THE INCRETIN SYSTEM

DR OGUNWALE O.O. MBBSSnr 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 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.

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 INCRETINSTHE 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=0.980392

THANK

YOU