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Chapter 3
Carbohydrates
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• Carbohydrates play a major role in human diets,
comprising some 40-75% of energy intake.
• Their most important nutritional property is
digestibility in the small intestine.
• In terms of their physiological or nutritional role,
they are often classified as available and
unavailable carbohydrates.
• Available carbohydrates are those that are
hydrolyzed by enzymes of the human
gastrointestinal system to monosaccharides that are
absorbed in the small intestine and enter the
pathways of carbohydrate metabolism.
• Unavailable carbohydrates are not hydrolyzed by
endogenous human enzymes, although they may be
fermented in the large intestine to varying extents.
• Carbohydrates are further classified
according to their degree of polymerization
(DP) as:
• sugars (mono- and disaccharides),
• oligosaccharides (contain three to nine
monosaccharide units), and
• polysaccharides (contain ten or more
monosaccharide units)
Structural Features
• Simple carbohydrates
– Monosaccharides
– Disaccharides
• Complex carbohydrates
– Oligosaccharides
– Polysaccharides
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Some biologically important
monosaccharide
1. Ribose a pentose present in RNA
2. Deoxyribose a pentose present in
DNA.
3. Glucose or grape sugar is the main
sugar of the blood.
4. Fructose is the sugar of the fruits.
5. Galactose present in milk sugar
lactose.
6. Mannose enter in the composition
of mucopolysaccharide.
Simple Carbohydrates
• Disaccharides
– Maltose
– Lactose
– Sucrose
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Disaccharides
• Condensation of 2 monosaccharides forms a disaccharide.
• The bond between them is called glycosidic bond.
• A disaccharide is reducing when it has free anomeric
carbon
Disaccharide
structure
bond
Reducing
Examples ofsource
disaccharides:
property
Sucrose
cane sugar
beat sugar
table sugar
α-D-glucose +
β-D-Fructose
α-1,2 glycosidic
bond.
not reducing
sugar
Lactose
milk sugar
β-D-galactose
+
α-Dglucose
β-1,4 glycosidic
bond
Reducing
sugar
Maltose
Malt sugar
2 molecules of
α-D-glucose
α-1,4 glycosidic
bond.
Reducing
sugar
B. The disaccharidases include:
1. Lactase (β-galactosidase) which hydrolyses lactose into two molecules
of glucose and galactose:
Lactase
Lactose
Glucose + Galactose
2. Maltase ( α-glucosidase), which hydrolyses maltose into two molecules
of glucose:
Maltase
Maltose
Glucose + Glucose
3. Sucrose (α-fructofuranosidase), which hydrolyses sucrose into two
molecules of glucose and fructose:
Sucrose
Sucrose
Glucose + Fructose
4. α - dextrinase (oligo-1,6 glucosidase) which hydrolyze (1 ,6) linkage of
isomaltose.
Dextrinase
Isomaltose
Glucose + Glucose
Complex Carbohydrates
• Oligosaccharides
– Raffinose
– Stachyoses
– Verbascose
• Polysaccharides
– Starch
– Glycogen
– Cellulose
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Digestion
• Polysaccharides
– Salivary -amylase - mouth
– Pacreatic -amylase - small intestine
– Resistant starches
• Digestion of disaccharides
– Disaccharidases - active in microvilli of
enterocytes
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Absorption
• Absorption is the movement of molecules across the
gastrointestinal (GI) tract into the circulatory system.
• Most of the end-products of digestion, along with
vitamins , minerals, and water, are absorbed in the
small intestinal lumen by four mechanisms for
absorption:
(1) active transport,
(2) passive diffusion,
(3) endocytosis, and
(4) facilitative diffusion.
• Active transport requires energy
Absorption, Transport, & Distribution
• Absorption of glucose & galactose
– Into cell: active transport - SGLT1
– Into blood: diffusion, GLUT2
• Absorption of fructose
– Into cell: facilitated transport - GLUT5
– Into blood: GLUT2
– Limited in 60% of adults
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Absorption, Transport, & Distribution
• Monosaccharide transport & cellular uptake
• Glucose transporters
– GLUT isoforms
• Integral proteins
• Each has specific combining site
• Undergoes a conformational change upon binding the
molecule
• Can reverse this change when unbound
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Absorption, Transport, & Distribution
– Specificity of GLUTs
• GLUT1 - basic supply of glucose to cells
• GLUT2 - low infinity transporter; glucose from
enterocyte to blood
• GLUT3 - high-affinity for brain & other glucosedependent tissues
• GLUT4 - insulin sensitive, in muscle & adipose tissues
• GLUT5 - for fructose
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Absorption, Transport, & Distribution
• Insulin
– Role in cellular glucose absorption
• Binds to membrane receptor
• Stimulates GLUT4 to move to membrane
• Maintenance of blood glucose levels
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Glycemic Response to Carbohydrates
• Glycemic index
– Increase in blood glucose during 2-hour period
after consumption of a certain amount of CHO
compared with equal CHO from reference food
• Glycemic load
– GI x g of CHO in 1 serving of food
2009 Cengage-Wadsworth
Introduction to Carbohydrate
Metabolism
• It is mainly Glucose metabolism which has
many anabolic and catabolic pathways:
• Major pathway for Glucose oxidation:
– Glycolysis
– Citric Acid Cycle
• Minor Pathways for Glucose oxidation:
– HMP (Hexose Monophosphate Pathway) shunt
• Glycogenesis
• Gluconeogenesis
• Conversion to other monosaccharides
2009 Cengage-Wadsworth
Dietary Carbohydrate
Glucose
Fructose
Galactose
Amino acids
Glycerol
Lactate
Glycogen
s
si
s
e
si
n
y
e
ol
og
n
c
e
y
og
Gl
c
y
Gl
Gluconeogenesis
Gluconeogenesis
Other
Carbohydrates
HMP
Pathway
Ribose-P
Energy
Glycolysis
Glucose
Carbon skeleton
of amino acids
NADPH
Glycerol-P
Pyruvate
Fatty Acids
ATP
Acetyl-CoA
ADP+Pi
Triacylglycerol
Electron
Transport
Chain
NADH
Kreb's Cycle
2CO2
Major Pathway of Glucose
Oxidation
• Definition:
– Conversion of Glucose to 2pyruvate(or lactate), then to
6CO2 & producing ATPs + reduced nucleotides
• Site:
– Glycolysis in all cells
– Krebs’ Cycle in all cells containing mitochondria
Steps:
Glucose
Anaerobic
Phase
( in Cytoplasm )
O2 absent
or present
t
O2 absent
2 Lactic Acid
2 Pyruvic Acid
O2 present
Aerobic Phase
(In mitochondria)
O2 present
6 CO2 + H2O
I. Glycolysis (Embden Meyerhof Pathway):
A. Definition:
1. Glycolysis means oxidation of glucose to give pyruvate (in the
presence of oxygen) or lactate (in the absence of oxygen).
B. Site:
cytoplasm of all tissue cells, but it is of physiological importance in:
1. Tissues with no mitochondria: mature RBCs, cornea and lens.
2. Tissues with few mitochondria: Testis, leucocytes, medulla of the
kidney, retina, skin and gastrointestinal tract.
3. Tissues undergo frequent oxygen lack: skeletal muscles especially
during exercise.
C. Steps:
Stages of glycolysis
1. Stage one (the energy requiring stage):
a) One molecule of glucose is converted into two molecules of
glycerosldhyde-3-phosphate.
b) These steps requires 2 molecules of ATP (energy loss)
2. Stage two (the energy producing stage(:
a) The 2 molecules of glyceroaldehyde-3-phosphate are converted into
pyruvate (aerobic glycolysis) or lactate (anaerobic glycolysis(.
b) These steps produce ATP molecules (energy production).
D. Energy (ATP) production of glycolysis:
ATP production = ATP produced - ATP utilized
• In the energy investment phase, ATP provides activation
energy by phosphorylating glucose.
– This requires 2 ATP per glucose.
• In the energy payoff
phase, ATP is
produced by
substrate-level
phosphorylation
and NAD+ is
reduced to NADH.
• 2 ATP (net) and
2 NADH are produced
per glucose.
Fig. 9.8
Energy Investment Phase (steps 1-5)
Fig. 9.9a
Fig. 9.9b
Energy-Payoff Phase (Steps 6-10)
Energy production of glycolysis:
ATP produced
ATP utilized
In absence of oxygen
(anaerobic
glycolysis)
4 ATP
(Substrate level
phosphorylation)
2ATP from 1,3 DPG.
2ATP from
phosphoenol
pyruvate
2ATP
2 ATP
From glucose to
glucose -6-p.
From fructose -6-p to
fructose 1,6 p.
In presence of
oxygen (aerobic
glycolysis)
4 ATP
(substrate level
phosphorylation)
2ATP from 1,3 BPG.
2ATP from
phosphoenol
pyruvate.
2ATP
6 ATP
-From glucose to
Or
glucose -6-p.
8 ATP
From fructose -6-p to
fructose 1,6 p.
+ 4ATP or 6ATP
(from oxidation of 2
NADH + H in
mitochondria).
Net energy
Differences between aerobic and anaerobic
glycolysis:
Aerobic
Anaerobic
1. End product
Pyruvate
Lactate
2 .energy
6 or 8 ATP
2 ATP
3. Regeneration of
NAD+
Through respiration
chain in mitochondria
Through Lactate
formation
4. Availability to TCA in Available and 2 Pyruvate Not available as lactate
mitochondria
can oxidize to give 30
is cytoplasmic substrate
ATP
Biological importance (functions) of glycolysis:
1. Energy production:
a) anaerobic glycolysis gives 2 ATP.
b) aerobic glycolysis gives 8 ATP.
2. Oxygenation of tissues:
Through formation of 2,3 bisphosphoglycerate, which decreases the
affinity of Hemoglobin to O2.
3. Provides important intermediates:
a) Dihydroxyacetone phosphate: can give glycerol-3phosphate, which is
used for synthesis of triacylglycerols and phospholipids (lipogenesis).
b) 3 Phosphoglycerate: which can be used for synthesis of amino acid
serine.
c) Pyruvate: which can be used in synthesis of amino acid alanine.
4. Aerobic glycolysis provides the mitochondria with pyruvate, which gives
acetyl CoA Krebs' cycle.
Comparison between
hexokinase enzymes:
glucokinase
Glucokinaase
and
Hexokinase
1. Site
Liver only
All tissue cells
2. Affinity to glucose
Low affinity (high km) i.e. it
acts only in the presence of
high blood glucose
concentration.
High affinity (low km) i.e. it acts
even in the presence of low blood
glucose concentration.
3. Substrate
Glucose only
Glucose, galactose and fructose
4. Effect of insulin
Induces synthesis of
glucokinase.
No effect
5. Effect of glucose-6-p
No effect
Allosterically inhibits hexokinase
6. Function
Acts in liver after meals. It
removes glucose coming in
portal circulation, converting
it into glucose -6-phosphate.
It phosphorylates glucose inside
the body cells. This makes glucose
concentration more in blood than
inside the cells. This leads to
continuous supply of glucose for
the tissues even in the presence of
low blood glucose concentration.
Importance of lactate production in anerobic
glycolysis:
1. In absence of oxygen, lactate is the end product of glycolysis:
Glucose  Pyruvate  Lactate
2. In absence of oxygen, NADH + H+ is not oxidized by the
respiratory chain.
3. The conversion of pyruvate to lactate is the mechanism for
regeneration of NAD+.
4. This helps continuity of glycolysis, as the generated NAD+ will be
used once more for oxidation of another glucose molecule.
• As pyruvate enters the mitochondrion, a
multienzyme complex modifies pyruvate to acetyl
CoA which enters the Krebs cycle in the matrix.
– A carboxyl group is removed as CO2.
– A pair of electrons is transferred from the
remaining two-carbon fragment to NAD+ to form
NADH.
– The oxidized
fragment, acetate,
combines with
coenzyme A to
form acetyl CoA.
Fig. 9.10
Citric acid Cycle
(Tricarboxylic Acid Cycle)
(Kreb’s Cycle)
Definition:
Complete oxidation of acetyl-CoA to 2 molecules
of CO2 and generating energy either directly as
ATP or in the form of reducing equivalents
(NADH or FADH2).
Location:
All cells that contain mitochondria (i.e. not in
RBCs)
Site:
All enzymes are found free in mitochondria
matrix except succinate dehydrogenase which is
found on the inner border of the inner
mitochondrial membrane.
The Krebs Cycle
• Occurs in the matrix of the mitochondrion
• Aerobic phase (requires oxygen)
• 2-carbon acetyl CoA joins with a 4-carbon
compound to form a 6- carbon compound
called Citric acid
• Citric acid (6C) is gradually converted back to the 4carbon compound
-ready to start the cycle once more
• The carbons removed are released as CO2
-enzymes controlling this process called
decarboxylases
• The hydrogens, which are removed, join with NAD to
form NADH2
-enzymes controlling the release of hydrogen are
called dehydrogenases
Functions of Citric Acid Cycle
Amphibolic Function
I- Energy production
II- Catabolic for glucose, fat &proteins
III- Anabolic Function
Functions of TCA:
I- Energy production
Functions of TCA
II- Catabolic To carbohydrate, fat & protein:
Functions of TCA
III- Anabolic Functions
Regulation of the citric acid cycle
-
NADH, ATP, succinyl
CoA, citrate
Krebs Cycle is a Source of Biosynthetic Precursors
Glucose
Phosphoenolpyruvate
The citric acid cycle
provides
intermediates for
biosyntheses
Summary for Complete
oxidation of Glucose
Complete aerobic oxidation of glucose in
glycolysis, citric acid cycle and ETC
produces 6 molecules of CO2 + 38
molecules of ATP (38 moles of ATP / one
mole of glucose)
N.B: Complete oxidation of one glucose
molecule in RBC gives 2 ATP + 2 lactate
molecules
Key Concepts
The TCA cycle accounts for more than two thirds
of the ATP generated from fuel oxidation.
All of the enzymes required for the TCA cycle are in the
mitochondria.
Acetyl CoA, generated from fuel oxidation, is the substrate
for the TCA cycle.
Acetyl CoA, when oxidized via the cycle, generates CO2,
reduced electron carriers, and GTP.
The reduced electron carriers [NADH, FADH2} donate
electrons to O2 via the electron-transport chain, which
leads to ATP generation from oxidative phosphorylation.
The cycle requires a number of cofactors to
function properly, some of which are derived from
vitamins. These include thiamin pyrophosphate
(derived from vitamin B1, thiamin), FAD (derived
from vitamin B2, riboflavin), and coenzyme A (derived from
pantothenic acid) and NAD (from niacin).
Intermediates of the TCA cycle are used for many
biosynthetic reactions and are replaced by anaplerotic
(refilling) reactions within the cell.
The cycle is carefully regulated within the mitochondria by
energy and the levels of reduced electron carriers. As
energy levels decrease, the rate of the cycle increases.
Impaired functioning of the TCA cycle leads to an inability
to generate ATP from fuel oxidation and an accumulation of
TCA cycle precursors.
Minor Pathway for oxidation of
glucose
• The hexosemonophosphate shunt
(pentose phosphate pathway)=pentose
shunt=HMP.
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Pentose Phosphate Pathway
Definition:
It is a pathway by which pentose phosphate is
produced from glucose (with production of two
molecules
of
NADPH),
or
from
other
monosaccharides.
No ATP is directly consumed or produced in
the cycle.
Location:
Mainly in liver, lactating mammary glands,
adipose tissue, adrenal cortex, gonads and
RBCs.
Site:
Cytoplasm
Steps:
The pentose phosphate pathway occurs in
two phases oxidative and nonoxidative
I- Oxidative Phase
This phase is irreversible; glucose- 6phosphate is converted to ribulose -5phosphate with production of two
molecules of NADPH.
II- Non-oxidative Phase
This phase is reversible. It catalyzes the
conversion of pentoses produced in phase
one into 2 molecules of Glyceraldehyde-3Phosphate and Fructose-6-Phosphate (By
the
enzymes
transketolase
and
transaldolase), which continue in the
glycolytic pathway.
Regulation of HMP
The regulated step is glucose-6-P
dehydrogenase (G6PD), which is
strongly inhibited by NADPH (its
product).
Importance of Pentose
Phosphate Pathway
I- It is the ONLY source of
ribose-5-phosphate
Ribose-5-phosphate forms phosphoribosyl pyrophosphate (PRPP) for
synthesis of nucleotides and nucleic
acids.
In tissues (e.g. muscles) which lack
the dehydrogenases of the oxidative
phase and in cases of deficiency of
G6PD, pentoses are formed by reversal
of the non-oxidative phase, starting from
fructose-6-P and glyceradehyde-3-P.
ll- It is
NADPH
the
main
source
of
required for the reaction of many
reductases, hydroxylases and NADPH
oxidase.
lll – It provides a way for utilizing
dietary C4-, C5-, and C7 sugars
Regulation of Metabolism
• 4 mechanisms:
– Negative or positive modulation of allosteric
enzymes
– Hormonal activation by covalent
modification/induction
– Directional shifts in reactions
– Translocation of enzymes within cells
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Anabolic Pathway
Glycogenesis and glycogenolysis
Glycogenesis
• Glycogen is a highly branched glucose polymer used for
carbohydrate storage in animals
• Glycogen stores are used to keep the blood sugar level
steady between meals
• Glycogenesis is the synthesis of glycogen from glucose-6phosphate
- it occurs when high levels of glucose-6-phosphate are
formed in the first reaction of glycolysis
- it does not operate when glycogen stores are full, which
means that additional glucose is converted to body fat
Diagram of Glycogenesis
• Glucose is converted to
glucose-6-phosphate,
using one ATP
• Glucose-6-phosphate is
converted to glucose-1phosphate, which is
activated by UTP,
forming UTP-glucose
• As UTP-glucose attaches
to the end of the
glycogen chain, UDP is
released (and converted
to UTP by ATP)
Formation of Glucose-6-Phosphate
• Glucose is converted to glucose-6-phosphate, using ATP, in
the first step of glycolysis
P O CH2
O
OH
OH
OH
OH
Glucose-6-phosphate
Formation of Glucose-1-Phosphate
• Glucose-6-phosphate is converted
to glucose-1-phosphate
P O CH2
H O CH2
O
O
OH
OH
OH
OH
OH
Glucose-6-phosphate
O P
OH
OH
Glucose-1-phosphate
Formation of UTP-Glucose
• UTP activates glucose-1-phosphate to form
UDP-glucose and pyrophosphate (PPi)
O
CH2OH
H
O
OH
O
O P O
OH
OH
O-
O
O
P O CH2
O-
N
N
O
UDP-glucose
OH
OH
Glycogenolysis
• Glycogenolysis is the breakdown of glycogen to glucose
• The glucose is phosphorylated as it is cleaved from the
glycogen to form glucose-1-phosphate
• Glucose-1-phosphate can be converted to glucose-6phosphate, which can enter glycolysis
• Phosphorylated glucose can’t be absorbed into cells
- in the liver and kidneys, glucose-6-phosphate can be
hydrolized to glucose
• Glycogenolysis is activated by glucogon in the liver and
epinephrine in muscles
- these are produced when blood glucose levels are low
• Glycogenolysis is inhibited by insulin
- insulin is produced when blood glucose levels are high
Overview of Glycogen Synthesis and Breakdown
Gluconeogenesis (Glucose Synthesis)
• Glucose is the
primary energy
source for the brain,
skeletal muscle, and
red blood cells
• Deficiency can
impair the brain
function
• Gluconeogenesis is
the synthesis of
glucose from carbon
atoms of
noncarbohydrates
- required when
glycogen stores are
depleted
GLUCONEOGENESIS
• Definition:
– It is synthesis of glucose from noncarbohydrate sources. Its main function is to
supply
blood
glucose
in
case
of
carbohydrate deficiency (fasting more than
10-18 hours).
• Location:
– It occurs mainly in the liver cells and to
lesser extent in kidneys
• Site:
– Cytoplasm except for the first step
(carboxylation of pyruvate) occurs in the
mitochondria.
Substrates for Gluconeogenesis
(Gluconeogenic Precursors)
 These are molecules that can be used to
produce glucose. They give directly or
indirectly pyruvate, oxaloacetate or any
intermediates of glycolysis or citric acid
cycle.
 1- Glucogenic Amino Acids
 2- Glycerol
 3- Lactate
Substrates for Gluconeogenesis
(Gluconeogenic Precursors)
• 1- Glucogenic Amino Acids
These are amino acids which are convertible to glucose.
They give pyruvate or oxaloacetate directly or indirectly by
giving intermediates of citric acid cycle
• 2- Glycerol
Glycerol released from hydrolysis of TAG in adipose
tissue, go to the liver via blood. In the liver the following
will occur:
NB. Adipose tissue has NO glycerol kinase
Substrates for Gluconeogenesis
(Gluconeogenic Precursors)
• 3- Lactate
It is produced by red blood cells and by
contracting muscles, then passes to the liver
where it is converted to glucose which is
released back into the circulation. (Cori’s
Cycle)
Importance of Gluconeogenesis
 1- Maintenance of blood glucose:
The main function of gluconeogenesis is
the maintenance of blood glucose when
carbohydrates are not available in sufficient
amounts e.g. fasting, starvation, stress,
prolonged exercise and dietary carbohydrate
deficiency for more than 10 – 18 hours.
 2- Removal of lactic acid
produced by red cells and contracting
muscles.
 3- Removal of glycerol
produced by lipolysis in adipose tissues.
A common intermediate in
the conversion of glycerol
and lactate is which of the following?
a. Pyruvate
b.Oxaloacetate
c. Malate
d. Glucose 6-phosphate
e. Phosphoenolpyruvate
Cori and Alanine Cycles
 Cori cycle prevents loss of lactate as waste
product in urine, and prevent its accumulation in
blood (acidosis)
 Both help to maintain blood glucose level
specially to tissues that dependant on it as their
primary source of energy.
 Both supply RBCs and contracting muscles with
glucose for reutilization and ATP production.
 Both spare energy in red cells and contracting
muscles.
Cori Cycle
Anaerobic
Glucose
Glucose
2 NAD+
Glycolysis
Gluconeogensis
Glucose
6 ATP
Urea
Urea
2 NADH+H+
2 ATP
ETC
2 Pyruvate
2 Pyruvate
4ATP
4 0r 6 ATP
Kidney
2 NH3
transamination
transamination
deamination
2 Alanine
2 Alanine
Liver
2 Alanine
Mucsle Cell
Alanine Cycle
In Alanine Cycle O2 and mitochondria are
required in the peripheral tissues
REGULATION OF GLUCONEOGENESIS
The
gluconeogenic
regulatory
key
enzymes are those which reverse the
glycolytic key enzymes.
• Glycolysis and gluconeogenesis
reciprocally controlled.
are
Factors which increase
gluconeogenesis
I- Availability of substrates:
Availability of gluconeogenic substrates
specially glucogenic amino acids provide
increased amounts of oxaloacetic acid.

Excess ATP (from FA oxidation) produces
allosteric inhibition of phosphofructokinase-1
and pyruvate kinase (glycolysis) and activate
F1,6-BPase (gluconeogenesis).

Excess acetyl-CoA, (from FA oxidation),
allosterically stimulates pyruvate carboxylase
enzyme and inhibits pyruvate dehydrogenase,
thus directs pyruvate to gluconeogenesis.
Cori Cycle
• When anaerobic conditions occur in active muscle,
glycolysis produces lactate
• The lactate moves through the blood stream to the liver,
where it is oxidized back to pyruvate.
• Gluconeogenesis converts pyruvate to glucose, which is
carried back to the muscles
• The Cori cycle is the flow of lactate and glucose between
the muscles and the liver
Cori Cycle
Anaerobic
Cori and Alanine Cycles
 Cori cycle prevents loss of lactate as waste
product in urine, and prevent its accumulation in
blood (acidosis)
 Both help to maintain blood glucose level
specially to tissues that dependant on it as their
primary source of energy.
 Both supply RBCs and contracting muscles with
glucose for reutilization and ATP production.
 Both spare energy in red cells and contracting
muscles.
Pathways for Glucose
Regulation of Glycolisis and Gluconeogenesis
• High glucose levels and insulin promote glycolysis
• Low glucose levels and glucagon promote gluconeogenesis
Hypoglycemia
• Preprandial vs. postprandial serum glucose
levels
• Types:
– Fasting hypoglycemia
• Usually caused by insulin, sulfonylureas
– Fed (reactive) hypoglycemia
• Impaired glucose tolerance, idiopathic postprandial
syndrome
2009 Cengage-Wadsworth