Dr Vivek Joshi, MD
 Introduction
 Biomedical
importance
 Glycogenesis
(Glycogen Synthesis)
 Glycogenolysis
 Regulation
 Glycogen
(Glycogen Breakdown)
of Glycogen Metabolism
Storage Disease (GSD)
 Glycogenesis-
Synthesis of Glycogen
 Glycogenolysis- Breakdown of Glycogen
Glycogen-Ideal storage form
Glucose residues in a linear sequence are linked to each other by a
1→4 glycosidic linkage
Branched hompolysaccharide of D-glucose
Branches every 8-12 residues along the chain, linked as
1→6 linkages
Branch
 NO OSMOTIC PRESSURE
 HIGHLY BRANCHED-READILY BROKEN DOWN-HORMONES
&ENZYMES
 WATER SOLUBLE
 MORE FREE GLUCOSE RESIDUES-NON REDUCING END
Glycogen –Storage
Form
Single reducing end
bound to Glycogenin
Nonreducing ends
Gn
Single reducing end bound to Glycogenin
Glycogen breakdown yields Glucose
Brain &RBC’S-Dependent on Glucose
Replenish Glucose in between meals, sleep, Fasting and
Early Starvation
Muscle Glycogen-Energy
Liver Glycogen-Maintains Blood Glucose(12-14 hrs of
Fasting)



Stores about 50-100gms of glycogen. Amounts to 200300gms with water of hydration
Glycogen used for maintenance of blood glucose
levels
Lasts about 12-14 hrs
MUSCLE Glycogen as a body energy store



Stores about 400-500gm in an average adult
Not available for blood glucose maintenance due to
absent Glucose 6-phosphatase
Provides energy during bursts of muscle activity
 Carbohydrates
in diet
 Sporadic
 Frequency unreliable
 Glycogen
 Significant storage
 Rapidly mobilized - fast response
 Total hepatic storage-enough to maintain blood
glucose levels during a 12-14 hr fast
 Gluconeogenesis
 Slow in reacting to a fall in blood glucose levels
Source of Glucose in the body
 Sites
of Synthesis:
 Most cells of the body significantly in the liver and
the muscle
 Sub
cellular site: Cytosol
 Steps:
 Glucose uptake -GLUT2 and GLUT4
 Conversion of Glucose to Glucose -6-P
 Conversion of Glucose-6-P to UDP-Glucose
 Elongation of chain: Glycogen Synthase (Glycogen
Fragment/Glycogenin to Initiate Glycogen
synthesis)
 Introduction of branches: Branching enzyme
GLUCOSE TRANSPORTERS (GLUT)
Name
Tissues
Km,Glucose
Functions
GLUT I
Most tissues
(Brain, Red cells)
~1 mM
Basal uptake of glucose
GLUT 2
Liver
Pancreatic beta
cells
~15 mM
Uptake and release of glucose by
the liver
Beta –cell Glucose sensor
GLUT 3
Most tissues
~1 mM
Basal uptake
GLUT 4
Skeletal muscle
Adipose tissue
~5mM
Insulin-stimulated glucose
uptake ;
Stimulated by exercise in skeletal
muscle
Normal Blood Glucose Level : 70-100 mg/dl
4-5.5 mmol/L
Branching enzyme [ Amylo -(1 4) (1 6)
transglucosidase] transfers 6-8 residues to the
neighbouring branch to create a branch point[
α (1 6) linkage]
 The above processes continues till a highly
branched Glycogen is formed.
 Rate limiting enzyme for synthesis of
Glycogen- Glycogen Synthase

Glycogen synthesis OR Glycogenesis
Glucose uptake (GLUT2 in the Liver/ GLUT4 in the Muscle)
Formation of UDP-Glucose
Glucose
ATP
ADP
Hexokinase /Glucokinase
Glucose-6-P
Phosphoglucomutase
Glucose-1-P
UTP
2Pi
Hydrolysis of PPi drives
the reaction forwards
PPi
UDP-Glucose
Glycogen synthesis OR Glycogenesis
Glycogen Fragment/Glycogenin to Initiate
Glycogen synthesis
Glycogenin
Tyrosine Glucose Glucose Glucose
Glycogenin/Pre
Existing Glycogen
Fragment
?
Glycogen
Synthase
Branching
Enzyme
UDP -Glucose
UDP
Elongation- Glycogen Synthase
Summary of Glycogen Synthesis
Glycogen Breakdown OR Glycogenolysis
 NOT
a reverse of Glycogenesis but a separate
pathway
 Site-Liver, Muscle
 Glycogen degradation requires the activity of
two
enzymes
Glycogen Phosphorylase
Debranching enzyme
 Glycogen
Phosphorylase
 Removes Glucose residues from the non
reducing end of Glycogen .
 It utilises the cytosolic phosphate for the above
process and releases glucose from glycogen as
Glucose-1-PO4
 The above process continues till 3-4 residues of
Glucose remain from the branch point.
Glycogenolysis
 Debranching
Enzyme
Dual Enzyme activity
[-(1 4) -(1 4) glucan transferase activity-
Transfers 3 glucose residues to the
neighbouring branch to expose the branch point
 [Amylo (1 6) transglucosidase activity breaks
the branch point to release free Glucose.
 90% of Glucose released from Glycogen as
Glucose-1-PO4 and 10% as free Glucose
Rate limiting enzyme for Glycogen DegradationGlycogen Phosphorylase
GLUCOSE
GLYCOGEN
PHOSPHORYLASE
Pi
Glucose-1-PO4
DEBRANCHING
ENZYME
Glycogenolysis
?
DEBRANCHING
ENZYME
Regulation of Glycogen Metabolism
Allosteric regulation
 Glycogen
Synthesis stimulated at high
levels of energy and substrate
 Glycogen Degradation increased when
energy and glucose supplies are low
MAJOR HORMONES IN METABOLISM
WATER SOLUBLE HORMONES IN METABOLISM
Live
r
INSULIN-ANABOLIC HORMONE
GLUCAGON
INSULIN
GLUCAGON
Glycogen Phosphorylase
(Glycogen Breakdown)
LESS ACTIVE
Glycogen Phosphorylase
(Glycogen Breakdown)
ACTIVE
Glycogen Synthase
(Glycogen synthesis)
ACTIVE
Glycogen Synthase
(Glycogen synthesis)
LESS ACTIVE
INSULIN
INSULIN
Liver and Muscle
GLUCAGON
Liver
GLYCOGEN SYNTHASE
INSULIN- Dephosphorylates key enzyme
GLUCAGON/EPINEPHRINE- Phosphorylates key enzyme
GLYCOGEN PHOSPHORYLASE
GLUCAGON
Liver
EPINEPHRINE
Liver and Muscle
Ca++ and AMP
Muscle
Covalent ModificationGlycogen Metabolism
The muscle does
not have receptors
for Glucagon
Covalent ModificationGlycogen Metabolism
Hormone independent Glycogen
Phosphorylase activation in the Muscle
Ca+2 by nerve stimulation (short bursts of
exercise)
AMP as a result of rapid ATP consumption
Glycogen Storage Diseases
(GSD)





Group of inherited disorders characterized by
defective mobilization of NORMAL GLYCOGEN
/Deposition of ABNORMAL GLYCOGEN
Classification based on the enzyme deficiency
and affected tissue.
GSD can affect the liver, the muscles or both
About Eleven known types of GSD
In general, GSDs - Autosomal-recessive
conditions EXCEPT, liver phosphorylase kinase
deficiency (GSD IX).
GSD-Diagnosis
 Patient
History (Individual's symptoms)
 Physical Examination
 Biochemical tests (CK-Level).
 Occasionally, a muscle or liver biopsy is
required to confirm the actual enzyme
defect.
GSD-TYPES
Primarily Liver involvement- I,IV,VI
 Primarily Muscle involvement- - II,V
 Both liver and muscle-III
 Adult onset-Mc Ardle’s(V)
 Most common, Clinically significant endorgan GSD with significant morbidity-Type –
I*
 GSD with significant mortality-Type –II*

GSD-TYPES
Clinicopathologic
Category
Specific Type
Enzyme Deficiency
Hepatic Type
Type I
Von Gierke disease
Liver
Glucose-6phosphatase
Generalized Type
Type II
Pompe disease
Liver, Skeletal and
Cardiac muscle
Lysosomal glucosidase
(acid maltase)
Myopathic Type
Type V
McArdle Syndrome
Skeletal muscle
Muscle phosphoylase
•Hyperlipidemia
 Children
with GSD I are unable to release
glucose from liver glycogen- “FASTING
HYPOGLYCEMIA”
 If
untreated this results in prolonged periods
when their blood sugar level is too low
 They
present in early childhood with sweating,
irritability, poor growth and muscle weakness
 Liver
enlargement -“HEPATOMEGALY”
occurs due to excessive accumulation of
Glucose-6-P AND glycogen (Cannot be broken
down normally).
 Primarily consists of giving glucose drinks
frequently during the day and, in most cases,
continuously overnight through a tube passed
down the nose into the stomach (a nasogastric
tube)
 As children get older, treatment with cornstarch,
which releases glucose slowly into the gut, may
be very effective.
 With such intensive treatment most children do
well and their symptoms improve as they reach
adulthood.
A
4-year old girl is brought to the hospital OPD
with the complaints of
sweating,headache,fatigue,nausea and loss of
weight with symptoms more severe in the
morning before breakfast. On Clinical
examination , the child had hepatomegaly with
severe fasting hypoglycemia.Further studies
reveal inherited enzyme deficiency.
Q1.What is your probable diagnosis ?
Q2. Which enzyme deficiency is responsible for
the above clinical condition?
Q3. What is the cause of fasting hypoglycemia?
 Some
amount of glycogen is continuously
degraded by the Lysosomal enzyme, acid maltase
 Deficiency
of the enzyme results in
accumulation of glycogen vacuoles in the
cytosol (liver, heart, muscle)
 GSD
II usually presents within the first months of
life with severe muscle weakness and heart
muscle involvement -“CARDIOMEGALY”.
 No
treatment has been found to prevent the
progression of the most severe (infantile) form
of this disorder
 Affected
children die from “HEART
FAILURE ”, usually before the age of 18
months
 There
are however, milder forms of GSD II in
which the heart is not affected and where
symptoms do not develop until later in
childhood or in adult life and the progression of
the illness is slower

A 12 month old girl shows slowly progressing muscle
weakness involving her arms and legs and developed
difficulty in breathing .Liver was enlarged and CT scan
revealed CARDIOMEGALY.A muscle biopsy showed
muscle degeneration with many enlarged prominent
Lysosome filled with clusters of electron dense
granules. Her parents were told that without treatment ,the
child’s symptom would continue to worsen and likely result
in death in 1-2 year. Enzyme replacement therapy was
initiated.
Q Which enzyme deficiency leads to the above condition?




Children with GSD III are often first diagnosed
with a swollen abdomen due to a very large
liver with large stores of normal glycogen
“Limit Dextrin” type of Glycogen (Glycogen
structure with short outer branch and single
glucose residue at alpha 1-6 of outer
branch) deposit in the liver &muscle cells
Some children have problems with low blood
sugars on fasting but this is not as common as
in GSD I.
Treatment consists of a high protein diet and
prevention of prolonged periods of fasting
 Patients affected by this rare myopathy are unable to produce
Glycogen phosphorylase, the enzyme involved in the cleavage of
glycogen to glucose-1- phosphate and glucose during anaerobic
exercise
 The consequence is exercise-induced myalgia and fatigue
 The disorder affects all skeletal muscle, which results in significant
disability.



People with Mc Ardle's disease experience symptoms
during anaerobic and sustained exercise.
These include fatigue and then pain occurring within
a few minutes of exercise, which if continued, leads to
muscle spasm known as a contracture.
Following severe exercise, muscle damage may occur
leading to myoglobinuria. This is a dark discolouration
of the urine and may be a warning sign for acute renal
failure, which results from excessive muscle breakdown



A simple blood test will usually reveal raised levels of
muscle creatine kinase (CK)
The diagnosis is confirmed by muscle biopsy, which
shows an excess of glycogen and absence of muscle
phosphorylase
In up to 85% of patients from Northern Europe, an
abnormality in the gene encoding for muscle
phosphorylase, called the R49X mutation, can be
detected on a blood test

Regular aerobic exercise would increase the ability
to switch to fat as the fuel source for the muscle

At the start of exercise, when pain occurs, exercise
should be slowed down or stopped until the pain
subsides (usually just for 30 seconds), then the
exercise tried again
 Continuing to exercise with intense pain would result in
muscle damage and should be avoided.

A sensible diet, rich in protein, to help replace
damaged muscle and avoiding excessive weight
gain is important

Tourniquets should not be used during operative
procedures
 Affected women do not seem to be disadvantaged by
pregnancy or childbirth. A normal childbirth is
possible in women with McArdle's disease
A
35 year old man came to the hospital OPD
with a history of limited capability to
perform strenous exercise .Patient gave a
history of muscle cramps and
Myoglobinuria after strenuous exercise.
Clinically patient was well developed and
had no abnormality at rest. On investigation
the patient was not hypoglycemic but ECG
abnormalities were recorded.
This condition is due to the deficiency in the
activity of which enzyme?

Characterized by Mild Fasting Hypoglycemia with
Hepatomegaly

Von Gierke’s v/s Her’s Disease
Breakdown of Glycogen
Gluconeogenesis
Glucose-1-P
Glucose-6-P
GLUCOSE