stream for
conversion back to glucose in the liver.
Lastly, catecholamines suppress insulin secretion by
binding to inhibitory alpha receptors ( Lee, 1997, Sieg et al., 2004,
Sharp, 1996, Debuyser, 1991, Nilsson et al, 1988 ). This inhibition
allows an unopposed release of fuels for use during exercise in the form
of gluconeogenesis, lipolysis, and glycogenolysis.
Glucagon’s Effect on Nutrient
Utilization During Exercise
The pancreas
contains a group of cells known as the islets of langerhans. These
cells can secrete glucagon, insulin, pancreatic polypeptide, and
somatostatin. More specifically, glucagon is secreted from alpha cells,
insulin by beta cells, pancreatic polypeptide by pp cells, and
somatostatin from delta cells.
The liver is a
major store house of fuels, and therefore plays a highly substantial
role in exercise. To accommodate its function, a portal system was
designed which carries hormones secreted by the pancreas almost directly
into the liver. A portal system can be defined as a circulatory system
which contains two beds of capillaries. In the body, blood is
circulated to and through most organs in the following fashion:
1. Blood is pumped from the heart via the left ventricle through the
aorta( and further elastic arteries), then to muscular arteries,
followed by arterioles.
2. Blood is then delivered to a bed of capillaries, where nutrient
exchange occurs.
3. Blood then enters venules, small veins, and finally large veins,
which end in the Vena Cava which carries blood back to the right
ventricle.
However, the liver receives two sources of blood. For nourishment, it
receives blood from the heart via the hepatic arteries. Secondly it
receives it from veins which carry blood that has just passed through
capillaries of organs involved in digestion, such as the stomach, small
intestine, large intestine, and pancreas. This blood which previously
coursed through the digestive organs, rather then going straight to the
heart, enters the ‘hepatic portal vein’ which then meets capillaries in
the liver where nutrient exchange occurs again. Therefore all the
nutrients from the GI tract, must first be filtered through the liver.
As a consequence, the liver is exposed to much higher hormone
concentrations then other organs. As such, it is subject to the law of
mass action, which states that a reaction is directly proportional to
the concentration of reactants. Therefore the liver is affected to a
greater extent than other organs by the secretion of pancreatic
hormones.
Glucagon is a
counter regulatory hormone in that its overall effect is hyperglycemia.
It is stimulated by hypoglycemic conditions, particularly when blood
glucose levels drop below 50 milligrams per deciliter, and blocked at
150 milligrams per deciliter.
(Galbo et al.
1977). Galbo et al. (1977) found that the effect of exercise on
glucagons secretion was highly diminished when participants were fused
with glucose. Further, catecholamines stimulate its release (Knudtzon,
1984) Insulin, directly inhibits glucagon, and when lowered glucagon
becomes relatively greater in its response to its secretagogue.
Secretagogues are defined as substances which stimulate the secretion of
a hormone. Amino acids serve as secretagogues for glucagon (Kraus-Friedmann,
1984).
This hormone, promotes glycogenolysis through the activation of protein
kinase A through a cAMP mechanism( Jiang and Zhang, 2003 ) . When
inactive, or dephosphorylated, the enzyme which breaks down glycogen is
known as glycogen phosphorylase B. When phosphorylated it is known as
glycogen phosphorylase A, which explains the name given to protein
kinase A.
Note:
In more detail protein kinase A, activates glycogen phosphorylase kinase,
which then phosphorylates glycogen phosphorylase (Jiang and Zhang,
2003)
Phosphorylase A
also phosphorylates the enzyme responsible for glycogen synthesis known
as glycogen synthase. Unlike glycogen phosphorylase, glycogen synthase
is inactivated when phosphorylated (Roach, 1990), which again
facilitates more glucose availability for exercise (Jiang and Zhang,
2003 ). Further, Glucagon stimulates the enzyme glucose 6 phosphatase
(Barthel and Schmoll, 2003). Glucose 6 phosphatase will be discussed in
the insulin section of this article.
Glucagon works with E and NE to stimulate the Cori cycle (Kusaka and Ui,
1977) The Cori cycle begins as glycogen phosphorylase breaks down
glycogen into glucose. Glucose is then released into the blood plasma,
where it enters skeletal muscle through specialized receptors known as
GLUT-4 receptors. As previously stated, the glucose enters the
enzymatic pathway glycolysis and can form the gluconeogenic substrates
pyruvate and lactate. If they enter the circulation and reach the
liver, they may be transformed back into glucose. Glucagon facilitates
this process through specific gluconeogenic enzymes. One such enzyme is
known as phosphoenolpyruvate carboxykinase (PEPCK) which is important in
the formation of glucose. It takes a substrate from the krebs cycle (
Oxaloacetic acid or OAA) and converts it to phosphoenolpyruvate ( this
is the substrate in glycolysis that is actually itself converted to
pyruvate)(Jiang and Zhang, 2003). Current evidence suggests that
glucagon actually increases PEPCK mRNA in the cell (Beale, 1984,
Iynedjian, 1985) (mRNA carries the nuclear instructions for building
PEPCK in the cell, the higher the concentration of these ‘instructions’
the more PEPCK that can be built) through a protein kinase A mechanism (Jiang
and Zhang, 2003).
Think of
gluconeogenesis as a reversal of glycolysis. For example, in glycolysis
one substrate known as fructose-6 phosphate is turned into
fructose-1,6-bisphosphate by the addition of a phosphate group. In
gluconeogenesis, this process is reversed, such that the phosphate group
is again removed (known as hydrolysis) to again form fructose-6
phosphate. The enzyme responsible for this dephosphorylation is known
as Fructose-1,6-bisphosphatase. ‘Phosphatase enzymes are removers of
phosphate groups. Glucagon is again postulated to stimulate the enzyme
through use of protein kinase A (Jiang
and Zhang, 2003).
Additionally
glucagon facilitates the glucose alanine cycle through increasing the
livers upake of amino acids(Kraus-Friedmann, 1984). In order for amino
acids to participate in the gluconeogenic process, the nitrogen
containing group must first be removed from the molecule, so that the
carbon skeleton can be used. This can occur through oxidative
deamination, or transamination. In Oxidative Deamination, the nitrogen
group is removed directly. For example the amino acid glutamate and the
coenzyme NAD+ enter the enzymatic complex glutamate dehydrogenase,
forming alpha keto glutarate + NADH + H+. Alpha keto glutarate is a
substrate which can be utilized for energy in the krebs cycle. The
Krebs cycle is the second pathway involved in the oxidation of glucose (
For more information on NAD+ see Wilson and Venom Energetic Transference
in the Biosphere ). However, in transamination, the nitrogen group is
transferred to an intermediate of the krebs cycle. Alanine is a primary
amino acid used in gluconeogenesis. In the liver, transamination of an
amino group from alanine to alpha keto glutarate produces pyruvate and
glutamate. Pyruvate then can be converted to glucose and complete the
glucose alanine cycle.
Glucagon also has a lipolytic role, in that it suppresses the lipogenic
enzyme known as Acetyl Co-Enzyme A Carboxylase (ACC) (Girard et al.,
1994). ACC catalyzes the reaction which produces malonyl co enzyme
A. Malonyl coA is an important substrate in the biosynthetic pathway
which forms triglycerides. It acts to inhibit carnitine transferase
from escorting fatty acids into the mitochondria.
Insulin’s Role in Nutrient Utilization during Exercise
Generally, insulin antagonizes the counter regulatory hormones. In
fact, many of the effects of counter regulatory hormones are indirect
and yet extremely powerful in their ability to suppress insulin
secretion. For example, when catecholamines suppress this hormone, fat
lipolysis is increased exponentially.
Insulin opposes
counter regulatory hormones by the degradation of cAMP. It stimulates
this process by activating the enzyme known as phosphodiesterase which
degrades cAMP. Enoksson et al. (1998) found that hyperinsulimea
decreased glycerol content in adipose by 40 % and in muscle tissue by 33
%( glycerol is a bi product of fat lipolysis or breakdown). However,
when participants were administered a phosphodiesterase blocker, the
decrease in glycerol content was counteracted. Insulin also stimulates
the dephosphorylation of enzymes(or lowers the activity of
phosphorylating protein kinases), thereby deactivating them. As an
illustration, glucagon and epinephrine stimulate the phosphorylation of
phosphorylase to its active A form, while insulin causes its
dephosphorylation to inactive B form. This dephosphorylation process
essentially negates cAMPs phosphorylating actions. Gabbay and Lardy
(1984) investigated the effect of insulin on the breakdown of glycogen
by blocking the action of phosphodiesterase. It was found that even
with maintained cAMP levels that insulin still antagonized its actions
on activating glycogen phosphorylase. Gabbay and Lardy (1987) suggest
that this occurs as insulin lowers cAMP dependent protein kinase’s
(which will phosphorylate glycogen synthase) affinity for cAMP.
Amino acids
stimulate insulin, as well as glucose levels above 80 mg per deciliter
in terms of plasma concentration. Circulating glucose binds to Glut-2
receptors on the beta cells of the islets. An enzyme known as
hexokinase (discussed shortly) or glucokinase then adds a phosphate
group to the glucose molecule. This stimulates potassium channels in
the cell to close (Hellman et al., 1994, Gylfe et al., 1998,
Sato et al., 1999).
The closure is linked to various mechanisms, which appear to be linked
to glucose metabolism (Meglasson and Matschinsky, 1986, Meglasson,
1990). For example, glucose increases the amount of ATP in the cell
(ATP/ADP ratio). ATP is postulated to directly close K+ channels (these
are known as ATP sensitive K+ channels – Sieg et al., 2004). The cell is
slightly negative relative to the outside or extra cellular
environment. Potassium leaking out of the cell through channels ( i.e.
positive charge leaving) helps this process. However, when potassium
channels close, the positive charge is trapped in the cell, making the
intracellular environment more positive. Therefore the polarity or
separation of charge in the cell relative to the outside of the cell is
dissipated. That is, the inside of the cell loses its negativity
relative to the outside. This is known as depolarization. Within the
cell are storage bins for calcium known as the sarcoplasmic reticulum.
They are stimulated to release calcium when the cell becomes positive.
Calcium binds to insulin vesicles and allows them to bind to the cell
membrane for exocytosis. The parasympathetic nervous system can also
directly stimulate insulin release, through its neurotransmitter
acetylcholine (Al-Majed, 2004). As mentioned earlier, catecholamines
inhibit insulin release
(Lee, 1997, Sieg et al., 2004, Sharp, 1996, Debuyser, 1991, Nilsson et
al, 1988).
In this context, Sieg et al. (2004), provided evidence that epinephrine
can activate a separate pool of K+ channels, which hyperpolarizes (makes
it more polar) beta cells, making it harder for them to be stimulated to
depolarize.
Insulin inhibits
lipolysis at low concentrations by increasing phosphodiesterase (Enoksson
et al. 1998, Hagstrom-Toft, 1995). This has the effect of degrading
cAMP. Therefore cAMP cannot activate the protein kinase responsible for
the activation of hormone sensitive lipase. At extremely high
concentrations insulin inhibits fatty acid oxidation as well as the
formation of triglycerides by stimulating the synthesis of (Saha et al.,
1995, Ruderman, 1999).
Insulin inhibits
glucose output by the liver in several ways. First, as discussed it
inhibits glycogen phosphorylase. Secondly, it antagonizes the synthesis
of the enzymes PEPCK and
fructose-1,6-bisphosphatase
( Barthel and
Schmoll, 2003). Thirdly insulin inhibits a key enzyme known as
glucose-6-phosphatase ( Barthel and Schmoll, 2003). In order to enter a
cell, glucose must first be phosphorylated. However, the phosphate
group contains a charge which traps the glucose in the cell. The
glucose-6-phosphatase enzyme effectively removes this phosphate, which
allows the glucose to enter the blood plasma. Muscle tissue lacks this
enzyme ( Wilson 2003,
Pre Contest Week - An In Depth
Analysis), however liver is specialized with it, to
elicit a hyperglycemic effect.
Interestingly
enough, glycolysis is stimulated by insulin (Hamer and Dickson, 1990, Probst et al. 1985, Probst et al.
1989, Meacci et al., 1993). The
main point is to
utilize glucose as fuel, as opposed to lipids when glucose is more
plentiful, such as during post absorptive (after eating) stages. For
example, Kelley et al. (1990) found that hyperinsulemia (high insulin
levels) increased the respiratory exchange ratio (RER) in the leg from
.74 to .99. The RER measures the rate of glucose or fat metabolism.
The closer the RER is to 0.7 the more fat is relied on, however the
closer it is to 1.0, the greater the reliance on glucose is. Therefore
an increase in RER, demonstrates that insulin may increase carbohydrate
utilization. It stimulates glycolysis through increasing the activity
of its rate limiting enzymes phosphofructokinase (PFK) (Silva, 2004)
pyruvate dehydroginase (PDH) (Johnson, 2003) as well as hexokinase (Hamer
and Dickson, 1990).
Further, insulin stimulates glucose uptake by triggering the
translocation of GLUT-4 receptors (Elmendorf and Pessin, 1999, Martin et
al., 1999) and up regulating hexokinase and glucokinase
(what hexokinase is called in the liver)( O'Keefe et al., 2004). Recall
that hexokinase is involved in the first step of glucose uptake into the
cell through its phosphorylation. This again entraps the glucose into
the cell.
Hexokinase (glucokinase
in the liver) is a fascinating enzyme. The isoform (particular subtype)
of hexokinase differs in skeletal muscle, and is meant to take up
glucose at lower levels of glucose concentration(Tsao, 1996), such as
during exercise, while glucokinase is specialized at taking up glucose
after a meal, or during higher blood sugar levels (Kietzmann et al.,
1998). The difference lies in a concept known as KM.
KM can be defined as the concentration needed of a substrate to saturate
half of the enzymes available in a solution. If a KM is high, then a
high concentration of a substrate is needed to saturate the enzyme. The
reaction rate is directly proportional to the number of enzymes
occupied. While the level of saturation refers to the percentage of
enzymes occupied. A low KM means that a small concentration of
substrate is needed for saturation or to cause a high reaction rate.
Skeletal muscle tissue’s hexokinase has a low KM and can therefore
facilitate glucose uptake at low concentrations, while the liver has a
high KM conducive to postprandial states.
Aside from
inhibiting fat lipolysis and oxidation, insulin directly stimulates
lipogenesis or the formation of lipids. As stated, malonyl co enzyme A
is the first step in the biosynthetic pathway for lipogenesis. Insulin
stimulates its formation by increasing the synthesis of ACC (Saha et
al., 1995, Ruderman, 1999). It also stimulates fat synthesis by
increasing the production of NADP and NADPH. In review, NAD+ and NADH
are coenzymes involved in glucose oxidation. These serve to oxidize
molecules. Oxidation is a process which takes electrons from other
molecules. The electrons are then taken to the electron transport
chain, and used to form ATP
(Again for an in depth discussion on this topic, see Wilson and Venom,
2004 - Energetic Transference in the Biosphere 1-3). Therefore NAD+ and
NADH are used for catabolic processes which release energy. NADP and
NADPH are identical to NAD+ and NADH with the exception of an added
phosphate group (Pi). They have the opposite function, in that they
serve to reduce molecules
(Mathews, et al, 1999).
Reduction is a process which adds electrons to atoms or molecules. This
is why the formation of molecules such as various lipids is known as
reductive biosynthesis. Insulin also increases production of the
molecule alpha glycerol phosphate, which again serves as the backbone of
a triglyceride.
This pancreatic
hormone accomplishes the above increases through a mechanism known as
the pentose monophosphate shunt (Gupte et al., 2005, Ammon, 1983). The
Pentose Monophosphate pathway, is a parallel pathway to glycolysis
(Mathews, et al, 1999).
Insulin increases enzymes involved in this pathway, which acts to accept
glucose as an alternative to glycolysis. This is why it is called a
shunting mechanism. The primary purpose of this pathway is the
production of alpha glycerol phosphate, NADP, and NADPH (Mathews,
et al, 1999).
Further, insulin reroutes fatty acids towards adipose tissue, and away
from muscle tissue by the opposite mechanism of the catecholamines in
that it stimulates adipose LPL, while inhibiting muscular LPL. Picard
et al. investigated the effect of a high carbohydrate meal on LPL
expression in adipose and muscle tissue in the soleus. It was found
that LPL in adipose increased 65 percent, while decreasing 25 % in the
soleus. To confirm that insulin was involved, a mechanism was used to
block insulin secretion. This negated the effect of the high
carbohydrate meal, suggesting that insulin has an adipose specific
lipogenic partitioning effect after its concentration has risen. A
further anabolic action of insulin is to activate the enzyme glycogen
synthase in muscle, adipose, and liver tissue( See Wilson, 2003,
Pre Contest Week - An In Depth Analysis).
Glycogen synthase is responsible for the synthesis of glycogen from
glucose residues. It is activated through dephosphorylation, which is
unlike other enzymes mentioned.
A further
lipogenic effect of insulin is to increase cellular uptake of glucose
into adipose tissue by increasing expression of glucose receptors.
Glucose taken up by adipose is used to form alpha glycerol phosphate.
Protein metabolism
is positively effected by insulin, in that it increases amino acid
update into muscle, inhibits protein degradation, and triggers the
translation of proteins (the synthesis of proteins) ( Maroni, 1986,
Wilkening, 1994, Henriksen, 1991).
Conclusion
In conclusion,
counteregulatory hormones appear to facilitate the release of substrates
for the elevated energetic needs of exercise. Insulin antagonizes these
effects, and places the body in an anabolic state. A clear
understanding of these processes will enhance the reader’s ability to
manipulate them through various exercise modalities.
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