1. 12.10.12gluce12.ppt1 METABOLISM OF GLUCOSE AND ITS DISTURBANCES, GLYOGENOSES Lecture from Pathological Physiology © O. Rácz, A. Chmelárová & E. Lovásová school year 2012/2013

2. 12.10.12 gluce12.ppt2 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)

3. 12.10.12 gluce12.ppt3 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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5. 12.10.12 gluce12.ppt5 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: k M 10 -5, glucokinase: 10 -2 (mmol/l)

6. 12.10.12 gluce12.ppt6 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

7. 12.10.12 gluce12.ppt7 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…

8. 12.10.12 gluce12.ppt8 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

9. 12.10.12 gluce12.ppt9 GALACTOSEMIA Lactose = Gal-Glu AR, 1/20 000 – 60 000, neonatal screening

10. 12.10.12 gluce12.ppt10 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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12. 12.10.12 gluce12.ppt12 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

13. 12.10.12 gluce12.ppt13 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)

14. 12.10.12 gluce12.ppt14 glycogen [Glu] n n = 2000 / 20000

15. 12.10.12 gluce12.ppt15 The structure of glycogen (1-4 bonds and 1-6 branching)

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18. 12.10.12 gluce12.ppt18 Hypoglycemia muscle fatigue, cramps

19. 12.10.12 gluce12.ppt19 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 (!) 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

20. 12.10.12 gluce12.ppt20 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)

21. 12.10.12 gluce12.ppt21 GLYCOGENOSES, WHICH ARE NOT “GLYCOGENOSES”, BUT MANIFEST WITH GLYCOGEN ACCUMULATION

22. 12.10.12 gluce12.ppt22 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 : GLUCOSEINSULIN INSULIN RECEPTOR GLUCOSE TRANSPORTER

23. 12.10.12 gluce12.ppt23 GLUT4 IR glucose

24. 12.10.12 gluce12.ppt24 GLUT4 IR INSULIN glucose

25. 12.10.12 gluce12.ppt25 GLUT4 IR INSULIN glucose

26. 12.10.12 gluce12.ppt26 GLUT4 IR glucose NO INSULIN – TYPE 1 DIABETES, PANCREATECTOMY...

27. 12.10.12 gluce12.ppt27 GLUT4 IR INSULIN RESISTANCE – PROBLEMS WITH THE RECEPTOR OR CASCADE glucose

28. 12.10.12 gluce12.ppt28 GLUT4 IR INSULIN RESISTANCE – COMPENSATORY HYPERSECRETION OF INSULIN glucose

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30. 12.10.12 gluce12.ppt30 Cellular Secretion of Insulin

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32. 12.10.12 gluce12.ppt32 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

33. 12.10.12 gluce12.ppt33 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

34. 12.10.12 gluce12.ppt34 GLUT2 GK MIT SUR1 KIR 6.2 K+K+ Ca ++ INSULIN GLUCOSE

35. 12.10.12 gluce12.ppt35 GLUT2 GK MIT SUR1 KIR 6.2 K+K+ Ca ++ INSULIN GLUCOSE

36. 12.10.12 gluce12.ppt36 GLUT2 GK MIT SUR1 KIR 6.2 K+K+ Ca ++ INSULIN GLUCOSE

37. 12.10.12 gluce12.ppt37 GLUT2 GK MIT SUR1 KIR 6.2 K+K+ Ca ++ INSULIN GLUCOSE ATP

38. 12.10.12 gluce12.ppt38 GLUT2 GK MIT SUR1 KIR 6.2 K+K+ Ca ++ INSULIN GLUCOSE ATP

39. 12.10.12 gluce12.ppt39 GLUT2 GK MIT SUR1 KIR 6.2 K+K+ Ca ++ INSULIN GLUCOSE ATP

40. 12.10.12 gluce12.ppt40 GLUT2, GLUCOKINASE, MITOCHONDRIAE Kir6.2-SUR1 – Potassium inward rectifier channel (K-channel) –ATP INCREASE –CLOSING OF K-CHANNEL –MEMBRANE DEPOLARISATION –Ca ++ ENTRY –INSULIN SECRETION

41. 12.10.12 gluce12.ppt41 GLUT2 GK MIT SUR1 KIR 6.2 K+K+ Ca ++ INSULIN GLUCOSE

42. 12.10.12 gluce12.ppt42 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)

43. 12.10.12 gluce12.ppt43 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)

44. 12.10.12 gluce12.ppt44 Hypoglycemia = diabetes mellitus (?) Errors and mistakes in diabetes treatment Increased insulin sensitivity (antagonist deficiency – m. Addison, panhypopituitarism) Nondiabetic hypoglycemia (insulinoma, glycogenoses, liver failure)

45. 12.10.12 gluce12.ppt45 Hypoglycemia – diff. dg. Reactive & postalimentary hypoglycemia Fasting organic hypoglycemia Exogeneous hypoglycemia –in diabetics –in nondiabetics

46. 12.10.12 gluce12.ppt46 Reactive & postalimentary Spontaneous after meal (ANS ?) Dumping sy. (gastrectomy) Latent diabetes mellitus (???) Fructose intolerance

47. 12.10.12 gluce12.ppt47 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 (???)

48. 12.10.12 gluce12.ppt48 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)