1. diae121.ppt1 Diabetes mellitus Lecture from pathological physiology © Oliver Rácz, 2007 - 2015 Šafárik University, Košice, Slovakia In cooperation with F. Ništiar, (immunology) A. Chmelárová, (biochemistry) D. Kuzmová, B. Jacobs (practical diabetology) and L. Szollár, Semmelweiss University, Budapest

2. diae121.ppt2 Diabetes mellitus - 1 Definition The scope of the problem Glucose homeostasis Mechanism of insulin action Insulin and its antagonists (repetition of physiology and biochemistry)

3. diae121.ppt3 Diabetes mellitus - 2 Symptomatology Classification Diagnostic criteria of diabetic syndromes Etiology and pathogenesis of Type 1 DM Etiology and pathogenesis of Type 2 DM and insulin resistance

4. diae121.ppt4 Diabetes mellitus - 3 Acute complications of diabetes and their management Chronic complications of diabetes and their prevention After diagnosis – monitoring of compensation MODY, Genetics of T1 and T2DM Perspectives in the treatment of diabetes Twists in the tale of diabetes history

5. diae121.ppt5 Definition of diabetes mellitus Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels.

6. diae121.ppt6

7. 7 THREE REASONS NONDIAGNOSED (FALSE) OBESITY (TRUE) LONGEVITY (TRUE)

8. diae121.ppt8 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

9. diae121.ppt9 GLUT4 IR glucose

10. diae121.ppt10 GLUT4 IR INSULIN glucose

11. diae121.ppt11 GLUT4 IR INSULIN glucose

12. diae121.ppt1222.8.2015diasnew1.ppt12 Glucose and insulin secretion GLUT2 – glucose transporter of B cells GK – glucokinase, glucose sensor of B cells MIT – mitochondriae, ATP production ATP sensitive K channel (Kir6.2-SUR1 – Potassium inward rectifier channel) Depolarisation Ca influc Insulin secretion

13. diae121.ppt1322.8.2015diasnew1.ppt13 GLUT2 GK MIT SUR1 KIR 6.2 K+K+ Ca ++ INSULIN GLUCOSE

14. diae121.ppt1422.8.2015diasnew1.ppt14 GLUT2 GK MIT SUR1 KIR 6.2 K+K+ Ca ++ INSULIN GLUCOSE

15. diae121.ppt1522.8.2015diasnew1.ppt15 GLUT2 GK MIT SUR1 KIR 6.2 K+K+ Ca ++ INSULIN GLUCOSE

16. diae121.ppt1622.8.2015diasnew1.ppt16 GLUT2 GK MIT SUR1 KIR 6.2 K+K+ Ca ++ INSULIN GLUCOSE ATP

17. diae121.ppt1722.8.2015diasnew1.ppt17 GLUT2 GK MIT SUR1 KIR 6.2 K+K+ Ca ++ INSULIN GLUCOSE ATP

18. diae121.ppt1822.8.2015diasnew1.ppt18 GLUT2 GK MIT SUR1 KIR 6.2 K+K+ Ca ++ INSULIN GLUCOSE ATP

19. diae121.ppt1922.8.2015diasnew1.ppt19 Glucose and insulin secretion GLUT2 – glucose transporter of B cells GK – glucokinase, glucose sensor of B cells MIT – mitochondriae, ATP production ATP sensitive K channel (Kir6.2-SUR1 – Potassium inward rectifier channel) Depolarisation Ca influc Insulin secretion

20. diae121.ppt20

21. diae121.ppt21 The secretion of insulin

22. diae121.ppt22 A big gene on 19 th chromosome (22 exons) 300 – 400 kDa transmembrane glycoprotein 4 subunits 3 domains Very conservative structure (drosophila) Tyrosinkinase autophosphorylation, phosphorylation

23. diae121.ppt23

24. diae121.ppt24 Time course for insulin action Immediate increase in Gucose 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

25. diae121.ppt25

26. diae121.ppt26 Insulin effects synthesis of glycogen glycolysis synthesis of fatty acids and their esterification synthesis of proteins glycogenolysis and gluconeogenesis oxidation of fatty acids and lipolysis INSULIN IS ANABOLIC HORMONE The younger sister of a big (10 member) family of growth factors (IGF)

27. diae121.ppt27 Insulin effects synthesis of glycogen (liver, fat, muscle) glycolysis (muscle) synthesis of fatty acids and their esterification (L,F) synthesis of proteins (muscle) glycogenolysis and gluconeogenesis (liver) oxidation of fatty acids and lipolysis (fat) INSULIN ACTS ALSO ON BRAIN AND NERVE CELL FUNCTION!!!

28. diae121.ppt28 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)