12.10.12gluce12.ppt1 metabolism of glucose and its disturbances, glyogenoses lecture from...
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12.10.12 gluce12.ppt 1
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 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)
-glucosidase blockade (treatment of obesity, type 2 diabetes)
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THE FATE OF GLUCOSE IN CELLS
1. Glycogen synthesis. In normal postprandial state 70 – 80 g in liver, 150 g in muscles.
2. Glycolysis and the following pathways (ATP formation)
3. Pentose cycle (antioxidant system, pentose formation)
4. Glucitol (sorbitol) pathway
5. 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-2,6-
bisphosphate 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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glycogen
[Glu]n n = 2000 / 20000
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The structure of glycogen (1-4 bonds and 1-6 branching)
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HC=O
HCOH
HOCH
HCOH
HCOHCH2OH
H2COH C=O
HOCH
HCOH
HCOHCH2OH
O
CH20H
GLUKÓZA FRUKTÓZAAldehyd Keton
C6H12O6
HC=O
HCOH
HOCH
HCOH
HCOHCH2OH
H2COH C=O
HOCH
HCOH
HCOHCH2OH
O
CH20H
GLUKÓZA FRUKTÓZAAldehyd Keton
C6H12O6
HC=O
HCOH
HOCH
HCOH
HCOHCH2OH
H2COH C=O
HOCH
HCOH
HCOHCH2OH
O
CH20H
GLUKÓZA FRUKTÓZAAldehyd Keton
C6H12O6
HC=O
HCOH
HOCH
HCOH
HCOHCH2OH
H2COH C=O
HOCH
HCOH
HCOHCH2OH
O
CH20H
GLUKÓZA FRUKTÓZAAldehyd Keton
C6H12O6
HC=O
HCOH
HOCH
HCOH
HCOHCH2OH
H2COH C=O
HOCH
HCOH
HCOHCH2OH
O
CH20H
GLUKÓZA FRUKTÓZAAldehyd Keton
C6H12O6
GLYCOGEN
[Glu]n n = 2000 / 20000
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HC=O
HCOH
HOCH
HCOH
HCOHCH2OH
H2COH C=O
HOCH
HCOH
HCOHCH2OH
O
CH20H
GLUKÓZA FRUKTÓZAAldehyd Keton
C6H12O6
HC=O
HCOH
HOCH
HCOH
HCOHCH2OH
H2COH C=O
HOCH
HCOH
HCOHCH2OH
O
CH20H
GLUKÓZA FRUKTÓZAAldehyd Keton
C6H12O6
HC=O
HCOH
HOCH
HCOH
HCOHCH2OH
H2COH C=O
HOCH
HCOH
HCOHCH2OH
O
CH20H
GLUKÓZA FRUKTÓZAAldehyd Keton
C6H12O6
HC=O
HCOH
HOCH
HCOH
HCOHCH2OH
H2COH C=O
HOCH
HCOH
HCOHCH2OH
O
CH20H
GLUKÓZA FRUKTÓZAAldehyd Keton
C6H12O6
HC=O
HCOH
HOCH
HCOH
HCOHCH2OH
H2COH C=O
HOCH
HCOH
HCOHCH2OH
O
CH20H
GLUKÓZA FRUKTÓZAAldehyd Keton
C6H12O6
GLYCOGEN
[Glu]n n = 2000 / 20000
Hypoglycemia muscle fatigue, cramps
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GLYCOGEN STORAGE DISEASES, GSDTHE PRINCIPLE!
LIVER – GLUCOSE FOR THE BODY von Gierke (I) not a true GSD: glucose-6-
phosphatase 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, GSDTHE PRINCIPLE!
MUSCLES – “SINGLE MINDED” No gluconeogenesisNo 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” similarGENERALIZED “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 GAMETHE PLAYERS OF THE GAME::GLUCOSEGLUCOSEINSULININSULININSULIN RECEPTORINSULIN RECEPTORGLUCOSE TRANSPORTERGLUCOSE TRANSPORTER
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GLUT4
IR
glucose
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GLUT4
IR
INSULIN
glucose
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GLUT4
IR
INSULIN
glucose
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GLUT4
IR
glucose
NO INSULIN – TYPE 1 DIABETES, PANCREATECTOMY...
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GLUT4
IR
INSULIN RESISTANCE – PROBLEMS WITH THE RECEPTOR OR CASCADE
glucose
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GLUT4
IR
INSULIN RESISTANCE – COMPENSATORY HYPERSECRETION OF INSULIN
glucose
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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)
Glucose transporter
glu
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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GLUT2
GK
MIT
SUR1
KIR6.2
K+
Ca ++
INSULIN
GLUCOSE
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GLUT2
GK
MIT
SUR1
KIR6.2
K+
Ca ++
INSULIN
GLUCOSE
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GLUT2
GK
MIT
SUR1
KIR6.2
K+
Ca ++
INSULIN
GLUCOSE
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GLUT2
GK
MIT
SUR1
KIR6.2
K+
Ca ++
INSULIN
GLUCOSE
ATP
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GLUT2
GK
MIT
SUR1
KIR6.2
K+Ca ++
INSULIN
GLUCOSE
ATP
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GLUT2
GK
MIT
SUR1
KIR6.2
K+Ca ++
INSULIN
GLUCOSE
ATP
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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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GLUT2
GK
MIT
SUR1
KIR6.2
K+
Ca ++
INSULIN
GLUCOSE
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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)
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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)