Integration of

Metabolism
By:
Dr/ Mahmoud G. Eldeib
Lecturer of biochemistry and molecular biology
The co-ordination between three metabolites (carbohydrates, lipids
and proteins) called Integration Of Metabolism.

• Significance of Integration of metabolism:

• It ensures a supply of suitable fuel for all tissues, at all the time (from
the fully fed state to the totally starved state)
Four major organs play a dominant role in fuel metabolism:
➢Liver
➢Adipose
➢Muscle
➢brain.
• These tissues contain unique sets of enzymes, such that each organ is
specialized for the storage, use, or generation of specific fuels.
• These tissues do not function in isolation, but rather form part of a
network in which one tissue may provide substrates to another, or
process compounds produced by other organs.
• The integration of energy metabolism is controlled primarily by the
actions of two peptide hormones: insulin and glucagon, with the
catecholamines epinephrine and norepinephrine playing a
supporting role.

• Changes in the circulating levels of these hormones allow the body to

store energy when food is available in abundance, or to make stored
energy available.
 INSULIN
Insulin is a polypeptide hormone produced by the β cells of the islets of
Langerhans of the pancreas.

Regulation of insulin secretion

1. Stimulation of insulin secretion:
insulin secretion is increased by:
a) Glucose:. Ingestion of glucose or a carbohydrate-rich meal leads to a rise
in blood glucose, which is a signal for increased insulin secretion (as well as
decreased glucagon synthesis and release).
Glucose is the most important stimulus for insulin secretion.
[Note: Glucose also increases expression of the gene for insulin.
b) Amino acids: Ingestion of protein causes a transient rise in plasma amino
acid levels, which, in turn, induces the immediate secretion of insulin.
c. Gastrointestinal hormones: Most gastrointestinal hormones favor
insulin release.
• The intestinal peptides cholecystokinin and gastric-inhibitory
polypeptide (glucose-dependent insulinotropic peptide) increase
insulin secretion in response to oral glucose, and so are referred to as
“incretins.”
• They are released from the small intestine after the ingestion of food
and cause an anticipatory rise in insulin levels.
• This may account for the fact that the same amount of glucose given
orally induces a much greater secretion of insulin than if given
intravenously.
2. Inhibition of insulin secretion:
The synthesis and release of insulin are decreased when there is a
deficiency of dietary fuels, and also during periods of stress (for
example, fever or infection).

• These effects are mediated primarily by epinephrine, which is

secreted by the adrenal medulla in response to stress, trauma, or
extreme exercise. Under these conditions, the release of epinephrine
is controlled largely by the nervous system.
Metabolic effects of insulin
Effects on carbohydrate metabolism:
❖ The effects of insulin on glucose metabolism promote glycolysis in
most prominent three tissues: liver, muscle, and adipose.
❖In the liver and muscle, insulin increases glycogen synthesis.
❖In the muscle and adipose, insulin increases glucose uptake by
increasing the number of glucose transporters (GLUT-4) in the cell
membrane.
❖In the liver, insulin decreases the production of glucose through the
inhibition of glycogenolysis and gluconeogenesis.
Effects on lipid metabolism: .
❖Decreased triacylglycerol degradation: Insulin decreases the level of
circulating free fatty acids by inhibiting the activity of hormone- sensitive
lipase that degrades triacylglycerol in adipose tissue. Insulin acts by
promoting the dephosphorylation and, hence, inactivation of the enzyme.
❖Increased triacylglycerol synthesis: Insulin increases the transport and
metabolism of glucose into adipocytes, providing the substrate glycerol 3-
phosphate for triacylglycerol synthesis. Insulin also increases the
lipoprotein lipase activity of adipose tissue by increasing the enzyme's
synthesis, thus providing fatty acids for esterification.

Effects on protein synthesis

In most tissues, insulin stimulates the entry of amino acids into cells, and
protein synthesis.
 GLUCAGON
• Glucagon is a polypeptide hormone secreted by the α cells of the
pancreatic islets of Langerhans.
• Glucagon, along with epinephrine, cortisol, and growth hormone (the
“counter-regulatory hormones”), opposes many of the actions of insulin
Stimulation of glucagon secretion
1. Low blood glucose:
A decrease in plasma glucose concentration is the primary stimulus for glucagon release.
During an overnight or prolonged fast, elevated glucagon levels prevent hypoglycemia

2. Amino acids:
Amino acids derived from a meal containing protein stimulate the release of both
glucagon and insulin.
The glucagon effectively prevents hypoglycemia that would otherwise occur as a result of
increased insulin secretion that occurs after a protein meal.

3. Epinephrine:
Elevated levels of circulating epinephrine produced by the adrenal medulla, or
norepinephrine produced by sympathetic innervation of the pancreas, or both, stimulate
the release of glucagon.

Inhibition of glucagon secretion

Glucagon secretion is significantly decreased by elevated blood glucose and by insulin.
Both substances are increased following ingestion of glucose or a carbohydrate-rich meal
Metabolic effects of glucagon
1. Effects on carbohydrate metabolism:
The intravenous administration of glucagon leads to an immediate rise in blood
glucose.
This results from an increase in the breakdown of liver (not muscle) glycogen and
an increase in gluconeogenesis.

2. Effects on lipid metabolism:

Glucagon activates lipolysis in adipose tissue.
The free fatty acids released are taken up by liver and oxidized to acetyl coenzyme
A, which is used in ketone body synthesis.
[Note: The catecholamines also activate lipolysis.]

3. Effects on protein metabolism:

Glucagon increases uptake of amino acids by the liver, resulting in increased
availability of carbon skeletons for gluconeogenesis. plasma levels of amino
acids are decreased.
The Feed/Fast Cycle
OVERVIEW OF THE ABSORPTIVE STATE
➢The absorptive (fed) state is the 2-4 hours period after ingestion of a
normal meal.
➢During this interval, transient increases in plasma glucose, amino acids,
and triacylglycerols (TAG) occur,

➢Islet tissue of the pancreas responds to the elevated levels of glucose and
amino acids with an increased secretion of insulin and a decreased release
of glucagon.
➢The elevated insulin to glucagon ratio and the ready availability of
circulating substrates make the absorptive state an anabolic period
characterized by increased synthesis of TAG and glycogen to replenish fuel
stores, and enhanced synthesis of protein.

➢During this absorptive period, virtually all tissues use glucose as a fuel.
LIVER: NUTRIENT DISTRIBUTION CENTER
The liver is uniquely situated to process and distribute dietary nutrients
because the venous drainage of the gut and pancreas passes through
the hepatic portal vein before entry into the general circulation.

During the absorptive period, the liver takes up carbohydrates, lipids,

and most amino acids. These nutrients are then metabolized
LIVER: NUTRIENT DISTRIBUTION CENTER
A) Carbohydrate Metabolism
1. Increased phosphorylation of glucose: Elevated levels of glucose within
the hepatocyte (as a result of elevated extracellular levels) allow glucokinase
to phosphorylate glucose to glucose 6-phosphate.

2. Increased glycogen synthesis: The conversion of glucose 6-phosphate to

glycogen is favored by the activation of glycogen synthase.

3. Increased activity of the hexose monophosphate pathway (HMP): The

increased availability of glucose 6-phosphate in the absorptive state,
combined with the active use of NADPH in hepatic lipogenesis, stimulate the
HMP
LIVER: NUTRIENT DISTRIBUTION CENTER
4. Increased glycolysis: In liver, glycolytic metabolism of glucose is significant
only during the absorptive period following a carbohydrate-rich meal. The
conversion of glucose to acetyl CoA is stimulated by the elevated insulin to
glucagon ratio that results in increased activity (and amount) of the
regulated enzymes of glycolysis, for example, pyruvate kinase. Pyruvate
dehydrogenase (PDH), which converts pyruvate to acetyl CoA, is active
Acetyl CoA is used as either a building block for fatty acid synthesis, or it
provides energy by oxidation in the tricarboxylic acid (TCA) cycle.
• 5. Decreased gluconeogenesis: Whereas glycolysis is stimulated in the
absorptive state, gluconeogenesis is decreased. Pyruvate carboxylase,
which catalyzes the first step in gluconeogenesis, is largely inactive due to
low levels of acetyl CoA
• B. Fat metabolism
• 1. Increased fatty acid synthesis: Liver is the primary tissue for
denovo synthesis of fatty acid. This pathway occurs in the absorptive
period, when dietary caloric intake exceeds energy needs by the body.
• Fatty acid synthesis is favored by the availability of substrates (acetyl
CoA and NADPH derived from the metabolism of glucose) and by the
activation of acetyl CoA carboxylase, both by dephosphorylation and
by the presence of its allosteric activator, citrate.
2- Increased TAG synthesis: TAG synthesis is favored because fatty acyl
CoA is available both from de novo synthesis from acetyl CoA and from
hydrolysis of the TAG component of chylomicron remnants removed
from the blood by hepatocytes.

• The liver packages TAG into very-low-density lipoprotein (VLDL)

particles that are secreted into the blood for use by extrahepatic
tissues, particularly adipose and muscle tissue
• C. Amino acid metabolism
• 1. Increased amino acid degradation: In the absorptive period, more
amino acids are present than the liver can use in the synthesis of
proteins.
• The surplus amino acids are not stored, but are either released into
the blood for all tissues to use in protein synthesis or are deaminated,
with the resulting carbon skeletons being degraded by the liver to
pyruvate, acetyl CoA, or TCA cycle intermediates.
• These metabolites can be oxidized for energy or used in fatty acid
synthesis
• Increased protein synthesis: The body cannot store protein in the
same way that it maintains glycogen or TAG reserves. However, a
transient increase in the synthesis of hepatic proteins does occur in
the absorptive state, resulting in replacement of any proteins that
may have been degraded during the previous postabsorptive period.
ADIPOSE TISSUE: ENERGY STORAGE DEPOT
Adipose tissue is second only to the liver in its ability to distribute fuel molecules.

Carbohydrate metabolism
1. Increased glucose transport: Glucose transport by GLUT-4 into adipocytes is
sensitive to the insulin concentration in the blood.
2. Increased glycolysis: The increased intracellular availability of glucose results in
an enhanced rate of glycolysis.
In adipose tissue, glycolysis serves a synthetic function by supplying glycerol
phosphate for TAG synthesis
3. Increased activity in the HMP: Adipose tissue can metabolize glucose by means
of the HMP, thereby producing NADPH, which is essential for fat synthesis
B. Fat metabolism
1. Increased synthesis of fatty acids: De novo synthesis of fatty acids
from acetyl CoA.
2. TAG synthesis: After consumption of a lipid-containing meal,
hydrolysis of the TAG of chylomicrons (from the intestine) and VLDL
(from the liver) provides adipose tissue with fatty acids.
Because adipocytes lack glycerol kinase, glycerol 3-phosphate used in
TAG synthesis comes from the metabolism of glucose.
3. Decreased TAG degradation: Elevated insulin favors the
dephosphorylated (inactive) form of hormone-sensitive lipase.
• TAG degradation is thus inhibited in the fed state.
RESTING SKELETAL MUSCLE
Carbohydrate metabolism
1. Increased glucose transport: The transient increase in plasma
glucose and insulin after a carbohydrate-rich meal leads to an increase
in glucose transport into muscle cells by GLUT-4.
• Glucose is phosphorylated to glucose 6- phosphate by hexokinase,
and metabolized to provide the energy needs of the cells.
2. Increased glycogen synthesis: The increased insulin to glucagon ratio
and the availability of glucose 6-phosphate favor glycogen synthesis,
particularly if glycogen stores have been depleted as a result of exercise
Fat metabolism
• fatty acids are of secondary importance as a fuel for muscle during the fed
state, in which glucose is the primary source of energy.

Amino acid metabolism

1. Increased protein synthesis: A spurt in amino acid uptake and protein
synthesis occurs in the absorptive period after ingestion of a meal
containing protein.
This synthesis replaces protein degraded since the previous meal.

2. Increased uptake of branched-chain amino acids: Muscle is the principal

site for degradation of branched-chain amino acids because it contains the
required transaminase.
BRAIN
• In the fed state, the brain uses glucose exclusively as a fuel,
completely oxidizing approximately 140 g/day to CO2 and H2O.

• Fat metabolism
• The brain has no significant stores of TAG, and the fatty acids
circulating in the blood make little contribution to energy production
because fatty acids bound to albumin do not efficiently cross the
blood-brain barrier.
LIVER IN FASTING
• Carbohydrate metabolism:
• The primary role of liver in energy metabolism during fasting is maintenance of blood
glucose through the synthesis and distribution of fuel molecules for use by other organs.

• The increased glucagon to insulin ratio causes a rapid mobilization of liver glycogen stores
(which contain about 80 g of glycogen in the fed state) due to phosphorylation (activation)
of glycogen phosphorylase

• Liver glycogen is nearly exhausted after 10–18 hours of fasting; therefore, hepatic
glycogenolysis is a transient response to early fasting.

Increased gluconeogenesis: The synthesis of glucose and its release into the circulation are
vital hepatic functions during fasting
The carbon skeletons for gluconeogenesis are derived primarily from glucogenic amino acids
and lactate from muscle, and glycerol from adipose.
• Fat metabolism
1. Increased fatty acid oxidation: The oxidation of fatty acids obtained
from TAG hydrolysis in adipose tissue is the major source of energy in
hepatic tissue in the postabsorptive state.

• Increased synthesis of ketone bodies: The liver is unique in being

able to synthesize and release ketone bodies, primarily 3-hydroxy
butyrate (formerly called β-hydroxybutyrate), for use as fuel by
peripheral tissues, but not by the liver itself
ADIPOSE TISSUE IN FASTING
• Carbohydrate metabolism
Glucose transport by insulin-sensitive GLUT-4 into the adipocyte and its metabolism are depressed
due to low levels of circulating insulin. This leads to a decrease in fatty acid and TAG synthesis.

• Fat metabolism
1. Increased degradation of TAG: The activation of hormone sensitive lipase and subsequent
hydrolysis of stored TAG are enhanced by the elevated catechol amines epinephrine and,
particularly, norepinephrine. These compounds, which are released from the sympathetic nerve
endings in adipose tissue.
• Glucagon also activates the lipase
2. Increased release of fatty acids: Fatty acids obtained from hydrolysis of stored TAG are primarily
released into the blood, Bound to albumin, they are transported to a variety of tissues for use as
fuel.
• The glycerol produced from TAG degradation is used as a gluconeogenic precursor by the liver.
RESTING SKELETAL MUSCLE IN FASTING
• Glucose transport into skeletal muscle cells via insulin-sensitive GLUT-4 proteins in the
plasma membrane and subsequent glucose metabolism are depressed because of low
levels o circulating insulin.

• Lipid metabolism
• During the first 2 weeks of fasting, muscle uses fatty acids from adipose tissue and
ketone bodies from the liver as fuels.
• After about 3 weeks of fasting, muscle decreases its use of ketone bodies and oxidizes
fatty acids almost exclusively. This leads to a further increase in the already elevated level
of circulating ketone bodies.
• [Note: The increased use of ketone bodies by the brain as a result of their increased
concentration in the blood is correlated with the decreased use of these compounds by
the muscle.]
• Protein metabolism
• During the first few days of fasting, there is a rapid breakdown of
muscle protein, providing amino acids that are used by the liver for
Gluconeogenesis

• Because muscle does not have glucagon receptors, muscle proteolysis

likely is initiated by the fall in insulin and sustained by the rise in
glucocorticoids.

• By several weeks of fasting, the rate of muscle proteolysis decreases

paralleling a decline in the need for glucose as a fuel for the brain,
which has begun using ketone bodies as a source of energy.
BRAIN IN FASTING
• During the first days of fasting, the brain continues to use glucose
exclusively as a fuel.
• In prolonged fasting (greater than 2–3 weeks), plasma ketone bodies
reach significantly elevated levels, and replace glucose as the primary
fuel for the brain.