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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)