Download THE INCRETIN SYSTEM

THE INCRETIN SYSTEM
DR OGUNWALE O.O. MBBS
Snr Registrar EDM Div. LUTH
OUTLINE
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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
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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
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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
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THANK
YOU