CARBOHYDRATES

METABOLISM

PREPARED BY:
MARIE LYNN SY-FAMA,MD, MHcA
BIOCHEMISTRY DEPARTMENT
VMUF-COLLEGE OF MEDICINE
• On the basis of mass, carbohydrates are the most
abundant class of biomolecules on earth

• More than half of all the organic carbon is found

in carbohydrates
• Play several crucial roles in living organisms

• GLYCOBIOLOGY study of the structure and

function of various carbohydrates in health and
disease
 MAJOR COMPONENT OF THE DIET

• More than 60% of our foods are carbohydrates.

• Starch, glycogen, sucrose, lactose and cellulose
are the chief carbohydrates in our food.
DIGESTION OF CARBOHYDRATES

Food carbohydrates:

60% - starches, dextrin and glycogen

- the most important food sources
30% - sucrose
5% - lactose
5% - other sugars
DIETARY FIBER

• consists primarily of polysaccharides from plant

cell walls: cellulose, hemicellulose, lectins,
lignins
• no caloric value
• delays postprandial rise in blood glucose
with consequent reduction in insulin
secretion
• reduces rebound fall in blood glucose that
stimulates appetite
• beneficial to diabetics and dieters
• Resistant starch (oats, maize, legumes, potatoes)
and other non-starch polysaccharides are
substrates of bacterial fermentation in the large
intestine
• Produce butyrate and short chain fatty acids:
- source of fuel for intestinal enterocytes
- butyrate has anti proliferative activity
which protects against colorectal cancer
 A. DIGESTION IN THE MOUTH

➢Enzyme : Salivary amylase or Ptyalin

➢ Bonds hydrolyzed : & 1, 4 – glycosidic bonds of
amylopectin, amylose, glycogen
at random
➢ Optimum pH : 6.7(readily inactivated at pH 4 and <
➢End products : dextrins, isomaltose, maltose, glucose
➢Usually insignificant digestion: short stay of food in the mouth
 B. DIGESTION IN STOMACH

➢ No enzymatic digestion
- high acidity which inactivates the
salivary amylase
➢ Limited acid hydrolysis
C. DIGESTION IN THE SMALL INTESTINES
- final stages of digestion, very large, surface area

Enzymes : a) Pancreatic amylase or Amylopsin

- same action as salivary amylase
: b) Oligosaccharidases/Disaccharidases
Oligosaccharidases/Disaccharidases
– from the brush border of the small intestines
- contained in the intestinal juice secreted by
the glands of Brunner and Lieberkuhn

a. Lactase (B-glucosidase) – acts on lactose

b. Maltase (&-glucosidase) – acts on maltose
c. Sucrase-isomaltase - a bifunctional enzyme
that splits sucrose as well as isomaltose
d. Alpha limit dextrinase-acts on dextrins
e. Trehalase-acts on trehalose
Trehalose, also known as mycose, a disaccharide of (&1-1 )
glucoside bonds, ubiquitous in other life forms but not in
mammals, a stress-responsive factor by prevent denaturation of
proteins under stress, safe for human consumption
• Congenital deficiency of
lactase: Lactose
Intolerance
• Bloating and diarrhea • Congenital deficiency of
sucrase-isomaltase:
• Failure to thrive when
Sucrose Intolerance
fed on breast milk and
infant formula • Bloating and diarrhea
• Failure to thrive when
fed diet containing
sucrose
END PRODUCT OF CARBOHYDRATE DIGESTION

➢Monosaccharides:
fructose, galactose and principally glucose
 THERE ARE TWO SEPARATE MECHANISMS FOR THE ABSORPTION
OF MONOSACCHARIDES IN THE SMALL INTESTINE

1. Active Transport (SGLT1) Na+ dependent coupled with Na/K pump

2. Facilitative Transport (GLUT5)- carrier mediated diffusion
3. Facilitative Transport (GLUT2)-carrier mediated diffusion, exit from the
intestinal cells into the capillaries
 ABSORPTION OF CARBOHYDRATES
➢ Actively absorbed ( SGLT-sodium dependent coupled with
Na/K pump), against concentration gradient
1. Galactose – most rapidly absorbed
2. Glucose
➢ Facilitative transport ( GLUT 5 carrier )
➢ - within or down their concentration gradient
1. Fructose
2. Mannose
3. Galactose
4. Glucose
• Fructose and sugar alcohols are only absorbed by diffusion
down their concentration gradient
• Moderately high intake: some may remain in the intestinal
lumen, acting as a substrate for bacterial fermentation
• Large intake: osmotic diarrhea
 ABSORPTION OF MONOSACCHARIDES

jejunum

portal venous system

liver
( stored or metabolized ) fructose and galactose are transformed into
glucose

systemic circulation
 FATES OF INGESTED GLUCOSE

• Uptake by the liver

- where galactose and fructose are converted into glucose
• Glucose utilization by tissues:
Oxidation
a) Major pathways (Glycolysis and Krebs' cycle) for production of energy (50%)
b) Hexose monophosphate pathway: for production of ribose, deoxyribose and NADPH
c) Uronic acid pathway, for production of glucuronic acid
Storage
a) Glycogen: glycogenesis. (10%)
b) Fat: lipogenesis (30-40%)

Conversion to substances of biological importance

a) ribose, deoxyribose in RNA and DNA
b) lactose in milk
c) glucosamine, galactosamine, glucorunic acid in mps
e) fructose in semen
GLYCOLYSIS

• Main pathway of glucose metabolism

• Occur in cytosol of all cells
• Can function aerobically or anaerobically
BIOMEDICAL IMPORTANCE

➢Provides glucose to the brain

- high requirement for glucose, 20% only from ketone bodies
➢Provides glucose to erythrocytes thru anerobic glycolysis
- lack mitochondria
➢Allows skeletal muscles to perform at high level of work output when
oxygen supply is insufficient
* heart muscle has low glycolytic activity thus has poor survival
under conditions of ischemia
• Glycolytic enzyme deficiencies:
-Pyruvate kinase deficiency- chronic hemolytic anemia
- impaired glycolysis, decreased ATP production, impaired N/K
pump in the rbc membrane, lost control of water entry, cell
swelling and hemolysis
- Phosphofructokinase deficiency- skeletal muscle fatigue
- impaired skeletal muscle glycolysis, decreased ATP production
• Hypermetabolism in cancer cachexia
- high rate of glycolysis in fast growing cancer cells, increased
production of pyruvate, increased reduction to lactate, acidic
local tumor environment,
- lactate is also substrate for gluconeogenesis in the liver, a
highly energy expensive process
 GLYCOLYSIS

- Sequence of reactions that oxidized glucose to pyruvate (aerobic condition) or

lactate (anaerobic condition) with concomitant production of ATP
Elucidated by: Embden, Meyerhof and Parnas
- The reactions of Glycolysis constitute the main pathway of glucose utilization
- Net reaction of Glycolysis from glucose to pyruvate:
Glucose + 2NAD+ + 2 Pi + 2 ADP = 2 pyruvate + 2 ATP + 2 NADH + 2 H2O
 Functions of Glycolysis

1. To produce energy in the form of ATP

- basically exergonic
2. Intermediates formed can be converted to other substances like amino
acids, fatty acids, etc.
 Their phosphate groups appear to have 3 functions:
1. Provide each intermediate with a polar, negatively charge group
2. As binding or recognition groups in the formation of enzyme-substrate
complexes
3. Function in the conservation of energy since they ultimately become the
terminal phosphate groups of ATP in the course of Glycolysis
 KINDS OF REACTIONS THAT OCCUR IN GLYCOLYSIS

1. Phosphoryl transfer
– a phosphoryl group is transferred from ATP to a glycolytic
intermediate, or vice versa
2. Phosphoryl shift
– a phosphoryl group is shifted within a molecule from one
oxygen atom to another
3. Isomerization
– a ketose is converted into an aldose or vice versa
4. Dehydration
– a molecule of water is eliminated
5. Aldol cleavage
– a carbon-carbon bond is split in a reversal of an aldol condensation
 TWO PHASES OF GLYCOLYSIS

1. Energy Investment Phase

- Priming Stage or Preparatory phase
2. Energy Generation Phase
- oxidoreduction-phosphorylation stage
 HEXOKINASE
• Secreted by all cells
• Has low Km (high affinity) for glucose and easily
saturated
• In the liver and pancreatic B islet cells, it acts at a
constant rate to provide glucose 6-phosphate to
meet the cell’s need.
• Reaction catalyzed is irreversible inhibited
allosterically by its product glucose 6-PO4
GLUCOKINASE
• Isoenzyme in liver
• Has a higher Km (lower affinity) for glucose but
higher vMax (more capacity)
• Phosphorylates more glucose
- provide glucose 6-phosphate in excess of
requirements for glycolysis, which will be used
for glycogenesis and lipogenesis
• Remove glucose from the hepatic portal blood
following a meal thus regulates concentration of
glucose available in the peripheral tissues
• In pancreatic B cells, it detects high concentration of
glucose, increased glucose 6 PO4 availability and
leads to the secretion of insulin
GLUCOKINASE effect on insulin secretion
• As more glucose is phosphorylated by glucokinase,
• there is increased glycolysis, leading to increased formation of ATP
• This leads to closure of an ATP-potassium channel causing membrane
depolarization and opening of a voltage gated calcium channel.
• The resultant influx of calcium ions leads to fusion of the insulin
secretory granules with the cell membrane, and the release of insulin.
GLUCOSE 6 PO4

• Central metabolite in glucose metabolism

• Glycolysis, Gluconeogenesis, Pentose Phosphate Pathway,
Glycogenesis, Glycogenolysis
ENZYMATIC CONTROL OF GLYCOLYSIS
-non equilibrium/irreversible /exergonic reactions

1. Hexokinase and Glucokinase

2. Phosphofructokinase
3. Pyruvate kinase
Phosphofructokinase (PFK)
– major control enzyme of glycolysis

- it is an allosteric enzyme with two binding sites for ATP: substrate and inhibitor
- high ATP concentration inhibits PFK
- inhibited by increased ATP/AMP ratio
- activated by ADP and AMP
Why is phosphofructokinase rather than hexokinase the
pacemaker of glycolysis?

• Glucose 6-phosphate is not solely a glycolytic intermediate.

• The first irreversible reaction unique to the glycolytic pathway,
the committed step, is the phosphorylation of fructose 6-phosphate
to fructose 1,6-bisphosphate catalyzed by PFK
• In general, the enzyme catalyzing the committed step in a metabolic
sequence is the most important control element in the pathway.
Fructose and obesity

• Fructose enters glycolysis by phosphorylation to fructose 1-phosphate,

bypassing the main regulatory steps
• Formation of more pyruvate and acetyl-CoA than is required for ATP formation
• In the liver and adipose tissue, this leads to increased lipogenesis
• High intake of fructose may be a factor in the development of obesity
 Glycolysis in erythrocytes forms 2,3 BPG

involves no net yield of ATP from glycolysis, but provides 2,3-bisphosphoglycerate,

which binds to hemoglobin, decreasing its affinity for oxygen, so making oxygen
more readily available to tissues
The oxidation of pyruvate to Acetyl-coA is the irreversible
route from glycolysis to the citric acid cycle

• Oxidative decarboxylation of pyruvate to acetyl-coA occur in the

mitochondria
• Catalyzed by multienzyme complex in the inner mitochondrial membrane:
Pyruvate Dehydrogenase Complex
• Thiamin Diphosphate is a cofactor
• Thiamin deficiency cause accumulation of pyruvate, shifting to lactate
production, causing lactic acidosis
 Pyruvate dehydrogenase complex

Pyruvate Acetyl CoA

Thiamine pyrophospate
Lipoic Acid
FAD

NAD+ NADH + H+
PYRUVATE DEHYDROGENASE COMPLEX

1.Pyruvate Dehydrogenase • TPP

2. Dihydrolipoyl Transacetylase • Lipoic Acid

3. Dihydrolipoyl Dehydrogenase ▪ FAD, NAD

 ACETYL COA
➢central metabolite
➢80% enters Kreb’s Cyle
➢20% use in the synthesis of
- triacylglycerol and other complex lipids
- prostaglandins
- cholesterol
- steroids
- bile acids
- ketone bodies
Anaerobic glycolysis
• Tissues that normally derived energy from lactate include: Brain, GIT,
Renal Medulla, Retina, Skin
• Tissues that oxidized lactate under hypoxic conditions: Liver, Kidneys,
Heart
• Conditions where lactate production is high: Vigorous exercise, Cancer
Cachexia, Septic shock
• Lactate produce becomes substrate of Gluconeogenesis, increased
metabolic rate, increased oxygen consumption, oxygen debt
• Glycolysis in erythrocytes always terminate in lactate, no mitochondria,
no oxidation of pyruvate
• When oxygen is in short supply, mitochondrial reoxidation of NADH
formed during glycolysis is impaired
• NADH is reoxidized by reducing pyruvate to lactate, so permitting
glycolysis to continue.

• Anaerobic Glycolysis has limited amount of ATP formed per mole of

glucose oxidized
Fate of lactate in anaerobic glycolysis

▪ exported out of the cell to be oxidized by tissues

▪ converted back to pyruvate
▪ enters Cori Cycle - carried to the liver to be converted back to blood
glucose via gluconeogenesis
GLYCOGEN
➢10% of engested glucose is converted to glycogen
➢Stored in the liver and muscle, modest amount in the brain
➢ Liver glycogen content is greater but 2/3 of all body glycogen is found in the muscle
because of greater muscle mass
➢Readily mobilizable storage form of glucose
➢Liver glycogen functions to
store and export glucose to
maintain blood glucose
between meals and during
fasting
➢ After 12–18 hours of
fasting, the liver glycogen is
almost totally depleted
➢Muscle glycogen is a readily
available source of glucose for
glycolysis within the muscle
itself, only-cannot export
glucose because it lacks
glucose 6 phosphatase
➢Pyruvate from glycolysis is
transaminated to Alanine and
exported for gluconeogenesis
 Carbohydrates loading by endurance athletes

➢The highly branched structure of glycogen provides a large number of

sites for glycogenolysis, permitting rapid release of glucose-1-phosphate
for muscle activity
➢Exercise to exhaustion to deplete muscle glycogen followed by high
carbohydrate meal resulting in rapid synthesis of glycogen with fewer
branch points-slower but sustained release of glucose
GLYCOGENESIS

• Intracellular synthesis of glycogen

• Occurs mainly in the liver and muscle
Initial step in glycogenesis

• Formation of Glycogenin, a 37-kDa enzyme protein that is glucosylated

by UDPGlc through its Tyrosine residues
• Glycogenin catalyzes the transfer of a further seven glucose residues
from UDPGlc, in 1 → 4 linkage, to form a glycogen primer that is the
substrate for glycogen synthase.
When a growing chain is at
least 11 glucose residues long,
branching enzyme transfers
a part of the 1 → 4-chain (at
least six glucose residues) to a
neighboring chain to form a
1 → 6 linkage, establishing a
branch point
GLYCOGENOLYSIS

• Intracellular breakdown of glycogen

• Although coordinately regulated, it is not the reverse
of glycogenesis but a separate pathway
Terminal glucosyl residues from the outermost
chains are removed sequentially until
approximately four glucose residues remain on
either side of
a 1 → 6 branch

The debranching enzyme has

two catalytic sites in a single polypeptide chain:
1)Glucan transferase that transfers a
trisaccharide unit from one branch
to the other, exposing the 1 → 6 branch point.
2) 1,6-glycosidase that catalyzes hydrolysis of
the 1 → 6 glycoside bond to liberate free
glucose
• CYCLIC AMP INTEGRATES THE
REGULATION OF GLYCOGENOLYSIS
& GLYCOGENESIS
➢Cyclic AMP (cAMP) - is formed from ATP by adenylyl cyclase at the inner surface of
cell membranes
➢Acts as an intracellular second messenger in response to hormones such as
epinephrine, norepinephrine, and glucagon
➢cAMP is hydrolyzed by phosphodiesterase, so terminating hormone action.
• Glycogen phosphorylase and glycogen synthase—are regulated in opposite
directions by:
1) allosteric mechanisms
2) covalent modification by reversible phosphorylation and
dephosphorylation
• Phosphorylation of glycogen synthase reduces its activity (b)
/Dephosphorylation increases its activity (a)
• Phosphorylation of glycogen phosphorylase increases its activity (a)
/Dephosphorylation decreases its activity (b)
REGULATION OF MUSCLE PHOSPHORYLASE DIFFERS

• muscle phosphorylase is also activated by 5’AMP

• it is a potent signal for the energy state of the muscle cell
• increase in its concentration is a signal for the need for substrates
for metabolism
Ca2+ synchronizes the activation of glycogen phosphorylase
with muscle contraction

• Glycogenolysis in muscle increases several hundred-fold at

the onset of contraction
• Both are activated by increased Ca2+ ion concentration
 Glycogen Storage Diseases Are Inherited

➢“Glycogen storage disease” is a generic term to describe a group of

inherited disorders characterized by deposition of an abnormal type or
quantity of glycogen in the tissues.

Reading assignment
 GLUCONEOGENESIS
• Process of synthesizing glucose from noncarbohydrate precursors
• The major substrates are the glucogenic amino acids, lactate, glycerol, and propionate.
• Liver and kidney are the major gluconeogenic tissues, the kidney may contribute up to 40% of
total glucose synthesis in the fasting state and more in starvation.
• The key gluconeogenic enzymes are expressed in the small intestine, but it is unclear whether or
not there is significant glucose production by the intestine in the fasting state.
▪ Gluconeogenesis maintains the supply of glucose especially for the nervous system
and erythrocytes, failure of gluconeogenesis is usually fatal, hypoglycemia causes
brain dysfunction, which can lead to coma and death.
▪ Maintains the level of intermediates of the Kreb’s cycle
▪ Clears lactate produced by muscle and erythrocytes and glycerol produced by adipose
tissue
▪ Clears propionic acid- the main product of carbohydrates metabolism in ruminants
Excessive gluconeogenesis occurs in critically ill patients
contributing to hyperglycemia

• associated with a poor outcome

• hyperglycemia leads to changes in osmolality of body fluids,
impaired blood flow, intracellular acidosis and increased
superoxide radical production resulting in deranged endothelial and
immune system function and impaired blood coagulation
• Excessive gluconeogenesis is also a contributory factor to
hyperglycemia in type 2 diabetes because of impaired
downregulation in response to insulin.
• Gluconeogenesis involves • The pathway of
Glycolysis, the Citric acid Gluconeogenesis is an
adaptation of Glycolysis
Cycle, plus some special
and Kreb’s Cycle but not
reactions the exact reversal
 Thermodynamic barriers prevent a simple reversal of glycolysis

Three nonequilibrium/irreversible reactions catalyzed by:

1.Pyruvate kinase
2.Phosphofructokinase
3.Hexokinase
 REVERSAL OF REACTIONS

1. Reversal of reaction catalyzed by Pyruvate Kinase involved 2

endothermic reactions:
a. Pyruvate Carboxylase
- carboxylation of pyruvate to OAA, requires 2 ATP’s
b. Phosphoenolpyruvate Carboxykinase (PEPCK)
- decarboxylation and phosphorylation of OAA to PEP
requires 2 GTP’s
2. Reaction catalyzed by Phosphofructokinase
- reversed by Fructose-1-6-Biphosphatase
- present in liver, kidney, striated muscle
- absent in the heart and smooth muscles

Fructose 2,6-bisphosphate plays a unique role in the regulation of glycolysis &

gluconeogenesis in liver: when there is an abundant supply of glucose, the
concentration of fructose 2,6-bisphosphate increases, stimulating glycolysis by
activating phosphofructokinase-1 and inhibiting fructose 1,6-bisphosphatase
3. Reaction catalyzed by Hexokinase is reversed by Glucose 6 phosphatase
- present in liver and kidney
- absent in muscle and adipose tissue thus cannot export glucose into
the blood stream
• Since glycolysis & gluconeogenesis share the same pathway
but in opposite directions, they must be regulated reciprocally
• Three mechanisms are responsible for regulating the activity of enzymes in
carbohydrate metabolism:
(1) changes in the rate of enzyme synthesis by induction or repression by
hormones-several hours
(2) covalent modification by reversible phosphorylation by cAMP dependent
protein kinase- rapid
(3) allosteric effects- change in the enzyme structure, instantaneous
Regulation of Gluconeogenesis
➢The concentration of blood
Glucose is regulated within
Narrow limits
▪ In the postabsorptive state, the concentration of blood glucose in most mammals
is maintained between 4.5 and 5.5 mmol/L.
▪ After the ingestion of a carbohydrate meal, it may rise to 6.5–7.2 mmol/L
▪ In starvation, it may fall to 3.3–3.9 mmol/L
▪ A sudden decrease in blood glucose will cause convulsions, as in insulin
overdose owing to the immediate dependence of the brain on a supply of
glucose.
▪ However, much lower concentrations can be tolerated, provided progressive
adaptation is allowed
➢Once a meal has been completely absorbed (typically three to
five hours after a meal), the metabolism changes to a fasting
state, which is synonymous with "post-absorptive state," in
contrast to the "post-prandial" state of ongoing digestion.
 SOURCES OF BLOOD GLUCOSE

1. From carbohydrates of the diet

2. From various glucogenic compounds, that undergo gluconeogenesis
- amino acids
- lactate
- glycerol
3. From liver glycogen by glycogenolysis
1. The digestible dietary carbohydrates yield glucose, galactose and fructose that are
transported via the hepatic portal vein to the liver where galactose and
fructose are readily converted to glucose
2. Glucose from liver glycogenolysis
3. Gluconegensis
a. glucogenic amino acids and glycerol from fatty acids
b. lactate, formed by glycolysis in skeletal muscle and rbc via Cori’s cycle or
Lactic Acid Cycle
The Glucose-Alanine cycle predominates in supplying glucose during
starvation
▪ In the fasting state, there is a considerable output of alanine from skeletal
muscle:
1) catabolized muscle proteins
2) transamination of pyruvate produced by glycolysis of muscle
glycogen
 Metabolic & Hormonal Regulation Of Blood
Glucose Concentration
(involves the liver, extrahepatic tissues, metabolic enzymes and hormones insulin
and glucagon)

Role of the liver

- freely permeable uptake of blood glucose
- liver, glycolysis, glycogenolysis and gluconeogenesis
- At normal peripheral blood glucose concentrations (4.5-5.5 mmol/L),
the liver is a net producer of glucose. However, as the glucose level
rises, the output of glucose ceases, and there is a net uptake.
Role of extrahepatic cells
• Extrahepatic cells uptake of blood glucose through their glucose transporters which
are controlled by insulin
• Uptake from the bloodstream is the rate-limiting step in the utilization of glucose in
extrahepatic tissues
Role of Glucokinase
• Glucokinase is important in regulating blood glucose after a meal
• It permits hepatic uptake of large amounts of glucose after a carbohydrate meal for
glycogen and fatty acid synthesis so that while the concentration of glucose in the
hepatic portal vein may reach 20 mmol /L after a meal, that leaving the liver into the
peripheral circulation does not normally exceed 8 to 9 mmol /L.
Insulin: central role in regulating blood glucose
• Produced by the β cells of the islets of Langerhans in the pancreas in
response to hyperglycemia
• The increase in [ATP] inhibits ATP-sensitive K+ channels, depolarization
of the cell membrane, increases Ca2+ influx , stimulating exocytosis of
insulin.
• Mechanism of action: sulfonylurea drugs tolbutamide and glyburide
• Also cause release of insulin: amino acids, nonesterified fatty acids,
ketone bodies, glucagon, secretin
• Insulin acts to lower blood glucose immediately by enhancing glucose
transport into adipose tissue and muscle by recruitment of glucose
transporters (GLUT 4)
• Insulin indirectly affect glucose uptake in the liver by its actions on the
enzymes controlling glycolysis, glycogenesis, and gluconeogenesis
Glucagon is the hormone produced by the α cells of the
• pancreatic islets in response to hypoglycemia.
• Both hepatic glycogenolysis (activation of glycogen phosphorylase) and
gluconeogenesis (amino acids and lactate) contribute to the
hyperglycemic effect of glucagon, whose actions oppose those of insulin.

Assign: Table: Tissue responses to insulin and glucagon

Other hormones affecting blood glucose
• Glucosuria occurs when the renal threshold for glucose is exceeded. The
capacity of the tubular system to reabsorb glucose is limited to a rate of
about 2 mmol/min (<10 mmol /L)
Hypoglycemia May Occur During Pregnancy & in the Neonate
• During pregnancy, fetal glucose consumption increases and there is a
risk of maternal, and possibly fetal, hypoglycemia,during long intervals
between meals or at night.

• Premature and low-birth-weight babies are more susceptible to

hypoglycemia since they have little adipose tissue to provide
nonesterified fatty acids for gluconeogenesis. The enzymes of
gluconeogenesis may not be fully developed at this time.
The Ability to Utilize Glucose May Be Ascertained by Measuring Glucose
Tolerance
• Glucose tolerance is the ability to regulate the blood glucose
concentration after the administration of a test dose of glucose (normally
1 g/kg body weight) – OGTT
• Impaired tolerance in DM

https://www.ncbi.nlm.nih.gov/books/NBK532915/
The Energy Cost of Gluconeogenesis Explains Why Very Low Carbohydrate
Diets Promote Weight Loss
• Very low carbohydrate diets of only 20 g per day or less but permitting
unlimited consumption of fat and protein, have been promoted as an
effective regime for weight loss
• Since there is a continual demand for glucose, there will be a
considerable amount of gluconeogenesis from amino acids
• The associated high ATP cost must then be met by oxidation of fatty
acids.
PENTOSE PHOSPHATE PATHWAY
- Hexose Monophosphate Shunt
- Warburg-Dickens Pathway
- Phosphogluconate Shunt
• Alternative route for the metabolism of glucose but does not
lead to formation of ATP
• Two major functions:
(1) the formation of NADPH
- for synthesis of fatty acids and steroids
- maintaining reduced glutathione for antioxidant
activity,
(2) the synthesis of ribose for nucleotide and nucleic acid
formation
 Reactions Of The Pentose Phosphate Pathway Occur In
The Cytosol
• NADP+ acts as the hydrogen acceptor of oxidation reactions
• Two phases:
1) irreversible oxidative phase: glucose-6-phosphate undergoes
dehydrogenation and decarboxylation to a pentose ribulose-5-phosphate;
NADPH is generated
2) reversible nonoxidative phase: ribulose-5-phosphate is converted back
to glucose-6-phosphate by a series of transketolase and transaldolase
reactions; generates Ribose precursors
Isoenzyme: Hexose-6-phosphate Dehydrogenase in the ER

• Provides NADPH for:

1) hydroxylation reactions by mixed function oxidase
2) 11-β-hydroxysteroid dehydrogenase-1 which catalyzes the
reduction of (inactive) cortisone to (active) cortisol in liver, the
nervous system, and adipose tissue.
• It is the major source of intracellular cortisol in these tissues and
may be important in obesity and the metabolic syndrome.
• Pentose Phosphate Pathway is active in tissues which utilizes
NADPH in reductive syntheses of fatty acids, steroids, amino acids
• liver, adipose tissue, adrenal cortex, thyroid, erythrocytes, testis,
and lactating mammary gland.
• Its activity is low in nonlactating mammary gland and skeletal
muscle.
Rate-limiting enzyme: Glucose-6-phosphate dehydrogenase (G6PD)
• Genetic deficiency of glucose-6-phosphate dehydrogenase causes
hemolytic anemia

• The Pentose Phosphate Pathway & glutathione peroxidase protect

erythrocytes against hemolysis
Accumulation of H2O2 may decrease the life span of the erythrocyte by causing
oxidative damage to the cell membrane, leading to hemolysis.
• The transketolase reaction requires Mg2+ and thiamin diphosphate
(vitamin B1) as coenzyme.
• Measurement of erythrocyte transketolase and its activation by
thiamin diphosphate provides an index of vitamin B1 nutritional
status
 Ribose Can Be Synthesized In Virtually All Tissues

• Little or no ribose circulates in the bloodstream, so tissues have to

synthesize the ribose they require for nucleotide and nucleic acid
synthesis using the pentose phosphate pathway
 THE URONIC ACID PATHWAY

• A pathway for the conversion of glucose to glucuronic acid, ascorbic acid and
pentose
• An alternative oxidative pathway for glucose that does not lead to the generation
of ATP
• Glucuronic acid serves as a precursor of ascorbic acid, but in human it is
converted to L-xylulose because they lack the enzyme L-gluconolactone oxidase
• UDP-glucuronate incorporated into proteoglycans or conjugated to bilirubin,
certain drugs, hormones
• Ingestion of large quantities of fructose has profound
metabolic consequences
• Diets high in sucrose or in high-
fructose syrups (HFS) lead to
large amounts of fructose (and
• Fructose undergoes more rapid
glucose) entering the glycolysis in the liver because it
hepatic portal vein bypasses the regulatory step
catalyzed by
phosphofructokinase
• Fructose flood the pathways in
the liver, leading to increased
fatty acid, triglyceride
synthesis, secretion of VLDL
and LDL
Galactose is needed for the synthesis of lactose, glycolipids,
proteoglycans, & Glycoproteins
• Galactose is readily converted to glucose in the liver. Galactose is
needed in the synthesis of lactose, glycopilids, glycoproteins,
proteoglycans

• In the genetic disorder Galactosemia, galactose is not properly

metabolized. Infants commoly are deficient in Galactose 1 PO4
uridyl transferase. Gal 1PO4 accumulates in the liver causing
jaundice and compromising liver function. May also affect the CNS
causing mental retardation.

• Screening can be done at birth and severe effects can be avoided by

excluding lactose from the diet
THANK YOU!