5.
0 HORMONAL CONTROL OF CARBOHYDRATE METABOLISM
Introduction:
Variety of hormones and other molecules regulate the carbohydrates
metabolism. Some of these have already been cited in previous sections.
The appropriate functions of the body are dependent on precise control of
the glucose concentration in the blood. 70-90 mg/100 mlisthe normal
fasting level of glucose in the blood. A condition called
hyperglycemia results if the concentration of glucose in blood is too high
(above 120 mg/100 ml). Hyperglycemia may temporarily exist as a result
of eating a meal rich in carbohydrates.When the concentration of glucose
is too low (below 70 mg/100 ml) the condition is called as hypoglycemia.
Hypoglycemia is characterized by general weakness, trembling,
headache,profuse perspiration, drowsiness, rapid heartbeat, and possible
loss of consciousness.
The liver and skeletal muscle self-regulate carbohydrate metabolism in
basically the same way as do other cells. Yet, these cell types are also
required to respond to external signals by altering their carbohydrate
metabolism. These two tissues, along with adipose tissue (which is
primarily involved in lipid metabolism), act as the major regulators of
nutrient levels in circulation during most metabolic conditions.
OBJECTIVES
To understand the significance of regulation of carbohydrate metabolism
by hormones to maintain the body homeostasis
To appreciate the regulatory mechanisms that play an important role in
maintaining the blood glucose level
To understand the responses of the body to different energy utilisation
conditions.
The regulation has two goals: 1) maintenance of normal circulating
glucose levels in the face of changing conditions, and (when necessary) 2)
support of physical activity. These tissues are tightly controlled by
external signals: the levels of the pancreatic hormones insulin and
glucagon, the adrenal hormones epinephrine and cortisol. In the case of
skeletal muscle, the neuronal signals govern muscle contraction. In
general, glucagon and epinephrine result in phosphorylation of regulatory
enzymes, whereas insulin results in removal of the phosphate; calcium
usually increases phosphorylation (one major exception is the
mitochondrial enzyme pyruvate dehydrogenase, wherein calcium
stimulates phosphate removal).
Regulation of glycolysis by pyruvate kinase
Some of the hormones, especially cortisol and insulin, and to a lesser
extent glucagon, alter the amounts of the enzymes present in the cell.
The phosphorylation and dephosphorylation events occur quickly, though
effects on enzyme concentration are relatively slow processes. The cells of
the liver and muscle must also use the same feedback regulatory
metabolites as do “normal cells”; these effects interact with the hormonal
signals to result in the overall metabolic changes that occur within these
cells.
The two diagrams below summarize the control of the various
pathways by metabolic and hormonal effects in liver and in skeletal
muscle.
Lets now see the regulation at various conditions of the body
5.1 Fed state During absorption of nutrients from the digestive tract,
circulating glucose levels typically become somewhat elevated. This
results in decreased glucagon levels and increased insulin. High insulin
levels result in increased glucose uptake in skeletal muscle and adipose
tissue (as a direct result of increased glucose transport due to the
movement of the transporters to the membrane). The muscle is capable
of dramatic increases in glucose uptake, a specialization that is related to
its increased glucose requirements during muscle contraction; the
organism uses this ability to rapidly deal with sudden increases in plasma
glucose. The glycogen storage in liver and muscle is induced by insulin. It
also increases glycolysis in liver. The increase in liver glycolysis has two
purposes: 1) it decreases glucose availability, and 2) it increases the
amount of intermediates that are used for biosynthetic reactions. Hexose
monophosphate pathway activity is also increased by insulin by increasing
the concentration of glucose-6-phosphate dehydrogenase; this also
increases both glucose breakdown and the cellular capacity for
biosynthetic processes. The net effect of these processes is the removal of
glucose from circulation to be stored, used for energy, or used to produce
other biologically relevant compounds.
The effect of insulin on the various metabolic pathways operating is
shown in the figure
5. 2 Exercise During exercise, the liver and muscle must respond
somewhat differently to the same external signals. The responses are
facilitated by three physiological signals: 1) increased epinephrine, 2)
increased calcium in muscle, and 3) decreased insulin levels. In both
muscle and liver there is an increase in glycogen breakdown. This is the
result of phosphorylation of both glycogen synthase and glycogen
phosphorylase in both tissues; phosphorylase is stimulated by
phosphorylation, while glycogen synthase is inhibited. The glucose is
released into the circulation by the liver; the muscle takes up glucose
from circulation, and also uses the glucose released from its own glycogen
stores. One method of simultaneously altering both gluconeogenesis and
glycolysis is to alter fructose-2,6-bisphosphate levels. The fructose-2,6-
bisphosphate stimulates phosphofructokinase and inhibits fructose-
bisphosphatase; fructose-2,6-bisphosphate therefore simultaneously
stimulates glycolysis and inhibits gluconeogenesis. The exercising muscle
must be able to do glycolysis; in contrast, during exercise, the liver must
turn off glycolysis and turn on gluconeogenesis. These contrasting events
are mediated by different isozymes of the PFK-2/FBPase-2 protein.
Phosphorylation of liver PFK-2/FBPase-2 results in decreased fructose-
2,6-bisphosphate levels (because it alters the enzyme conformation to
favor the phosphatase activity). In contrast, phosphorylation of the
muscle PFK-2/FBPase-2 isozyme results in an increase in the fructose-
2,6-bisphosphate levels, and thus in an increase in the muscle capacity
for glycolysis.
As with other biochemical pathways, hormones affect
gluconeogenesis by varying the concentrations of allosteric effectors and
the key rate-determining enzymes. As stated previously, glucagon
depresses the synthesis of fructose- 2,6-bisphosphate, which releases the
inhibition of fructose-1,6-bisphosphatase, and thereby inactivates the
glycolytic enzyme pyruvate kinase. Hormones also affect gluconeogenesis
by altering enzyme synthesis. For example, cortisol, a steroid hormone
produced in the cortex of the adrenal gland that facilitates the body’s
adaptation to stressful situations stimulates the synthesis of
gluconeogenic enzymes. In conclusion, insulin action leads to the
synthesis of new molecules of glucokinase, PFK-1 (SREBP1c-induced), and
PFK-2 (glycolysis favoured). Insulin also depresses the synthesis (also via
SREBP1c) of PEP carboxykinase, fructose- 1,6-bisphosphatase, and
glucose-6-phosphatase. The action of glucagon leads to the synthesis of
additional molecules of PEP carboxykinase, fructose-1,6- bisphosphatase,
and glucose-6-phosphatase (gluconeogenesis favoured). The hormones
that regulate glycolysis and gluconeogenesis alter the phosphorylation
state of certain target proteins in the liver cell, which in turn modifies
gene expression. The vital point to remember is that insulin and glucagon
have opposing effects on carbohydrate metabolism. The direction of
metabolite flux, (i.e., whether either glycolysis or gluconeogenesis is
active) is largely determined by the ratio of insulin to glucagon. The
insulin/glucagon ratio is high after a carbohydrate meal and glycolysis in
the liver predominates over gluconeogenesis.
After a period of fasting or following a high-fat, low-carbohydrate
meal, the insulin/glucagon ratio is low and gluconeogenesis in the liver
predominates over glycolysis. The availability of ATP is the second
significant regulator in the reciprocal control of glycolysis and
gluconeogenesis in that high levels of AMP, the low-energy hydrolysis
product of ATP, increase the flux through glycolysis at the expense of
gluconeogenesis, and low levels of AMP increase the flux through
gluconeogenesis at the expense of glycolysis. Even though control at the
PFK-1/fructose- 1,6-bisphosphatase cycle would appear to be sufficient
for this pathway, control at the pyruvate kinase step is key because it
permits the maximal retention of PEP, a molecule with a very high
phosphate transfer potential.
The liver also contains an isozyme of pyruvate kinase that is inhibited by
phosphorylation. The phosphorylation does not affect muscle pyruvate
kinase. Exercising muscle tends to release some lactate into circulation;
the liver uses this as substrate for gluconeogenesis. This exchange of
materials between the liver and the muscle is known as the Cori cycle.
The net effect of these metabolic changes is increased glucose release by
the liver and uptake and utilization by the muscle to support generation of
mechanical energy by the muscle.
Cori Cycle:
During muscle contractions, ATP is constantly being used to supply
energy and more ATP is produced to replenish supplies.At first glycolysis
produces pyruvic acid which is then converted into acetyl CoA and is
metabolized in the citric acid cycle to make ATP using the electron
transport chain.If muscular activity continues, the availability of oxygen
for use at the end of the electron transport chain becomes the limiting
factor and the cells soon exhaust their supplies of oxygen. When this
occurs, the citric acid cycle is inhibited and causes pyruvic acid to
accumulate.However, glycolysis continues even under anaerobic
conditions even though the citric acid cycle works only under aerobic
conditions.
Figure below shows that epinephrine at (1) stimulates the enzymes to
work on glycogen as discussed in the above panel. Glycogenolysis at (2)
is stimulated to make more glucose-6-phosphate.When the cells become
anaerobic, glycolysis (3) continues if pyruvic acid is converted to lactic
acid (4). Remember that the synthesis of lactic acid requires NADH from
Step 5 in glycolysis and produces NAD+so that Step 5 can continue.The
formation of lactic acid buys time and shifts part of the metabolic
burden to the liver.Even though not as much ATP can be furnished by
glycolysis alone, it is an important source of ATP when muscular activity
continues for any extent of time. The concluding limiting factor in
continued muscular activity is the build up of lactic acid. The lactic acid
ultimately produces muscular pain and cramps which force discontinuation
of activity. Generally before this happens and after activity has finished,
lactic acid diffuses out of the muscle cells and into the blood where it
enters the liver.
The body is very efficient in that lactic acid is sent in the blood (5) to the
liver which can convert it back to pyruvic acid (6) and then to glucose
through gluconeogenesis (8). The glucose can enter the blood (9) and be
carried to muscles and instantly used. If by this time the muscles have
stopped activity, the glucose can be used to reconstruct supplies of
glycogen through glycogenesis (10). This recycling of lactic acid is
referred to as the Cori Cycle. This Cori cycle also functions more
efficiently when the muscular activity has ceased. At this time the oxygen
debt can be made up so that the citric cycle and electron transport chain
also initiate to function again. In order for most of the lactic acid to be
converted to glucose, some must be converted to pyruvic acid and then to
acetyl CoA (7). The citric acid cycle and electron transport chain must
provide ATP to "fuel" the gluconeogenesis of the remainder of the lactic
acid to glucose.
5.3 Starvation During starvation, insulin levels decrease whereas
glucagon and cortisol levels increase resulting in a variety of metabolic
changes. One major effect is the breakdown of muscle protein to provide
amino acids for gluconeogenesis. The liver responds by increasing
glycogen breakdown and by increasing glucose release. It also responds
by greatly increasing gluconeogenesis, using amino acids released by the
muscle as substrates.The net effect is the release of glucose from the
liver for the use by other tissues, with breakdown of muscle fat to supply
the requisite energy and intermediates.
5. 4. Insulin deprivation Diabetes mellitus is a relatively common
disorder resulting either from destruction of the cells that release insulin
or from lack of response by the tissues to insulin. The absence of insulin
action results in a condition that is similar to starvation; tissues are
broken down to provide substrates for liver gluconeogenesis. The liver
then works very hard to produce glucose to release into circulation,
raising plasma glucose levels to concentrations that have deleterious
effects. This effect is exacerbated by the fact that the individual typically
continues to eat, and therefore absorb nutrients, and by the fact that the
skeletal muscle and adipose tissue require insulin for uptake of glucose.
The net effect is a dramatic increase in plasma glucose concentration,
because the liver is releasing glucose while the other tissues are not
taking up glucose and are performing reduced levels of glycolysis.
Conclusion
Most cells are capable of regulating their carbohydrate metabolism based
on their current energy necessities. This is attained by feedback inhibition
or stimulation of regulatory enzymes by various metabolites. The
important metabolites involved in regulation of carbohydrate metabolism
include ATP, NADH, glucose-6- phosphate, citrate, and fructose-2,6-
bisphosphate. Many cell types respond to hormonal and neuronal signals
that allow the coordination of metabolism at the level of the entire
organism. For carbohydrate metabolism, the liver and skeletal muscles
have the most important roles. The liver either takes up glucose for
storage in the form of glycogen, or releases glucose for use by other
tissues. The muscle takes up glucose for storage or for conversion to
mechanical energy; it can release free amino acids derived from protein
breakdown to act as substrates for liver gluconeogenesis. Both synthesis
and degradation are controlled through a complex mechanism involving
insulin, glucagon, and epinephrine, as well as allosteric regulators.
Glucagon is released from the pancreas when blood glucose levels drop in
the hours after a meal. It binds to receptors on hepatocytes and initiates
a signal transduction process that elevates intracellular cAMP levels. camp
increases the original glucagon signal and initiates a phosphorylation
cascade that leads to the activation of glycogen phosphorylase along with
a number of other proteins. Within seconds, glycogenolysis leads to the
release of glucose into the bloodstream. When occupied, the insulin
receptor becomes an active tyrosine kinase enzyme that causes a
phosphorylation cascade that ultimately has the opposite effect of the
glucagon/cAMP system: the enzymes of glycogenolysis are inhibited and
the enzymes of glycogenesis are activated. Insulin also increases the rate
of glucose uptake into several types of target cells, but not liver or brain
cells. Emotional or physical stress releases the hormone epinephrine from
the adrenal medulla. Epinephrine stimulates glycogenolysis and inhibits
glycogenesis. In emergency conditions, when epinephrine is released in
relatively large quantities, enormous production of glucose provides the
energy required to manage the situation.
