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‘40 minute famine’ ® Gareth

‘40 minute famine’ ® Gareth. CAT FOOD!. Presentation and history:. A 3-year old boy, Mark, suffering from stupor and very rapid breathing (hyperpnoea). His mother reports he has sweats, trembling and occasionally convulsions after more than a few hours without food.

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‘40 minute famine’ ® Gareth

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  1. ‘40 minute famine’®Gareth CAT FOOD!

  2. Presentation and history: • A 3-year old boy, Mark, suffering from stupor and very rapid breathing (hyperpnoea). • His mother reports he has sweats, trembling and occasionally convulsionsafter more than a few hours without food. • enlarged abdomen and hepatomegaly (an enlarged liver). • xanthomas (nodules of lipid) around his body. • An 'instant' blood glucose reading = only 2 mM. • After i.v. glucose, Mark's condition stabilised  further tests

  3. What is the likely cause of the sweats, convulsions, etc? A Hypoglycaemia B Hyperglycaemia C Hypoinsulinaemia D Hyperlipidaemia ‘instant’ BSL = 2mM

  4. Initial blood tests

  5. Where does bilirubin come from? A The breakdown of bile salts B The breakdown of cholesterol C The breakdown of red blood cells D Artificial food colourings in the diet E None of the above What normally happens to bilirubin? A Excreted in urine B Sent from liver to gall bladder C Oxidised to carbon dioxide RBC can only use glucose

  6. What is a high blood [uric acid] indicative of? A A low cellular 'energy charge' B An increased rate of deamination of adenosine C A decrease in ATP D A marked rise in AMP E All of the above Alanine aminotransferase (ALT) is not just found in the liver. How could we be sure that the ALT measured here was from the liver? A Measure the Km in an enzyme dependent assay B Measure the Vmax in an enzyme dependent assay C Look at the isoenzyme banding pattern on gel D We couldn't be sure

  7. How could triglycerides be in the blood? A High rate of VLDL release from liver B High rate of lipolysis in adipose tissue C Failure to clear LDL When are fatty acids released into the bloodstream? A When insulin levels are high B When glucagon levels are low C When insulin levels are low VLDL = high in TGs BSL  insulin   lipolysis   FA + glycerol

  8. What processes can lead to increased blood lactate? A  liver gluconeogenesis B liver glycolysis C muscle glycolysis D  muscle PDH activity E All of the above lactate is a substrate lactate is a product of rapid glycolysis lactate is a substrate

  9. aim to maintain blood glucose Which processes are normally functioning after a few hours of fasting? A. Glycogenolysis B. Glycogen synthesis C. Lipolysis D. Lipogenesis E. Gluconeogenesis F. Insulin secretion G. Glucagon secretion release glucose from store insulin   lipolysis   FA + glycerol glucose req’d for brain, RBCs BSL  glucagon from pancreas Mark’s problem could be with one of these processes

  10. Initial blood tests So, Mark is secreting glucagon: are his cells responding?

  11. Glucagon tolerance test This involved infusing Mark with intravenous glucagon Mark is not making glucose: what would happen in a normal person? normal Mark

  12. What process does NOT  glycogenolysis in response to glucagon? A cAMP production B Activation of Protein Phosphatase I C Activation of Protein Kinase A D Phosphorylation of phosporylase

  13. a GTP ATP low blood glucose N Glucagon LIVER GPCR C cAMP cAMP cAMP cAMP cAMP cAMP cAMP cAMP cAMP Protein Kinase A ACTIVE

  14.  blood [glucose]  GLUCAGON   cAMP PKA cAMP cAMP fructose 1, 6- bis phosphatase glycogen synthase glycogen phosphorylase pyruvatekinase glycolysis glycogen synthesis glycogenolysis gluconeogenesis

  15.  blood [glucose]  GLUCAGON   cAMP PKA cAMP cAMP P P P P fructose 1, 6- bis phosphatase glycogen synthase glycogen phosphorylase pyruvatekinase glycolysis glycogen synthesis glycogenolysis gluconeogenesis

  16. blood [glucose]  GLUCAGON  cAMP protein kinase A cAMP cAMP P P P P fructose 1, 6- bis phosphatase glycogen synthase glycogen phosphorylase pyruvatekinase glycolysis glycogen synthesis glycogenolysis gluconeogenesis  blood GLUCOSE

  17. blood [glucose]  GLUCAGON  cAMP protein kinase A cAMP cAMP P P P P fructose 1, 6- bis phosphatase glycogen synthase glycogen phosphorylase pyruvatekinase glycolysis glycogen synthesis glycogenolysis gluconeogenesis CO-ORDINATED  Available glucose

  18. glycogen (n) debranching enzyme glycogen phosphorylase P glucose 1-P glycogen (n-1) phosphoglucomutase P glycolysis Glucose 6- phosphatase glucose glucose 6-P

  19. Gluconegenesis stimulated by • substrates (lactate, glycerol, certain amino acids • glucagen (stimulates F16bP’tase) • FA oxidatn AcCoA + Pyr Carboxylase, - PDH glycolysis gluconeogenesis stim by glucagon

  20. Which one of these does not participate in a pathway that allows glucose production in response to glucagon? A Phosphorylase B Glucose 6 phosphatase C Glucokinase D GLUT-2 What is NOT an effect of glucagon? A An increase in WAT lipolysis B Stimulation of glucose release from the liver C Production of glucose from lactate by the liver D Breakdown of muscle glycogen glucose  g6P in liver: high Km, so active only when  [glucose]  glycogen

  21. 4 2 glycogenolysis in response to glucagon in liver, not muscle 2 GLUT-2 in liver (high Km) active only when glucose high, gets last dibs on glucose (1st brain, muscle)GLUT-4 in muscle

  22. What is NOT an effect of glucagon? A An increase in WAT lipolysis B Stimulation of glucose release from liver C Production of glucose from lactate by liver D Breakdown of muscle glycogen muscle glycogen breakdown in response to adrenaline, no glucagon receptors

  23. see glucagon TT Can Mark make glucose in response to glucagon? A Yeah B Nope C Can’t tell Can Mark enter glycolysis in response to glucagon? A Yeah B Nope C Can’t tell Can Mark breakdown glycogen in response to glucagon? A Yeah B Nope C Can’t tell Probably: glucagon TT   lactate glucagon TT   lactate

  24. Glucagon tolerance test Mark can break down glycogen  lactate from glycolysis but is not making glucose…….? normal Mark

  25. Marks main problem is low blood glucose: What other sources of glucose should he be able to access?

  26. Galactose tolerance test This involved infusing Mark with 200 mg/kg galactose via one of his veins. What is the GI of galactose? A negligible - very low B medium (50-60 ish) C 100 (same as pure glucose) normal Mark

  27. Does Mark have a problem clearing galactose from the blood? A Yes B No C Can’t tell galactose  lactate galactose  glycolysis

  28. Galactose Metabolism What do you think is the next step in "Normal Glucose Metabolism"? A Fructose 6-P B UDP-Glucose C Glucose 6-P D Glucose

  29. galactokinase galactose galactose 1- P UDP glucose transferase epimerase UDP galactose 1- P glucose mutase 6- P glucose glucose G6 phosphatase glycolysis

  30. What would you expect the main route of disposal of galatose to be? A  carbon dioxide in muscle B  glucose in liver C  fat in adipose tissue What do you notice about Mark's Lactate response? A Even at time zero, he has hyperlactemia B Galactose causes a rise in blood lactate C Glucagon causes a rise in blood lactate D All of the above only the liver has galactose enzymes

  31. What processes can lead to increased blood lactate? A  liver gluconeogenesis B liver glycolysis C muscle glycolysis D  muscle PDH activity E All of the above lactate is a substrate lactate is a product of rapid glycolysis lactate is a substrate

  32. see galactose tolerance test Can Mark make glucose from galactose? A Yes B No Can Mark enter glycolysis from galactose? A Yes B No Can Mark make glucose in response to glucagon? A Yes B No Can Mark enter glycolysis in response to glucagon? A Yes B No galactose  lactate see glucagon tolerance test glucagon  glycogenolysis lactate

  33. so…. LACTATE in response to glucagon (gluconeogenesis and glycogenolysis) and to galactose BUT cannot make glucose galactose

  34. Which is the ‘branch point’ between glycolysis and glucose common to glycogenolysis and galactose catabolism? A fructose 6 phosphate B Fructose 1,6 bisphosphate C glucose 1 phosphate D Glucose 6-phosphate

  35. Which enzyme is common to glycogenolysis and galactose catabolism? A Lactate dehydrogenase B Fructose 1,6 bisphosphatase C Glucose 1 phosphatase D Glucose 6-phosphatase

  36. In what other process is g6p’tase? A glycolysis B lipolysis C gluconeogenesis D glycogen synthesis

  37. Dual-labelled glucose infusion This involved infusing Mark with intravenous glucose which is labelled with 14C on every carbon atom but with 3H (tritium) on C2.

  38. Which glucose is [U14C] labelled (red dot = 14C) A B C D

  39. Which glucose is [3H] labeled on C2 (red dot = 3H)? A B C D

  40. glycolysis H P- exchange of H+ with medium * * H * P- P- P- glucose glucose 6-P fructose 6-P fructose 1,6-bis P hexokinase isomerase PFK

  41. gluconeogenesis H P- H P- P- P- glucose glucose 6-P fructose 6-P fructose 1,6-bis P G 6- P’tase isomerase F 1,6 b iP’tase + glucagon

  42. all C are retained 21. At which step is 14C lost from U14C-glucose? A Glucose --> G6P B G6P ---> F6P C F6P ---> F16BP D F16PB ---> DHAP + glyceraldehyde 3P E None of the above 22. At which step is 3H lost from the C2 on glucose? A Glucose --> G6P B G6P ---> F6P C F6P ---> F16BP D F16PB ---> DHAP + glyceraldehyde 3P E None of the above 23. Normally, can F6P be made into glucose? A Yes B No exchange with H+ from medium

  43. What happens to the 3H and 14C content of [2-3H, U-14C] glucose when the glucose goes to F16BP and back again? A Both the 3H and 14C content goes down B Both the 3H and 14C content goes up C The 3H goes up and 14C stays the same D The 3H goes down and 14C stays the same E The 3H stays the same and 14C goes down the RATIO of 3H:14C goes DOWN

  44. What happens to the 3H and 14C content of [2-3H, U-14C] glucose when gluconeogenesis is faulty? A The 3H : 14C ratio goes down B The 3H : 14C ratio goes up C The ratio does not alter

  45. What happens to the 3H and 14C content of [2-3H, U-14C] glucose in Mark? A The 3H : 14C ratio goes down B The 3H : 14C ratio goes up C The ratio does not alter Mark also has a fault in gluconeogenesis

  46. What is needed to allow glucose to go to F6P and back again? A Phosphofructokinase B Fructose 1,6 bisphosphatase C GLUT-2 D Glucose 6 phosphatase If we took a liver biospy from Mark and measured the rate of glycolysis from glucose in isolated hepatocytes, would it be: A Higher than normal B Normal C Lower than normal

  47. Which is the ‘branch point’ between glycolysis and glucose common to glycogenolysis, gluconeogenesis and galactose catabolism? A fructose 6 phosphate B Fructose 1,6 bisphosphate C glucose 1 phosphate D Glucose 6-phosphate

  48. trace which bits Mark can and can’t do: where is the road block? galactose

  49. Which is the ‘branch point’ between glycolysis and glucose common to glycogenolysis, gluconeogenesis and galactose catabolism? A fructose 6 phosphate B Fructose 1,6 bisphosphate C glucose 1 phosphate D Glucose 6-phosphate

  50. Which enzyme is common to glycogenolysis, gluconeogenesis and galactose catabolism? A Lactate dehydrogenase B Fructose 1,6 bisphosphatase C Glucose 1 phosphatase D Glucose 6-phosphatase

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