METABOLISM OF GLUCOSE AND ITS DISTURBANCES GLYOGENOSES Lecture

METABOLISM OF GLUCOSE AND ITS DISTURBANCES, GLYOGENOSES Lecture from Pathological Physiology © O. Rácz, A. Chmelárová & E. Lovásová school year 2012/2013 12. 10. 12 gluce 12. ppt 1

DISORDERS OF GLUCOSE METABOLISM – OVERVIEW EXOGENEOUS Glucose has a central role in SOURCES: the energetic metabolism but NOT SWEET it is not an important Ø Polysaccharides: starch, component of the diet glycogen (300 -350 g/d); degraded in GIT by amylase, saccharidases DISORDERS: SWEET Disaccharidase, lactase Ø Saccharose (sugar) deficiency (malabsorption, lactose (milk sugar) diarrhoe) fructose (fruit) n ENDOGENEOUS a-glucosidase blockade SOURCES (treatment of obesity, type 2 Ø Gluconeogenesis diabetes) gluce 12. ppt 2 12. 10. 12 Ø Glycogenolysis n

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 12. 10. 12 gluce 12. ppt 3

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COMMENTS – 1 n n n 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: k. M 10 -5, glucokinase: 10 -2 (mmol/l) 12. 10. 12 gluce 12. ppt 5

COMMENTS – 2 n n n 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 synthesis 12. 10. 12 gluce 12. ppt 6

DISORDERS OF GLYCOLYSIS Some of them manifest as „glycogenoses“ Hereditary - congenital n Phosphofructokinase deficiency – muscle fatigue n Haemolytic anemias – red cell enzymopathies Acquired? n Lactate acidosis: Hypoxia, pyruvatdehydrogenase deficiency, thiamin deficiency (alcoholics), As, F, Hg intoxication, sometimes in diabetes mellitus n Randl cycle. Increased fatty acid oxidation (obesity, diabetes) NADH and acetylcoenzyme A overproduction. Block of glycolysis and glycogen synthesis Increased gluconeogenesis in liver… 12. 10. 12 gluce 12. ppt 7

SEVERE (BUT RARE) DISORDERS OF MONOSACCHARIDE METABOLISM n Galactosemia AR, 1/20 000 – 60 000 – Accumulation of galactose, gal-1 -P, galactitol cataract, mental retardation, liver cirrhosis, haemolysis, kidney failure Ä diet without milk n 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 Ä omit them 12. 10. 12 gluce 12. ppt 8

GALACTOSEMIA Lactose = Gal-Glu AR, 1/20 000 – 60 000, neonatal screening 12. 10. 12 gluce 12. ppt 9

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 n Fructosuria – Fructose does not enter into metabolism, excretion through urine n 12. 10. 12 gluce 12. ppt 10

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GLYCOGEN STORAGE DISEASES, GSD* n Synthesis of glycogen (energy from ATP & UTP) – – n G 6 P G 1 P 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 G 1 P – debranching makes glucose *Originally I – VII, 2000 IX, Fernandes 2008 – more than 15 12. 10. 12 gluce 12. ppt 12

GLYCOGEN STORAGE DISEASES, GSD The control of synthase & phosphorylasde through signal systems (c. AMP, Ca) and phosphorylation – dephosphorylation n Postprandial state n – synthase in state on (I) phosphorylase off (b) n We need glucose!!! – adrenaline, glucagon c. AMP, phosphokinases – Synthase off (D) phosphorylase on (a) 12. 10. 12 gluce 12. ppt 13

glycogen [Glu]n n = 2000 / 20000 12. 10. 12 gluce 12. ppt 14

The structure of glycogen (1 -4 bonds and 1 -6 branching) 12. 10. 12 gluce 12. ppt 15

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Hypoglycemia muscle fatigue, cramps 12. 10. 12 gluce 12. ppt 18

GLYCOGEN STORAGE DISEASES, GSD THE PRINCIPLE! LIVER – GLUCOSE FOR THE BODY von Gierke (I) not a true GSD: glucose-6 phosphatase deficiency, hepatomegaly, hypoglycaemia, growth retardation for low insulin (!) n Cori (III) deficiency of debranching – as “I”, less severe n Andersen (IV) deficiency of branching – bad prognosis n Hers (VI) deficiency of phosphorylase – as “I”, less severe n 12. 10. 12 gluce 12. ppt 19

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 n “III”, “IV” similar GENERALIZED n “II” – Pompe, heart hypertrophy, muscle hypotonia, bad prognosis (not logical) n 12. 10. 12 gluce 12. ppt 20

GLYCOGENOSES, WHICH ARE NOT “GLYCOGENOSES”, BUT MANIFEST WITH GLYCOGEN ACCUMULATION 12. 10. 12 gluce 12. ppt 21

Glucose homeostasis Insulin lowers blood glucose (yes, but. . . ) n Insulin enables glucose metabolism in cells (yes, but. . . ) n Insulin exerts its effect through insulin receptor a transmembrane protein with kinase activity n Key point of postreceptor events (a complicated cascade) is the translocation of glucose transporter GLUT 4 to the membrane of muscle and fat cells n THE PLAYERS OF THE GAME: 12. 10. 12 GLUCOSE INSULIN RECEPTOR GLUCOSE TRANSPORTER gluce 12. ppt 22

glucose IR GLUT 4 12. 10. 12 gluce 12. ppt 23

INSULIN glucose IR GLUT 4 12. 10. 12 gluce 12. ppt 24

INSULIN glucose IR GLUT 4 12. 10. 12 gluce 12. ppt 25

NO INSULIN – TYPE 1 DIABETES, PANCREATECTOMY. . . glucose IR GLUT 4 12. 10. 12 gluce 12. ppt 26

INSULIN RESISTANCE – PROBLEMS WITH THE RECEPTOR OR CASCADE glucose IR GLUT 4 12. 10. 12 gluce 12. ppt 27

INSULIN RESISTANCE – COMPENSATORY HYPERSECRETION OF INSULIN glucose IR GLUT 4 12. 10. 12 gluce 12. ppt 28

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Cellular Secretion of Insulin 12. 10. 12 gluce 12. ppt 30

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Time course for insulin action Immediate increase in glucose uptake into cells (seconds) n Changes in enzymatic activity (minutes) n Increase in enzyme synthesis: glucokinase, PFK 1, pyruvate kinaase (hours to days) n glu Glucose transporter PFK 1 enzyme activity Changes in gene expression 12. 10. 12 gluce 12. ppt 32

INSULIN SECRETION IN LANGERNAS ISLETS n GLUT 2 – glucose transporter of B cells n GK – glucokinase, glucose sensor n MIT – mitochondriae, ATP production n Kir 6. 2 -SUR 1 – Potassium inward rectifier channel (K-channel) with receptorom for sulphanylurea 12. 10. 12 gluce 12. ppt 33

GLUCOSE GLUT 2 GK MIT INSULIN K+ SUR 1 12. 10. 12 Ca ++ gluce 12. ppt KIR 6. 2 34

GLUCOSE GLUT 2 GK MIT INSULIN K+ SUR 1 12. 10. 12 Ca ++ gluce 12. ppt KIR 6. 2 35

GLUCOSE GLUT 2 GK MIT INSULIN K+ SUR 1 12. 10. 12 Ca ++ gluce 12. ppt KIR 6. 2 36

GLUCOSE GLUT 2 GK MIT INSULIN ATP K+ SUR 1 12. 10. 12 Ca ++ gluce 12. ppt KIR 6. 2 37

GLUCOSE GLUT 2 GK MIT INSULIN Ca ++ ATP K+ SUR 1 12. 10. 12 gluce 12. ppt KIR 6. 2 38

GLUCOSE GLUT 2 GK MIT INSULIN Ca ++ ATP K+ SUR 1 12. 10. 12 gluce 12. ppt KIR 6. 2 39

n GLUT 2, GLUCOKINASE, MITOCHONDRIAE n Kir 6. 2 -SUR 1 – Potassium inward rectifier channel (K-channel) – ATP INCREASE – CLOSING OF K-CHANNEL – MEMBRANE DEPOLARISATION – Ca++ ENTRY – INSULIN SECRETION 12. 10. 12 gluce 12. ppt 40

GLUCOSE GLUT 2 GK MIT INSULIN K+ SUR 1 12. 10. 12 Ca ++ gluce 12. ppt KIR 6. 2 41

Insulin and its antagonists Glucagon – glycogen breakdown, gluconeogenesis glycolysis blockade in liver n Adrenaline, noradrenaline – glycogen breakdown and gluconeogenesis in muscles, lactate glucose in liver n Growth hormone (anabolic hormone), lipolysis, proteosynthesis n Glucocorticoids – gluconeogenesis, block of proteosynthesis n Thyroid hormones and oestrogens n In physiological conditions synergism (counter-regulation)gluce 12. ppt 12. 10. 12 42

Hyperglycemia = diabetes mellitus n No insulin (type 1 dm, removal of pancreas, etc. ) n Deficient action of insulin (type 2 dm) n Antagonists (glucocorticoids, adrenaline, growth hormone, gravidity) n Stress (MI, stroke) 12. 10. 12 gluce 12. ppt 43

Hypoglycemia = diabetes mellitus (? ) n Errors and mistakes in diabetes treatment n Increased insulin sensitivity (antagonist deficiency – m. Addison, panhypopituitarism) n Nondiabetic hypoglycemia (insulinoma, glycogenoses, liver failure) 12. 10. 12 gluce 12. ppt 44

Hypoglycemia – diff. dg. n Reactive & postalimentary hypoglycemia n Fasting organic hypoglycemia n Exogeneous hypoglycemia – in diabetics – in nondiabetics 12. 10. 12 gluce 12. ppt 45

Reactive & postalimentary n Spontaneous after meal (ANS ? ) n Dumping sy. (gastrectomy) n Latent diabetes mellitus (? ? ? ) n Fructose intolerance 12. 10. 12 gluce 12. ppt 46

Fasting organic n Insulin producing tumors of L. I. n Insulin (or like) producing extrapancreatic tumors n Antagonist deficiency (m. Addison, hypopituitarism) n Inborn errors of metabolism (pediatry) n Malnutrition (severe) n Liver and kidney failure n Gravidity (? ? ? ) 12. 10. 12 gluce 12. ppt 47

Exogeneous n Mistakes and errors in insulin treatment – overdose, exercise, omitting of meal, insufficient education n Overdose of oral antidiabetics (sulfonylurea) n Alcohol (both in diabetics and nondiabetics) n Drugs (sulfonylurea like) 12. 10. 12 gluce 12. ppt 48