A quick revision of Carbohydrate metabolism with case- based discussions and multiple- choice questions

A Quick Revision Of
Carbohydrate Metabolism
Namrata Chhabra
MHPE, FAIMER Fellow, MD, M.B.B.S,
131-Dec-20 Namrata Chhabra -Our Biochemistry

Case study 1
• A 45-year-old morbidly obese woman has been attempting to lose
weight using a low- carbohydrate diet.
• After 2 months of little success, she confides in her son that she does
add glucose to her coffee in the morning and after dinner but feels
only some of this will be absorbed and should not be the cause of her
limited success.
• Her son, a medical student, states that glucose is almost completely
absorbed from the gut.

Case study 1
What type of transport does glucose utilize for gastrointestinal
absorption?
A. Active- Carrier mediated, against the concentration gradient and
energy dependent
B. Facilitated- Carrier mediated, down the concentration gradient
C. Passive- Down the concentration gradient
D. Active and facilitated
E. Passive and facilitated

Answer
D. Active and facilitated

Absorption of monosaccharides
• Glucose and galactose are
absorbed by a sodium-
dependent process.
• They are carried by the same
transport protein (SGLT 1) and
compete for intestinal
absorption.
• The carrier protein carries
sodium along with Glucose

Glucose uptake in peripheral tissues
Transporter Occurrence Function
GLUT1 and
GLUT3
Nearly all mammalian cells Responsible for basal glucose uptake
GLUT2 Liver and pancreatic beta cells, and serosal
surface of intestinal cells
Biological sensors of glucose load,
cause insulin release
and transportation of glucose from
intestinal cells to portal blood.
GLUT4 Adipose tissue, skeletal and cardiac muscle Insulin mediated glucose uptake
GLUT5 Small intestine, testes, seminal vesicles
and kidney,
Function primarily as fructose
transporters.
GLUT 6 A product of pseudo gene -
GLUT-7 At the surface of endoplasmic reticulum Export of glucose from endoplasmic
reticulum to cytoplasm, after the
action of glucose-6 phosphatase 731-Dec-20 Namrata Chhabra -Our Biochemistry

Pathways of
glucose
utilization
Glucose
Glycolysis
HMP Pathway
Uronic acid
pathway
Glycogen
31-Dec-20 Namrata Chhabra -Our Biochemistry 8

Glycolysis
• Glycolysis is the stepwise degradation of glucose (and other
simple sugars).
• Carried out in the cytosol of cells,
• it is unique, in that it can function either aerobically or
anaerobically, depending on the availability of oxygen and the
electron transport chain.

Hexokinase versus Glucokinase
Characteristics Hexokinase Glucokinase
Tissue distribution: Most tissues Liver and β cells of Pancreas
Km Low (0.05 mM/L) High (10 mM/L)
Vmax Low High
Inhibition by G6P Yes No
Inducible No Inducible(the amount
present in the liver is
controlled by insulin)
Clinical significance Deficiency causes hemolytic
anemia
Patients with diabetes
mellitus show less activity
Biological Significance Involved in maintaining
intracellular glucose
concentration
Involved in maintaining
blood glucose concentration
31-Dec-20 11Namrata Chhabra -Our Biochemistry

R.L. Shunt
31-Dec-20 12Namrata Chhabra -Our Biochemistry

Energetics of Glycolysis
13
S. No. Reaction catalyzed Mode of ATP formation ATP per molecule of
Glucose
1. Glyceraldehyde 3-phosphate
dehydrogenase
Respiratory chain
oxidation of 2 NADH
6/5
2. Phosphoglycerate kinase Substrate level
phosphorylation
2
3. Pyruvate kinase Substrate level
phosphorylation
2
4. Consumption of ATP for reactions of hexokinase and
phosphofructo kinase
-2
5. Net ATP yield 8/7
Under anaerobic conditions Electron transport chain does not operate therefore, the ATP is only formed by substrate
level phosphorylation. Hence the total energy yield through glycolysis in the absence of oxygen is only 2 ATP per mol
of Glucose.

Sources and Fate of Pyruvate
14
Sources Fate

Components of Pyruvate dehydrogenase complex
1) Enzymes- The pyruvate dehydrogenase complex is a large, highly
integrated complex of 2 types of enzymes-
A)- Catalytic enzymes
a) Pyruvate dehydrogenase (E1)
b) Dihydrolipoyl transacetylase (E2)
c) Dihydrolipoyl dehydrogenase (E3)
B)- Regulatory Enzymes
a) PDH Kinase
b) PDH Phosphatase
15Namrata Chhabra -Our Biochemistry31-Dec-20

Components of Pyruvate dehydrogenase complex
(contd.)
2) Coenzymes of PDH complex
Five coenzymes:
• Thiamine pyrophosphate (TPP),
• Lipoic acid,
• CoASH,
• FAD and
• NAD+ participate in the overall reaction
16Namrata Chhabra -Our Biochemistry31-Dec-20

Pyruvate to Acetyl co A conversion

Case study-2
• A 2-year-old girl child was referred to
the hematologist after her pediatrician
found her severely anemic with
splenomegaly and jaundice.
• Her mother gave a possible history of a
“blood problem” in her family but did
not know for sure.
Anemia
Jaundice
Splenomegaly

Case study-2 (contd.)
• Her hemoglobin electrophoresis was normal,
and the complete blood count (CBC) revealed a
normocytic anemia.
• On the peripheral smear, there were many
bizarre erythrocytes, including spiculated cells.
• She was diagnosed with pyruvate kinase
deficiency.
• What is the biochemical basis of this
disorder?

Case discussion
• Pyruvate kinase deficiency (PKD) is
an erythrocyte enzymopathy
involving the Embden-Meyerhof
(glycolytic)pathway.
• Erythrocytes have evolved without
oxidative phosphorylation to form
adenosine triphosphate (ATP), the
compound essential for providing
the erythrocyte energy.

Biochemical basis of Anemia
21
Pyruvate kinase activity is critical for the pathway and therefore
critical for energy production.
Energy is required to maintain the Na+/K+ balance within the RBC
and to maintain the flexible discoid shape of the cell.
In the absence of sufficient pyruvate kinase activity and therefore
ATP, the ionic balance fails, and the membrane becomes misshapen.
Cells reflecting a change in membrane composition are removed
from the circulation by the macrophages of the spleen.

Multiple choice question-1
Phosphoglycerate kinase functions in carbohydrate metabolism to
produce ATP via:
a) oxidative phosphorylation
b) substrate level phosphorylation
c) oxidative decarboxylation
d) phosphorolysis
e) oxidative deamination

Answer
b) substrate level phosphorylation

MCQ 2
The enzyme that catalyzes the second substrate level phosphorylation
of glycolysis
a) is called Phosphoglucomutase
b) produces lactate as a product
c) uses phosphoenolpyruvate as a substrate
d) is found in the mitochondria
e) is reversible

Answer
c) uses phosphoenolpyruvate as a substrate

Citric Acid Cycle
• The citric acid cycle (Krebs cycle,
tricarboxylic acid cycle) includes a
series of oxidation-reduction reactions
in mitochondria that result in:
• the oxidation of an acetyl group (C2)
to two molecules of carbon dioxide
• reduction of the coenzymes that are
reoxidized through the electron
transport chain, linked to the
formation of ATP.

27
TCA CYCLE

Amphibolic role of TCA cycle

Case study-3
• A full-term female infant failed to gain
weight in the neonatal period.
• A physical examination at 6 months
showed:
ofailure to thrive,
ohypotonia,
osmall muscle mass,
osevere head lag.

Case study-3
• Blood gas analysis revealed-
acidosis (pH 7.0–7.2)
• Blood lactate, pyruvate, and
alanine were greatly elevated.
• Treatment with thiamine did
not alleviate the lactic acidosis.
• What might be the probable
diagnosis?

Case discussion
• The child is most probably suffering from
pyruvate dehydrogenase complex
deficiency.
• Pyruvate dehydrogenase complex (PDC)
converts pyruvate to acetyl-coenzyme A
(CoA), which is one of the two essential
substrates needed to produce citrate.

Pathophysiology
1) Energy Deficit-A deficiency in this enzymatic complex limits the
production of citrate.
• Because citrate is the first substrate in the citric acid cycle, the cycle
cannot proceed.
• Alternate metabolic pathways are stimulated in an attempt to
produce acetyl-CoA; however, an energy deficit remains, especially in
the CNS.
• The magnitude of the energy deficit depends on the residual activity
of the enzyme.

Pathophysiology (contd.)
2) Neurological deficit
• Severe enzyme deficiencies may lead to congenital brain
malformation because of a lack of energy during neural development.
• Underlying neuropathology is not usually observed in individuals
whose onset of pyruvate dehydrogenase complex deficiency is in
childhood.

MCQ
A 3-year-old child presents with a history of recurrent rash upon sun
exposure and passage of purple colored urine.
The child is diagnosed with Congenital Erythropoietic Porphyria, a disorder
of pathway of heme biosynthesis.
Which of the following intermediates of TCA cycle is used as a precursor for
heme biosynthesis ?
a) Succinyl co A
b) Acetyl co A
c) Succinate
d) Malate
e) Pyruvate

Answer
a) Succinyl co A

Gluconeogenesis
• Gluconeogenesis is the process of converting noncarbohydrate
precursors to glucose or glycogen.
• Gluconeogenesis meets the needs of the body for glucose when
sufficient carbohydrate is not available from the diet or glycogen
reserves.
• A supply of glucose is necessary especially for the nervous system and
erythrocytes.
• Failure of gluconeogenesis is usually fatal.

Reactions of
Gluconeogenesis

Cori’s cycle
• The liver furnishes glucose to contracting skeletal muscle, which derives ATP from the
glycolytic conversion of glucose into lactate.
• Contracting skeletal muscle supplies lactate to the liver, which uses it to synthesize
glucose.
• These reactions constitute the Cori cycle

MCQ
Which of the following substrates cannot contribute to net
gluconeogenesis in mammalian liver?
a) Alanine
b) Glutamate
c) Palmitate
d) Pyruvate
e) α-Keto glutarate.

Answer
c) Palmitate

An overview of HMP Pathway
HMP Pathway
Oxidative
phase
NADPH Pentoses
Non –
Oxidative
Phase
Glycolytic
intermediates

Glycolysis V/S HMP pathway
Characteristics Glycolysis HMP pathway
Occurrence All cells of the body Active in liver, adipose tissue, adrenal cortex, thyroid,
erythrocytes, testis, and lactating mammary glands.
Coenzyme NAD + NADP+
CO2 production No CO2 production CO2 is produced.
Pentose production Pentoses are not produced Pentoses are produced.
Intermediates Intermediates can be in the
mono or bisphosphate forms
Intermediates are never in the bisphosphate form.
Energy ATP is utilized as well as
produced
ATP is neither utilized nor produced.
Glycolytic intermediates may enter glycolytic pathway to
produce energy
Biological
Significance
Energy production both in
aerobic and anaerobic
conditions
NADPH is required for reductive biosynthesis and Pentoses are
required for synthesis of coenzymes and nucleotides.

Summary of HMP
Pathway
43
Major outcomes:
• NADPH
• Pentoses
• Glycolytic intermediates
• CO2

Significance of NADPH
44
Significance of Pentoses

Case study-4
• A 34-year-old African–American man
was seen with fever and shortness of
breath.
• Shortly afterwards he developed
pancreatitis and was treated with an
antibiotic, clindamycin and
primaquine.
• After four days into this therapy the
onset of hematuria was noted.

• The patient’s hemoglobin (Hb) fell
from 11.0 g/dL to 7.4 g/dL,
• Total bilirubin increased from 1.2
mg/dL to 4.3 mg/dL and
• Lactic dehydrogenase (LDH)
increased from 248 IU/L to 612 IU/L.
• What might be the probable
diagnosis?

Case discussion
The patient is most probably suffering from
Glucose-6-phosphate dehydrogenase deficiency.
The hemolysis is primaquine induced which
is an oxidant drug.
The rise in bilirubin is due to hemolytic
jaundice and
The rise in lactic dehydrogenase (LDH) is
commonly observed in hemolytic anemias.

Glycogen Metabolism
• Glycogen is a readily mobilized storage form
of glucose
• It is stored mainly in liver and muscle
• The liver content of glycogen is greater than
that of muscle,
• Since the muscle mass of the body is
considerably greater than that of the liver,
about three-quarters of total body glycogen
is in muscle

Reasons for storing Glycogen as a fuel
• Glycogen serves as a buffer to maintain blood-glucose levels.
• Glucose is virtually the only fuel used by the brain, except
during prolonged starvation.
• The glucose from glycogen is readily mobilized and is
therefore a good source of energy for sudden, strenuous
activity.
• Unlike fatty acids, the released glucose can provide energy
in the absence of oxygen and can thus supply energy for
anaerobic activity.

Phases of Glycogenesis
50
Activation Initiation Elongation
Glycogen
Branching

Glycogen degradation is not just the reverse of
glycogenesis
Glycogenesis
➢ Glucose-> Glucose-6-P
➢ Glucose-6-P –> Glucose-1-P
➢ Polymerization
➢ Branching
➢ Polymerization
• Glycogenolysis
• Depolymerization- Removal of
glucose as glucose-1-P
• Debranching
• Depolymerization
• Conversion of Glucose-1-P to
Glucose-6-P
• Conversion of Glucose-6-P to
free Glucose

Glycogenesis versus Glycogenolysis
• Glycogenolysis and
Glycogenesis are not
the just the reverse
of each other.
• The reaction
pathways, enzymes
and coenzymes are
all different and,
• both the ways are
reciprocally
regulated.

Case study-5
53
The patient was a 12-year-old girl who had a grossly
enlarged abdomen. She had a history of frequent episodes
of weakness, sweating and pallor that were eliminated by
eating.
Her development had been slow, she sat at the age of 1
year, walked unassisted at the age of 2 years, and was
doing poorly in the school.

54
Physical examination revealed normal blood pressure, temperature
and a normal pulse rate but a subnormal weight (23 Kg).
The liver was enlarged, firm and was descended into pelvis.
The spleen was not palpable, nor were the kidneys.
The remainder of the physical examination was within the normal
limits.

55
Laboratory investigation report revealed, low blood glucose, low pH, high
lactate, triglycerides, ketones and high free fatty acids.
The liver biopsy revealed high glycogen content.
Hepatic glycogen structure was normal.
The enzyme assay performed on the biopsy tissue revealed very low glucose-6-
phosphatase levels.
What might be the probable diagnosis?

Case discussion
56
The girl is suffering from Von Gierke’s disease.
Glycogen storage disease (GSD) Type I, is also known as Von Gierke’s
disease or hepatorenal glycogenesis.
The clinical picture, biochemical findings, hypoglycemia and
increased hepatic glycogen stores are all characteristic of Von
Gierke’s disease.

Von Gierke’s
Disease

Case study-6
A 3-year-old boy was brought to the emergency department after
several episodes of vomiting and lethargy.
After a careful history, it was observed, that these episodes occur after
ingestion of certain types of food, especially high in fructose.
His blood sugar was checked in the emergency department and was
extremely low (42 mg/dL).
The test for reducing sugar in urine was positive.
What is the most likely diagnosis?

Case details
59
The child is most probably suffering from ‘Hereditary fructose
intolerance’.
The onset of symptoms after ingestion of fructose or fructose
containing diet is a sign of ‘hereditary fructose intolerance’.
All these symptoms of vomiting, lethargy, failure to thrive,
hypoglycemia and liver failure are characteristic of this disease.

Hereditary fructose intolerance
• In the liver, kidney, and
intestine, fructose can be
converted to
glycolytic/gluconeogenic
intermediates by the actions of
three enzymes :
ofructokinase,
oaldolase B, and
otriokinase (also called triose
kinase).

Hereditary fructose intolerance (contd.)
• Pathophysiology
oA defect in the aldolase B
gene results a build-up of F1P
levels in the hepatocytes.
oBecause the maximal rate of
fructose phosphorylation by
fructokinase is high,
intracellular levels of both
ATP and inorganic phosphate
(Pi) are significantly
decreased.
Higher catalytic rate of
Fructokinase compared to
aldolase B causes ATP trapping
and a state of energy deficit.

Hereditary fructose intolerance
(contd.)
• The drop in ATP concentration
adversely affects several cellular
events, including detoxification
of ammonia, and ribonucleic acid
(RNA) and protein synthesis.
• The decrease in intracellular
concentrations of Pi leads to a
hyperuricemic condition as a
result of an increase in uric acid
formation.

Case study-7
A newborn developed an increasing
degree of jaundice, became indolent and
difficult to feed.
His serum bilirubin rose to 14 mg/dL. The
exchanged blood transfusion was
performed three times, but the serum
bilirubin concentration remained high.
On the 9th day of life, the boy began
vomiting, the liver enlargement was
noted, and the cerebral symptoms
became accentuated.

Case study-7
64
A positive test for reducing sugar had already been obtained on the
6th day after birth.
A repeated test performed on the 7th day was positive, whereas at
the same time, a test specific for glucose was negative.
Hereditary galactosemia was then suspected.
What are the biochemical effects of galactosemia?

Galactosemia
Galactose-1-
phosphate uridyl
transferase (GALT)
deficiency is the most
common enzyme
deficiency that causes
galactosemia.

Case study-8
66
A 35-year-old- male was referred to the biochemical
laboratory for the study of his mellituria.
The urinary sugar had been discovered during a
hospitalization for the repair of an inguinal hernia when
the patient was 20 years of age, and he was then refused
operation because of "diabetes."

67
Numerous blood sugar analyses were reported normal.
The patient was in excellent health and had no symptoms of
diabetes but was concerned about his condition .
L- xylulose was present excessively in urine.
The patient was diagnosed with “Essential pentosuria” after
extensive investigations.

Essential Pentosuria
• Pentosuria is the condition in which one of the pentose sugars, is
constantly excreted in urine and gives a positive reaction on testing
with Benedict's solution.
• It is a rare hereditary disease which has been included by Garrod
(1923) among the inborn errors of metabolism.
• Its occurrence was first described in 1892, but since then only about
200 cases have been recorded in the literature, the disorder occurred
almost entirely in the Jewish race.

• Biochemical defect- The enzyme that
causes conversion of L-Xylulose to Xylitol
is deficient. As a result excess of L-
Xylulose is excreted in urine.
• Clinical Manifestations- It may go
unnoticed or it may be a chance finding
on routine examination of urine.
• There are no signs and symptoms
associated with it.
Xylitol dehydrogenase

Laboratory diagnosis
It can be misdiagnosed with renal glycosuria or mild diabetes mellitus.
Bial's test and fasting blood glucose estimation can rule out renal
glycosuria and diabetes mellitus.
The identification of urinary xylulose has been greatly facilitated by the
introduction of paper chromatography.
Treatment- No treatment is required for this defect.

MCQ
A 3-month-old infant presents with hepatosplenomegaly and failure to
thrive. A liver biopsy reveals glycogen with an abnormal, amylopectin
like structure with long outer chains and missing branches. Which of
the following enzymes would most likely be deficient?
A. Alpha Amylase
B. Branching enzyme
C. Debranching enzyme
D. Glycogen phosphorylase
E. Glucose-6-phosphatase

Answer
• The answer is-B- Branching enzyme.
• During the process of glycogen synthesis, branching enzyme creates
branch points and further elongation is carried out by Glycogen
synthase.
• In its deficiency stored glycogen is abnormal in chemistry, in the form
of long polysaccharide chains with few branch points, resembling the
structure of Amylopectin, thus this defect is also called
Amylopectinosis.

MCQ
Which of the following complications is less likely to occur in type II
diabetics, as opposed to type I diabetics?
A. Retinopathy
B. Weight gain
C. Cardiovascular disease
D. Hypoglycemic coma
E. Nonketotic hyperosmolar coma

Answer
The answer is-D
Hypoglycemic coma occurs as a result of insulin over dosage in Type
1diabetes Mellitus.
It is not observed in Type 2 diabetes.
Weight gain can occur in both types, it is the result of treatment with
insulin or certain hypoglycemic drugs.
Non ketotic hyperosmolar coma is a frequent complication of coma
especially in the elderly group.

MCQ
The major metabolic product produced under normal circumstances by
erythrocytes and by muscle cells during intense exercise is recycled
through liver in the Cori cycle. The metabolite is-
A. Oxaloacetate
B. Alanine
C. Glycerol
D. Lactate
E. NADH

Answer
The answer is-D
Lactate, the end-product of glycolysis in erythrocytes and during
intense exercise in skeletal muscle, is mobilized through Cori cycle to
liver to provide glucose by the process of gluconeogenesis.
(Erythrocytes lack mitochondria so the end-product of glycolysis is
always lactate.
The mode of glycolysis during intense exercise is anaerobic; hence
lactate is formed as a result of glycolysis.

Thank you

A quick revision of Carbohydrate metabolism with case- based discussions and multiple- choice questions

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A quick revision of Carbohydrate metabolism with case- based discussions and multiple- choice questions