1. ILA: DIABETES Ass Prof Dr. Gihan Sharara

2. Questions (Based on basic biochemistry) What is hyperglycemia? Why was there hyperglycemia in this patient? Explain why there is increased urination (polyuria) with this high blood glucose? Why Hoda had increased appetite (polyphagia) despite high glucose levels? Discuss normal glucose metabolism Suggest the possible alterations in glucose storage and break down that might occur in this clinical problem.

3. What is hyperglycemia? Hyperglycemia is the elevation of blood glucose levels above the normal range. Normal fasting blood glucose: 70 – 100mg/dl

4. Why was there hyperglycemia in this patient? INSULIN DEFICIENCY: 1.decreases uptake of glucose by cells. 2.insulin dependent enzymes are less active Net effect: A.inhibition of glycolysis B.Inhibition of glycogenesis (glycogen synthesis) C.stimulation of gluconeogenesis D.Stimulation of glycogenolysis (glycogen degradation)

5. MAJOR METABOLIC EVENTS THAT LEAD TO HYPERGLYCEMIA INSULIN GLUCAGON Glucose uptake by the tissues Glycogenolysis Hepatic output Of glucose HYPERGLYCEMIA Gluconeogenesis Breakdown of tissue proteins

6. Explain why there is increased urination (polyuria) with this high blood glucose? When the blood glucose levels exceed the renal sugar threshold glucose is excreted in urine (glucosuria) Due to the osmotic effect of glucose, more water accompanies glucose excretion Polyuria (increase in volume of urine excretion)

7. When the blood glucose levels exceed the renal sugar threshold glucose is excreted in urine (glucosuria) osmotic effect of glucose water accompanies glucose excretion Polyuria (increase in volume of urine excretion)

8. To compensate for the water loss Thirst centre is stimulated More water is is taken (polydepsia: always thirsty, drinks a lot)

9. Why Hoda had increased appetite (polyphagia) despite high glucose levels? Although the blood glucose level is high but glucose is not taken up by the cells due to insulin deficiency therefore the cells are starved The patient will take more food (polyphagia) to compensate for the loss of glucose and also loss of protein

10. Although the blood glucose level is high BUT glucose is NOT taken up by the cells due to insulin deficiency the cells are starved The patient will take more food (polyphagia) to compensate for the decrease of glucose and ATP intracellulary BUT

11. Discuss normal glucose metabolism

13. GLUCOSE Insulin + GLUCOSE glycolysis + ACETYL COA Pyruvate + PDH CITRIC ACID CYCLE MITOCHONDRIA ATP

14. GLUCOSE -6- PHOSPHATE 1)OXIDATION a) For energy production (glycolysis & Krebs cycle) b) For production of pentose P and NADPH (HMS) c) For production of uronic acid. 2) Conversion to other hexoses: 3)Conversion to non essential amino acids. 4)Storage in the form of glycogen or fats. Fructose, galactose

15. Biological effects of insulin Overall effect Direct effect Action of insulin on the enzyme Key enzyme PATHWAY Hypoglycemia Stimulation dephosphorylation of the enzymes Glucokinse PFK-1 Pyruvate kinase Glycolysis Hypoglycemia Inhibition Dephosphorylation of the enzymes *Pyruvate carboxylase *PEPCK *F1,6 diphosphatase *Glucose 6 phosphatase Gluconeo- genesis

16. Overall effect Direct effect Action of insulin on the enzyme Key enzyme PATHWAY Hypoglycemia Glycogen storage Activation dephosphorylation of the enzymes Glycogen synthase Glycogen synthesis Hypoglycemia Glycogen storage Inactivation dephosphorylation of the enzymes Glycogen phosphorylase Glycogen degradation Biological effects of insulin

17. In Diabetes Mellitus all these effects are reversed because INSULIN GLUCAGON A.inhibition of glycolysis B.Inhibition of glycogenesis (glycogen synthesis) C.stimulation of gluconeogenesis D.Stimulation of glycogenolysis (glycogen degradation)

18. Suggest the possible alterations in glucose storage and break down that might occur in this clinical problem. A.Inhibition of glycogenesis (glycogen synthesis) B.Stimulation of glycogenolysis (glycogen degradation)

19. GLUCAGON in liver Hormone receptor complex Adenyl Cyclase ATP cAMP Inactive protein kinase ACTIVE protein kinase Inactive phosphorylase kinase ACTIVE phosphorylase kinase Inactive phosphorylase ACTIVE phosphorylase P ATP ADP ACTIVATION OF GLYCOGEN BREAKDOWN ACTIVE Glycogen Synthase INACTIVE Glycogen Synthase ATP ADP INHIBITION OF GLYCOGEN SYNTHESIS P

20. ATPcAMP Inactive protein kinase ACTIVE protein kinase Inactive phosphorylase kinase ACTIVE phosphorylase kinase Inactive phosphorylase ACTIVE phosphorylase P ATP ADP PHOSPHODIESTERASE AMP INSULIN + PROTEIN PHOSPHATASE Pi H2O + Insulin dephosphorylates and inactivates phosphorylase and inhibits glycogenolysis

21. ATPcAMP Inactive protein kinase ACTIVE protein kinase P ATP ADP PHOSPHODIESTERASE AMP INSULIN + PROTEIN PHOSPHATASE Pi H2O + ACTIVE Glycogen Synthase INACTIVE Glycogen Synthase Insulin dephosphorylates and activates Glycogen synthase and activates glycogenesis

22. Therefore, in DM when insulin is deficient PROTEIN PHOSPHATASE PHOSPHODIESTERASE No activation of cAMP Phosphorylation of the key enzymes of glycogenolysis and glycogenesis INACTIVE Glycogen Synthase INHIBITION OF GLYCOGEN SYNTHESIS ACTIVE phosphorylase ACTIVATION OF GLYCOGEN BREAKDOWN