Carbohydrates pdf - د. سمير

Carbohydrates

[CHO]

Chemistry of Carbohydrates

  All  carbohydrates  contain  C          O  &OH-functional  groups  &
are classified into:

1-Monosaccharides... Simple sugar that can not hydrolyzed to a
simpler form, it may contain three, four, five, six or more carbon
atoms known respectively as trioses, tetroses, pentoses, hexoses
& so on.
  Monosaccharides  may  be  aldoses  or  ketoses  depending  upon
whether  they  have  an  aldehyde  or  ketone  group  respectively.
Most  important  monosaccharides  are  hexoses  like  glucose,
galactose  &  fructose  which  are  reducing  substances  because  it
contains aldehyde or ketone groups.
  Monosaccharides  have  stereoisomer  property  which  could  be
D  (common)  or  of  its  mirror  image  L  (D  on  right  &  L  on  left)
depending  on  position  of  hydroxyl  group  at  carbon  atom
adjacent to the terminal alcohol carbon ((C

in glucose))

2-Disaccharides...  They  are  products  of  chemical  reaction
between two monosaccharides with loss  of a molecule of water
(can be hydrolyzed), the linkage between two  monosaccharides
known as glycosidic link.
Examples of disaccharides are maltose, lactose & sucrose.
  If the glycosidic link between aldehyde or ketone group of one
monosaccharide

the

hydroxyl

group

another

monosaccharide  the  produced  disaccharide  have  reducing
property as in maltose (glucose + glucose) & lactose (glucose +
galactose  )  while  if  the  glycosidic  link  between  aldehyde  or
ketone  group  of  the  two  molecules  of  monosaccharide  the
produced  disaccharide  have  no  reducing  property  as  in  sucrose
(glucose + fructose).

3-Oligosaccharides...They  are  products  of  condensation  of  3-
10 monosaccharide units as in maltotriose.

4-Polysaccharides…  They  are  products  of  condensation  of
more than 10 monosaccharide units; examples are:-

A-Starch-  Polysaccharide  of  plant  origin  consist  of  amylose
(one  unbranched  chain  of  glucose  molecules  linked  by  α-1,  4-
glucosidic  linkages  with  only  terminal  aldehyde  is  free)  &
amylopectin  (contain  α-1,  4-glucosidic  linkages  +  α-1,  6-
branched glucosidic linkages of glucose molecules).
B-Glycogen-Polysaccharide  of  animal  origin,  it  has  structure
similar to amylopectin except that branching is more extensive.

Fate of Carbohydrates

  Carbohydrates  account  for  a  large  proportion  of  daily  intake,
dietary digestible  carbohydrates include mainly starch , sucrose
and to less extent lactose.
  In order of carbohydrates to be absorbed it should be converted
to monosaccharides by digestion.
  The absorbed monosaccharides (glucose, fructose & galactose)
from small intestine reach the liver through portal vein, glucose
is the only carbohydrate to be directly used for energy  or stored
as glycogen while galactose & fructose are mainly converted to
glucose in the liver before they can be used.
Pentoses  as  xylose,  arabinose  &  ribose  are  important  in
nucleotides, nucleic acids & several coenzymes.
  Carbohydrate  (mainly  glucose)  is  a  main  source  of  human
energy  &  it  is  a  unique  source  of  energy  to  some  tissues  as
nervous  system  including  the  brain  &  in  RBC,  therefore,  we
concern with glucose.
  After absorption of glucose it converted to glucose-6 phosphate
inside the cells which may follow one of the following pathways
depending  on  energy  requirement,  type  of  tissue  &  state  of
glycogen storage.
1-Glycolysis… Produce energy.
2-Hexose  monophosphate  shunt  {phosphogluconate  oxidative
pathway, pentose phosphate pathway}...Nucleotide synthesis.
3-Glycogenesis... Storage.

Glycolysis

   Glycolysis  is  the  major  pathway  for  glucose  metabolism,
occurs  in  the  cytosol  of  all  cells  ((outside  the  mitochondria))
through  Embden-Meyerhof  pathway.  Its  unique  in  that  it  can
function either aerobically  or anaerobically,  however , anaerobic
conditions limit the amount of energy liberated /mole of glucose
, therefore , more glucose are needed..
To  oxidize  glucose  beyond  pyruvate  (the  end  product  of
glycolysis)  requires  oxygen,  mitochondrial  enzyme  system
,

the

citric

acid

cycle

the

respiratory

chain.

The ability of glycolysis to provide ATP in the anaerobic
conditions are especially important in RBC which lack
mitochondria & completely depend on glucose as their metabolic
fuel,

also

skeletal

muscle

anoxic

episodes.

However,  in  heart  muscle,  which  is  adapted  for  aerobic
performance,  has  relatively  low  glycolytic  activity  &  poor
survival under conditions of ischemia.

The  steps  of  glycolysis  ((Embden-Meyerhof  pathway))  are  the
followings:
Reaction 1: Phosphate Ester Synthesis
  In  all  body  tissues  except  the  liver,  brain  &  pancreatic  β  islet
cells,  the  transport  of  glucose  into  the  cell  is  regulated  by
insulin.
  Following  entry  of  glucose into the cells , phosphate is added
to the glucose present in the cytoplasm at the C-6 position using
ATP as the phosphate donor in the presence of magnesium ion,
this  reaction  is  irreversible  inhibited by its product ((glucose 6-
phosphate))  &  it's  catalyzed  by  the  enzymes  hexokinase  or
glucokinase.

Glucose + ATP

Glucose 6-P+ADP

Hexokinase

Glucokinase

  Hexokinase has a high affinity for its substrate (glucose) & its
even  act  at  lower  speed  on  other  hexoses,  in  the  liver  &
pancreatic β islet cells hexokinase is saturated under all normal
conditions,  therefore,  both  the  liver  &  pancreatic  β  islet  cells
also  contain  an  isoenzyme  of  hexokinase  called  glucokinase,
which has lower affinity for its substrate (specific on glucose) so
it acts at a higher glucose concentration.
  The  function  of  glucokinase  in  the  liver  is  to  remove  glucose
from the blood following a meal, providing glucose 6-phosphate
in excess of requirements for glycolysis, which will be used for
glycogen synthesis and lipogenesis.
  In  the  pancreas,  the  glucose

6-phosphate formed by

glucokinase signals increased glucose availability & leads to the
secretion of insulin.

Glucose 6-phosphate is an important compound at the junction

of several metabolic pathways (glycolysis, gluconeogenesis,

pentose phosphate pathway, glycogenesis & glycogenolysis).

Reaction 2: Isomerization
The glucose-6-phosphate is changed into an isomer, fructose-6-
phosphate. This means that the number of atoms is unchanged,
but their positions have changed (aldose to ketose conversion)
.This reversible reaction is catalyzed by phosphohexose
isomerase (phosphoglucoisomerase) enzyme.

Glucose-6-P Phosphohexose Fructose-6-p
Isomerase

Reaction 3: Phosphate Ester Synthesis
This reaction is virtually identical to reaction 1. The fructose-6-
phosphate is reacted with phosphate from ATP to make
fructose-1, 6 -bisphosphate again this reaction using ATP as the
phosphate donor in the presence of magnesium ion.

This reaction is irreversible, catalyzed by phosphofructokinase
enzyme & it has a major role in regulating the rate of glycolysis.

Fructose-6-P + ATP

Mg

Phosphofructokinase

Fructose-1, 6-bisphosphate + ADP

Reaction 4: Split Molecule in half
The six carbon fructose-1, 6-bisphosphate is split into two
trioses phosphate carbon compounds which are
dihydroxyacetone-phosphate & glyceraldehyde 3-phosphate
.The slit is made between the C-3 and C-4 of the fructose. This
reversible reaction is catalyzed by Aldolase enzyme.

The dihydroxyacetone phosphate & glyceraldehyde-3-phosphate

are interconverted by the enzyme phosphotriose

isomerase.

Fructose-1, 6-bisphosphate

Aldolase

Dihydroxyacetone-                   Glyceraldehyde
phosphate                                    3-phosphate
                       Phosphotriose
                           Isomerase

Reaction 5: Oxidation/Phosphate Ester Synthesis
This reversible reaction is first an oxidation involving the
coenzyme NAD

. Glyceraldehyde 3-phosphate is oxidized to an

acid as an intermediate through the conversion of NAD

NADH + H

. Then an inorganic phosphate (Pi) is added in a

phosphate ester synthesis to form 1, 3-bisphosphoglycerate.
This and all the remaining reactions occur twice for each
glucose-6-phosphate (six carbons), since there are now two
molecules of 3-carbons each.

This reaction is catalyzed by glyceraldehyde-3-phosphate
dehydrogenase enzyme which is a tetramer (consist of four
monomers) containing SH-groups , therefore , this
dehydrogenase enzyme may be inactivated by SH poison
iodoacetate which stop glycolysis at this point , therefore ,
iodoacetate used as a preservative of blood sample to prevent in
vitro glycolysis .

Glyceraldehyde 3-phosphate +NAD

Pi Glyceraldehyde-3-

phosphate dehydrogenase

1, 3-bisphosphoglycerate+ NADH + H

Reaction 6: Hydrolysis of Phosphate; Synthesis of ATP
One of the phosphate groups of 1, 3-bisphosphoglycerate
undergoes hydrolysis to form 3-phosphoglycerate and a
phosphate ion is transferred directly to an ADP to make ATP,
therefore, at this stage two molecules of ATP are produced /
molecule of glucose undergo glycolysis, this reversible reaction
is catalyzed by Phosphoglycerate kinase enzyme in the
presence of magnesium ion.

1, 3-bisphosphoglycerate + ADP

Mg

Phosphoglycerate kinase

3-phosphoglycerate + ATP

The toxicity of arsenic is due to competition of arsenate with inorganic
phosphate in the above reactions to give l-arseno-3-phosphoglycerate,
which hydrolyzes spontaneously to give 3-phosphoglycerate + heat,
without generating ATP.

Reaction 7: Isomerization
In this reaction the phosphate group moves from the 3 position of 3-
phosphoglycerate to the 2 position in an isomerization reaction
producing 2-phosphoglycerate.
This reversible reaction is catalyzed by Phosphoglycerate mutase
enzyme.

3-phosphoglycerate

Phosphoglycerate mutase.

2-phosphoglycerate

Reaction 8: Alcohol Dehydration (Enolation)
In this reversible reaction, dehydration of 2-phosphoglycerate
forming phosphoenolpyruvate, this reaction is catalyzed by
Enolase enzyme which is dependent on the presence of either
Mg

or Mn

ions

& inhibited by fluoride which is used as a

preservative of blood sample to prevent in vitro glycolysis in the
estimation of glucose.

/ Mn

2-phosphoglycerate Phosphoenolpyruvate

Enolase

+ H

Reaction 9: Phosphate Ester Hydrolysis, Synthesis of ATP
this is the final reaction in glycolysis. phosphate group of
phosphoenolpyruvate is transferred to ADP forming ATP while
Phosphoenolpyruvate is converted into enolpyruvate which
undergoes spontaneous (nonenzymic) isomerization to pyruvate
,therefore , at this stage two molecules of ATP are produced /
molecule of glucose undergo glycolysis.
This irreversible reaction is catalyzed by pyruvate kinase
enzyme in the presence of magnesium.

Phosphoenolpyruvate + ADP

Pyruvate kinase

Pyruvate + ATP

Fate of pyruvate depending on availability of aerobic or
anaerobic conditions:
1-Aerobic condition: pyruvate is transported from the cytoplasm
to the mitochondria via special pyruvate transporter & within
the mitochondria it's oxidatively decarboxylated into acetyl Co-
A (active acetate) by several different enzymes working
sequentially in a multienzyme complex called collectively as
pyruvate dehydrogenase complex system.

Pyruvate + NAD

+ CoA-SH

Pyruvate dehydrogenase complex

Acetyl CoA+NADH+H

+CO

The presence of arsenate or deficiency of thiamin inhibit
pyruvate dehydrogenase allowing pyruvate to accumulate , also
it is inhibited by the product (Acetyl CoA) , therefore , any
source that give rise to acetyl Co-A can inhibit pyruvate
dehydrogenase system as amino acids & fatty acids.
Acetyl Co-A enter citric acid cycle for further energy
production.
2-Anaerobic condition : pyruvate is reduced to lactate by
NADH

produced in reaction( 5) of glycolysis, this reversible

reaction catalyzed by lactate dehydrogenase enzyme with
production of NAD

allowing glycolysis to proceed in anaerobic

conditions by regenerating sufficient NAD

for reaction( 5) to

continue.

Pyruvate+NADH+H

lactate

Lactate+NAD

dehydrogenase

Therefore, tissues that can function under hypoxic condition can
produce lactate as in skeletal muscle & RBC (even under
aerobic condition because it has no mitochondria).

Conclusion

1-Glycolysis is represented simply as:
glucose + 2 NAD

+ 2 ADP + 2 P 2 pyruvate + 2 ATP + 2

NADH + 2 H

2-Glucose with six carbons is converted into two pyruvate
molecules with three carbons each. The ATP produced is as
follow:-

A-Anaerobic  conditions:-2  ATP  are  produced  (2ATP  produced
at  reaction  6  +  2  ATP  at  reaction  9  -  2ATP  consumed  at
reactions 1 &3).
B-Aerobic conditions:-
  2 ATP are produced as in anaerobic conditions.

5 ATP are produced from entrance of two NADH

molecules

produced at reaction 5 to respiratory chain (each NADH

molecule produce 2.5 ATP molecules)

+5 ATP molecules generated by entrance of two NADH

molecules  (produced  from  conversion  of  two  molecules  of
pyruvate  into  two  molecules  of  acetyl-CoA  /  one  molecule  of
glucose) to respiratory chain.
+ 20 ATP are produced from the citric acid cycle.
Therefore  the  total  ATP  molecules  that  produced  at  aerobic
conditions are 2+5+5+20= 32 ATP molecules.
3-Three  reactions  ((1,  3,  and  9))  are  irreversible  regulating
glycolysis while the rest of reactions are reversible.
4-Glycolysis  reaction  can  be  blocked  at  reaction  5  by
iodoacetate & at reaction 8 by fluoride, therefore, iodoacetate &
fluoride  are  used  as  preservative  of  blood  sample  for  glucose
estimation.

Clinical Aspects

1-Inhibition  of  Pyruvate  Metabolism  Leads  to  Lactic  Acidosis,
the main causes of this inhibition are:-
A-Arsenite inhibit pyruvate dehydrogenase complex.
B-Thiamin is a coenzyme for pyruvate dehydrogenase, therefore,
its deficiency lead to lactic acidosis..

C-Inherited  pyruvate  dehydrogenase  deficiency  presented  with
lactic acidosis, particularly after a glucose load.
Because  of  its  dependence  on  glucose  as  a  fuel.  ,  brain  is  a
prominent  tissue  where  these  metabolic  defects  manifest
themselves in neurological disturbances.
2-  Inherited  aldolase  deficiency  &  pyruvate  kinase  deficiency  in
erythrocytes cause hemolytic anemia.
3-

The

exercise

capacity

patients

with

muscle

phosphofructokinase deficiency is low, particularly on high-
carbohydrate diets.
4- Competition of arsenate with inorganic phosphate to give l-
arseno-3-phosphoglycerate, which hydrolyzes spontaneously to give
3-phosphoglycerate + heat, without generating ATP.

Citric Acid Cycle {Krebs cycle , Tricarboxylic Acid Cycle }

It is a series of reactions discovered by Hans Krebs in 1937
occur in the mitochondria that oxidize acetyl-CoA to CO

in addition to the production of reducing equivalents (NADH

and FADH

) that upon reoxidation in the respiratory chain ATP

are formed.
Its dependant on oxygen availability, therefore, absence (anoxia)
or deficiency (hypoxia) of oxygen leads to total or partial
inhibition of the cycle respectively.

Overview of Acetyl Co- A Metabolism

1-Acetyl  Co-A  is  at  the  confluence  of  the  major  metabolic
pathways of carbohydrate, lipid & protein.
2-Acetyl  Co-A  serves  as  source  of  acetyl  units  in  the  anabolic
processes  responsible  for  synthesis  of  long  chain  fatty  acids,
cholesterol, steroid & ketone bodies.
3-Catabolism of acetyl Co-A in the citric acid cycle.

Importance of Citric Acid Cycle

1-Final  common  pathway  for  the  aerobic  oxidation  of
carbohydrate,  lipid  &  protein  because  glucose,  fatty  acids  &
most amino acids are metabolized to acetyl-CoA or intermediates
of the cycle.
2-Central role in gluconeogenesis,  lipogenesis & interconversion
of amino acids.
3-Liberation  of  much  free  energy  from  oxidation  of
carbohydrate, lipid & protein.
4-Formation of reducing equivalents which enter the respiratory
chain for energy production.

Reactions of Citric Acid Cycle

Reaction 1: Synthesis of Citrate
Condensation  of  acetyl  Co-A  &  oxaloacetate  to  form  citrate  &
release  of  CoA-SH,  this  irreversible  reaction  is  catalyzed  by
citrate synthase enzyme.

Acetyl Co-A + Oxaloacetate + H

Citrate synthase

Citrate + CoA-SH

Reaction 2: Dehydration & Rehydration
Citrate is isomerized to isocitrate by the enzyme aconitase
((aconitate hydratase)) in the presence of iron in the Fe

state.

This reversible reaction takes place in two steps :
Step 1/dehydration of citrate to cis-aconitate (intermediate)
which is enzyme bound.
Step 2 /rehydration of cis-aconitate to isocitrate.
The poison fluoroacetate is toxic because fluoroacetyl-CoA
condenses with oxaloacetate to form fluorocitrate, which inhibits
aconitase, causing citrate to accumulate.

Citrate
H

Aconitase Fe

Cis-aconitate
H

Aconitase Fe

Isocitrate

Reaction 3: Dehydrogenation & Decarboxylation
Isocitrate in the presence of NAD

is converted to

α-ketoglutarate

Although this reaction is reversible its directed

more toward the production of α-ketoglutarate & is catalyzed by
the enzyme isocitrate dehydrogenase & it occurs in two steps:

Step 1/dehydrogenation of isocitrate in the presence of NAD

oxalosuccinate ((intermediate& enzyme bound)) +NADH+H

Step2/decarboxylation of oxalosuccinate to α-ketoglutarate +
+CO

or Mg

is an important component of the

decarboxylation reaction.

Isocitrate + NAD

Isocitrate Dehydrogenase

Oxalosuccinate +NADH +H

Isocitrate Mn

++ /

Dehydrogenase

α-ketoglutarate +CO

Reaction 4:Oxidation&Decarboxylation (Oxidative decarboxylation)

α-ketoglutarate undergoes oxidative decarboxylation (similar to
conversion of pyruvate into acetyl Co-A) .This irreversible
reaction is catalyzed by α-ketoglutarate dehydrogenase
complex which require also identical cofactors to that of
pyruvate dehydrogenase as thiamin diphosphate& is inhibited
by arsenate causing accumulation of α-ketoglutarate.
In this reaction α-ketoglutarate in the presence of NAD

CoA-SH result in the formation of succinyl -CoA (contain high
energy bond) +NADH + H

+ CO

α-ketoglutarate + NAD

+ CoA-SH

α-ketoglutarate
dehydrogenase complex

Succinyl –CoA + CO

+ NADH + H

Reaction 5: Hydrolysis of Succinyl-CoA, Synthesis of ATP
Succinyl-CoA in the presence of ADP & inorganic phosphate
(Pi) is converted into succinate +ATP + CoA-SH.

This is the only reaction in the citric acid cycle include the
generation of ATP at substrate-level.
This reversible reaction is catalyzed by succinate thiokinase
enzyme in the presence of Mg

Succinate thiokinase also share in gluconeogenesis

Succinyl-CoA + Pi + ADP

Mg

Succinate thiokinase

Succinate + ATP +CoA-SH

Reaction 6: Dehydrogenation
Dehydrogenation of succinate into fumarate by transfer of
hydrogen directly from substrate into a flavoprotein it is the only
dehydrogenation reaction in the cycle involving direct transfer
of hydrogen from substrate into a flavoprotein, without
participation of NAD, this reversible reaction is catalyzed by
succinate dehydrogenase enzyme which is inhibited by
malonate resulting in succinate accumulation.

Succinate+FAD Fumarate+FADH

Succinate
dehydrogenase

Reaction 7: Hydration
Hydration of the double bond of fumarate to form L-Malate.
This reversible reaction is catalyzed by fumarase (fumarate
hydratase) enzyme.

Fumarate + H

O L-Malate

Fumarase

Reaction 8: Dehydrogenation
This is the final reaction of the citric acid cycle where
dehydrogenation of malate in the presence of NAD

into

oxaloacetate + NADH + H

.This reversible reaction is catalyzed

by the enzyme Malate dehydrogenase.
The oxaloacetate produced in this reaction condense with
acetyl-CoA (Reaction 1: Synthesis of Citrate) & so the cycle
continue again.

L-Malate +NAD

Malate dehydrogenase

Oxaloacetate + NADH + H

Energetic of Citric Acid Cycle

Reaction 3-produce oneNADH

molecule which

enter the

respiratory chain producing 2.5 ATP molecules .
Reaction 4- produce oneNADH

molecule which

enter the

respiratory chain producing 2.5 ATP molecules .
Reaction 5-produce 1 ATP molecule.
Reaction 6-produce one FADH

molecule which

enter the

respiratory chain producing 1.5 ATP molecules.
Reaction 8- produce oneNADH

molecule which

enter the

respiratory chain producing 2.5 ATP molecules.
Therefore , 10 ATP molecules are produced for each cycle
from one molecule of acetyl-CoA.
Energy produced of one molecule of glucose under aerobic
conditions when enter citric acid cycle is as follow:
7 ATP molecules up to pyruvate synthesis.
+5 ATP molecules generated by two NADH

molecules

produced from conversion of two molecules of pyruvate into
two molecules of acetyl-CoA / one molecule of glucose
+20 ATP molecules from entrance of two molecules of acetyl-
CoA / one molecule of glucose to citric acid cycle.
Therefore , 32 ATP molecules are produced.

Regulation of Citric Acid Cycle

1-Proper function of respiratory chain which depend mainly on
the availability of oxygen , ADP & NAD

2-Regulatory reactions ((irreversible or nearly irreversible)) in
the cycle which are:
Reaction 1: Synthesis of Citrate.
Reaction 3: Dehydrogenation & Decarboxylation.
Reaction 4:Oxidation&Decarboxylation (Oxidative decarboxylation).

Role of Vitamins in Citric Acid Cycle

Vitamins play a key role in the citric acid cycle.
(1) Riboflavin, in the form of flavin adenine dinucleotide (FAD)
in reaction 6 (Dehydrogenation).
(2) Niacin, in the form of nicotinamide adenine dinucleotide
(NAD) in three dehydrogenation reactions in the cycle (Reactions
3, 4&8).
(3) Thiamin,

as thiamin diphosphate, the coenzyme for

α-ketoglutarate dehydrogenase reaction.
(4) Pantothenic acid, as part of coenzyme A.

Clinical Aspects

The few genetic defects of citric acid cycle enzymes that have
been reported are associated with severe neurological damage as
a result of very considerably impaired ATP formation in the
central nervous system.

Glycogen is the major carbohydrate storage in animals including
human, it present mainly in:
1-liver: glycogen represent up to 5% of liver weight, its concern
with maintenance of blood glucose level between the meals.
After 12-18 hours of fasting the liver glycogen is almost totally
depleted.
2-Muscle: glycogen represent up to 0.7% of muscle weight but
because of great muscle mass its about 3-4 times to that of liver ,
its concern as a source of glucose for glycolysis within the
muscle itself.
Metabolisms of glycogen include synthesis (glycogenesis) &
degradation (glycogenolysis); these two processes are not
simply the reversal of one series of reactions but they are
separated reactions.

Glycogenesis

Glycogenesis is the process of glycogen synthesis, in which
glucose molecules are added to chains of glycogen.
Glycogen synthesis depends on the demand for glucose and
ATP (energy). If both are present in relatively high amounts,
then the excess of insulin promotes the glucose conversion into
glycogen for storage in liver and muscle cells.

Reaction 1
Glucose is phosphorylated to glucose 6-phosphate in irreversible
reaction catalyzed by hexokinase in muscle & glucokinase in
liver in the presence of magnesium ion.

Glucose+ATP Hexokinase Glucose 6-P+ADP
Glucokinase

Reaction 2
Glucose 6-phosphate is isomerized to glucose 1-phosphate in a
reversible reaction catalyzed by phosphoglucomutase enzyme
in the presence of magnesium ion.

Glucose6-p Glucose1-p

phosphoglucomutase

Reaction 3
Glucose 1-phosphate reacts with uridine triphosphate (UTP) to
form the active nucleotide uridine diphosphate glucose
(UDPGlc) & inorganic pyrophosphate (PPi); this reaction is
catalyzed by UDPGlc Pyrophosphorylase enzyme.

                                   UDPGlc
UTP+Glucose1-p                         UDPGlc+PPi
                            Pyrophosphorylase

Although this reaction is reversible but subsequent hydrolysis of
PPi pull the reaction to right.
Reaction 4
Glycogen synthase catalyzes the formation of a glucosidic bond
between C

of the activated glucose of UDPGlc and C

of a

terminal glucose residue of glycogen primer producing 1         4
Glucosyl units with liberation of uridine diphosphate (UDP).
Therefore the preexisting glycogen primer must be present to
initiate this reaction. This glycogen primer may in turn be
formed on a primer known as glycogenin, which is a protein that
is glycosylated on a specific tyrosine residue by UDPGlc.
This reaction is irreversible.

UDPGlc +Glycogenin

Glycogen primer

Glycogen synthetase

UDPGlc

UDP

1 4 Glucosyl units

Reaction 5
In reaction 4 the branches of the glycogen (tree) become
elongated as successive 1, 4 linkages occur & when the chain
has been lengthened to at least11 glucose residue a second
enzyme called branching enzyme transfer a part of 1,4-chain
(minimum 6 glucose residues) to a neighboring chain to form
1,6 -linkage thus establishing a branch point in the molecule
then the branches grow by further addition of 1 4 glucosyl
units producing glycogen.
This reaction is irreversible.

1 4 Glucosyl units

Branching enzyme

1 4 &1 6 Glucosyl units

((Glycogen))

The rate limiting reaction of glycogenesis is that reaction
catalyzed by glycogen synthase enzyme.
The incorporation of 1 mol of glucose into glycogen requires
two high energy phosphates (ATP in reaction 1 & UTP in
reaction 3).

Glycogenolysis

Reaction 1
Glycogenolysis is initiated by the reaction catalyzed by
glycogen phosphorylase enzyme which cause phosphoroylytic
cleavage of 1,4 link of glycogen until approximately 4 glucose
residues remain on either side of 1,6-branch where another
enzyme called (α-[1 4] α-[1 4] glucan transferase)
transfers a trisaccharide unit from one branch to the other,
exposing the 1 6 branch point. Hydrolysis of the 1 6
linkages requires the debranching enzyme. Further
phosphorylase action can then proceed.
The rate limiting reaction in glycolysis is that catalyzed by
phosphorylase enzyme.
Therefore, the combined action of irreversible reactions
catalyzed by these three enzymes convert glycogen to glucose 1-
phosphate.

Reaction 2
Glucose 1-phosphate is converted to glucose 6-phosphate by
reversible reaction catalyzed by phosphoglucomutase enzyme
in the presence of magnesium ion.

Glucose1-p Glucose6-p

phosphoglucomutase

Reaction 3
This irreversible reaction occurs only in the liver & kidney (not
in muscle) to remove phosphate from glucose 6-phosphate
enabling glucose to diffuse from the cell to blood, this reaction
is catalyzed by glucose 6-phosphatase enzyme.

Glucose 6-phosphatase
Glucose6-p+H

O Glucose + Pi

Regulation of Glycogen Metabolism

Glycogenesis

Glycogenesis is controlled by glycogen synthetase enzyme,
there are two forms of glycogen synthetase which are:
1- Synthetase-a:-Unphosphorylated & most active form.
2- Synthetase-b: - Phosphorylated & inactive.
Synthetase-a is converted to synthetase-b (inactivation) by a
phosphorylation reaction catalyzed by protein kinase enzyme
while conversion of synthetase-b to synthetase-a (activation) by
dephosphorylation reaction catalyzed by protein phosphatase
enzyme which is under the positive control of glucose-6-
phosphate & negative control of cAMP.
Two forms of the protein kinases are present which are:-
A-Ca

dependent protein kinase: Stimulated by calcium.

B-cAMP-dependent protein kinase: Stimulated by cAMP.

Glycogenolysis

Glycogenolysis is controlled by glycogen phosphorylase
enzyme there are two forms of glycogen phosphorylase which
are:-
1-Phosphorylase-a: Phosphorylated & active , inhibited by
glucose 6-phosphate.
2-phosphorylase-b: Unphosphorylated & inactive.
Conversion from a to b forms (inactivation) require
dephosphorylation reaction catalyzed by protein phosphatase
enzyme while conversion of b to a forms (activation) require
phosphorylation reaction catalyzed by phosphorylase kinase
enzyme.
Two forms of phosphorylase kinases are present which are:-
A-cAMP-dependent phosphorylase kinase: Stimulated by
cAMP.
B-Ca-dependant phosphorylase kinase: Stimulated by calcium.
In muscle glycogen phosphorylase enzyme is immunologically
distinct form & it’s more sensitive to c-AMP.
Therefore; cAMP which is stimulated by certain hormones(( as
epinephrine in muscle & glucagon in liver)) inhibit glycogenesis

synchronously with the activation of glycogenolysis through the
following mechanism:-
I)-cAMP inhibits glycogenesis by:-
1-Inhibition of protein phosphatase enzyme.
2-Stimulation of cAMP-dependent protein kinase enzyme.
II)-cAMP stimulates glycogenolysis by:-
1-Inhibition of protein phosphatase enzyme.
2-Stimulation of cAMP-dependent phosphorylase kinase enzyme.
Calcium ion which may follow muscle contraction inhibit
glycogenesis synchronously with the activation of glycogenolysis
through the following mechanism:-
I)-Stimulate glycogenolysis through the activation of Ca-
dependant phosphorylase kinase.
II)- Inhibit glycogenesis through the activation of Ca dependent
protein kinase.
Insulin inhibit glycogenolysis synchronously with the activation
of glycogenesis through the following mechanism:-
Insulin increasing cellular glucose uptake leads to elevation of
glucose 6-phosphate which inhibit the activity of phosphorylase
a enzyme in glycogenolysis together with stimulation protein
phosphatase enzyme in glycogenesis .

Conclusion
Inhibition of glycogenolysis enhances net glycogenesis & vice
versa inhibition of glycogenesis enhances net glycogenolysis. This
occurs by many factors as cAMP , calcium ion & insulin.

Glycogen Storage Diseases((Glycogenosis))

The term ((Glycogen Storage Disease)) is a generic term that
describe a group of inherited disorders (Types) characterized by
deposition of abnormal type or quantity of glycogen due to
partial or complete absence of certain enzymes.
Since glycogen molecules can become enormously large, an
inability to degrade glycogen can cause cells to become
pathologically engorged; it can also lead to the functional loss of
glycogen as a source of cell energy and as a blood glucose
buffer.
The following table summarizes the types of glycogen storage
diseases.

Hexose monophosphate shunt {phosphogluconate

oxidative pathway, pentose phosphate pathway

}

The pentose phosphate pathway is an alternative route for the
metabolism of glucose. It does not generate ATP but has two
major functions:
(1) Formation of NADPH for reduction processes & for synthesis
of fatty acids & steroids.
(2) Synthesis of ribose 5-phosphate for nucleotide & nucleic acid
formation.

Reactions of Pentose Phosphate Pathway
The reactions of the pathway occur in the cytoplasm.
The sequences of reactions are divided into two phases:-
1-Oxidative nonreversible phase.
2-Nonoxidative reversible phase.

Oxidative Nonreversible Phase

Oxidation (dehydrogenation) of glucose 6-phosphate into ribulose
5-phosphate is achieved through the following steps:-
Step 1
Dehydrogenation (oxidation) of glucose 6-phosphate into
6-phosphogluconate occurs via the formation of
6-phosphogluconolactone.
-Dehydrogenation (oxidation) of glucose 6-phosphate into 6-
phosphogluconolactone is catalyzed by glucose-6-phosphate
dehydrogenase enzyme in the presence of NADP

which is

converted into NADPH + H

The hydration of 6-phosphogluconolactone into 6-phosphogluconate
is accomplished by the enzyme gluconolactone hydrolase.
Both reactions of this step require cofactors which are calcium or
magnesium ions.

Step 2
Dehydrogenation (oxidation) with decarboxylation of
6- Phosphogluconate into a ketopentose known as ribulose 5-
phosphate.
This reaction is catalyzed by the enzyme 6-phosphogluconate
dehydrogenase in the presence of NADP

which is converted

into NADPH + H

This reaction requires cofactors which are calcium or magnesium
ions.

Nonoxidative Reversible Phase

All reactions of this phase are reversible except that reaction
catalyzed by fructose 1, 6-bisphosphatase enzyme which is
irreversible. By this phase ribulose 5-phosphate is end in the
formation of glucose 6-phosphate through the following steps.
Step 1
Ribulose 5-phosphate is the substrate for two enzymes which are:
- A-Ribulose 5-phosphate 3-epimerase alters the configuration
about carbon 3, forming another ketopentose known as
Xylulose 5-phosphate.
B-Ribose 5-phosphate ketoisomerase converts ribulose 5-
phosphate which is a ketopentose to the corresponding

aldopentose known as ribose 5-phosphate, which is the precursor
of the ribose required for nucleotide & nucleic acid synthesis.

Step 2
Transketolase enzyme catalyze the conversion of a ketose sugar
into an aldose with two carbons less & simultaneously converts an
aldose sugar into a ketose with two carbons more.
The reaction requires Mg

& thiamin diphosphate (vitamin B

)

as coenzyme.
Therefore, transketolase catalyzes the transfer of the two-carbon
unit from the five-carbon ketose (xylulose 5-phosphate) to the five-
carbon aldose (ribose 5-phosphate), producing the seven-carbon
ketose (sedoheptulose 7-phosphate) & the three-carbon aldose
(glyceraldehyde 3-phosphate).

Step 3
Transaldolase allows the transfer of three-carbons (carbons1-3)
from the ketose (sedoheptulose 7-phosphate) onto the aldose
(glyceraldehyde 3-phosphate) to form the six-carbon ketose
(fructose 6-phosphate) & the four-carbon aldose (erythrose 4-
phosphate).

Step 4
Transketolase catalyze reaction that involve xylulose 5-
phosphate to donates a two-carbon unit to erythrose 4-phosphate
to form glyceraldehyde 3-phosphate & fructose 6-phosphate.
The reaction requires Mg

& thiamin diphosphate (vitamin B

)

as coenzyme.

Step 5

In order to oxidize glucose completely, there must be:-

A- Conversion of two molecules of glyceraldehyde 3-phosphate
into one molecule of glucose 6-phosphate .This involves reversal
of glycolysis in addition to the enzyme known as fructose 1, 6-
bisphosphatase.
In tissues that lack fructose 1, 6-bisphosphatase, glyceraldehyde
3-phosphate follows the normal pathway of glycolysis to pyruvate.

B-Conversion of fructose 6-phosphate to glucose 6-phosphate by
phosphohexose isomerase.
Therefore, the net result of pentose phosphate pathway is that
three molecules of glucose 6-phosphate give rise to three
molecules of CO

, two molecules of glucose 6-phosphate & one

molecule of glyceraldehyde 3-phosphate. Since two molecules of
glyceraldehyde  3-phosphate  can  regenerate  glucose  6-phosphate,
the pathway can account for the complete oxidation of glucose.
The  rate  limiting  step  of  pentose  phosphate  pathway  is  mainly
controlled by glucose-6-phosphate dehydrogenase enzyme.

Although glucose 6-phosphate is common to both pentose
phosphate pathway & glycolysis, the pentose phosphate pathway
is markedly different from glycolysis by:-
1-Oxidation utilizes NADP rather than NAD.
2-CO

, which is not produced in glycolysis, is a characteristic

product of pentose phosphate pathway.
3- No ATP is generated in the pentose phosphate pathway,
whereas ATP is a major product of glycolysis.

Reductive function of NADPH

The main reductive function of NADPH is found in
erythrocytes, in which NADPH +H

share in the reduction of

oxidized glutathione in a reaction catalyzed by glutathione
reductase enzyme.
The reduced glutathione remove H

in a reaction catalyzed by

glutathione peroxidase enzyme to be converted back into
oxidized form. This reaction is important, since H

decrease

the life span of the erythrocyte by causing oxidative damage to
the cell leading to hemolysis.

Clinical Aspect of Pentose Phosphate Pathway

Glucose-6-Phosphate Dehydrogenase Deficiency ((G6PD
Deficiency)) or Favism :- It’s the main clinical aspect of pentose
phosphate pathway in which there is a genetic deficiency of
glucose-6-phosphate dehydrogenase enzyme with consequent
impairment of the generation of NADPH + H

,this disease is

common in populations of Mediterranean & Afro-Caribbean
origin.
The defect is manifested as red cell hemolysis (hemolytic anemia)
when susceptible individuals are subjected to oxidants that
contains H

because glutathione peroxidase which remove

is dependent upon a supply of NADPH, which in

erythrocytes can be formed only via the pentose phosphate
pathway.
These oxidants that contains H

include mainly drugs as

primaquine, aspirin, sulfonamides or when they have eaten fava
beans[hence the term favism].

Uronic Acid Pathway

Uronic acid pathway is an alternative pathway for glucose
metabolism, but like the pentose pathway it does not lead to the
generation of ATP.
Uronic acid pathway catalyzes the conversion of glucose into
glucuronic acid, pentoses& in animal ascorbic acid.
-Glucuronic acid (glucuronate) is important in:
A-Incorporated into proteoglycans.
B- Steroid hormones, bilirubin & number of drugs are conjugated
with glucuronate to be excreted in urine or bile.
-Pentoses produced from uronic acid pathway mainly xylulose 5-
phosphate which enter the pentose phosphate pathway.
-Vitamin C is produced in animal from uronic acid pathway while
in human & other primates can not synthesized due to lack of
certain enzyme involved in this synthesis.

Metabolism of other hexoses

They include mainly fructose & galactose metabolism.

Fructose Metabolism

Fructose enters the liver from the small intestine through the
hepatic portal vein.
Inside the body ((mainly in the liver)) fructose is converted
mainly into glucose or to a less extent into the intermediates of
glycolysis & in minor amounts is converted into fatty acids
((increase in excess fructose intake)), this process occurs
through the following pathways:-
Major pathway: - It’s the main pathway for fructose
metabolism, it occurs in the liver & to less extent in the kidney
&intestine through the following steps:-
(1)- Pathway is initiated by a specific kinase enzyme present in
the liver & to less extent in the kidney &intestine known as
fructokinase, which catalyzes the irreversible phosphorylation
reaction of fructose to fructose 1-phosphate in the presence of ATP
which is converted into ADP. This enzyme (fructokinase) not acts
on glucose & unlike glucokinase; its activity is not affected by

fasting or by insulin, which may explain why fructose is cleared
from the blood of diabetics at a normal rate.
(2)-Fructose 1-phosphate is cleaved into glyceraldehyde &
dihydroxyacetone phosphate by reversible reaction catalyzed by
hepatic fructose 1-phosphate aldolase enzyme.
(3)-Phosphorylation of glyceraldehyde to glyceraldehyde 3-
phosphate by irreversible reaction catalyzed by triokinase enzyme
in the presence of ATP which is converted into ADP.
(4)-The two triose phosphates ((dihydroxyacetone phosphate &
glyceraldehyde 3-phosphate)), may be:-
  A-Substrates for aldolase & hence gluconeogenesis, which is the
fate of much of the fructose metabolized in the liver.
  B-Degraded by glycolysis.
Fructose undergoes more rapid glycolysis in the liver than does
glucose because it bypasses the regulatory step of glycolysis
catalyzed by phosphofructokinase enzyme.

Minor pathway: - In extrahepatic tissues, hexokinase enzyme
catalyzes the phosphorylation of fructose into fructose 6-
phosphate which enter glycolysis pathway. However, glucose
inhibits this phosphorylation of fructose since it’s a better
substrate for hexokinase; therefore, this pathway is consider as a
minor pathway.

Note:- Minor amount of pyruvate ((produced from the entering of
fructose metabolites into the glycolysis)) is converted into fatty acids,
this conversion is increase by excess fructose intake.

Clinical Aspects of Fructose Metabolism

1) - Loading of the liver with fructose: - as occur with
intravenous infusion or following very high fructose intakes, may
cause the followings:-
A-Hyperlipidemia because excess fructose in the liver
increases fatty acid synthesis & so VLDL secretion, leading to
increased LDL cholesterol which can be regarded as potentially
atherogenic.

B-Hyperuricemia because excess fructose intakes, causes
sequestration of inorganic phosphate in fructose 1-phosphate & so
diminished ATP. As a result there is less inhibition of denovo
purine synthesis by ATP & so uric acid formation is increased,
causing hyperuricemia, which is a cause of gout.
2)-Essential fructosuria: - Inborn error of metabolism due to
lack of hepatic fructokinase, the condition is benign.
3)-Hereditary fructose intolerance:- Inborn error of metabolism
due to absence of hepatic fructose 1-phosphate aldolase lead to the
following presentations that usually occur during infancy when
baby start to eat fructose containing diets.
  A- Fructose-induced hypoglycemia because accumulation of
fructose 1-phosphate inhibits the activity of liver phosphorylase
causing hypoglycemia despite the presence of high glycogen
reserves, this especially evident after fructose administration.
  B-Hyperuricemia because sequestration of inorganic phosphate
by the accumulated fructose 1-phosphate leads to depletion of
ATP ,therefore, there is less inhibition of denovo purine synthesis
by ATP & so uric acid formation is increased causing
hyperuricemia which is a cause of gout.
C-Liver impairment due to the accumulation of fructose 1-
phosphate in the liver.
D-Failure to thrive.
Diagnosis by detecting fructose in urine after administration of
fructose, more precise diagnosis by measurement of hepatic
fructose 1-phosphate aldolase activity.
Treatment by diets low in fructose, sorbitol & sucrose (because
they converted into fructose).

Galactose Metabolism

Galactose is derived from the intestinal hydrolysis of the
disaccharide known as lactose which is the sugar of milk. It’s
readily converted in the liver to glucose by the following steps:-
(1)-Galactose is phosphorylated to galactose 1-phosphate in the
presence of ATP which is converted into ADP in the irreversible
reaction catalyzed by galactokinase enzyme, this reaction need
magnesium ion as a cofactor.

(2)-Galactose 1-phosphate reacts with uridine diphosphate
glucose (UDPGlc) to form uridine diphosphate galactose
(UDPGal) & glucose 1-phosphate, in the reversible reaction
catalyzed by galactose 1-phosphate uridyl transferase enzyme.
(3)-The conversion of UDPGal to UDPGlc is by reversible
reaction catalyzed by UDPGal 4-epimerase enzyme.
(4)-Finally, glucose is liberated from UDPGlc after it enters the
glycogenesis pathway followed by the glycogenolysis.
Note:- Since the epimerase reaction is reversible. Therefore;
glucose can be converted to galactose, so that galactose is not a
dietary essential. However, galactose is required in the body not
only in the formation of lactose but also as a constituent of
glycolipids, proteoglycans & glycoproteins.

Clinical Aspect of Galactose Metabolism

Galactosemia: - Inborn error of metabolism characterize by the
inability to metabolize galactose , its caused mainly by inherited
defects of galactose 1-phosphate uridyl transferase & to less
extent by defect in galactokinase or UDPGal 4-epimerase, the
clinical features of galactosemia usually start to appear after the

baby start sucking milk which contain lactose, these clinical
features include mainly:-
1-Cataract:-The excess galactose concentration in the eye is
reduced to galacticol, which accumulates, causing cataract due to
its osmotic effect.
2-Failure to thrive.
3-Liver impairment:-especially in galactose 1-phosphate uridyl
transferase deficiency because of the accumulation of galactose 1-
phosphate in the liver.
4-Hypoglycemia.
Diagnosis by detection of galactose in urine.
Treatment by galactose-free diets. As the UDPGal 4-epimerase is
present in adequate amounts in most cases of galactosemia, the
galactosemic individual can still form UDPGal from glucose so
that normal growth & development can occur regardless of these
galactose-free diets.

Gluconeogenesis

Gluconeogenesis is the term used to include all the pathways
responsible for converting noncarbohydrate precursors to glucose
or glycogen. These noncarbohydrate precursors include
glucogenic amino acids, lactate & glycerol.
Liver & kidney are the major gluconeogenic tissues.

Importance of gluconeogenesis

1-Meets the needs of the body for glucose which is important in
supplying energy especially for the nervous system& erythrocytes.
2- Clears lactate produced by the muscles & erythrocytes.
3- Clears glycerol produced by adipose tissue.
Therefore, failure of gluconeogenesis is usually fatal.

Pathways of gluconeogenesis

The pathway of gluconeogenesis involves reversal of glycolysis,
the citric acid cycle & some special reactions.
Three irreversible reactions of glycolysis ((catalyzed by
hexokinase, phosphofructokinase & pyruvate kinase enzymes))
prevent simple reversal of glycolysis for glucose syntheses by
gluconeogenesis.They are circumvented as follows:-
(1)- The conversion of  pyruvate into phosphoenolpyruvate , to
achieve a reversal of glycolysis is through the following steps:
  A)-Mitochondrial pyruvate carboxylase enzyme catalyzes the
carboxylation of pyruvate ((present in the mitochondria)) to
oxaloacetate, this irreversible reaction require ATP in the
presence of the vitamin biotin as a coenzyme.
  B)-Oxaloacetate does not cross the mitochondrial inner
membrane; it should be converted to malate inside the
mitochondria by Krebs cycle in reaction catalyzed by malate
dehydrogenase enzyme, then malate is transported into the
cytosol & in the cytosol is converted back to oxaloacetate by
malate dehydrogenase enzyme.
C)-Phosphoenolpyruvate carboxykinase enzyme catalyzes the
decarboxylation & phosphorylation of oxaloacetate which present
in the cytoplasm to phosphoenolpyruvate ,this irreversible

reaction require GTP (Guanosine triphosphate) as the phosphate
donor which is converted into GDP (Guanosine diphosphate).
(2)-The conversion of fructose 1, 6-bisphosphate to fructose 6-
phosphate, to achieve a reversal of glycolysis, is catalyzed by
fructose- 1, 6-bisphosphatase enzyme which present in the
liver, kidney & skeletal muscle but is probably absent from heart
& smooth muscle.
(3)-The conversion of glucose 6-phosphate to glucose, to
achieve a reversal of glycolysis, is catalyzed by glucose-6-
phosphatase enzyme which present in the liver & kidney but
absent from muscle & adipose tissue, which, therefore, cannot
export glucose into the bloodstream.
Therefore by reversal of glycolysis & by citric acid cycle as
described above glucose can be formed from the following
noncarbohydrate precursors:-
1- Glucogenic amino acids after transamination or deamination
of these amino acids they yield either pyruvate or intermediates
of the citric acid cycle as α-ketoglutarate , oxaloacetate or
fumarate which enters the gluconeogenic pathway.
2-Lactate by a reaction catalyzed by lactate dehydrogenase
enzyme is converted into pyruvate which enters the
gluconeogenic pathway.
3-Glycerol which is converted into dihydroxyacetone phosphate
which enters gluconeogenesis through the reverse of glycolysis,
the conversion of glycerol into dihydroxyacetone phosphate
occurs through the following steps:-
Step 1:-Glycerol is released from adipose tissue as a result of
lipolysis & only tissues such as liver & kidney that possess
glycerol kinase enzyme that catalyzes the irreversible conversion
of glycerol to glycerol 3-phosphate in the presence of ATP which
is converted into ADP.

                              Glycerol kinase
Glycerol + ATP                             Glycerol 3-phosphate + ADP

Step 2:-Glycerol 3-phosphate is oxidized into dihydroxyacetone
phosphate by reversible reaction catalyzed by glycerol 3-

phosphate dehydrogenase enzyme in the presence of NAD

which is converted into NADH + H

Glycerol 3-phosphate + NAD

Glycerol 3-phosphate dehydrogenase

Dihydroxyacetone phosphate + NADH + H

Note: - Gluconeogenesis pathway requires energy which is
derived mainly from fatty acid oxidation.

Regulation of Gluconeogenesis

1-Pyruvate carboxylase enzyme in gluconeogenesis requires
acetyl-CoA as an activator & at the same time acetyl-CoA inhibit
pyruvate dehydrogenase complex which convert pyruvate into
acetyl-CoA to enter citric acid cycle.
Because acetyl-CoA is derived also from the oxidation of fatty
acids, this explains the action of fatty acid oxidation in sparing the
entering of pyruvate to the citric acid cycle & in stimulating
gluconeogenesis.

2-Fructose-2, 6-bisphosphate is most potent positive stimulator of
glycolysis ((through its stimulation of phosphofructokinase)) &
inhibitor of gluconeogenesis ((through its inhibition of fructose
1, 6 bisphosphatase)).
Fructose 2, 6-bisphosphate is formed by phosphorylation of
fructose 6-phosphate by phosphofructokinase-2 enzyme which
is under the positive control of fructose 6-phosphate
Therefore, when glucose is abundant it elevate the concentration
of fructose 6-phosphate which increase the concentration of

fructose 2, 6-bisphosphate ((stimulate glycolysis & inhibit
gluconeogenesis)) while when glucose is low the concentration of
fructose 6-phosphate & fructose 2, 6-bisphosphate is reduced lead
to stimulation of gluconeogenesis & inhibition of glycolysis.
3-Hormones that regulate gluconeogenesis acting through the
enzymes that control the irreversible reactions of gluconeogenesis,
these enzymes are pyruvate carboxylase, Phosphoenolpyruvate
carboxykinase, fructose- 1, 6-bisphosphatase& glucose-6-
phosphatase.
These hormones are the following:-
A-Glucocorticoids, glucagon & epinephrine stimulate
gluconeogenesis through their induction of the enzymes that control
the irreversible reactions of gluconeogenesis.
B-Insulin inhibits gluconeogenesis through its repression of the
enzymes that control the irreversible reactions of gluconeogenesis.

Hormonal Control of Carbohydrate Metabolism

1-Glycolysis is stimulated by insulin & is inhibited by glucagon &
epinephrine.
2-Glycogenesis is stimulated by insulin & is inhibited by glucagon
& epinephrine.
3-Glycogenolysis is stimulated by glucagon & epinephrine & is
inhibited by insulin.
4-Gluconeogenesis is stimulated by glucocorticoids, glucagon &
epinephrine & is inhibited by insulin.

Blood Glucose Level

The concentration of blood glucose is regulated within narrow limits
ranging from 3.3 mmol/L ((60 mg/dL)) in starvation up to 7.2
mmol/L ((130 mg/dL)) after the ingestion of a carbohydrate meal.
A sudden decrease in blood glucose will cause convulsions due to
the immediate brain dependence on a supply of glucose.
However, much lower concentration can be tolerated, provided
progressive adaptation is allowed by gluconeogenesis & ketone
bodies formation.

Sources of Blood Glucose

I ))-Diet:-

The digestible dietary carbohydrates yield glucose,

galactose& fructose that are transported to the liver via the
hepatic portal vein. Galactose & fructose are readily converted
to glucose in the liver .
II ))-Gluconeogenesis:-

glucose is formed from the following

two groups of compounds that undergo gluconeogenesis .
(A) Compounds that involved a direct conversion to glucose
within the liver including most of glucogenic amino acids &
glycerol.
(B) Compounds which are the products of the metabolism of
glucose in the tissues as lactate & the amino acid alanine
through the following cycles:
1-Lactic Acid (Cori) Cycle:- Lactate which formed by the
glycolysis in the skeletal muscles & erythrocytes, is transported
to the liver & kidney via circulation where it reforms glucose by
gluconeogenesis, this formed glucose reach skeletal muscle &
erythrocytes through the circulation again to become available for
glycolysis & so on the cycle continue again. This process is
known as the Cori cycle or lactic acid cycle.
2- Glucose-Alanine Cycle:- Most important amino acid
transported via circulation from skeletal muscle to the liver
during fasting state is alanine which forms by transamination of
pyruvate. In the liver alanine is converted into glucose by
gluconeogenesis, this formed glucose reach skeletal muscle
through the circulation again to become available for glycolysis &
alanine formation so that the cycle continue again. This process is
known as the glucose-alanine cycle.
III ))-Glycogenolysis:- Another source of blood glucose is from
glycogenolysis of the liver glycogen.

Glucosuria

Normally glucose is continuously filtered by the glomeruli but its
completely  reabsorbed  in  the  renal  tubules;  therefore,  normally
there  is  no  glucose  in  urine.  This  happen  when    venous  blood
glucose  concentration  is  below  the  renal  threshold  for  glucose
{171-180 mg/dl (9.5-10.0 mmol/L) }
The presence of glucose in urine (glucosuria) suggest:
1-Hyperglycemia  when  venous  blood  glucose  concentration
exceeds  the  renal  threshold  for  glucose  as  occurs  in  diabetes
mellitus.
2- Reduction of renal threshold for glucose as occurs in:
A-Renal  glucosuria  which  is  harmless  condition  with  no  obvious
cause for it.
B-During pregnancy which is due to hypervolemia that occur during
pregnancy.

Diabetes Mellitus

Diabetes mellitus is a family of disorders that is characterized by
hyperglycemia. The disorders of diabetes differ in their etiology
, symptoms & in the consequences of disease.
In Mosul, more than 10% of the population suffers from
diabetes.

Classification of Diabetes Mellitus

Diabetes have been classified into four forms which are:-
-Type 1 diabetes mellitus.
-Type 2 diabetes mellitus.
-Gestational diabetes mellitus.
-Other specific types of diabetes mellitus.

Type1 Diabetes Mellitus

  Type 1 diabetes usually represents about 5-10% of diabetes &
it  is  due    to  lack  of  insulin  production  &  secretion  by  the  beta
cells of the pancreas.
Type1diabetes  manifests  itself  usually  during  childhood  &
adolescents.
Treatment by insulin replacement, diet management & exercise .
  Type1diabetes is subclassified into:-
A-Immune  mediated  :  represent  the  common  form  of  type  1
diabetes in which there is an autoimmune destruction of the beta
cells  of  the  pancreas  by  autoantibodies  leading  to  absolute
insulin deficiency.
There  is  a  genetic  susceptibility  for  the  development  of  these
autoantibodies,

with

certain

histocompatibility

antigens

predominant (HLA-DR3 &DR4) . However, the development of
disease is complex; triggering factors, such as rubella, mumps,
& other viral infection & chemical contact may be necessary for
progression of disease.
B-Idiopathic:  represent  the  rare  form  of  type  1  diabetes  in
which  there  is  no  any  obvious  cause  for  the  development  of
disease.

Type 2 Diabetes Mellitus

It forms the most common type of diabetes

& it is either due to

the body does not produce enough insulin or reduction of
cellular

effects of insulin ((insulin resistance)).

The etiology of type 2 diabetes is

polygenic which means that

both hereditary & environmental factors(

obesity, lack of

physical activity & certain racial groups)

are important for its

appearance.
Other factors important in the development of disease are

previous history of gestational diabetes, increasing age,
dyslipidemia & hypertension.

Type 2 diabetes usually affects obese people older than 40
years.

Treatment usually by weight reduction, diet management & oral
hypoglycemic drugs. Insulin may be prescribed for type 2
diabetics who fail to achieve glycemic control with other
measures.

Gestational Diabetes Mellitus (GDM)

It’s defined as diabetes that is diagnosed first time during
pregnancy , it affects about 4% of all pregnant women.
During pregnancy there is

reduction of cellular effects of insulin

((insulin resistance))

. Most pregnant women will compensate

with increased secretion of insulin; those individuals who are
unable to compensate may develop gestational diabetes .
The hyperglycemia of gestational diabetes diminishes after
delivery; however, the individual who has developed gestational
diabetes is at higher risk for the development of type 2 diabetes
thereafter

specially those showing autoantibodies at the time of

delivery

Other Specific Types of Diabetes

It’s previously called secondary diabetes. These specific types
include mainly:-

TABLE 4-1

-Genetic defects of beta cell function.
-Genetic defects in insulin action.
-Diseases of the exocrine pancreas such as cystic fibrosis.
-Endocrinopathies such as Cushing’s syndrome.

-Drug or chemical-induced such as glucocorticoids.
-Infections.
-Uncommon forms of immune-mediated diabetes.

Impaired Glucose Tolerance

(Impaired Fasting Glucose, Prediabetes)

  Impaired  glucose  tolerance  represents  a  blood  glucose  levels
are higher than normal but not high enough to be characterized
as  overt  diabetes  (borderline  stage).  Persons  with  impaired
glucose tolerance have a higher risk for macroangiopathy & the
cardiovascular mortality than those with normal person.
20-30% of people with impaired glucose tolerance will develop
clinically  overt  diabetes  mellitus  within  10  years.  Therefore,
persons  with  impaired  glucose  tolerance  need  follow-up  &
weight reduction.

Diagnosis of Diabetes Mellitus

Usually by measuring plasma glucose as follow:-

1-Fasting plasma glucose test:- Measures plasma glucose after
at least 8 hours without eating. This test is used to detect
diabetes or pre-diabetes as follow:-

Fasting Plasma Glucose Result (mg/dL)

Diagnosis

70-99

Normal

100 to 125

Pre-diabetes
(impaired fasting glucose)

126 and above

Diabetes

2-Oral  glucose  tolerance  test  (OGTT):-  Measures  plasma
glucose  after  at  least  8  hours  without  eating  &  2  hours  after
drink  a  liquid  containing  75  gm  glucose.  This  test  is  more
precise  in  diagnose  diabetes  or  especially  pre-diabetes  as
follow:-

2-Hour Plasma Glucose Result (mg/dL)

Diagnosis

139 and below

Normal

140 to 199

Pre-diabetes
(impaired glucose tolerance)

200 and above

Diabetes

In gestational diabetes it’s diagnosed by a special form of OGTT
in which measures plasma glucose after at least 8 hours without
eating then we measures plasma glucose 1 hour , 2 hours & 3
hours after drink a liquid containing 100 gm glucose. If plasma
glucose levels in at least two of four reading reach the value
found in following table, it means that the pregnant women have
gestational diabetes.

When

Plasma Glucose Result (mg/dL)

Fasting

95 or higher

At 1 hour

180 or higher

At 2 hours

155 or higher

At 3 hours

140 or higher

Long Term Complications of Diabetes Mellitus

1- Microangiopathy resulting in the development of retinopathy,
nephropathy & neuropathy.
2-

Macroangiopathy r

esulting in atherosclerosis & coronary

heart disease.