BIOCHEM A

Carbohydrate Metabolism – Dra. Santos

Fates of Ingested Glucose  Degradation via HMP shunt

 50% – converted to energy (glycolysis)  Enters uronic acid pathway
o First pathway that glucose enters is glycolysis
 30% – 40% - converted to fat Glucose-6-phosphate is also known as a central metabolite because it
 10% – converted to glycogen can enter a lot of pathways

When we talk about blood sugar, we refer to glucose. Why
is it that we only talk about glucose? What happens to the
other sugars? They are all converted to glucose when they
reach the liver
First Reaction Undergone by Glucose inside the Cell
 Phosphorylation reaction
 Irreversible reaction – you cannot use the same enzyme for the
backward reaction
 To reverse the reaction you have to use glucose 6 phosphatase
which is found only in the liver
 Why are there two enzyme? Are you going to use them at the
same time? NO
o First enzyme to use is the hexokinase because it can act
even if the level of glucose is low
o Glucokinase can only act if the level of glucose is high
 When the levels of glucose-6-phosphate is high, it will inhibit your
hexokinase (feedback inhibition)
 Glucokinase is not inhibited by glucose-6-phosphate, so even
though the hexokinase is already inhibited, glucokinase will still
convert glucose to glucose-6-phosphate
 ENDERGONIC REACTION
Hexokinase
 Low Km for glucose, so it can convert glucose in the micromolar
range to glucose-6-phosphate in the millimolar range
 Inhibited by high levels of glucose-6-phosphate (feedback
inhibition)
 Acts on other hexoses such as fructose, mannose, etc
GLYCOLYSIS
 Found in all cells of the body
 Major pathway for glucose utilization
 Plays a key role in energy metabolism by providing a significant
portion of the free energy used by most organisms and by
preparing glucose and other compounds for further oxidative
degradation
 A unique pathway since it can utilize oxygen if available (aerobic)
or it can function in the absence of oxygen (anaerobic)
o Aerobic glycolysis produces pyruvate
 Needs mitochrondria
o Anaerobic glycolysis produces lactate
 Some of the tissues in the body utilize this because
they lack mitochondria
 The pathway used by all cells of the body to extract part of the
chemical energy inherent in the glucose molecule
 It sets the stage for the complete oxidation of glucose to H2O and
CO2
 It also provides the main pathway for the metabolism of fructose
and galactose derived from the diet
 It is a sequence of reactions that converts glucose to pyruvate and
lactate with concomitant production of ATP
 Location: it takes place in the cytosol
 It is basically an exergonic process
o But a part of this pathway is also endergonic
o So glycolysis is both exergonic and endergonic
o But exergonic is more than endergonic (produces more ATP
than what it used)
 All intermediates between glucose and pyruvate are
phosphorylated
 The word glycolysis is derived from the Greek words “glykos”
meaning “sweet” and “lysis” meaning “splitting” or “loosing”
Functions of Glycolysis
 To produce energy in the form of ATP
 Intermediates formed can be converted to other substances like
amino acids, fatty acids, etc.

Glucokinase Tissues That Depend On Glycolysis as Their Major Mechanism for ATP
 High Km for glucose, so it can function only when the Production:
concentration of glucose is relatively high  RBC, cornea, lens, regions of the retina – lack mitochondria so
 Not inhibited by glucose-6-phosphate they utilize anaerobic glycolysis
 Acts on glucose only o Only use 40g of glucose per day
 Kidney medulla, testis, leukocytes and white muscle fibers - they
Fates of Glucose-6-phosphate are almost totally dependent on glycolysis as source of ATP
 Conversion to glycogen (glycogenesis) because they have relatively few mitochondria.
 Enter glycolysis  Combined, the tissues that are dependent primarily on glycolysis
 Conversion to fatty acids and cholesterol for ATP production consume about 40 grams of glucose per day in
 Conversion to blood glucose the normal human adult.
 Oxidative degradation to CO2 - energy formation  Brain - it has an absolute need for glucose and processes most of
o Continuation of glycolysis it via glycolysis. Approximately 120 grams of glucose is used by
o The product must enter oxidative degeneration the adult human brain each day in order to meet its extraordinary
o Kreb’s cycle need for ATP.

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 The heart muscle, which is adapted for aerobic performance, has
relatively poor glycolytic ability, and poor survival under
conditions of ischemia.
 In fast growing cancer cells, glycolysis proceeds at a much higher
rate than is required by the Kreb’s cycle-- more pyruvate
produced than can be metabolized -- excessive production of
lactate -- lactic acidosis.

Two Phases of Glycolysis

According to Harper:
 Energy investment phase
o Also called priming stage
o Endergonic part
o Glucose Fructose 1,6-bisphosphate
 Energy generation phase
o Also called energy recovery phase
o Produces energy
o Splitting stage
 Fructose 1,6- bisphosphate  DHAP + glyceraldehyde  Energy splitting phase begins at reaction #4
–3– PO4  Whatever happens to glyceraldehyde will also happen to
o Oxidoreduction dihydroxyacetone phosphate
 Phosphorylation stage  The amount of energy you produce in glyceraldehyde will be
 Glyceraldehyde – 3 –PO4  Pyruvate or lactate multiplied by two because dihydroxyacetone phosphate will also
 The only one that should be under the energy produce it
generation stage  In reaction #6
o 2.5 ATP is produced per NADH, but since there are 2
Pathway of glycolysis pathways (2.5ATP x 2) there will be 5 ATPs produced when
the NADH enters the malate aspartate shuttle
o 1.5 ATP is produced per NADH. There will be a total of 3
ATPs produced when NADH enters the glycerol phosphate
shuttle
 Reaction #7
o There is an ATP produced even though it didn’t enter the
ETC  substrate level phosphorylation
o 2 ATPs are produced
 Reaction #8
o An example of phosphoryl shift wherein the location of
phosphate changed from position #3 to #2
 Reaction #9
o Dehydration step
o Catalyzed by enolase
 Inhibited by fluoride
 Reaction #10
o Third irreversible step
 All the irreversible step is a control point o Produces 2 ATP
 Committed step – you are sure that it will go to glycolysis  If the tissue lacks mitochondria, NADH cannot enter the ETC, so it
 Why is the first reaction not the committed step? converted the pyruvate to lactate in the presence of lactate
o Because glucose-6-phosphate can go to other pathways dehydrogenase (anaerobic glycolysis)
besides glycolysis o The only source of ATP production is the substrate level
phosphorylation therefore only 4 ATPs will be produced in
anaerobic glycolysis

ATPs produced in 1 mole of glucose

Gross Net
Aerobic (MAS) 9 7
Aerobic (GPS) 7 5
Anaerobic 4 2

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Enzymatic Control of Glycolysis
 Phosphofructokinase
o Inhibited by: ↑ ATP, citrate, H+ ions, cyclic AMP, increased
ATP/AMP ratio
o stimulated by: ↑ATP, ↑AMP, decreased ATP/AMP ratio
 Hexokinase
o Inhibited by glucose-6-phosphate
 Pyruvate kinase
o Inhibited by: ATP, alanine, fatty acids, acetyl CoA
o Stimulated by: Fructose-1, 6-bisphosphate
Inhibitors of the Glycolytic Pathway
 2-Deoxyglucose
o Inhibits the reaction catalyzed by hexokinase.
 Sulfhydryl reagents
o Example is iodoacetate
o They inhibit glyceraldehyde-3-phosphate dehydrogenase.
 Fluoride
o A potent inhibitor of enolase
o Mg2+ and Pi form an ionic complex with fluoride ion, which
is responsible for inhibition of enolase by interfering with
binding of its substrate (Mg2+ 2-phospho-glycerate).
 Pentavalent arsenic or arsenate
o Arsenic poisoning inhibits those enzymes which require
lipoic acid as coenzyme like pyruvate dehydrogenase and
α-ketoglutarate dehydrogenase
FATES OF PYRUVIC ACID
 Reversible reduction to lactate
 Conversion back to glucose
 Formation of oxaloacetate or malate
 Transamination to form alanine
 Oxidative decarboxylation to Acetyl CoA
Pyruvate dehydrogenase complex
 Pyruvate should be converted to acetyl CoA in order for it to enter
the Kreb’s cycle
 Important link between glycolysis and Kreb’s cycle
 Must occur otherwise energy production is not maximized
 If pyruvate is not converted to acetyl coA it will proceed to
anaerobic glycolysis  lactic acidosis
Enzymes of pyruvate dehydrogenase complex
Pyruvate Dehydrogenase Is Regulated By:
 Endproduct inhibition
o Pyruvate dehydrogenase is inhibited by its products, Acetyl
CoA and NADH.
 Covalent modification
o Pyruvate dehydrogenase is regulated by phosphorylation by
a kinase of 3 serine residues on the pyruvate dehydrogenase
component, resulting in decreased activity
o Also regulated by dephosphorylation by a phosphatase that
cause an increase in activity. The kinase is activated by
increases in the ATP/ADP ratio and acetyl CoA/CoA ratio,
and NADH/NAD+ ratio.
Inhibitors of Pyruvate Dehydrogenase
 Arsenite and mercuric ions react with the – SH groups of lipoic
acid and inhibit pyruvate dehydrogenase.
 Thiamine deficiency – Nutritionally deprived alcoholics are
thiamine-deficient and may develop potentially fatal pyruvic and
lactic acidosis.
Inborn Errors Of Metabolism Associated With Glycolysis:
 Inhibited Aldolase A deficiency  hemolytic anemia
 Inherited pyruvate kinase deficiency  hemolytic anemia
 Muscle phosphofructokinase deficiency  exercise capacity of
patients is low, particularly on high carbohydrates diet.
 Inherited pyruvate dehydrogenase deficiency – due to defects in
one or more of the components of the enzyme complex;
manifested by lactic acidosis, particularly after a glucose load.
Fate of lactate in the anaerobic glycolysis
 Much of the lactate produced in skeletal muscle cells is carried by
the blood to the liver where it is used to synthesize glucose thru
gluconeogenesis  Cori cycle or lactic acid cycle
ACETYL COA
 Central metabolite
o Can come from different pathways
 Insulin is needed for acetyl CoA to enter the Kreb’s cycle
o Insulin has a permissive effect on Kreb’s cycle
 If acetyl coA cannot enter the Kreb’s more of it will be channeled
to ketone bodies formation which lead to ketoacidosis
o It can also be channeled to cholesterol formation 
atherosclerosis
Fate of Acetyl CoA
 80% must enter the Kreb’s cycle for maximum energy production
from carbohydrates
 20% is channeled to ketone body production, cholesterol
formation, steroid hormone, prostaglandin and TAG
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KREB’S CYCLE
 Citric acid cycle
 Tricarboxylic acid cycle
 Final common pathway of metabolism
o Common to all kinds of food you eat
 Amphibolic pathway
o There is catabolic
 Breakdown for the generation of ATP
o There is anabolic
 Use of intermediates of the pathway to synthesize
other substances
Function
 Major degradative pathway for the generation of ATP
 Provides intermediates for biosynthesis (Amphibolic pathway)
o Alpha-ketoglutarate – precursor of glutamic acid
o Oxaloacetate – precursor of aspartic acid
o Citrate – precursor of extra mitochondrial acetyl CoA for
fatty acid biosynthesis – thru the ATP-citrate lyase reaction
o Citrate + ATP + CoA  Acetyl CoA + Oxaloacetate + ADP + Pi
o Succinyl CoA – for the synthesis of heme
 Take note of the enzymes producing the highlighted products
 Shuttle systems are not needed because the Kreb’s cycle is
already located at the mitochondria
Reactions in the pathway:
 1st Reaction: oxaloacetate condense with Acetyl CoA to form
citrate
o Catalyzed by citrate synthetase (originally called condensing
enzyme)
o Rate limiting step
o Major control point
 2nd Reaction: Conversion of citrate to isocitrate via-aconitate.
o Catalyzed by aconitase
 3rd Reaction: Oxidation of Isocitrate to Alpha-ketoglutarate
o Catalyzed by isocitrate dehydrogenase
 4th Reaction: Oxidative decarboxylation of alpha-ketoglutarate to
succinyl CoA
o Catalyzed by alpha-ketoglutarate dehydrogenase complex.
 5th Reaction: Deacylation of succinyl CoA to form succinate
o Catalyzed by succinate thiokinase
 6th Reaction: Dehydrogenation of succinate to fumarate
o catalyzed by succinate dehydrogenase
 7th Reaction: hydration of Fumarate to Malate.
o Catalyzed by fumarate hydratase, more commonly known as
fumarase
 8th Reaction: Malate is dehydrogenated to form oxaloacetate
o Catalyzed by malate dehydrogenase
 Products of Kreb’s cycle: 2 water, 2 CO2, 3 NADH, 1 FAD, 1 ATP
 A total of 10 ATP is produced
Control Points In The Kreb’s Cycle
 Acetyl CoA + Oxaloacetate  Citrate
o Catalyzed by citrate synthase
o Inhibited by ATP
 Isocitrate  Alpha-ketoglutarate
o Catalyzed by isocitrate dehydrogenase
o ADP is a positive modulator
 Alpha-ketoglutarate  Succinyl CoA
o Catalyzed by alpha-ketoglutarate dehydrogenase complex
o Inhibited by succinyl CoA, NADH+ and high energy charge
 Succinate  Fumarate
o Catalyzed by succinate dehydrogenase
o Inhibited by oxaloacetate
o Malonate is a competitive inhibitor of the enzyme
 Irreversible formation of acetyl CoA from pyruvate
High energy charge  decreased activities of citrate synthetase,
isocitrate dehydrogenase, and alpha-ketoglutarate dehydrogenase - 
decreased Kreb’s cycle
Regulation Of The Kreb’s Cycle
The rate of the Kreb’s cycle depends upon two factors:
 Energy requirements of the cell.
 Requirement of the cell for carbon precursors.
Vitamins That Play Important Roles In The Kreb’s Cycle
 Vitamin B-2 or Riboflavin – FAD (Flavin adenine dinucleotide)
o Cofactor in the alpha-ketoglutarate dehydrogenase complex
o Cofactor of succinate dehydrogenase.
 Niacin or nicotinic acid –NAD (Nicotinamide adenine dinucleotide)
o Coenzyme for isocitrate dehydrogenase, alpha-
ketoglutarate dehydrogenase, and malate dehydrogenase.
 Thiamine or Vitamin B1- thiamine pyrophosphate or TPP
o Coenzyme for decarboxylation in the alpha- ketoglutarate
dehydrogenase reaction.
 Pantothenic acid
o As part of coenzyme A, the cofactor attached to “active”
carboxylic acid residues such as acetyl CoA and succinyl CoA.
The Citric Acid Cycle Plays a Key Role in the Following Metabolic
Pathways
 Gluconeogenesis
o All major members of the Kreb’s Cycle, from citrate to
oxaloacetate are potentially glucogenic.
o Phosphoenolpyruvate carboxykinase (PEPCK) – key enzyme
that facilitates the net transfer out of the Kreb’s cycle into
the main pathway of gluconeogenesis.
 Transamination and deamination
o These reactions produce pyruvate from Ala, oxaloacetate
from Asp, and alpha-ketoglutarate from glutamic acid.
 Fatty Acid Synthesis
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 o Acetyl CoA is the major building block for long chain fatty
acid synthesis in nonruminants
Anaphlerotic Reactions or Filling-up Reactions
 Reactions that fill up the Kreb’s cycle if your run out of the
intermediates
 Formation of malate from pyruvate
 Formation of alpha-ketoglutarate from glutamate
 Enzymatic carboxylation of pyruvate to form oxaloacetate
o Catalyzed by pyruvate carboxylase
 Major anaphlerotic enzyme
o This is the most important anaphlerotic reaction in the liver
and kidneys
o Requires biotin (vitamin B7) as coenzyme
o Requires acetyl coA as positive modulator/activator
o Occurs in two steps:
GLUCONEOGENESIS
 Synthesis of new glucoses
 Takes place in the liver and kidneys
 Reverse of Glycolysis and Krebs
 HYPERGLYCEMIC PATHWAY: ↑ blood sugar level
 Includes all pathways and mechanisms responsible for converting
non-carbohydrates to glucose or glycogen.
The major gluconeogenic precursors are:
 Lactate
 Glycerol – from fats
 Glucogenic amino acids
 Proprionate – in animals
Importance of Gluconeogenesis:
 It meets the needs of the body for glucose when sufficient CHO is
not available from the diet or glycogen reserves.
o 1st – glycogen reserves
 GLYCOGENOLYSIS: breakdown of glycogen to glucose
 Glycogen will maintain blood sugar level for 1 DAY.
o 2nd – fats
 LIPOLYSIS → fatty acids + glycerol
 Glycerol becomes Glucose
 Will maintain blood sugar level depending on how
much fat is available.
 Glucose is also important in maintaining the level of intermediates
of the Krebs cycle even when fatty acids are the main source of
acetyl CoA in the tissues.
 Gluconeogenesis clears lactate produced by muscle and
erythrocytes and glycerol produced by adipose tissues.
 Reverse of GLYCOLYSIS (cytosol) and KREBS (mitochondria); starts
at bottom, end in GLUCOSE
 Gluconeogenesis involves both cytosol and mitochondria
The 3 irreversible steps in glycolysis must be reversed in
gluconeogenesis:
 Phosphoenolpyruvate → Pyruvate
o Pyruvate kinase step
o No SINGLE enzyme that can reverse this step.
o Needs to enter the mitochondria
 Pyruvate → Oxaloacetate → Malate → goes out to
cytosol → Oxaloacetate → Phosphoenolpyruvate →
2-Phosphoglycerate → 3-Phosphoglycerate →
1-3, Diphosphoglycerate → Glyceraldehyde-3- PO 4 →
Fructose-1,6-bisPO 4 → Fructose-6-PO 4 → Glucose-
6-PO 4 → GLUCOSE
o Enzyme used to reverse this reaction includes pyruvate
carboxylase (pyruvate to oxaloacetate) and
phosphoenolpyruvate carboxykinase (PEPCK) which
catalyzes the conversion of oxaloacetate to
phosphoenolpyruvate
 Fructose-6-phosphate → Fructose 1,6 bisphosphate
o Catalyzed by fructose 1,6-bisphosphatase
o Enzyme is present in liver and kidney; absent in heart
muscle and smooth muscle
 Glucose → Glucose-6-phosphate
o Reversed by glucose-6-phosphatase
o Enzyme is present in liver and kidney; absent from muscle
and adipose tissues
“BYPASS PATHWAYS”
 Bypassing the irreversible steps
 All the enzymes that are used to bypass are CONTROL ENZYMES
of gluconeogenesis
 Includes: Glucose-6-phosphatase; Fructose 1,6 bisphosphatase;
Pyruvate Carboxylase and Phosphoenolpyruvate Carboxykinase
(PEPCK)
Glycerol to glucose
 Glycerol → Glycerol-3-PO 4 → DHAP
 DHAP is the entry point of glycerol in glycolysis
 DHAP + Glyceraldehyde-3-PO4 → Fructose-1,6-bisPO4
 Fructose-1,6-bisPO 4 → Fructose-6-PO 4 → Glucose-6-PO 4 →
GLUCOSE
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Lactate to Glucose
 First: Lactate → Pyruvate (enzyme: Lactate Dehydrogenase)
 Pyruvate → Oxaloacetate → Malate → goes out to cytosol →
Oxaloacetate → Phosphoenolpyruvate → 2-Phosphoglycerate →
3-Phosphoglycerate → 1-3, Diphosphoglycerate →
Glyceraldehyde-3- PO 4 → Fructose-1,6-bisPO 4 → Fructose-6-PO
4 → Glucose-6-PO 4 → GLUCOSE
Two Major Functions:
 Generation of NADPH for reductive synthesis
o Fatty acid and steroid biosynthesis
o Reduction of glutathione
 Production of ribose for nucleotide and nucleic acid biosynthesis
Other function: Interconversion of sugars

Amino acids to Glucose Hexose Monophosphate Shunt (HMP Shunt)

 Convert amino acid first to ketoacid by doing deamination
o Remove the amino group
 Alanine, serine, cysteine, glycine and threonine
o Converted to pyruvic acid
 Glutamic acid, glutamine, arginine, proline, histidine
o Converted to alpha-ketoglutarate
 Asparagine and aspartic acid
o Converted to oxaloacetate

Fructose 2,6 bisphosphate

 Play a role in the regulation of glycolysis and gluconeogenesis in
the liver
 Most potent positive allosteric activator of PFK-1 and inhibitor of
fructose 1,6-bisphosphatase in the liver

Generation of High Energy Bonds In The Catabolism Of Glucose

 1st stage: oxidative stage

o Production of 2 NADPH
o Glucose-6-phosphate is converted to the five carbon
compound ribuose-6-phosphae
 2nd stage: non oxidative stage
o 2 enzymes responsible for the interconversion of sugars:
transketolase and transaldolase
 Transketolase – transfers 2 carbons and require TTP
 Transaldolase – transfers 3 carbons and doesn’t
require TTP
o Transketolation reactions is between ribose and xylulose
 Transfer of two carbons of ribose to xylulose
 Ribose will become glyceraldehyde-3-phosphate
 Xylulose will become sedoheptulose-7-phosphate
 This is an example of interconversion of sugars
wherein the transfer of carbon atoms will give you
new sugars but the total number of carbons is just the
same
 Products of transketolation will undergo
transaldolation
o Transaldolation reaction
 Transfer 3 carbons from sedoheptulose to
glyceraldehyde
 Seduloheptulose will become erythose-4-phosphate
 Glyceraldehyde will become fructose-6-phosphate
HEXOSE MONOPHOSPHATE SHUNT o Thiamine deficiency – no transketolation
 Manifestations of thiamine deficiency: severe muscle
Other names: weakness, lactic acidosis, pentosemia and pentosuria
 Pentose phosphate pathway
 Warburg-Dickens Pathway
 Phosphogluconate shunt

Location: located in the cytosol

Rate-Limiting enzyme: Glucose-6-phosphate dehydrogenase (G-6-P-D)

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G6PD Deficiency
 Inborn error of metabolism
 Absence of G6PD
 HMP shunt stops because G6PD is the rate limiting step for HMP
 no NADPH production
o NADPH is needed for the reduction of glutathione
o Reduced glutathione is needed to detoxify hydrogen
peroxide and convert it to water
o Accumulation of H2O2  hemolysis of RBC
Wernicke-Koraskoff syndrome
 Occurs in alcoholics
 Develops thiamine deficiency because alcohol prevents
absorption of thiamine
 Lack of thiamine in the diet
 Transketolation does not occur
 Glucose cannot enter the Kreb’s cycle
 Neuropsychiatric disorder
 Paralysis of eye movement, abnormal gait, markedly deranged
mental function and severely impaired memory
PATHWAY OF GLYCOGENESIS AND GLYCOGENOLYSIS IN THE LIVER
Structure of glycogen
 Highly branched molecule
 Alpha 1-4 linkage (linkage between two glucose units in the
straight chain) and alpha 1-6 linkage (branching parts)
Glycogenesis (shades of green boxes)
 Synthesis of glycogen
 Needs a primer
 Purpose is to add more glucose units and create many branches
 1st step: activation of glucose to become UDP-G
o UDP-G is the kind of glucose that you add to the chain
 2nd step: addition of glucose units at the a1,4 linkage
o Catalyzed by glycogen synthase
 3rd step: forming branches
o When there are already 11 glucose units added to the chain
you can now transfer a minimum of six so that you can form
a new branch
o Enzyme that forms branches is called the branching enzyme
 Alternate elongation and branch formation
Glycogenolysis (shades of blue boxes)
 Breakdown of glycogen
 Remove glucose units at the alpha 1,4 linkage
o Phosphorylase – counterpart of glycogen synthase
 Once there are only 4 glucose units left, you transfer 3 units so
that you expose the branching point
o Glucan transferase
 Once the branching point is exposed, you use the debranching
enzyme to remove the glucose
 Removes glucose as glucose-1-phosphate
Hormones that control the pathway:
 Glucagon and epinephrine
o Same effect
o Glucagon is produced by the pancreas
o Epinephrine is produced by the adrenal medulla
o Stimulate cAMP  activate phosphorylase
o Promotes glycogenolysis
 Insulin
o Inhibits cAMP no activation of phosphorylase
o Inhibits glycogenolysis and activates glycogenesis
Activation and Inactivation of Liver Phosphorylase
 Phosphorylase exists in two forms
o Activated upon addition of phosphate
o Inactivation upon removal of phosphate
 The initial activity of glucagon and epinephrine is to activate
adenylyl cyclase which converts ATP to cAMP
o cAMP activates phosphorylase kinase
o Phosphorylase kinase adds phosphate to phosphorylase
thus activating it
o At the same time, upon activating phosphorylase you
inactivate glycogen synthase
o When phosphate is removed and phosphorylase become
inactive, glycogen synthase will be activated
 Insulin on the other hand deactivates phosphorylase by removing
phosphate and activating the glycogen synthase
o Favors glycogenolysis
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 CONVERSION OF GALACTOSE TO GLUCOSE

Glycogen Storage Diseases

 3 enzymes that will cause galactosemia if absent or deficient

o Galactokinase
o Galactose 1-phosphate uridyl transferase
o Uridine diposphogalactose 4-epimerase
 Galactosemia manifestations:
o Mental retardation
o Cataract formation
o Hepatomegaly

CONVERSION OF FRUCTOSE TO GLUCOSE

URONIC ACID PATHWAY

 Pathway that converts glucose to ascorbic acid
 However this does not occur in man because we lack
gulonolactone oxidase
o That is the enzymes that converts gulonolactone to
ketogulonolactone
o Animals have this enzyme
 Main function of this pathway in humans: produce UDP-G and
glucuronic acid (glucoronate)
o Glucoronic acid is for the conjugation of bilirubin and is a
component of proteoglycans (GAGs)

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 Occurs in three steps:
o Conversion of fructose to fructose 6 phosphate via
hexokinase
o Conversion of fructose-6-phosphate to glucose-6-phosphate
via isomerase
o Conversion of glucose-6-phosphate to glucose via glucose-6-
phosphatase
SOURCES OF GLUCOSE
 From Carbohydrates in the diet
 From various glucogenic compounds that undergo
gluconeogenesis
o Amino acids
 If amino acids is used, it is not physiological anymore
 Amino acids have greater function than to maintain
glucose: protein synthesis, digestion
o Lactate
o Glycerol
 From liver glycogen thru glycogenolysis
CONTROL OF BLOOD GLUCOSE CONCENTRATION
 Role of the liver
o Liver glycogenolysis
o Gluconeogenesis
 Insulin
o Only hormone that lowers blood sugar
 Insulin antagonists
o Increases blood sugar
PHYSIOLOGIC EFFECTS OF INSULIN
Effects on carbohydrate metabolism
 Increases utilization of glucose by the cells
o Effect on membrane transport of glucose – insulin promotes
mobilization of glucose transport (mainly in the adipose
tissues)
 Insulin also facilitates simple diffusion of glucose in
the hepatic cells
o Insulin increases hepatic glycolysis – stimulates glucokinase,
PFK and pyruvate kinase (control enzymes of glycolysis)
 Insulin increases glycogenesis (liver muscles)
o Inhibits cyclic AMP thereby activating glycogen synthase
 Insulin inhibits glycogenolysis – inhibits cAMP thereby inactivating
phosphorylase
 Insulin inhibits gluconeogenesis – decreases amount of hepatic
PEPCK (rate limiting enzyme for gluconeogenesis)
Effects on Lipid metabolism
 Insulin stimulates lipogenesis in adipose tissue
 Insulin inhibits lipolysis in liver and adipose tissue
Effects on Protein metabolism
 Stimulates protein synthesis
o Decreasing amount of amino acids to enter gluconeogenesis
 Stimulates uptake of amino acids into muscles
Insulin Antagonists
 Glucagon – Increase blood glucose level by promoting liver
glycogenolysis and by increasing gluconeogenesis
o Glucagon binds to cell membrane  activates adenylate
cyclaseincrease cAMP  promotes glycogenolysis in the
liver
o Glucagon has no effect on glycogenolysis in muscles
o Glucagon stimulates PEPCK  increased gluconeogenesis
o Glucagon inhibits glycolysis by promoting phosphorylation
of pyruvate kinase thereby inactivating it
o Primary target of glucagon – LIVER
o Major signal for the release of glucagon – decreased blood
sugar level
 Epinephrine – Catecholamines
o Increases blood sugar level by:
 Increasing glycogenolysis, decreasing glycogenesis –
same mechanism as glucagon
 Increasing gluconeogenesis
 Decreasing insulin release
 Increasing glucose uptake in muscles and other organs
 Growth hormone
o Produced by the pituitary gland
o Increases blood sugar level by:
 Increasing liver gluconeogenesis
 Decreasing peripheral utilization of glucose by
inhibiting glycolysis; inhibits glucose transport
 Cortisol – glucocorticoids (renal cortex)
o Increases blood sugar level by:
 Increasing gluconeogenesis (by increasing protein
catabolism in the peripheral tissues
 Decreasing glucose uptake and utilization by
extrahepatic tissues
 Thyroid hormone
o Increases blood sugar level by increasing glucose absorption
in the small intestines.
DIABETES MELLITUS
Diagnosis:
 Fasting Blood Sugar (FBS)
o Normal Blood Sugar Level: 60-120 mg/dL
o Fasting Blood Sugar taken 3 times for 3 days in a row
o Fasting for 8-10 hours before the test is needed
o Do not over fast to avoid discrepancies – patients can
manipulate so we don’t usually rely on this test for the
diagnosis
o Consistent above normal findings for 3 consecutive reading
is indicative of Diabetes Mellitus
o May be performed together with glycosylated hemoglobin
Glycosylated hemoglobin
o Not affected by fasting
o Gives the patient’s blood sugar for the past 2-3 months
o If it gives a high result, it is indicative of DM even if FBS
reading is normal
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 Oral glucose tolerance test (OGTT)
o Measure FBS first, then give the prepared glucose syrup
o More reliable than FBS
o Blood extraction done 5 times to test for blood glucose
testing
o Glucose Tolerance – is the ability to utilize glucose
3 parts of the glucose tolerance test curve (GTT curve)
 Normal Fasting Blood Sugar Level
 30 minutes – 1 hour
o Blood Sugar Level increases and reaches its peak
o “Temporary State of Hyperglycemia”
o Due to the absorption of glucose
 2 hours
o Blood Sugar Level goes down
o It may overshoot causing blood sugar level to decrease
more than the original level
o “Temporary State of Hypoglycemia”
o Due to action of insulin
Prolonged GTT curve
 Present in Diabetes Mellitus
 It starts with a high FBS level, the elevation is long, and does not
go down to normal in 2 hours’ time
Flatt GTT Curve
 GTT curve neither increases nor decreases
 Failure to absorb glucose
 Present in cases of malabsorption
Inverted Curve
 A reverse curve
 Blood sugar decreases further upon intake of glucose
 Present in patients with Insulinoma (tumor producong a lot of
insulin) manifested by hyperinsulinemia
Types of DM:
 TYPE 1
o Insulin-dependent diabetes mellitus
o Youth onset
o Pancreas is totally not producing insulin
o Complications set in at a young age (E.g. Diabetic
Ketoacidosis)
o Treatment: Insulin administration
 TYPE 2
o Non-insulin dependent diabetes mellitus
o Maturity Onset
o Usually develops 40 y/o and above
o Pancreas produces insufficient amount of insulin
o Treatment: Drugs that helps the pancreas produce more
insulin
 You don’t give insulin yet unless the patient is not
responding to 3 types of drugs
 e.g. Sulfonylureas, Biguanides
 TYPE 3
o Youth Onset Type 2
o Non-insulin dependent but occurs in young age
o Insulin is normal, abnormal receptors
o Also known as insulin resistance
o Regular exercise stimulates production of receptors
 Best exercise: brisk walking 1 hour everyday
o Treatment: Drugs to stimulate the formation of more
receptors (more expensive than sulfonyl ureas)
 e.g. Glitazones
 TYPE 4
o Endocrine type of diabetes
o Normal Insulin, normal receptor, normal pancreas, but
blood sugar is extremely high (400-500)
o Present in patients with pituitary tumor
o Increase in production of all trophic hormones that includes:
 Growth hormones
 Adrenocorticotropic hormones - stimulates adrenal
glands to produce glucocorticoids
 Thyroid stimulating hormone -increases thyroid
hormone synthesis
 TYPE 5
o Glucagon resistance diabetes
o Glucagon is normally stimulated when blood sugar goes
down and it stops when blood sugar is normal
o In glucagon resistance, even if blood sugar is already high, it
does not stop its activity making blood sugar level increase
further
o Treatment: Drugs that suppress glucagon effect
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