Overview of Metabolism & the Provision of Metabolic Fuels Includes adaptation to periods of May result from nutritional

Harper’s 30th Edition Chapter 14 | Dra. Viliran fasting, starvation, exercise, deficiency, enzyme deficiency,
1Z pregnancy, and lactation abnormal secretion of hormones, or
2017 the actions of drugs and toxins
*A 70-kg adult human being requires about 8-12 MJ (1920-2900 kcal) from
BIOMEDICAL IMPORTANCE metabolic fuels each day, depending on physical activity.
 Metabolism: the term used to describe the interconversion of: *Growing children and animals have a proportionally higher requirement to
o chemical compounds in the body allow for the energy cost of growth.
o pathways and interrelationships taken by individual molecules *For human beings, this energy requirement is met from:
o mechanisms that regulate the flow of metabolites through the
CHO 40%-60%
pathways
Examples: CHO metabolism, Nucleotide/ Nucleic acid metabolism, Lipid Lipids (mainly 30%-40%
metabolism, CHON metabolism triacylglycerol)
CHON 10%-15%
 Metabolic pathways fall into 3 categories: Alcohol
o Anabolic Pathways *The mix of carbohydrate, lipid, and protein being oxidized varies, depending
o Catabolic Pathways on:
o Amphibolic Pathways o whether the subject is in the fed or fasting state
Pathway Definition Examples o duration and intensity of physical work
Anabolic Pathways -Involved in the synthesis of Protein *There is a constant requirement for metabolic fuels throughout the day.
synthesis of larger and from amino acids,  Average physical activity increases metabolic rate only by about
more complex synthesis of reserves 40%-50% over the basal or resting metabolic rate.
compounds from of triacylglycerol and Basal Metabolic Rate (BMR)
small precursors glycogen -energy expenditure by the body when at rest, but not asleep,
-Endothermic (glycogenesis) under controlled conditions of thermal neutrality, measured
Catabolic Pathways -Involved in the ETC, glycolysis, about 12 hours after the last meal, and depends on weight, age,
breakdown of larger lipolysis, β-oxidation, and gender.
molecules, commonly glycogenolysis  However, most people consume their daily intake of metabolic
involving oxidative fuels in 2 or 3 meals, so there is a need to form reserves of:
reactions - Virtually, all o CHO (glycogen in liver and muscle)
-Exothermic energy released o Lipid (triacylglycerol in adipose tissue)
-Producing reducing from the oxidation o Labile protein stores (during the period after a meal)
equivalents, and of CHO, fat, and -For use during the intervening time when there is no intake of
mainly via the CHON is made food.
respiratory chain, available in *In addition to water, the diet must provide metabolic fuels (CHO and fat)
ATP mitochondria as for body growth and activity, protein for synthesis of tissue proteins, fiber
reducing for bulk in the intestinal contents, minerals for specific metabolic
equivalents. functions, polyunsaturated FA of the n-3 and n-6 families, and vitamins-
-These are organic compounds needed in small amounts for essential functions.
funneled into the *If the intake of metabolic fuels is *If the intake of metabolic fuels is
respiratory chain, consistently greater than energy lower than energy expenditure,
where they are expenditure, the surplus is stored, there are negligible reserves of fat
passed down a largely as triacylgycerol in adipose and carbohydrate, and amino acids
redox gradient of tissue leading to the development arising from protein turnover are
carriers to their of obesity and its associated health used for energy-yielding
final reaction with hazards. metabolism rather than
oxygen to form replacement protein synthesis,
water. leading to emaciation, wasting,
and eventually, death.
Amphibolic -Occur at the Citric acid *Overnutrition leads to excess *Undernutrition occurs in 2
Pathways “crossroads” of cycle/Krebs/ energy intake and is associated extreme forms:
metabolism acting as Tricarboxylic acid with noncommunicable diseases a)Marasmus (adults and children)
links between the cycle such as obesity, type 2 diabetes, b)Kwashiorkor (children)
anabolic and catabolic atherosclerosis, cancer, and **Chronic illness can lead to
pathways hypertension undernutrition (cachexia) as a
result of hypermetabolism
Citric acid Cycle/Krebs/Tricarboxylic acid cycle
-the final pathway for the oxidation of CHO, lipid, and CHON In the fed state, after a meal: In the fasting state:
-Common end metabolite: Acetyl-CoA reacts with oxaloacetate to form There is an ample supply of CHO, Glucose must be spared for use by
citrate and the metabolic fuel for most the CNS (which is largely
-by a series of dehydrogenations and decarboxylations, citrate is tissues is glucose. dependent on glucose) and the
degraded reducing coenzymes releasing 2 CO2, and regenerating RBCs (which are wholly reliant on
oxaloacetate glucose)
-major pathway for the formation of ATP; located in the mitochondrial *Tissues that can use fuels other than glucose:
matrix adjacent to the enzymes of the respiratory chain and oxidative
Muscle Liver
phosphorylation
-amphibolic, because in addition to oxidation it is important in the Oxidize FA
provision of: synthesizes ketone bodies from
 carbon skeletons for gluconeogenesis FA to export to muscle and
 Acetyl CoA for FA synthesis other tissues
 interconversion of amino acids *As glycogen reserves become depleted, amino acids become depleted, amino
acids arising from protein turnover are used for gluconeogenesis.
Normal Metabolism Abnormal Metabolism

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 Gluconeogenesis- process of synthesizing glucose or glycogen from
noncarbohydrate precursors; particular importance when CHO is not
available from the diet.
Significant substrates: amino acids, lactate, glycerol and propionate
Liver- regulates the blood glucose concentration after a meal because it
contains the high-Km glucokinase that promotes increased hepatic
utilization of glucose.
*The formation and utilization of reserves of triacylglycerol and glycogen,
and the extent to which tissues take up and oxidize glucose, are largely
controlled by the hormones: insulin and glucagon
Insulin Glucagon
-secreted as a direct response to -secreted as a response to
hyperglycemia; stimulates the liver hypoglycemia and activates both
to store glucose as glycogen and glycogenolysis and
facilitates uptake of glucose into gluconeogenesis in the liver,
extrahepatic tissues. causing release of glucose into the
blood
*Diabetes Mellitus-leading to severe derangement
Type I DM Type II DM
-sometimes called Juvenile onset/ -sometimes called Adult
Insulin-dependent diabetes onset/Noninsulin-dependent
diabetes
-impaired synthesis and secretion -impaired sensitivity of tissues to
of insulin. insulin action
PATHWAYS THAT PROCESS THE MAJOR PRODUCTS OF
DIGESTION
*The nature of the diet sets the basic pattern of metabolism.
 There is a need to process the products of digestion of dietary CHO
(glucose), lipid (FA and glycerol), and CHON (amino acids).
*All the products of digestion are metabolized to a common product, acetyl
CoA, which is then oxidized by the citric acid cycle.
Outline of the pathways for the catabolism of CHO, CHON, and fat. All
these pathways lead to the production of acetyl-CoA, which is oxidized in
the citric acid cycle, ultimately yielding ATP by the process of oxidative
phosphorylation.
 CHO Metabolism is centered on the Provision & Fate of Glucose
 Lipid Metabolism is concerned mainly with FA & Cholesterol
Ako si darna …ay Cinderella pala 
Overview of CHO metabolism showing the major pathways and end-
products. Gluconeogenesis is not shown.
 Glucose- major fuel of most tissues; metabolized to pyruvate by
the pathway of glycolysis
 Aerobic tissues metabolize pyruvate to acetyl-CoA, which can
enter the citric acid cycle for complete oxidation to CO2 and H2O
linked to the formation of ATP in the process of oxidative
phosphorylation
Role of the respiratory chain of mitochondria in the conversion of food
energy to ATP. Oxidation of the major foodstuffs leads to the generation
of reducing equivalents (2H) that are collected by the respiratory chain for
oxidation and coupled generation of ATP.
 Glycolysis can also occur anaerobically (in the absence of oxygen)
when the end product is lactate
 Glucose and its metabolites also take part in the processes:
o Synthesis and storage of polymer glycogen in skeletal muscle
and liver
Glycogen- represents the principal storage CHO in the body, mainly in the
liver and muscle.
**In the liver, its main function is to provide glucose for extrahepatic
tissues.
**In muscle, it serves mainly as a ready source of metabolic fuel for use in
muscle. Muscle lacks glucose-6-phosphatase and cannot release free
glucose from glycogen.
Glycogen is synthesized from glucose by the pathway of glycogenesis;
broken down by glycogenolysis
o Pentose phosphate pathway (an alternative pathway of
glycolysis)
-source of reducing equivalents (NADPH) for FA synthesis
Lipogenesis (FA synthesis): converts acetyl-CoA to palmitate and
requires NADPH, ATP, Mn2+, biotin, and pantothenic acid as cofactors.
-source of ribose for nucleotide and nucleic acid synthesis
 Triose phosphate intermediates in glycolysis give rise to glycerol
moiety of triacylglycerols.
 Pyruvate and intermediates of the citric acid cycle provide the
carbon skeletons for the synthesis of nonessential or dispensable amino
acids
Alanine, Asparagine, Aspartate, Cysteine, Glutamate, Glutamine,
Glycine, Hydroxyproline, Hydroxylysine, Proline, Serine Tyrosine
 Acetyl-CoA- precursor of FA and cholesterol and hence all the steroid
hormones synthesized in the body
Lipogenesis (synthesis of long-chain FA) is carried out by 2 enzymes:
acetyl-CoA carboxylase and FA synthase.
**Acetyl-CoA carboxylase -converts acetyl-CoA to malonyl-CoA
**FA synthase- a multienzyme complex consisting of 2 identical
polypeptide chains, each containing 6 separate enzymatic activities
and ACP; catalyzes the formation of palmitate from 1 acetyl-CoA and
7 malonyl-CoA molecules.
Cholesterol
-precursor of all other steroids in the body (e.g. corticosteroids, sex
hormones, bile acids, and vitamin D); important role in membranes
and in the layer of lipoproteins; synthesized in the body entirely from
acetyl-CoA (3 molecules of acetyl CoA form mevalonate catalyzed by
HMG-CoA reductase)
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  The source of long-chain FA is either dietary lipid or de novo form part of a subcellular pattern
synthesis from acetyl-CoA derived from CHO or amino acids. of metabolic pathways
 Fatty acids may be oxidized to acetyl-CoA (β-oxidation) or  At the Tissue & Organ Level, the Blood Circulation Integrates
esterified with glycerol, forming triacylglycerol as the body’s main Metabolism
fuel reserve.  Amino acids resulting from digestion of dietary protein and
Acetyl-CoA formed by β-oxidation of FA may undergo 3 fates: glucose resulting from the digestion of CHO are absorbed via
1) As with acetyl-CoA arising from glycolysis, it is oxidized to CO2 + hepatic portal vein.
H2O via the citric acid cycle.  The liver has the role of regulating the blood concentration of
2) It is the precursor of synthesis of cholesterol and other steroids. these water-soluble metabolites.
3) In the liver, it is used to form the ketone bodies (acetoacetate and 3-
hydroxybutyrate) which are important fuels in prolonged fasting and
starvation.
*Acetone- formed nonenzymatically by decarboxylation of acetoacetate.
*Fatty acid oxidation in mitochondria leads to the generation of large
quantities of ATP by a process called β-oxidation that cleaves acetyl-CoA
units sequentially from fatty acyl chains. The acetyl-CoA is oxidized in the
citric acid cycle, generating further ATP.
*Ketone bodies (acetoacetate, 3-hydroxybutyrate, and acetone) are
formed in hepatic mitochondria when there is a high rate of FA oxidation.
*Pathway of ketogenesis involves synthesis and breakdown of 3-hydroxy-
3 –methylguaryl-CoA (HMG-CoA) by 2 enzymes: HMG-CoA synthase
and HMG-CoA lyase.
*Ketosis- mild in starvation but severe in DM.
 Much of Amino Acid Metabolism involves Transamination
 Amino acids are required for protein synthesis.

Transport and fate of major CHO and amino acid substrates and
metabolites. Note that there is little free glucose in muscle, since it is
rapidly phosphorylated following uptake.
 In the case of glucose, this is achieved by taking up glucose in
excess of immediate requirements and using it to synthesize
glycogen (glycogenesis) or fatty acids (lipogenesis)
 Between meals, the liver acts to maintain the blood glucose
concentration by breaking down glycogen (glycogenolysis) and
together with the kidney, by converting noncarbohydrate
metabolites (lactate, glycerol, and amino acids) to glucose
(gluconeogenesis)
 The maintenance of an adequate blood concentration of glucose is
essential for those tissues for which it is either the major fuel (the
brain) or the only fuel (erythrocytes).
Overview of amino acid metabolism showing the major pathways and
 The liver also synthesizes the major plasma proteins (e.g.
end-products
albumin) and deaminates amino acids that are in excess of
requirements, synthesizing urea, which is transported to the kidney
Essential/indispensable amino Nonessential/dispensable amino and excreted.
acids acids Hepatic urea synthesis takes place in part in the mitochondrial matrix and
in part in the cytosol.
- must be supplied in the diet, since -supplied in the diet, but can also  Skeletal muscle utilizes glucose as a fuel, both aerobically,
they cannot be synthesized in the be formed from metabolic forming CO2, and anaerobically, forming lactate; stores glycogen
body. intermediates by transamination as a fuel for use in muscle contraction and synthesizes muscle
using the amino group from other protein from plasma amino acids.
amino acids
Muscle accounts for approximately 50% of body mass and consequently
Arginine, Histidine, Isoleucine, Alanine, Asparagine, Aspartate, represents a considerable store of protein that can be drawn upon to supply
Leucine, Lysine, Methionine, Cysteine, Glutamate, Glutamine, amino acids for gluconeogenesis in starvation.
Phenylalanine, Threonine, Glycine, Hydroxyproline,
 Lipids in the diet are mainly triacylglycerol and fatty acids in the
Tryptophan, Valine Hydroxylysine, Proline, Serine
gut, then reesterified in the intestinal mucosa. Here they are
Tyrosine
packaged with protein and secreted into the lymphatic system and
 After deamination, amino nitrogen is excreted as urea, and the thence into the bloodstream as chylomicrons (largest of the plasma
carbon skeletons that remain after transamination may: lipoproteins).
o be oxidized to CO2 via the citric acid cycle
o be used to synthesize glucose (gluconeogenesis)
o form ketone bodies or acetyl CoA which may be
oxidized or used for synthesis of FA
 Several amino acids are also the precursors of other compounds
(e.g, purines, pyrimidines, epinephrine, thyroxine, and
neurotransmitter)
METABOLIC PATHWAYS MAY BE STUDIED AT DIFFERENT
LEVELS OF ORGANIZATION
At the tissue and organ level At the subcellular level
-the nature of the substrates -each cell organelle (e.g.
entering and metabolites leaving mitochondrion) or compartment
tissues and organs can be (e.g. cytosol) has specific roles that
measured.

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Transport and fate of major lipid substrates and metabolites.
LPL-lipoprotein lipase; MG-monoacylglycerol; NEFA-nonesterified fatty
acids; TG-triacylglycerol; VLDL-very low density lipoprotein
4 Major Groups of Lipoproteins:
Lipoproteins Roles
Chylomicrons Transport lipids resulting from
digestion and absorption
Very low density lipoprotein Transport triacylglycerol from the
(VLDL) liver
Low density lipoprotein (LDL) Deliver cholesterol to the tissues
High density lipoprotein (HDL) Remove cholesterol from the
tissues and return it to the liver for
excretion in the process known as
reverse cholesterol transport
 Chylomicrons also contain other lipid-soluble nutrients, including
Vitamins A, D, E, and K
 Unlike glucose and amino acids from the small intestine,
chylomicron triacylglycerol is not taken up directly by the liver.
-first metabolized by lipoprotein lipase, which hydrolyzes the TG,
releasing FA that are incorporated into tissue lipids or oxidized as
fuel.
 Chylomicron remnants are cleared by the liver.
 The other major sources of FA is synthesis (lipogenesis) from
CHO, in adipose tissue and the liver.
*Lipogenesis-regulated at the acetyl-CoA carboxylase step by allosteric
modifiers, phosphorylation/ dephosphorylation, and induction and
repression of enzyme synthesis.
*The enzyme is allosterically activated by citrate and deactivated by long-
chain acyl-CoA.
*Dephosphorylation (e.g. by insulin) promotes its activity, while
phosphorylation (e.g. glucagon or epinephrine) is inhibitory.
 Adipose tissue triacylglycerol- the main fuel reserve of the body;
hydrolyzed (lipolysis) and glycerol and nonesterified (free) fatty
acids are released into the circulation.
 Glycerol-is a substrate for gluconeogenesis
 Fatty acids are transported bound to serum albumin; taken up by
most tissues (but not brain or erythrocytes) and either esterified to
TG for storage or oxidized as a fuel.
 In the liver, newly synthesized TG and TG from chylomicron
remnants is secreted into the circulation in VLDL.
 Partial oxidation of FA in the liver leads to ketone body production
(ketogenesis)
Ketone bodies- are exported to extrahepatic tissues, where they provide a
fuel in prolonged fasting and starvation.
 At the subcellular Level, Glycolysis occurs in the Cytosol & the Citric
Acid Cycle in the Mitochondria
 Compartmentalization of pathways in separate subcellular
compartments or organelles permits integration of metabolism.
 Not all pathways are of equal importance in all cells
Ako si darna …ay Cinderella pala 
 The central role of the mitochondrion is immediately apparent,
since it acts as the focus of CHO, lipid, and amino acid
metabolism.
-contains the enzymes of the citric acid cycle, β-oxidation of FA
and ketogenesis, respiratory chain and ATP synthase
 Occur in the cytosol
-Pentose phosphate pathway
-FA synthesis
 In gluconeogenesis
-substrates (lactate and pyruvate) which are formed in the cytosol,
enter the mitochondrion to yield oxaloacetate (precursor for the
synthesis of glucose in the cytosol
 The membrane of the endoplasmic reticulum contains the enzyme
system for triacylglycerol synthesis and the ribosomes are
responsible for protein synthesis
Triacylglycerols -the major energy-storing lipids
Ribosomal RNA (rRNA), transfer RNA (tRNA), and messenger RNA
(mRNA), are directly involved in protein synthesis.
THE FLUX OF METABOLITES THROUGH METABOLIC
PATHWAYS MUST BE REGULATED IN A CONCERTED MANNER
 Regulation of the overall flux through a pathway is important to
ensure an appropriate supply of the products of that pathway
-achieved by the control of 1 or more key reactions in the pathway,
catalyzed by regulatory enzymes.
 The physiochemical factors that control the rate of an enzyme-
catalyzed reaction, such as substrate concentration, are of primary
importance in the control of the overall rate of a metabolic
pathway.
*Substrates for most enzymes are usually present at a concentration close
to their Km. This facilitates passive control of the rates of production in
response to changes in levels of metabolic intermediates.
*Active control of metabolite flux involves changes in the concentration,
catalytic activity, or both of an enzyme that catalyzes a committed, rate-
limiting reaction.
 Nonequilibrium reactions are Potential Control Points
 In a reaction of equilibrium, the forward and reverse reactions
occur at equal rates, and there is therefore no net flux in either
direction.
A↔C↔D
 In vivo, under “steady-state” conditions
-there is a flux from left to right because there is continuous supply
of substrate A and continuous removal of product D
 In practice
-there are normally one or more nonequilibrium reactions in a
metabolic pathway, where the reactants are present in
concentration that are far from equilibrium.
 In attempting to reach equilibrium
-large doses of free energy occur, making this type of reaction
essentially irreversible
-pathway has both flow and direction
 Enzymes catalyzing nonequilibrium reactions are usually
present in low concentrations and are subject to a variety of
regulatory mechanisms
 Most reactions is metabolic pathways cannot be classified as
equilibrium or nonequilibrium, but fall somewhere between the 2
extremes.
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 The Flux-Generating Reactions is the 1st reaction in a Pathway that is -Acetyl-CoA (and hence any substrate that yield acetyl-CoA) can NEVER be
Saturated with the Substrate used for gluconeogenesis.
 First reaction in glycolysis: *The (relatively rare) FA with an odd number of carbon atoms yield propionyl
-catalyzed by hexokinase CoA as the product of the final cycle of β-oxidation, and this can be a
-flux-generating step because its Km for glucose of 0.05 mmol/L is substrate for gluconeogenesis, as can the glycerol released by lipolysis of
well below the normal blood glucose concentratiom of 3-5 mmol/L adipose tissue triacylglycerol reserves.
*Most of the amino acids in excess of requirements for protein synthesis
ALLOSTERIC & HORMONAL MECHANISMS ARE IMPORTANT IN (arising from the diet or from tissue protein turnover) yield:
THE METABOLIC CONTROL OF ENZYME-CATALYZED o pyruvate or
REACTIONS o 4- and 5-C intermediates of the citric acid cycle
*Pyruvate-can be carboxylated to oxaloacetate; Oxaloacetate- primary
substrate for gluconeogenesis
*other intermediates of the cycle also result in a net increase in the formation
of oxaloacetate, which is then available for gluconeogenesis
-these amino acids are called glucogenic
*2 amino acids: Lysine and Leucine
-yield only acetyl-CoA on oxidation, and hence cannot be used for
gluconeogenesis
*4 amino acids: phenylalanine, tyrosine, tryptophan, and isoleucine
-give rise to both acetyl CoA and intermediates that can be used for
gluconeogenesis.
*Amino acids that give rise to acetyl-CoA are referred to as ketogenic
-because in prolonged fasting and starvation, much of the acetyl-CoA is used
for synthesis of ketone bodies in the liver.
A SUPPLY OF METABOLIC FUELS IS PROVIDED IN BOTH THE
FED & FASTING STATES
 Glucose is always required by the CNS and Erythrocytes
Erythrocytes Brain
-lack mitochondria -can metabolized ketone bodies to
-wholly reliant on (anaerobic) meet about 20% of its energy
glycolysis and pentose phosphate requirements: the remainder must
pathway at all times be supplied by glucose.
 The metabolic changes that occur in the fasting state and starvation serve:
o to preserve glucose and the body’s limited glycogen reserves for use
by the brain and RBCs
o to provide alternative metabolic fuels for other tissues
 In Pregnancy
-Fetus requires a significant amount of glucose, as does the
synthesis of lactose in lactation
A↔B→C↔D
* A↔B and C↔D are equilibrium reactions and B→C is a nonequilibrium
reaction
*The flux through this pathway can be regulated by the availability of
substrate A.
- depends on its supply from the blood, which in turn depends on either food
intake or key reactions that replace substrates from tissue reserves into the
bloodstream
e.g. Glycogen phosphorylase in liver
Hormone-sensitive lipase in adipose tissue
-depends on the transport of substrate A into the cell
*Muscle and adipose tissue only take up glucose from the bloodstream in
response to the hormone insulin.
*Flux is also determined by removal of the endproduct D and the availability
of cosubstrates or cofactors represented by X and Y.
*Enzymes catalyzing non-equilibrium reactions are often allosteric proteins
subject to the rapid actions of “feedback” or “feed-forward” control by
allosteric modifiers, in immediate response to the needs of the cell.
*Frequently, the end-product of a biosynthetic pathway inhibits the enzyme
catalyzing the first reaction in the pathway.
*Other control mechanisms depend on the actions of hormones responding to
the needs of the body as a whole; they may act:
o rapidly by altering the activity of existing enzyme molecule or
o slowly by altering the rate of enzyme synthesis
MANY METABOLIC FUELS ARE INTERCONVERTIBLE
*CHO in excess of requirements for immediate energy-yielding metabolism
and function of glycogen reserves in muscle and liver can readily be used for
synthesis of FA, and hence TG in both adipose tissue and liver (whence it is  In the Fed State, Metabolic Fuel reserves are laid down
exported in VLDL) Energy yields, Oxygen consumption, and CO2 production in the
*Importance of lipogenesis in humans: unclear Oxidation of Metabolic Fuels
*High intake of fat inhibits lipogenesis in the adipose tissue and liver. Energy O2 CO2 RQ Energy
*Fatty acids (and ketone bodies formed from them) cannot be used for the Yield Consumed produced (CO2 (kJ)/L
synthesis of glucose. (kJ/g) (L/g) (L/g) produced/ O2
*The reaction of pyruvate dehydrogenase, forming acetyl-CoA that enters the O2
Citric acid cycle, there is a loss of 2C atoms as CO2 before oxaloacetate is consumed
reformed.
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 CHO 16 0.829 0.829 1.00 ~20
CHON 17 0.966 0.782 0.81 ~20
Fat 37 2.016 1.427 0.71 ~20
Alcohol 29 1.429 0.966 0.66 ~20
 For several hours after a meal, while the products of digestion are being
absorbed, there is an abundant supply of metabolic fuels.
 Glucose is the major fuel for oxidation in most tissues, observed as
an increase in the respiratory quotient (ratio of CO2 produced/
oxygen consumed) from about 0.8 in the fasting state to near1.
 Glucose uptake into muscle and adipose tissue is controlled by insulin,
which is secreted by the β-islet cells of the pancreas in response to an
increased concentration of glucose in the portal blood.
 In the fasting state
 The glucose transporter of muscle and adipose tissue is in
intracellular vesicles: GLUT4
 An early response to insulin
-migration of these vesicles to the cell surface, where they fuse with the
plasma membrane, exposing active glucose transporters
 These insulin-sensitive tissues only take up glucose from the bloodstream
to any significant extent in the presence of the hormone.
-As insulin secretion falls in the fasting state, so the receptors are
internalized again reducing glucose uptake.
 In skeletal muscles: the increase in cytoplasmic calcium ion
concentration in response to nerve stimulation stimulates the migration
of the vesicles to the cell surface and exposure of active glucose
transporters whether or not there is significant insulin stimulation.
 Uptake of glucose into the liver
-independent of insulin, but liver has an isoenzyme of hexokinase
(glucokinase) w/ a high Km, so that as the concentration of glucose
entering the liver increases, so does the rate of synthesis of glucose-6-
phosphate
-this is in excess of the liver’s requirement for energy-yielding
metabolism and is used mainly for synthesis of glycogen
 In both liver and skeletal muscle
-Insulin acts to stimulate glycogen synthetase and inhibit glycogen
phosphorylase
 Some of the additional glucose entering the liver may also be used for
lipogenesis and TG synthesis.
 In adipose tissue
-Insulin stimulates glucose uptake, its conversion to FA, and their
esterification to TG.
-Insulin inhibits intracellular lipolysis and the release of NEFA
 Products of lipid digestion enter the circulation as chylomicrons (largest
of the plasma lipoproteins, which are especially rich in TG)
 In adipose tissue and skeletal muscle
-Extracellular lipoprotein lipase is synthesized and activated in
response to insulin
-the resultant NEFA are largely taken up by the tissue and used for
synthesis of TG while the glycerol remains in the bloodstream and is
taken up by the liver and used for either gluconeogenesis and glycogen
synthesis or lipogenesis.
 FA remaining in the bloodstream are taken up by the liver and
reesterified. The lipid-depleted chylomicron remnants are cleared by
the liver, and the remaining TG is exported, together with that
synthesized in the liver in VLDL.
 Under normal conditions, the rate of tissue protein catabolism is more
or less constant throughout the day.
 Increased rate of CHON catabolism
-only in cachexia associated w/ advanced cancer and other diseases
 Net protein catabolism in the fasting state
-when the rate of protein synthesis falls
 Net protein synthesis in the fed state
-when the rate of synthesis increases by 20% to 25%
 Increased rate of protein synthesis
-in response to increased availability of amino acids and metabolic fuel
is again a response to insulin action.
 CHON synthesis- an energy expensive process
-may account for up to 20% of resting energy expenditure after a meal
-but only 9% in the fasting rate
 Metabolic Fuel Reserves are Mobilized in the Fasting State
 Plasma glucose
-small fall in the fasting state
-little change as fasting is prolonges into starvation
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 Plasma NEFA-increased in fasting but then rise little more in
starvation.
 As fasting is prolonged-the plasma concentration of ketone bodies
(acetoacetate and 3-hydroxybutyrate) increases markedly
 In the fasting state
-As the concentration of glucose in the portal blood coming from
the small intestine falls, insulin secretion, decreases; skeletal
muscle and adipose tissue take up less glucose
 Increase in secretion of glucagon by alpha cells of the pancreas
-inhibits glycogen synthetase, and activates glycogen
phosphorylase in the liver
 The resulting glucose-6-phosphate-hydrolyzed by glucose-6-
phosphatase, and glucose is released into the bloodstream for use
by brain and RBCs
 Muscle glycogen-cannot contribute directly to plasma glucose,
since muscle lacks glucose-6-phosphate for energy-yielding
metabolism in the muscle itself.
 Acetyl-CoA- formed by oxidation of FA in muscle
-inhibits pyruvate dehydrogenase, leading to an accumulation of
pyruvate
-Most is transaminated to alanine, at the expense of amino acids
arising from breakdown of muscle protein
 Alanine, as much of the keto acids resulting from this
transamination are exported from muscle, and taken up by the liver
where the alanine is transaminated to yield pyruvate,
 Resultant amino acids are largely exported back to muscle, to
provide amino groups for formation of more alanine, while the
pyruvate provides a substrate for gluconeogenesis in the liver
 In adipose tissue: decrease in insulin & increase in glucagon
-results in inhibition of lipogenesis, inactivation and internalization
of lipoprotein lipase, and activation of intracellular hormone lipase
-leads to release from adipose tissue of increased amounts of
glycerol (substrate for gluconeogenesis in the liver) and NEFA,
which are used by the liver, heart, and skeletal muscle as their
preferred metabolic fuel, so sparing glucose.
 Although muscle preferentially takes up and metabolizes NEFA in
the fasting state, it cannot meet all of its energy requirements by
beta-oxidation
 Liver- has a greater capacity for beta-oxidation than is required to
meet its own energy needs
>As fasting becomes more prolonged forms more acetyl CoA
that can be oxidized.
 Acetyl CoA-used to synthesize ketone bodies; ketone bodies-
major metabolic fuels for skeletal and heart muscle and can meet
up to 20% of the brain’s energy needs
 In prolonged starvation
-Glucose may represent less than 10% of whole body energy-
yielding metabolism
*Were there no other source of glucose
> Liver and muscle glycogen would be exhausted after about 18
hours of fasting
>As fasting becomes more prolonged, so an increasing amount of
the amino acids released as a result of CHON catabolism is utilized
in the liver and kidneys for gluconeogenesis.
Plasma concentrations of Metabolic Fuels (mmol/L) in the Fed state
Fed 40h Fasting 7 Days
Starvation
Glucose 5.5 3.6 3.5
NEFA 0.30 1.15 1.19
Ketone bodies Negligible 2.9 4.5
CLINICAL ASPECTS
*In prolonged starvation:
-As adipose tissue reserves are depleted, there is a very considerable increase
in the rate of CHON catabolism to provide amino acids, not only as substrates
for gluconeogenesis, but also as the main metabolic fuel of all tissues.
*Death-results when essential tissue proteins are catabolized and not replaced
*In patients with cachexia
-as a result of release of cytokine s in response to tumors and disease
-there is an increase in the rate of tissue protein catabolism, as well as
considerably increased metabolic rate, so they are in a state of advanced
starvation.
-Again, death results when essential tissue CHON are catabolized and not
replaced.
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*High demand for glucose by the fetus, and for lactose synthesis in lactation,
can lead to ketosis.
-may be seen as mild ketosis with hypoglycemia in human beings
*In poorly controlled type I DM-Patients may become hyperglycemic
o Result of lack of insulin to stimulate uptake and utilization of
glucose
o Because in the absence of insulin to antagonize the actions of
glucagon
-there is increased gluconeogenesis from amino acids in the liver
-at the same time, the lack of insulin to antagonize the actions of
glucagon results in increased lipolysis in adipose tissue, and the
resultant NEFA are substrates for ketogenesis in the liver.
*Utilization of the ketone bodies in muscle (and other tissues) may be
impaired-- because of the lack of oxaloacetate (All tissues have a requirement
for some glucose metabolism to maintain an adequate amount of oxaloacetate
for citric acid cycle activity.)
*In uncontrolled diabetes
-Ketosis may be severe enough to result in pronounced acidosis (ketoacidosis)
-Acetoacetate and 3-hydroxybutyrate are relatively strong acids
*Coma
-results from both the acidosis and also the considerably increased osmolality
of ECF (mainly as a result of the hyperglycemia, and diuresis resulting from
the excretion of glucose and ketone bodies in the urine)

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