1. THE INCRETIN SYSTEM DR OGUNWALE O.O. MBBS Snr Registrar EDM Div. LUTH

2. OUTLINE BACKGROUND DEFINITION THE INCRETINS EFFECT OF INCRETINS INCRETINS IN DM CLINICAL APPLICATION OF INCRETIN SYSTEM CONCLUSION REFERENCES

3. BACKGROUND In 1929, La Barre purified the glucose- lowering element from gut extracts, and named it incretin (INtestine seCRETtion INsulin) However, Incretin was forgotten for 3 decades until RIA to measure insulin became available in the 1960s.

4. BACKGROUND Insulin levels higher with oral glucose ingestion compared to i.v.*

5. BACKGROUND 1970 : GIP, 1 st Incretin Isolated 1971 : Demonstrated to inhibit Gastric acid secretion giving it its 1 st name 70s*&80s**:Glucose-dependent Insulin secreting effect demonstrated→ 2 nd name 80s : Immunological depletion of GIP found not to stop glucose-dependent insulin secretion*** 80s: GLP-1 isolated & incretin effect demonstrated

6. DEFINITION Incretins : Hormones fulfilling 2 conditions (1)secreted during glucose ingestion (2)capable of stimulating insulin secretion during similar glycaemic levels & in those concentrations reached during glucose ingestion*

7. THE INCRETINS GI Hormones like Gastrin, CCK, Secretin, GIP (Glucose-dependent Insulinotropic Peptide ) & GLP-1 (Glucagon-like Peptide-1) are produced in response to glucose meals and also stimulate Insulin. Also Glucagon* But only GIP & GLP-1 meet the criteria for Incretins (See Above)

8. THE INCRETINS GIP : Produced by K cells in duodenal & jejunal mucosa. 42 aas Large doses Inhibit Gastric secretion and Motility hence also called Gastric Inhibitory Peptide. GLP-1 : produced by L cells in distal jejunum &ileum from a polypeptide complex*. 31 aas Both degraded by Dipeptidyl Peptidase IV enzyme

9. THE INCRETINS

10. GIP : stimulated after absorption of nutrients i.e. Glucose, lipids and protein. t½ = 4-5” However GLP-1 is 1st stimulated by presence of food in of proximal small intestine Stretch of lumen → neurotransmitter release i.e. Ach & GRP* (1 st phase) 2 nd phase : Direct response of L cells to food in lumen (distal small intestine). t½ ~ 2”

11. THE INCRETINS Incretins (GIP & GLP-1) are peptide hormones Bind to G- protein coupled receptors (GIPR & GLP-1R respectively) Receptors on surface of β-islet cells & other cells Carry out action thru cAMP-mediated Insulin release in anticipation of postprandial glucose rise *

12. THE INCRETINS

16. EFFECT OF INCRETINS Increase β-cell sensitivity to glucose Facilitate Glucose dependent Insulin production Inhibit& Stimulate Glucagon(GLP-1 & GIP respec.) Inhibit Gastric Emptying Induces Satiety (GLP-1) Inhibits Beta cell Apoptosis Enhances Beta cell proliferation & neogenesis*

17. THE INCRETINS

18. INCRETINS IN DM ↓ GLP-1 produced in T2DM* Slightly ↓ GIP in T2DM* Poor β-cell response to GIP even at high doses but good response to GLP-1** Obesity (↑BMI) and long duration/severity of T2DM has profound deleterious effects Metformin has beneficial effects***

19. INCRETINS IN DM

20. CLINICAL APPLICATION OF INCRETIN SYSTEM Exendin-4: GLP-1-like & from saliva of Gila Monster which eats 1ce or 2ce a year! Uses salivary substance to proliferate pancreas & small intestine mucosa

21. CLINICAL APPLICATION OF INCRETIN SYSTEM Exendin-4 Derivative: Exenatide, Long-acting Exenatide GLP-1 Analogue: Liraglutide DPP IV Inhibitors : “Gliptins” Wt. ↓/neutrality 6-month HbA1C ↓ btw 0.8-1.5

22. CONCLUSION The Incretin System connotes post-prandial production of peptide hormones (incretins) that facilitate glucose-dependent insulin secretion Incretins exert various means of facilitating glucose control which have been exploited in the clinical management of Diabetes (T2DM) Also have cardioprotective,anabolic and neuro-enhancing properties.

23. REFERENCES Yabe D, Seino Y. Two incretin hormones GLP-1 and GIP: comparison of their actions in insulin secretion and β cell preservation. Prog Biophys Mol Biol. 2011 Nov;107(2):248-56 Holst JJ, Knop FK, Vilsbøll T, Krarup T, Madsbad S. Loss of Incretin Effect Is a Specific, Important, and Early Characteristic of Type 2 Diabetes. Diabetes Care 2011 May;34(2):251–57 Hinnen D, Nielsen LL,, Waninger A, Kushner P. Incretin Mimetics and DPP-IV Inhibitors: New Paradigms for the Treatment of Type 2 Diabetes. J Am Board Fam Med 2006;19:612–20 Egan JM, Kim W. The Role of Incretins in Glucose Homeostasis and Diabetes. Pharmacol Rev. 2008 December ; 60(4): 470–512. Nauck MA, Vilsbøll T, Gallwitz B, Garber A, Madsbad S. Incretin-Based Therapies. Viewpoints on the way to consensus. Diabetes Care 2009 Nov;32(2):223-231 Buse JB, Polonsky KS, Burant CF. Type 2 Diabetes Mellitus In Melmed S, Polonsky KS, Larsen PR, Kronenberg HM (eds.), Williams Textbook of Endocrinology, 12th ed. Saunders, 2011. Ch.31. pp 1394- 96

24. REFERENCES Gardner DG, Shoback D.(eds.) Pancreatic Hormones and Diabetes. Greenspan’s Basic & Clinical Endocrinology. 8th ed. McGraw-Hill Barrett KE, Barman SM, Boitano S, Brooks HL. Endocrine Function Of The Pancreas And Regulation Of Carbohydrate Metabolism. Ganong’s Review of Medical Physiology. 23rd ed. McGraw-Hill.2010 Ch.21 Barrett KE, Barman SM, Boitano S, Brooks HL. Overview Of Gastrointestinal Function And Regulation. Ganong’s Review of Medical Physiology. 23rd ed. McGraw-Hill.2010. Ch.26 http://www.bmj.com/open-data/incretin http://courses.washington.edu/conj/bess/incretins/incretins.htm http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2851388/#!po=0.9 80392

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