METABOLISM OF GLUCOSE AND
ITS DISTURBANCES,
GLYOGENOSES
Lecture from Pathological Physiology
© O. Rácz, A. Chmelárová & E. Lovásová
school year 2012/2013
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DISORDERS OF GLUCOSE METABOLISM –
OVERVIEW

EXOGENEOUS
SOURCES:
NOT SWEET
 Polysaccharides: starch,
glycogen (300-350 g/d);
degraded in GIT by
amylase, saccharidases
SWEET
 Saccharose (sugar)
lactose (milk sugar)
fructose (fruit)
 ENDOGENEOUS
SOURCES
 Gluconeogenesis
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 Glycogenolysis
Glucose has a central role in
the energetic metabolism but
it is not an important
component of the diet
DISORDERS:
Disaccharidase, lactase
deficiency (malabsorption,
diarrhoe)
a-glucosidase blockade
(treatment of obesity, type 2
diabetes)
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THE FATE OF GLUCOSE IN CELLS
1.
2.
3.
4.
5.
Glycogen synthesis. In normal postprandial
state 70 – 80 g in liver, 150 g in muscles.
Glycolysis and the following pathways (ATP
formation)
Pentose cycle (antioxidant system, pentose
formation)
Glucitol (sorbitol) pathway
Hexosamine and uronic acid pathway
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COMMENTS – 1





The beginning is ATP-dependent
Hexokinase phosphorylates everything
(different monosaccharides), entering the cell
and metabolized at mininal concentrations
Glukokinase in liver is glucose specific,
removes postprandial glucose
Glukokinase in Langerhans islets is the
glucose sensor – glucokinase diabetes
Hexokinase: kM 10-5, glucokinase: 10-2
(mmol/l)
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COMMENTS – 2





The main regulatory enzyme of glycolysis is
the phosphofructokinase.
Typical inhibitor is ATP (enough energy)
Activators: AMP and fructose-2,6bisphosphate
The production of 2,6-FBP in liver is increased
in hyperglycaemia
Glucagon inhibits its synthesis
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DISORDERS OF GLYCOLYSIS
Some of them manifest as „glycogenoses“
Hereditary - congenital
 Phosphofructokinase deficiency – muscle fatigue
 Haemolytic anemias – red cell enzymopathies
Acquired?
 Lactate acidosis: Hypoxia, pyruvatdehydrogenase
deficiency, thiamin deficiency (alcoholics), As, F, Hg
intoxication, sometimes in diabetes mellitus
 Randl cycle. Increased fatty acid oxidation (obesity,
diabetes)  NADH and acetylcoenzyme A
overproduction. Block of glycolysis and glycogen
synthesis  Increased gluconeogenesis in liver…
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SEVERE (BUT RARE) DISORDERS OF
MONOSACCHARIDE METABOLISM

Galactosemia AR, 1/20 000 – 60 000
– Accumulation of galactose, gal-1-P, galactitol 
cataract, mental retardation, liver cirrhosis,
haemolysis, kidney failure  diet without milk

Fructose intolerance AR, 1/20 000
– Accumulation of fructose & F-1-P  block of
glucose metabolism (glycolysis,
gluconeogenesis, glycogenolysis) 
hypoglycaemia after sweet fruits and sweets 
omit them
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GALACTOSEMIA
Lactose = Gal-Glu
AR, 1/20 000 – 60 000, neonatal screening
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LESS SEVERE (BUT RELATIVELY COMMON)
DISORDERS OF SUGAR METABOLISM
Milk intolerance – opposite mutation
– Lactose is important source of energy for small
children
– The activity of lactase is high up to age 4 years,
later decreases
– Milk intolerant adult people are the nonmutants
– People able consume milk in adulthood are
mutants – their off switch is not working
– Selection according to life style – hunters contra
farmers
 Fructosuria
– Fructose does not enter into metabolism, excretion
through urine

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GLYCOGEN STORAGE DISEASES, GSD*

Synthesis of glycogen (energy from ATP & UTP)
–
–
–
–

G6P  G1P no problem
Activation with UTP  UDP-glucose
primer, 1-4 polymerisation & 1-6 branching after 10
20 nm particles
Glycogenolysis
– phosphorylase (different from amylase) makes G1P
– debranching makes glucose
*Originally I – VII, 2000 IX, Fernandes 2008 – more than15
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GLYCOGEN STORAGE DISEASES, GSD

The control of synthase & phosphorylasde
through signal systems (cAMP, Ca) and
phosphorylation – dephosphorylation
 Postprandial state
– synthase in state on (I) phosphorylase off (b)

We need glucose!!!
– adrenaline, glucagon cAMP, phosphokinases
– Synthase off (D) phosphorylase on (a)
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CH20H
H2COH


O
C=O

HOCH
CH
CH20H
CH20H
20H
H
H2COHCH0H
H
HC=O
HC=O
2COH
2COH


 HCOH
 
O
O
O
O


C=O 
C=O
C=O
HCOH
HCOH

HCOH


HOCH
HOCH
HOCH

HOCH
HOCH

CH2OH 
OH 
HCOH
HCOH
HCOH
HCOH
HCOH
glycogen


ÓZA  FRUKTÓZA
HCOHKeton
HCOH
HCOH
HCOH
d HCOH
[Glu]n n = 2000 / 20000




C6H12O6
CH2OH
CH2OH
CH
CH
CH
2OH
2OH
2OH
12.10.12 GLUKÓZA
FRUKTÓZA
GLUKÓZA
FRUKTÓZA
Keton
Aldehyd
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FRUKTÓZA
Keton
14
The structure of glycogen
(1-4 bonds and 1-6 branching)
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CH 2 0H
H 2C O H
H C =O


O

C =O
HCOH


HOCH
OCH
CH 2 0H
2 0H
H
C O HCH
H 2 C O H C H 2 0H
H 2CCO
=OHCH 2 0H

H2C=O



 H C O H

O
O
O
O


HCOH

C =O
C =O

H CC=O
OH

H CO
H

HCOH

HCOH

CH
HOCH

HH
OO
CCH
H

HHOOCH

C H 2 O H 
C H 2 O H 
H
C OHH
HCOH
HH
CCO
O HH
HHCO
GLYCOGEN


G LU K Ó ZA 
FR U K T Ó ZA
H
C OHHK eton
HCOH
HH
CCO
O HH
A ldehyd HHCO
[Glu]n n = 2000 / 20000



C 6 H 12
O6
C H2 O
C H 2O H
OOHH
CCH
H 2O
HH
CH
HH
2O
2O
Ó
TÓ
ZA
ZA
FR
U KÓ
TÓ
ZA
G
LU K
FR U K T Ó ZA
G
LU
ZA
FRU
KÓ
T ZA
Ó ZA
d
K eton
AKldehyd
K eton
Aldehyd
eton
C 6 H 12 O 6
C 6 H 12 O 6
C 6 H 12 O 6
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CH 2 0H
H 2C O H
H C =O


O

C =O
HCOH


HOCH
HOCH
CH 2 0H
2 0H
H
C O HCH
H 2 C O H C H 2 0H
H 2CCO
OH 
=OHCH 2 0H
H2C=O






O
O
O
HCOH
O


HCOH

O 
C =O
C =O

H
H CC=O
OH
H CO
H

HCOH

HCOH

H
CH
HOCH

HH
OO
CCH
H

HHOOCH

C H 2 O H 
C H 2 O H 
OHH
C OHH
HCOH
HH
CCO
O HH
HHCO
GLYCOGEN


G LU K Ó ZA 
FR U K T Ó ZA
OHH
C OHHK eton
HCOH
HH
CCO
O HH
A ldehyd HHCO
[Glu]n n = 2000 / 20000



C 6 H 12
O6
H2 O
C H2 O
C H 2O H
HH
CCH
H 2O
HH
CH
HH
2O
2O
2O
KÓ
TÓ
ZA
ZA
FR
UK Ó
TÓ
ZA
G
LU K
FR U K T Ó ZA
G
LU
ZA
FRU
KÓ
T ZA
Ó ZA
nyd
K eton
AKldehyd
K eton
Aldehyd
eton
C 6 H 12 O 6
C 6 H 12 O 6
C 6 H 12 O 6
Hypoglycemia
muscle fatigue,
cramps
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GLYCOGEN STORAGE DISEASES, GSD
THE PRINCIPLE!
LIVER – GLUCOSE FOR THE BODY




von Gierke (I) not a true GSD: glucose-6phosphatase deficiency, hepatomegaly,
hypoglycaemia, growth retardation for low
insulin (!)
Cori (III) deficiency of debranching – as “I”, less
severe
Andersen (IV) deficiency of branching – bad
prognosis
Hers (VI) deficiency of phosphorylase – as “I”,
less severe
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GLYCOGEN STORAGE DISEASES, GSD
THE PRINCIPLE!
MUSCLES – “SINGLE MINDED”
No gluconeogenesis
No glucose-6-phosphatase (don’t need it)
Only 1 % glycogen but altogether more than in the liver
“V” Mc Ardle deficiency of muscle
phosphorylase  without hypoglycaemia but
muscle manifestation, not very severe
 “III”, “IV” similar
GENERALIZED
 “II” – Pompe, heart hypertrophy, muscle
hypotonia, bad prognosis (not logical)

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GLYCOGENOSES, WHICH ARE NOT
“GLYCOGENOSES”, BUT MANIFEST WITH
GLYCOGEN ACCUMULATION
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Glucose homeostasis




Insulin lowers blood glucose (yes, but...)
Insulin enables glucose metabolism in cells (yes,
but...)
Insulin exerts its effect through insulin receptor a
transmembrane protein with kinase activity
Key point of postreceptor events (a complicated
cascade) is the translocation of glucose transporter
GLUT4 to the membrane of muscle and fat cells
THE PLAYERS OF THE GAME:
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GLUCOSE
INSULIN
INSULIN RECEPTOR
GLUCOSE
TRANSPORTER
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glucose
IR
GLUT4
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INSULIN
glucose
IR
GLUT4
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INSULIN
glucose
IR
GLUT4
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NO INSULIN – TYPE 1 DIABETES,
PANCREATECTOMY...
glucose
IR
GLUT4
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INSULIN RESISTANCE – PROBLEMS WITH THE
RECEPTOR OR CASCADE
glucose
IR
GLUT4
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INSULIN RESISTANCE – COMPENSATORY
HYPERSECRETION OF INSULIN
glucose
IR
GLUT4
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Cellular Secretion of Insulin
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Time course for insulin action



Immediate increase in
glucose uptake into cells
(seconds)
Changes in enzymatic
activity (minutes)
Increase in enzyme
synthesis: glucokinase,
PFK1, pyruvate kinaase
(hours to days)
glu
Glucose
transporter
PFK1
enzyme activity
Changes in gene expression
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INSULIN SECRETION IN
LANGERNAS ISLETS
GLUT2 – glucose transporter of B cells
 GK – glucokinase, glucose sensor
 MIT – mitochondriae, ATP production
 Kir6.2-SUR1 – Potassium inward
rectifier channel (K-channel) with
receptorom for sulphanylurea

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GLUCOSE
GLUT2
GK
MIT
INSULIN
K+
SUR1
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Ca ++
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KIR
6.2
34
GLUCOSE
GLUT2
GK
MIT
INSULIN
K+
SUR1
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Ca ++
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KIR
6.2
35
GLUCOSE
GLUT2
GK
MIT
INSULIN
K+
SUR1
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Ca ++
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KIR
6.2
36
GLUCOSE
GLUT2
GK
MIT
INSULIN
ATP
K+
SUR1
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Ca ++
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KIR
6.2
37
GLUCOSE
GLUT2
GK
MIT
INSULIN
Ca ++
ATP
K+
SUR1
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KIR
6.2
38
GLUCOSE
GLUT2
GK
MIT
INSULIN
Ca ++
ATP
K+
SUR1
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KIR
6.2
39

GLUT2, GLUCOKINASE, MITOCHONDRIAE

Kir6.2-SUR1 – Potassium inward
rectifier channel (K-channel)
– ATP INCREASE
– CLOSING OF K-CHANNEL
– MEMBRANE DEPOLARISATION
– Ca++ ENTRY
– INSULIN SECRETION
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GLUCOSE
GLUT2
GK
MIT
INSULIN
K+
SUR1
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Ca ++
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KIR
6.2
41
Insulin and its antagonists
Glucagon – glycogen breakdown,
gluconeogenesis glycolysis blockade in liver
 Adrenaline, noradrenaline – glycogen breakdown
and gluconeogenesis in muscles, lactate 
glucose in liver
 Growth hormone (anabolic hormone), lipolysis,
proteosynthesis
 Glucocorticoids – gluconeogenesis, block of
proteosynthesis
 Thyroid hormones and oestrogens

In physiological conditions synergism
(counter-regulation)gluce12.ppt
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Hyperglycemia = diabetes mellitus
No insulin (type 1 dm, removal of
pancreas, etc.)
 Deficient action of insulin (type 2 dm)
 Antagonists (glucocorticoids,
adrenaline, growth hormone, gravidity)
 Stress (MI, stroke)

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Hypoglycemia = diabetes mellitus (?)
Errors and mistakes in diabetes
treatment
 Increased insulin sensitivity (antagonist
deficiency – m. Addison,
panhypopituitarism)
 Nondiabetic hypoglycemia (insulinoma,
glycogenoses, liver failure)

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Hypoglycemia – diff. dg.
Reactive & postalimentary
hypoglycemia
 Fasting organic hypoglycemia
 Exogeneous hypoglycemia

– in diabetics
– in nondiabetics
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Reactive & postalimentary
Spontaneous after meal (ANS ?)
 Dumping sy. (gastrectomy)
 Latent diabetes mellitus (???)
 Fructose intolerance

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Fasting organic

Insulin producing tumors of L. I.

Insulin (or like) producing extrapancreatic tumors
Antagonist deficiency (m. Addison,
hypopituitarism)
 Inborn errors of metabolism (pediatry)
 Malnutrition (severe)
 Liver and kidney failure
 Gravidity (???)

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Exogeneous

Mistakes and errors in insulin treatment
– overdose, exercise, omitting of meal,
insufficient education
Overdose of oral antidiabetics
(sulfonylurea)
 Alcohol (both in diabetics and
nondiabetics)
 Drugs (sulfonylurea like)

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