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THE INCRETIN SYSTEM DR OGUNWALE O.O. MBBS Snr Registrar EDM Div. LUTH OUTLINE • • • • • • • • BACKGROUND DEFINITION THE INCRETINS EFFECT OF INCRETINS INCRETINS IN DM CLINICAL APPLICATION OF INCRETIN SYSTEM CONCLUSION REFERENCES BACKGROUND • In 1929, La Barre purified the glucoselowering 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. BACKGROUND • Insulin levels higher with oral glucose ingestion compared to i.v.* BACKGROUND • 1970 : GIP, 1st Incretin Isolated • 1971 : Demonstrated to inhibit Gastric acid secretion giving it its 1st name • 70s*&80s**:Glucose-dependent Insulin secreting effect demonstrated→ 2nd name • 80s : Immunological depletion of GIP found not to stop glucose-dependent insulin secretion*** • 80s: GLP-1 isolated & incretin effect demonstrated 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* 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) 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 THE INCRETINS THE INCRETINS • 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* (1st phase) • 2nd phase : Direct response of L cells to food in lumen (distal small intestine). t½ ~ 2” 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 * THE INCRETINS THE INCRETINS 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* THE INCRETINS 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*** INCRETINS IN DM 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 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 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. 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 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 THANK YOU