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Transcript
ILA: DIABETES Ass Prof Dr. Gihan Sharara • 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. What is hyperglycemia? • Hyperglycemia is the elevation of blood glucose levels above the normal range. • Normal fasting blood glucose: • 70 – 100mg/dl 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) MAJOR METABOLIC EVENTS THAT LEAD TO HYPERGLYCEMIA INSULIN Glucose uptake by the tissues GLUCAGON Breakdown of tissue proteins Glycogenolysis Gluconeogenesis Hepatic output Of glucose HYPERGLYCEMIA • 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) When the blood glucose levels exceed the renal sugar threshold glucose is excreted in urine (glucosuria) osmotic effect of glucose Polyuria (increase in volume of urine excretion) water accompanies glucose excretion • To compensate for the water loss • Thirst centre is stimulated • More water is is taken (polydepsia: always thirsty, drinks a lot) • 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 Although the blood glucose level is high BUT 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 • Discuss normal glucose metabolism GLUCOSE GLUCOSE + Insulin glycolysis + + Pyruvate PDH ACETYL COA MITOCHONDRIA CITRIC ACID CYCLE ATP GLUCOSE -6- PHOSPHATE 1)OXIDATION a) For energy production (glycolysis & Krebs cycle) b) For production of pentose P and NADPH (HMS) 2) Conversion to other hexoses: Fructose, galactose 3)Conversion to non essential amino acids. 4)Storage in the form of glycogen or fats. c) For production of uronic acid. Biological effects of insulin PATHWAY Key enzyme Glycolysis Glucokinse Stimulation dephosphorylation PFK-1 of the enzymes Pyruvate kinase *Pyruvate Inhibition Gluconeogenesis Action of insulin on the enzyme carboxylase *PEPCK Dephosphorylation *F1,6 diphosphatase of the enzymes *Glucose 6 phosphatase Direct Overall effect effect Hypoglycemia Hypoglycemia Biological effects of insulin PATHWAY Key enzyme Action of insulin on the enzyme Glycogen synthesis Glycogen synthase Activation Direct effect Overall effect Glycogen Hypoglycemia dephosphorylation storage of the enzymes Glycogen degradation Glycogen phosphorylase Glycogen Hypoglycemia dephosphorylation storage Inactivation of the enzymes • • • • 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) • 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) GLUCAGON in liver ACTIVE Glycogen Synthase ATP Hormone receptor complex ADP P Adenyl Cyclase cAMP ATP Inactive protein kinase INACTIVE Glycogen Synthase INHIBITION OF GLYCOGEN SYNTHESIS ACTIVE protein kinase Inactive phosphorylase kinase ATP ACTIVATION OF GLYCOGEN BREAKDOWN ACTIVE phosphorylase kinase ADP ACTIVE Inactive phosphorylase ATP phosphorylase ADP P ATP cAMP PHOSPHODIESTERASE + ACTIVE protein kinase Inactive protein kinase AMP INSULIN Insulin ACTIVE Inactive dephosphorylates phosphorylase phosphorylase kinase and inactivates kinase ADP phosphorylase andATP ACTIVE Inactive inhibits phosphorylase phosphorylase glycogenolysis ATP + ADP PROTEIN PHOSPHATASE INSULIN Pi H2O P ATP cAMP AMP PHOSPHODIESTERASE Inactive protein kinase + ACTIVE protein kinase INSULIN INACTIVE Glycogen Synthase ACTIVE Glycogen Synthase ATP Insulin dephosphorylates and activates Glycogen synthase and activates glycogenesis Pi ADP PROTEIN PHOSPHATASE H2O + INSULIN P Therefore, in DM when insulin is deficient No activation of PHOSPHODIESTERASE PROTEIN PHOSPHATASE cAMP Phosphorylation of the key enzymes of glycogenolysis and glycogenesis ACTIVE INACTIVE Glycogen Synthase phosphorylase INHIBITION OF GLYCOGEN SYNTHESIS ACTIVATION OF GLYCOGEN BREAKDOWN