2. DR SYED SHAHID HABIB MBBS DSDM FCPS Assistant Professor Dept. of Physiology College of Medicine & KKUH PANCREAS & INSULIN

4. Insulin structure, Its mechanism of secretion and functions Role of different hormones in glucose homeostasis The effects of insulin deficiency OBJECTIVES At the end of this lecture you should be able to describe:

5. Adipose tissue Carbohydrates Fats Proteins AA FFA G 22 % 77 % 1 % G FFA AA INTERMEDIARY METABOLISM

6. PANCREAS FUNCTIONAL ANATOMY

7.  Alpha cells (A cells) secrete the hormone glucagon.  Beta cells (B cells) produce insulin and are the most abundant of the islet cells.  Delta cells (D cells) secrete somatostatin  Gamma cells (F cells) secrete a pancreatic polypeptide ISLET CELLS ISLETS of Langerhan

8. Source β Cells of Islets of Langerhan Chemistry Peptide [51 aa] Molecular Weight 5808 Half Life 5-10 min Basal Levels 3 ng/ml or < 10 mIU/ml Fate Endocytosis and Proteolysis (80 % in Liver & Kidneys) Species Specificity (Bovine & Human) Chromosome 11 INSULIN

9. Ribosomes on Rough ER Packed in Golgi Apparatus (Secretory Vesicles) Pro Insulin Cleaved in Endoplasmic Reticulum Pre Pro Insulin Insulin + C-Peptide Released by Exocytosis Insulin C-Peptide SYNTHESIS OF INSULIN

11. INSULIN STRUCTURE

12. B Chain A Chain INSULIN STRUCTURE

14. IRS-1 Tyrosine Kinase Tyrosine Kinase PP HEXOSE TRANSPORTERS HOW GLUCOSE IS TRANSPORTED?

15. SGLT 1 SGLT 2 Absorption of Glucose Small Intestine, Renal Tubules Renal Tubules Absorption of Glucose SODIUM DEPENDANT GLUCOSE COTRANSPORT Only in GIT & Kidneys

16. Peritubular Capillary LumenEpithelial Cells BLOOD Na ATP Na K G SGLT 2 G GLUT 2 Early PCT GLUCOSE REABSORPTION IN NEPHRON Tm for Glucose is 320 mg/min G G

17. ECFLumenEpithelial Cells BLOOD Na ATP Na K G SGLT 1 G GLUT 2 F GLUT 5 F GLUCOSE REABSORPTION IN GIT G G

18. GLUT 5GLUT 7GLUT 1GLUT 2GLUT 3 GLUT 4 GLUT 6 GLUT 1. Basal Gluc Uptake GLUT 2. B Cell Gluc Sensor, Intest and Renal Epith GLUT 3. Basal Gluc Uptake GLUT 4. Insulin Stimulated Gluc Uptake GLUT 5. Fructose Transport None GLUT 7. Gluc 6 Po4 transporter in ER Liver, Other Tissues Placenta, BBB, Brain, RBCs, Kidneys, Colon B Cells of Islets, Liver, Epith Cells of Small Intest, Kidneys Brain, Placenta, Kidneys Skeletal & Cardiac Ms, Adipose Tissue Jejunum, Sperm Pseuodogene

19. INSULIN ACTIONS RapidIntermediateDelayed Increased transport of Glucose, Amino Acids and K+ into insulin Sensitive Cells Stimulation of Protein Synthesis Activation of Glycolysis & Glycogen Synthesis Inhibition of Gluconeogenesis Increase in mRNAs for lipogenic and other enzymes Skeletal Ms Cardiac Ms Adipose Tissue HORMONE OF ABUNDANCE

20. Neelam Valley

21. HOW INSULIN SECRETION IS CONTROLLED?

22. G GG GG ATP Ca ++ K+K+ K+K+ K+K+ Amino acids Fatty acids Acetylcholine gastrin Secretin GIP CCK GLUT 2 BETA CELL K+K+ K+K+ GLUT 2 Glycolysis G G SU

23. IRS-1 Tyrosine Kinase Tyrosine Kinase PP MECHANISM OF ACTION

24. IRS-1 Tyrosine Kinase Tyrosine Kinase PP ECF ICF Phospho Kinase GLUT-4 G G G GG Grb2&SOS RAS RAF MAP-K G InsIns

25. Stimulatory agents or conditions Hyperglycemia Amino acids, Fatty acids GIT hormones GIP-GLP1-Gastrin-Secretin, CCK Acetylcholine Sulfonylureas Inhibitory agents or conditions Somatostatin Norepinephrine Epinephrine Chemical Hormonal Neural FACTORS AFFECTING INSULIN SECRETION

26. HOW INSULIN IS RELEASED? Insulin secretion is continuous BASAL INSULIN SECTRETION Increases after carbohydrate consumption BIPHASIC

27. Loss of the first phase result in elevation of the postprandial glucose. Delayed second phase- can result in post- meal hypoglycemia. NORMAL TYPE 2 DM 153002035525401045505560 Time (Minutes) Plasma Insulin (uU/ml) %%%%%% HOW INSULIN IS RELEASED? (Cont.) TYPE 1 DM

28. Insulin IGF1 GlucagonGHT 3 T 4 Catechol amines Steroids

29. Ushu

30. WHAT ARE THE EFFECTS OF INSULIN DEFICIENCY?

31. Insulin Deficiency Decreased Glucose Uptake Increased Protein Catabolism Increased lipolysis Increased Plasma Amino acids Hyperglycemia Glycosuria Increased plasma FFA Dehydration Acidosis Coma & Death

32. Swat

33. DIABETES MELLITUS DEFINITION Diabetes Mellitus (DM) is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin actions or both (ADA. Clinical Practice Recommendations Diabetes Care 2004) (ADA. Clinical Practice Recommendations Diabetes Care 2004)