METABOLISM

Metabolism is the biochemical reactions occurring in the cell

.after the absorption of the foodstuffs

Metabolism

Anabolism Catabolism
Building up. Break down.
Needs energy Releases energy
(endergonic) (exergonic)

Bioenergetics
 It is the study of the energy changes accompanying
biochemical reactions.
 Energy is considered the capacity of the organism to do
work. Two types of energy are considered in our body:
o Heat energy: It maintains the body temperature.
o Free energy: It is available for the performance of
work
a) Bioenergetic system needs:
o A source of energy.
o A mechanism for the degradation of the food stuffs to
release energy.

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 o A mechanism for the collection and storage of the
free energy liberated in the form of high energy
phosphate bonds.

a) Sources of energy:
Oxidation of food stuffs mainly carbohydrates.
b) Degradation of food stuffs:
Some free energy is obtained from the breakdown of small
molecules as glucose, glycerol, amino acids and fatty acids to
acetyl Co-A, which via Krebs’ cycle forms free energy, CO 2
and water.
Energy level of hydrolizable bonds:
Energy bonds are divided into 2 groups:

Energy Bonds
I- Low energy bonds:
 Give 2000 – 3000 cal/bond.
 Designed as ordinary dash (-).
 e.g. glucose-6-phosphate.
II- High energy bonds:
 Give 10,000-16,000 cal/bond.
 Designed as (~).
 e.g.: ATP, ADP, creatine phosphate.

Collection and storage of free energy:

Free energy liberated during the degradation of foodstuffs
is collected and stored in the form of high energy phosphate
bonds in ATP and creatine phosphate.
Mechanism of collection of energy:
Free energy is collected in the form of high energy
phosphate bonds at 2 levels:
a- Substrate level phosphorylation:
A high energy bond is formed in the substrate while being
oxidized, then ATP is generated, e.g.:

2
 Pyruvatekinase
Phosphoenol Pyruvate Enol-pyruvate + ATP
+ ADP

b- Respiratory chain (Electron Transport Chain, ETC):

It is a series of hydrogen and electron carriers present near
the inner mitochondrial membrane. Its function is to
transfer hydrogen and electrons from reduced substrates
,resulting from biological reactions, to oxygen forming
water and producing energy.

Reduced substrate

FP
ATP ATP ATP
Reduced NAD FP Q Cyt b Cyt C 1 Cyt C Cyt a Cyt a3 O
substrate

ADP+P1 ADP+P1 ADP+P 1

Site I Site II Site III

Respiratory Chain

 Respiratory chain shows that the oxidation and

phosphorylation are taking place at the same time; a
process called coupled oxidative phosphorylation
 If these two processes are uncoupled the process of
oxidation will occur without phosphorylation and so
energy will be lost in the form of heat
 Substances which uncouple respiratory chain
oxidation from phosphorylation are called
uncouplers e.g.: dicumarol, arsenate, thyroxin and
calcium ions.
 From respiratory chain the oxidation of NADH + H +
produces 3 ATP (P/O = 3/1) while oxidation of
FADH2 gives only 2 ATP (P/O = 2/1).

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 Carbohydrate Metabolism

I-Digestion
In The mouth:
Starch Salivary Amylase Maltose

In the stomach:
Disaccharides (maltose, sucrose and lactose) HCl
monosaccharides

In the small intestine:

Starch, dextrin Pancreatic amylase Maltose

Maltose Maltase 2 Glucose.

Lactose Lactase Glucose + Galactose.

Sucrose Sucrase Glucose + Fructose.

II- Absorption
 It occurs mainly in the small intestine.
 Polysaccharides and oligosaccharides are not absorbable.
 Monosaccharides are absorbed from the jejunum.
 Absorption of sugars occurs by:

1- Passive diffusion:
This depends on the concentration gradient of the sugar
between the intestinal lumen, mucosal cells and blood
plasma.

2- Active transport:
 There are 2 active transport systems, one for glucose and
galactose and the other for other hexoses.
 The first system needs simultaneous absorption of Na + by
a common carrier present in the brush border of the
mucosal cells in the presence of ATP.

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  Absorption increases by T4 and corticosteroids but insulin
has no effect.
 It decreases in case of diarrhea.

Core of villus
ATP ADP+Pi
Lumen Na+ Na+
ATPase
Na+ carrier

Glucose Glucose
Glucose

Brush Basal
Border border

Fate of absorbed sugars:

1- Diffusion:
When the blood glucose level increases, it passively
diffuses through the blood capillaries to the interstitial fluid.

2- Uptake by tissues:
This occurs by facilitated diffusion, i.e. requires a carrier
protein.

3- Utilization by tissues in the form of:

A-Oxidation:
a- Major pathways: Via glycolsis, oxidative decarboxylation
and Krebs’ cycle.
b- Minor pathways: Via pentose shunt and uronic acid
pathway.
B-Conversion to other substances such as:
1- Ribose and deoxyribose in the structure of RNA and DNA.
2- Galactose in lactose of milk and galactolipids.
3- Fructose in semen.
4- Glucuronic acid in the liver for detoxication.

5
4-Storage:
Excess glucose is stored as glycogen in liver and muscles and
as triglycerides in adipose tissues.

5- Excretion in urine:
 Excess blood glucose excreted by the kidney in the
urine if the blood level exceeds the normal renal
threshold (180 mg %)
 Normally, no detectable glucose in urine.

Major Pathway of Glucose Oxidation

A- Glycolysis (Embden-Meyerhoff Pathway)

 It is the anaerobic phase of glucose oxidation into pyruvate

in the presence of O2 or to lactate in absence of O2.
 It occurs in the cytosol of every cell. Physiologically, it
ends with lactate only in muscles during exercise (due to
lack of oxygen) and in RBCs (due to absence of
mitochondria).

Steps of glycolysis: See the diagram.

Comment on glycolysis:

1- All reactions are reversible except glucokinase (GK),

phosphofructokinase (PFK) and pyruvate kinase (PK).
2- Hexokinase is present in all tissues except adult liver. It is
of low specificity, not affected by insulin, carbohydrate
feeding or starvation. It is allosterically inhibited by
glucose-6- phosphate.
3- Glucokinase is present in adult liver. It acts only on
glucose. Its synthesis is increased by insulin and
carbohydrate feeding but decreased by starvation.

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Regulation:
1- Glycolysis is regulated by factors which control the
activity of the 3 irreversible reactions.
2- Insulin induces the synthesis of GK, PFK, PK, while
glucagons and adrenaline inhibit this synthesis.
3- Carbohydrate feeding increases insulin secretion, thus
increasing the synthesis of the 3 irreversible enzymes in
the liver. So, glycolysis will be increased in the liver.
4- During starvation, there is decreased secretion of insulin
and increased secretion of anti-insulin hormones. This
decreases the synthesis of GK, PFK and PK. This inhibits
glycolysis in the liver.

Importance of glycolysis:
1- Glycolysis provides the mitochondria with pyruvate, an
important source of oxaloacetate which is the primer of
Krebs’ cycle.
2- It provides dihydroxyacetone phosphate, which is
convertible to glycerol for lipogenesis.
3- It liberates a little amount of energy from glucose. This is
very important during muscular exercise and also
provides most of the energy required by RBCs.
4- Energy yield in the absence of O2:
- 2 ATP in step 1 and 3 (glucokinase)
+2 ATP in step 7 (phosphoglycerate kinase).
+2 ATP in step 10 (pyruvate kinase).
+ 2 ATP

5- Energy yield in the presence of O2:

In addition to the 2 ATP obtained in absence of O2, 6 more
ATP are obtained from the oxidation of 2 NADH + H+
through the respiratory chain.

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8
 B- Aerobic Oxidation
In the presence of oxygen, pyruvate enters the
mitochondria to be oxidized to CO2 and H2O. The process
starts by oxidative decarboxylation of pyruvate to acetyl-
CoA.
1- Oxidative decarboxylation
 It is an irreversible reaction that requires a multienzyme
complex: the pyruvate dehydrogenase complex, which is
composed of 3 enzymes. It requires Mg++ , TPP, FAD,
NAD+, CoASH and lipoic acid.

O
II CO 2
CH3-C-COOH Pyruvate-DH-complex CH3-CO~SCoA

NAD+ NADH + H+

 Pyruvate dehydrogenase is inhibited by high

(NADH+H+/NAD+) and (acetyl-CoA/CoASH). It is
activated by insulin.

Sources and fates of pyruvate:

Alanine GPT Pyruvate LDH Lactate

Malic enzyme
Oxidative
Decarboxylation Malate
Oxaloacetate
Acetyl~Co A

Citrate

Krebs’ cycle

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 Citric Acid Cycle
(Krebs' Cycle)

Site: In the mitochondria of every cell.

 It begins with condensation of acetyl- Co A and
oxaloacetate; both of which are derived mainly from
pyruvate.
 Acetyl- CoA can be produced from the partial oxidation of
carbohydrates, fats and proteins.

Steps: See the diagram.

Comment on Krebs' cycle:

1- All reactions are reversible except citrate synthase and α-
ketoglutarate dehydrogenase steps.

2-Eight hydrogen atoms produced in Krebs’ cycle are

oxidized to 4 molecules of water through the respiratory
chain. Two molecules of H2O are utilized in the citrate
synthase and fumarase steps, so the total gain is 2 molecules
of H2O through oxidation of acetyl- CoA in Krebs' cycle.

3-Specific inhibitors:
a- Malonate inhibits succinate dehydrogenase.
b- Fluoro- citrate inhibits aconitase.

4-Succinyl- CoA is important for heme- synthesis and

ketolysis (breakdown of ketone bodies).

5-Energy yield in Krebs' cycle:

Hydrogen atoms produced will be oxidized through the
respiratory chain, producing energy in the form of ATP.
One molecule of acetyl- CoA, through Krebs' cycle, yields 12
ATP as follows:
- 1 ATP from succinyl CoA (through GTP).
- 2 ATP from oxidation of FADH2.

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 - 9 ATP from oxidation of NADH+H+ (isocitrate DH, α-
ketoglutarate DH and malate DH).
Net = 12 ATP.
+ 3 ATP from oxidative decarboxylation of pyruvate.
15 ATP
So, oxidation of one mole of glucose gives:
15 X 2 = 30 ATP
+ 8 ATP from glycolysis.
_______
38 ATP

6- CO2 fixation:
CO2 liberated in Krebs’ cycle is utilized in various
reactions, such as:
1- Pyruvate + CO2 Oxaloacetate.
2- Acetyl- CoA + CO2 Malonyl CoA.
3- Pyruvate + CO2 Malic Acid.
4-CO2 + NH3 Urea
5-CO2 + NH3 Pyrimidine

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12
 Minor Pathways of Glucose Oxidation

These processes of minor pathways for glucose

oxidation include pentose shunt and uronic acid pathways.
They occur in certain organs.

I-Hexose Monophosphate Shunt (HMP)

(Pentose shunt)

It is an alternative pathway for oxidation of glucose

which involves pentose as intermediates. It occurs in the
cytoplasm of the cell especially in the liver, adipose tissue,
lactating mammary gland, suprarenal cortex, eye, testis,
ovaries and placenta.

Glucose-6-P-dehydrogenase
Glucose-6-phosphate Ribose-5-phosphate

NADP+ CO2 NADPH+H+

Significance of HMP:
1- Production of ribose 5-phosphate for nucleotides and
nucleic acid synthesis. Ribose of diet is excreted in
urine as there is no pentokinase for phosphorylation.
2- NADPH produced through the HMP is important
for:
a. Fatty acid synthesis: which is important for
lipogenesis . So, HMP is very active in the
liver, adipose tissue and lactating mammary
gland.
b. Steroid synthesis: HMP is active in the adrenal
cortex, testis, ovaries and placenta.
c. NADPH is important for retinal reductase
enzyme which is necessary for the
transformation of retinal into retinol in the eye.
That is why HMP is active in the eye.

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 d. Keep iron of hemoglobin in the reduced form,
thus preserving its capacity to carry oxygen.
Favism: It is a congenital disease resulting from glucose-6-
phosphate dehydrogenase deficiency. Normally, NADPH
produced from HMP is important to keep glutathione in the
reduced form. Reduced glutathione is important to get rid of
H2O2 produced from metabolism. When a person suffering from
glucose-6-P-dehydrogenase deficiency eats Fava Beans or takes
drugs such as Aspirin, H2O2 production increases. This will
destroy the wall of RBCs leading to hemolysis.

II- Uronic Acid Pathway

It is an alternative pathway for oxidation of glucose. It occurs in

the cytoplasm of the liver.

Comment:

UDP- glucuronic acid is the "active" form of glucuronic acid

for different biological reactions, e.g.:
1- Detoxication reactions which occur in the liver.
2- Incorporation into chondroitin sulphate and other
mucopolysaccharides.

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 Glycogen Metabolism

1-Glycogenesis:
Formation of glycogen from excessive glucose or other
hexoses.
Site of formation:
Liver and muscles and to a lesser extent in other tissues.

Steps:

 Glycogen synthase transfers glucose from UDPG and

connects it to the outer glucose unit of glycogen primer
(part of old glycogen) by α-1-4-glucosidic linkage, and
the process is repeated.
 When the chain becomes between 6 and 11 glucose
units, the branching enzyme transfers part of the α-1-4-
chain to a neighboring chain attaching it by α-1, 6-
glucosidic linkage.

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 Regulation of glycogenesis:
1. glycogen synthase is the key enzyme of glycogenesis, it
exists in 2 forms:
a. Active form: Synthase I (dephosphorylated)
b. Inactive form: Synthase D (phosphorylated)
2. Protein kinase converts the active form to the inactive
form. It can only work in the presence of cyclic-AMP
(cAMP) which is formed from ATP by adenyl cyclase
enzyme which is activated by thyroxin, adrenaline and
glucagons. Thus, these hormones decrease
glycogenesis.

Thyroxin, Adrenaline, Glucagon Insulin

+ +

Adenyl cyclase Phosphodiesterase

ATP 3,5 cAMP AMP
PPi H2O
+ P

Glycogen
Glycogen Synthase I Protein Kinase Synthase D

ATP Mg2+ ADP

Synthase Phosphatase

Pi H2O

3. Nutritional state:
In normal person, glycogenesis occurs after a
carbohydrate meal to store excess glucose.
During fasting, secretion of adrenaline and glucagon
inhibits glycogenesis.
2- Glycogenolysis:
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 It is the break down of glycogen in the liver into blood
glucose and in muscle to lactate.

Site:
1-In the liver to maintain the level of blood glucose during
fasting.
2-In muscles, to supply energy during muscular exercise.

Mechanism:
 Phosphorylase enzyme acts on the α 1,4-glucosidic linkage
of glycogen, producing glucose-1-phosphate, until each
branch reaches 4 glucose units. Then transferring enzyme
transfers 3 glucose units from the end of one branch to the
end of the other branch.
 Debranching enzyme hydrolyses the α 1,6-glucosidic
linkage and then the process is repeated.

Regulation of glycogenolysis:
 Glycogen phosphorylase is the key enzyme. It is present in
2 forms, the active form (a) which is phosphorylated and
the inactive form (b) which is dephosphorylated.
 The activation of (b) to (a) is catalyzed by phosphorylase
kinase which is present in 2 forms:
1- Active phosphorylase -kinase (a) (phosphorylated).
2- Inactive phosphorylase-kinase (b)
(dephosphorylated).
 The main regulator of glycogenolysis is cAMP which
catalyzes the conversion of inactive protein-kinase to the
active form which catalyzes the conversion of inactive
phosphorylase (b) kinase to the active form (a).
 Active phosphorylase-kinase (a) stimulates the conversion
of phosphorylase (b) to the active form.

Hormonal Regulation of Glycogenolysis:

1-Insulin decreases glycogenolysis in the liver and muscles by
decreasing cAMP level.

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2-Glucagon, in liver, and adrenaline, in liver and muscles,
stimulate glycogenolysis by increasing cAMP level which
activates protein kinase and phosphorylase kinase, so stimulate
glycogenolysis.

Thyroxin, Adrenaline, Glucagon Insulin

+ +

Adenyl cyclase Phosphodiesterase

ATP 3,5 cAMP AMP
PPi H2O
+

Protein Kinase Protein Kinase

(Inactive) (Active)

+
Phosphorylase Kinase (b) Phosphorylase
(Inactive) Kinase (a) (Active)
ATP Mg2+ ADP

Phosphorylase (b) Phosphorylase (a)

(Inactive) (Active)
ATP Mg2+ ADP

 Glycogen Storage Diseases: (Glycogenosis)

Inherited deficiencies in specific enzymes of glycogen
metabolism in liver and muscles lead to these diseases. The
most common is Von Gierke's disease type I . It is related
to deficiency of glucose-6-phosphatase. It is characterized by
enlargement of the liver and kidneys, fasting hypoglycemia,
hyperlipemia, hypercholesterolemia and hyperuricemia.

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  Muscle Glycogen and blood glucose:
Muscle glycogen can be converted into blood glucose via
indirect pathway known as Cori's cycle during muscle
exercise or by glucose-alanine cycle during starvation as
follows:

Liver Blood Muscles

Glycogen Glycogen

G-6-P Glucose Glucose Glucose G-6-P

Pyruvate Pyruvate

LDH LDH
Lactate Lactate Lactate

Alanine Alanine Alanine

The differences between liver and muscle glycogen:

Liver glycogen Muscle glycogen
1. Sources Dietary hexoses, Blood glucose
gluconeogenesis
2. Amount 100-150 gm 250-350 gm
3. Fate Blood glucose Lactate
4. Fasting Decreases Not depleted
5. Exercise Slightly reduced Deplete it markedly
6. Adrenaline Slightly reduced Deplete it markedly
7. Glucagon Decreased No effect

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 Gluconeogenesis
Definition:
Gluconeogenesis is the synthesis of glucose or glycogen from
non-carbohydrate sources, such as glucogenic amino acids,
lactate, glycerol and odd chain fatty acids (propionyl CoA).

Importance:
It maintains the blood glucose level during starvation and in low
carbohydrate diet.

Site:
Mainly in the cytosol of the liver cells and to a lesser extent in
kidneys, not in adipose tissues or muscles.

Steps and Mechanism:

It occurs by reversal of glycolysis. The three irreversible
reactions in glycolysis can be reversed as follows:
1-Pyruvate kinase reaction is reversed by pyruvate
carboxylase and phosphoenol pyruvate carboxykinase (PEP-
carboxykinase).

Pyruvate Pyruvate carboxylase Oxaloacetate PEP-carboxykinase PEP

ATP ADP+Pi GTP GDP

Mitochondria Cytosol

2-Phosphofructokinase reaction is reversed by fructose-1,6-

bisphosphatase.

F 1,6-bisphosphate F1,6-bisphosphatase F-6-P

H2O Pi
3-Glucokinase reaction is reversed by glucose-6-phosphatase.

G-6-P G-6-phosphatase Glucose

H2O Pi

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Gluconeogenic Precursors:

1-Lactate:
It is released from skeletal muscles during exercise. Then, via
Cori's cycle, it is transferred to the liver to form pyruvate then
glucose.

2-Glycerol:
Produced from the digestion of fats and from lipolysis:

Glycerol Glycerkinase α-Glycerol phosphate

ATP ADP

Dehydrogenase

Glucose Dihydroxy-acetone-phosphate
Glycolysis

3-Glucogenic amino acids:

Some amino acids by deamination give pyruvate or oxaloacetate
directly. Others give intermediates of Krebs’ cycle as α-
ketoglutarate, succinate and fumarate then glucose.
e.g.: Glutamic acid α-ketoglutarate
Aspartic acid oxaloacetic acid.
Alanine Pyruvic acid

4-Propionyl~CoA gives succinyl-CoA:

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 Lipogenesis
It is the formation of triglycerides from carbohydrates.
This process takes place in liver and adipose tissue and is
stimulated by insulin. The following is a summary for the
process:

Glycolysis G.6.P Glycolysis

Pyruvic
Dihydroxy acetone-P
Oxid.
Decarboxylation

Reduction Active acetate

ATP
HMP Condensation

NADPH
α-glycerol-P Triglycerides
Fatty acids

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 Blood Glucose and Its Regulation
Sources of blood glucose:
1. Dietary carbohydrates.
2. glycogenolysis.
3. gluconeogenesis.

Concentration of blood glucose:

Normal fasting blood glucose (8-12) hours after last meal
is 70-105 mg/dl. It increases after meal but returns to fasting
level within two hours.

Regulation of blood glucose:

Four factors are important in regulating blood glucose level:
I- Gastrointestinal tract.
II- Liver
III-Kidney
IV-Hormones

[I] Gastrointestinal tract:

1. Maximum rate of absorption of glucose is one g/kg body

weight/hour. An average person weighing 70 kg will
absorb 70 g glucose per hour.
2. Glucose given orally stimulates more insulin than
intravenous glucose. This may be due to secretion of
glucagon like substance by intestine which stimulates β-
cells of pancreas to secrete more insulin. This is called
anticipatory action.

[II] Liver (role of liver in carbohydrate metabolism)

Liver is considered to be the main glucostat in the body; i.e.

it tries to maintain the blood glucose level within normal by the
following mechanisms:
1. If the blood glucose level increases, it decreases this high
level through:

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 a. Oxidation of glucose via the major and minor
pathways.
b. Glycogenesis.
c. Lipogenesis.
2. If the blood glucose level decreases, it will increase it
through:
a. Glycogenolysis.
b. Gluconeogenesis.
c. Interconversion of different hexoses as fructose and
galactose into glucose.

[III] Kidney:

All glucose in the blood is filtered through the kidneys,

then completely returned to blood by tubular reabsorption via
phosphorylation mechanism. If blood glucose level exceeds the
renal threshold, it will pass to the urine (glucosuria).
Renal threshold is the maximum rate of reabsorption of glucose
by the renal tubules. Normally, the renal threshold for glucose is
180 mg/100 ml.

[IV] Hormones:

1. Anterior pituitary hormones:

Growth hormone and ACTH are hyperglycemic hormones
that elevate the blood glucose level by:
 Inhibition of glucose uptake by peripheral tissue.
 Stimulation of gluconeogenesis.
2. Thyroxin: increases the blod level by:
 increasing the rate of absorption of glucose from
intestine.
 Stimulation of gluconeogenesis and glycogenolysis.
 Inhibition of glycogenolysis.
3. Adrenaline:
It increases the blood glucose level by increasing
glycogenolysis.
4. Glucagon:

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 Hyperglycemic factor secreted by alpha cells of pancreas.
It stimulates glycogenolysis.
5. Insulin: (Hypoglycemic hormone):
It is a protein hormone secreted by beta-cells of islets of
Langerhans of the pancreas.

Chemistry of insulin:
Insulin contains 51 amino acids arranged in 2 chains, A-chain
containing 21 amino acids, and B-chain containing 30 amino
acids. The two chains are linked together through disulphide
linkages-S-S.

Mechanism of action:
Insulin is the only hypoglycemic hormone. It decreases the
blood glucose level by the following mechanisms:
1-It stimulates the transfer of glucose to the intracellular
compartment.
2- It stimulates the oxidation of glucose as it exerts a
suppressive effect on the synthesis of enzymes responsible for
reversal of glycolysis.
3- It stimulates glycogenesis as it enhances glycogen synthetase
activity.
4- It inhibits glycogenolysis by inhibiting phosphorylase
through cAMP.
5- It inhibits gluconeogenesis by promoting synthesis of proteins
from amino acids.
6- It stimulates lipogenesis by oxidation of glucose which
supplies active acetate, α-glycerol-P, NADPH and ATP.

25
Catabolism of Insulin:
Insulin is inactivated mainly in the liver, but also in the kidney
and muscles by the enzyme insulinase which causes reductive
cleavage of S-S bonds.

Mechanism of blood glucose regulation: (Glucose

Homeostasis)
The blood glucose level is regulated by the balance between the
action of insulin and anti-insulin hormones (hyperglycemic
hormones). After a carbohydrate meal the blood glucose level
increases, stimulates the secretion of insulin which tends to
decrease the blood glucose level. On the other hand during
fasting, the blood glucose level decreases stimulating the
secretion of anti-insulin hormones (hyperglycemic hormones)
which increase the blood glucose level. So, it is clear that there
are factors adding glucose to blood and others removing it from
blood (opposing factors). The result is a condition of glucose
equilibrium; this is "Homeostatic Mechanism".

Glucose Tolerance

It is the ability of the body to utilize glucose. It is

determined by the nature of the blood sugar curve following the
administration of a known amount of glucose (oral glucose
tolerance test).

Oral glucose tolerance test (OGTT):

The patient is given orally one g of glucose/kg body

weight or a standard dose between 50-100 grams glucose. This
is done 12 hours fasting. Samples of blood and urine are taken
before the administration of glucose and at intervals of half an
hour after, for 3 hours.

The concentration of glucose in blood is measured and

plotted against time. Detection of glucosuria is also reported.
Normally the fasting blood sugar is 70-105 mg/100ml which

26
increases to a maximum of about 120-150mg/100ml in one hour
due to absorption of glucose.

At the end of 2.5 hours a return almost to fasting level

occurs, preceded by a drop of glucose level due to lag in the
regulatory mechanisms.

%Mg

180 Renal threshold

160
Utilization Diabetic
120 Insulin
Absorption

80
Normal
1
F /2 1 11/2 2 Time
Oral Glucose Tolerance Curve

27
 Diabetes Mellitus

This is a metabolic disease characterized by a decrease in the

ratio between insulin and anti-insulin hormones.

Types and Causes:

There are two main types of Diabetes Mellitus:
I-Primary: Due to decreased action of Insulin.
II-Secondary: Due to increased elaboration of the antagonistic
hormones ,e.g. thyroxin, corticoids, growth hormone.

Primary Diabetes includes Type I and Type II.

Type I (Juvenile): Due to decreased production of insulin , e.g.
due to atrophy of β-cells.
Type II (Maturity onset): Due to insulin resistance.

Symptoms: 1-Polyuria. 2-Polydepsia.

3-Polyphagia. 4-Loss of weight.

Metabolic disturbances:
A- Carbohydrate disturbances:
1. Hyperglycemia due to decreased ability of the peripheral
tissues to take up glucose.
2. Glucosuria.
3. Excessive gluconeogenesis.
B- Fat disturbances
1. Increased lipolysis.
2. Ketosis: FA is oxidized in the liver into acetyl-CoA which
exceeds the capacity of the Krebs’cycle. Condensation of
acetyl-CoA ketone bodies which increase in
blood (Ketonemia) and urine (Ketonuria).
C-Protein disturbances:
1. Negative N2 balance.
2. N2 in urine increases.
3. Protein synthesis decreased.

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Degree of diabetes:
1. Mild diabetes: Fasting blood glucose 120-150 mg/100ml.
2. Moderate diabetes: Fasting blood glucose 150-180
mg/100ml.
3. Severe diabetes: Fasting blood glucose more than 180
mg/100ml.

Detection of diabetes: (by glucose tolerance test)

The blood sugar curve of diabetics after oral glucose
administration is characterized by:
1. Higher fasting blood glucose level than normal.
2. Maximal level of blood glucose is greater than
180mg/100ml.
3. Slower return to fasting level.
4. Glucosuria: Glucose is detected in urine in one or more
samples during OGTT. In severe diabetes, glucose is
detected in urine even in the fasting sample.

Glucosuria

Definition: Presence of detectable amounts of glucose in urine

(normally glucose excreted in urine in an amount which can’t
be detected by the ordinary methods.)

Causes:
1. Diabetes mellitus glucosuria: discussed before
2. Adrenaline glucosuria: (emotional glucosuria ).
Stress,fear and anxiety  stimulate adrenaline secretion
 hyperglycemia, if it rises above the adrenal threshold
glucosuria.
3. Renal glucosuria: Due to abnormally decreased renal
threshold, which is a pathological condition.
4. Alimentary glucosuria: Due to ingestion of large
amounts of carbohydrates after deprivation.

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5. Pregnancy glucosuria: occurs in 20% of pregnancies. It
is partly due to decreased renal threshold and partly due to
decreased glucose tolerance.
6. Phlorrhizin glucosuria: Phlorrhizin inhibits
phosphorylation of glucose in the kidney  glucosuria.

Detection of glucosuria:
1. Reduction of Fehling and Benedict solutions by
glucose in the urine. Benedict is more sensitive than
Benedict as Benedict, being less alkaline, will not be
reduced by other reducing substances in urine, e.g. Vit.
C, uric acid or creatinine.
2. Glucose strips.

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 Lipid Metabolism
Dietary Lipids:
1. Triglycerides: present mainly in meat, liver &butter.
2. Phospholipids: in liver, brain & meat.
3. Cholesterol: in egg yolk & liver.
4. Fat soluble vitamins: (A, D, E, K).

Importance: Fat is a good source of energy, as 1 gram yields

9.3 calories.

Digestion
A-Triglycerides: (TG)
1. In the mouth: No digestion due to absence of the
lipolytic enzymes.
2. In the stomach: By gastric lipase only in infants as
the pH is suitable.
3. In the intestine:

Lipase Lipase
TG 1,2 –Diacylglycerol 2- monoacylglycerol
H2O R3 H2O R1

Isomerase

Lipase
Glycerol 1-Monoacylglycerol
R2 H2O

Intestinal lipase is present inside the cells and is of low activity.

- 25% of TG are complerely digested into glycerol and
3 fatty acids.
- 75% of TG are partially digested into 2 fatty acids
and 2- monoglyceride and few 1-mono-glyceride and 2 fatty
acids.

B-Cholesterol:
Pancreatic
Cholesteryl ester Cholesterol + fatty acids
Sterol esterase

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 C-Phospholipids:

Pancreatic Phospholipase
Phospholipids Lysophospholipids +FA
H2O

Absorption
The digested lipids undergoing absorption from the small
intestine consist of a mixture of monoglycerides and fatty
acids, with much smaller amount of di- and triglycerides.
This mixture, in combination with bile salts, becomes highly
emulsified forming very fine absorbable particles called
"micelles".
Glycerol is absorbed by diffusion, short chain fatty acids go to
the portal vein. Long chain fatty acids are activated as follows:

Thiokinase
R-COOH + CoASH R-Co~SCoA
(acyl-CoA)

Cholesterolmonoglycerides
Chylomicrons TG
Phospholipids diglycerides
+ Proteins
Glycerol-P
Intestinal Phosphatidic (from glycolysis)
lymphatics acid

Defects in digestion and absorption of fats:

- Steatorrhea (fatty diarrhea):
It is the presence of large amounts of fats in stools due to:
1- Deficiency of pancreatic lipase as in obstruction of
pancreatic duct or after pancreatectomy or chronic
pancreatitis.

32
 2- Deficiency of bile salts as in obstruction of bile duct and
also in hepatitis.
3- Diseased epithelial wall (malabsorption syndromes).

Plasma lipids
(400-700 mg %)

Cholesterol TG Phospholipids FFA

(120-240 mg%) (50-150 mg%) (150-250 mg%) (30-90 mg%)

- All plasma lipids are attached to the water soluble proteins

to form lipoprotein and can be transferred in the plasma.
- Plasma lipoproteins can be separated by:
1- Electrophoresis.
2- Ultracentrifugation: depends on the density of
the lipoproteins.
- After fatty meal, the amount of plasma lipids increases
post-prandial lipemia), causing turbidity of the plasma.
This turbidity is cleared by lipoprotein lipase which is
activated by heparin.

Fate of absorbed fats

1-Uptake by tissues:
Absorbed chylomicrons are taken up by tissues after
hydrolysis to glycerol and fatty acids.

Chylomicrons  Fatty acids  extrahepatic tissues  blood


Glycerol

Liver, kidney
2-Utilization by tissues:
a- Oxidation of fatty acids.
b- Conversion to glucose.

33
c- Formation of tissue fat.
3-Storage: in the form of depot fat.
4- Excretion: by sebaceous glands in sebum or by lactating
mammary glands into milk.

Oxidation of Fatty Acids

The major pathway for oxidation of saturated, even number

fatty acids is the β-oxidation to form acetyl- CoA and energy.

Site: In the mitochondria of tissues especially of liver.

Steps: See the diagram.

Comments:
1. Fatty acids oxidation is a major source of energy during
starvation.
2. Energy yield: Oxidation of one mole of palmitic acid
(16 C) results in the production of 8 acetyl- CoA by
passing through (7) β-oxidation cycles. Each β-
oxidation cycle yields one molecule of FADH2 and one
NADH+H+, the hydrogens of which are oxidized via the
respiratory chain forming 5 ATP. Thus we get 5X 7 = 35
ATP from oxidation of palmitic acid to acetyl- CoA. 8
moles of acetyl- CoA, by oxidation in Krebs’ cycle
yield 12 X 8 = 96 ATP.
Thus the total gain is 35 + 96 = 131 ATP. Since 2 ATPs were lost
in the activation of FA into acetyl-CoA , therefore the net is 131-
2=129 ATP.

34
35
Origin of acetyl-CoA (active acetate):
1- From carbohydrates:

glycolysis oxidative
Glucose pyruvic acid
decarboxylation
Acetyl-CoA

2- From fats:
glycolysis
TG Glycerol Pyruvic acid

β - oxidation
FA acetyl- CoA.

2- From proteins:
Ketogenic amino acids  acetyl-CoA.
Glucogenic amino acids  pyruvic acid.

Fate of Acetyl – CoA:

Acetyl-CoA:

oxaloacetate Citrate  Krebs’ cycle  CO2 + H2O + E

Fatty Acids  TG

Ketone bodies

Cholesterol

Acetylcholine and N-acetyl-glucosamine

36
 Lipogenesis

Definition: This is the biosynthesis of TG mainly from

glucose in adipose tissue, liver and lactating mammary
gland.
It is concerned with the storage of excess glucose. It
includes:
1- Synthesis of fatty acids, then by activation forming
acyl – CoA.
2- Synthesis of glycerol phosphate from glycerol.
3- Condensation of acyl-CoA + α-glycerol phosphate
 TG  Depot fat.
Lipogenesis is stimulated by insulin.

Depot Fat (Variable Element)

It is the fat stored in fat cells of adipose tissue. Its amount varies
according to the nutritional state of the individual and so it is
called the variable element.
a) Origin of depot fat:
1. Excess fat in diet.
2. Lipogenesis.

b) Composition: it consists mainly of TG and is generally

rich in saturated fatty acids.
c) Importance:
1. Storage of energy.
2. Heat insulator
d) Fate of depot fat:
Triaclyglycerol of adipose tissues are continually
undergoing hydrolysis (lipolysis) and re-esterification. The
resultant of these 2 processes determines the amount of FA
released from adipose tissues into the blood.

37
 Lipolysis
It is the hydrolysis of TG from the adipose tissues to glycerol
and fatty acids, then via blood to the liver

TG Hormone Sensitive Fatty acidsbloodliver

Lipase

Regulation of lipolysis:
Lipolysis is controlled by the hormone sensitive lipase which is
present in 2 forms
1. Phosphorylated form(active).
2. Dephosphorylated form (inactive).

Thyroxin, Adrenaline, Glucagon Insulin Caffeine

+ + -

Adenyl cyclase Phosphodiesterase

ATP 3,5 cAMP AMP
PPi H2O
+ P

Hormone Sensitive
Hormone Sensitive Protein Kinase Lipase (Inactive)
Lipase (Inactive)
ATP Mg2+ ADP

Synthase Phosphatase

Pi H2O

38
 Tissue fat (constant element)
It is the fats present in every cell, its amount is not affected
by nutritional state (constant).
1. Composition: mainly phospholipids and cholesterol, fatty
acids are mainly unsaturated.
2. Importance:
a. In plasma membrane, it regulates its permeability.
b. In mitochondria, it is an important component of
respiratory chain enzymes.
c. In myelin sheath acts as insulator to nerve impulses.
Differences between depot fat and tissue fat:
Depot fat Tissue fat
1-Variable -Constant.
2-Present in certain tissues as -Present in every cell.
adipose tissue.
3-Composition:
A-Mainly neutral fat. -Mainly cholesterol,
phospholipids and glycolipids.
B-Fatty acids present are mainly -Unsaturated fatty acids mainly.
saturated fatty acids.
4-Imprtance: -Regulates permeability of
A-Storage of energy. plasma membrane.
B-Heat insulator -Important component of
respiratory chain enzymes in
mitochondria .
-Insulator to nerve impulses in
myelin sheath.

39
 Ketone Body Metabolism

Types:
1- Acetoacetic acid CH3-CO- CH2-COOH
2- β-hydroxybuteric acid CH3-CHOH- CH2-COOH
3- Acetone CH3-CO- CH3

1- Ketogenesis:
It is the synthesis of ketone bodies in the mitochondria of the
liver from acetyl-CoA.

Thiolase
Acetyl-CoA Acetoacetyl-CoA
H2O
Acetyl-CoA CoASH
Acetyl-CoA

HMG-CoA-
Synthase
CoASH

Hydroxy methyl glutryl-CoA

HMG-CoA Lyase
Acetyl-CoA

Acetone Acetoacetic acid

NADH + H+
CO2

NAD+
β-hydroxybuteric acid

40
 Regulation of ketogenesis:
- Ketogenesis increases during starvation, high fat meal and low
carbohydrate in diet.
- It decreases after carbohydrate and protein feeding.

2- Ketolysis:
It is the complete oxidation of ketone bodies to CO2, H2O and
energy. This occurs mainly in the mitochondria of extrahepatic
tissues due to high activity of thiophorase and acetoacetate
thiokinase.

β-hydroxybuteric acid
NAD+
Dehydrogenases

NADH + H+

Succinyl-CoA Acetoacetic acid ATP

Thiopherase Acetacetate-
thiokinase
Acetoacetyl-CoA AMP+PPi
Succinic acid
CoASH Thiolase

2 Acetyl-CoA
Oxaloacetate CO2+H2O+Energy
Krebs’ Cycle

Regulation of ketolysis:
Ketolysis increases by insulin which increases oxidation of
glucose by tissues and decreases gluconeogenesis from
oxaloacetate.
Ketolysis decreases by anti-insulin hormones.

Importance:
It completes the oxidation of FA and it is a major source of
energy to extrahepatic tissues during starvation.

41
Ketosis:
It is a condition characterized by increased ketone bodies in the
blood (ketonemia) and in urine (ketonuria).

Causes:
This is due to excess production of ketone bodies in the liver
rather than due to deficiency in the utilization by extrahepatic
tissues.
It occurs in the following conditions:
1-Diabetes mellitus.
2- Starvation.
3- Excess fat in diet and low carbohydrate in diet.

Ketogenic substances: Are those leading to the formation of

acetoacetic acid, e.g. fatty acids and anti-insulin hormones.
Antiketogenic substances: Are those which lead to the
formation of utilizable carbohydrates. These are:
In normal person:
1- Diet rich in carbohydrates: Excess glucose
stimulates Krebs’ cycle.
2- Glucogenic amino acids.
In diabetic person: Insulin will stimulate carbohydrate
metabolism which will take active acetate into Krebs’ cycle.

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 Cholesterol Metabolism

Sources:
1. From diet as egg yolk, liver and brain.
2. Synthesized in the body from acetyl-CoA.

Biosynthesis of cholesterol: In the cytoplasm of the cell, all

tissues can synthesize and degrade most of their cholesterol such
as the liver, intestine, adrenal cortex, testis, aorta and skin.
Plasma cholesterol is synthesized mainly in the liver and
intestine.

Transport of cholesterol in blood: Normal level of blood

cholesterol is 150-250 mg%. it is transported in blood in the
form of lipoproteins, 25% on α-lipoproteins and 75% on B-
lipoproteins. Also 150 mg/100ml of cholesterol are present in
blood in the form of cholesterol ester (esterified with fatty acids)
and 50 mg/100 ml as a free non esterified state.

Fate and importance of cholesterol:

1. Enters the structure of every cell.
2. It is oxidized in the liver into bile acids, this oxidation is
enhanced by thyroxin.
3. In the liver, oxidation of cholesterol also gives:
UVL
7-dehydrocholesterol
Under skin
Vitamin D3
4. Cholesterol in adrenal cortex, testis and ovaries gives
steroid hormones

Abnormal cholesterol metabolism:

a) Hypercholesterolemia: plasma cholesterol exceeds the normal
level, due to:
1. High fat and carbohydrate in diet.
2. Hypothyroidism, due to decrease in the oxidation into bile
acids.
3. Diabetes Mellitus.
4. Obstructive jaundice.

43
 5. Nephrosis.
b) Hypocholesterolemia: decrease in the level of cholesterol due
to:
1. Starvation.
2. Low carbohydrate and fat in diet.
3. Liver disease.
4. Hyperthyroidism.

Metabolism of Phospholipids

Sources:
1. Exogenous in diet such as eggs, brain and liver.
2. Endogenous: in all cells. Liver is responsible for plasma
phospholipid synthesis and degradation.
Level: the total plasma phospholipids are 200 mg/100ml : 60%
lecithin, 25% cephalins and 15% sphingomyelin.

Importance of phospholipids:
1. They enter in the structure of cell membrane and thus
affecting its permeability.
2. Intermediates in triglycerides absorption from
gastrointestinal tract as well as their biosynthesis in liver
and adipose tissue.
3. Sphingomyelin acts as electric insulator, so play a role in
nerve impulse conduction.
4. In blood clotting; factor III and IV are phospholipids in
nature.
5. Important for some enzymatic actionm e.g. cytochromes.
Degradation: by phospholipases.

Fatty liver

The lipid content of the normal liver is approximately 4%

of which only about 30% is triglycerides. The other 70% are
phospholipids and cholesterol. Fatty liver is the accumulation of
excessive amounts of lipids mainly triglycerides in the liver. In
severe cases, it may reach up to 40% of the liver weight. If the

44
condition is prolonged, the liver cells die and become replaced
with fibrous tissue leading to liver cirrhosis and impaired liver
functions.
4. Decreased oxidation
1. Over feeding of Of fatty acids as in
Carbohydrates. ++ -- Deficiency of carnitine and
pantothenic acid (CoA).
2. Over feeding of 5. Decreased mobilization of
Fat. ++ fat from liver to blood as
e.g. in:
3. Over mobilization LIVER Deficiency of essential
-- amino acids.
Of fat from depot
Toxic factors as CCl4
liver. ++
cloroform, phosphorus
arcenic.
Abetalipoproteinemia.

6. Decreased phospholipids
-- synthesis e.g. in:
Deficiency of essential
fatty acids.
Deficiency of choline.
Deficiency of inositol

Lipotropic factors: there are factors which help the

mobilization of fat from the liver. They include the substances
essential for the biosynthesis of phospholipids and proteins, thus
helping the formation of lipoproteins which are necessary for
the mobilization of triglyceride from the liver. They include:

I-Substances important for synthesis of proteins: Essential

amino acids.
II-Substances important for synthesis of phospholipids:
a) Essential fatty acids
b) Inositol
c) Choline
d) Factors important for choline synthesis:
1. Substances containing labile methyl groups as methionine
and glycine betaine.
2. Substances involved in synthesis of methyl groups as folic
acid and vitamin B12.

45