Pharmacological Reviews
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Published online before print December 12, 2008

0031-6997/08/6004-470-512$7.00
Pharmacol Rev 60:470-512, 2008

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
pr.108.000604v1
pr.108.000604v2
60/4/470    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kim, W.
Right arrow Articles by Egan, J. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kim, W.
Right arrow Articles by Egan, J. M.

The Role of Incretins in Glucose Homeostasis and Diabetes Treatment

Wook Kim and Josephine M. Egan

National Institute on Aging/National Institutes of Health, Baltimore, Maryland

Abstract
I. Background and Introduction
II. General Description of Incretins
    A. Glucose-Dependent Insulinotropic Peptide
    B. Glucagon-Like Peptide-1
III. Synthesis, Secretion, and Degradation of Incretins
    A. Synthesis, Secretion, and Degradation of Glucose-Dependent Insulinotropic Peptide
        1. Pro-Glucose-Dependent Insulinotropic Peptide Gene Structure, Expression and Post-Translational Processing.
        2. Glucose-Dependent Insulinotropic Peptide Secretion and Degradation.
    B. Synthesis, Secretion and Degradation of Glucagon-Like Peptide-1
        1. Proglucagon Gene Structure and Expression.
        2. Tissue-Specific Post-Translational Processing of Proglucagon, Product Secretion, and Degradation.
    C. Incretin Secretion in Type 2 Diabetes
IV. Incretin Receptors
    A. Glucose-Dependent Insulinotropic Peptide Receptor
    B. Glucagon-Like Peptide-1 Receptor
V. The Incretin Effect
    A. The Incretin Effect of Glucose-Dependent Insulinotropic Peptide and Its Impact in Type 2 Diabetes
    B. The Incretin Effect of Glucagon-Like Peptide-1 and Its Impact in Type 2 Diabetes
VI. The Pleiotropic Effect of Incretin in Pancreas
    A. The Pleiotropic Effects of Glucose-Dependent Insulinotropic Peptide in Pancreas
        1. Effects on β Cells.
        2. Effects on Glucagon Secretion.
    B. Pleiotropic Effects of Glucagon-Like Peptide-1 in Pancreas
        1. Effects on β Cells.
        2. Effects on Glucagon Secretion.
        3. Effects on Pancreatic Exocrine and Ductal Cells.
VII. Extrapancreatic Effects of Incretins
    A. Extrapancreatic Effects of Glucose-Dependent Insulinotropic Peptide
        1. Central Nervous System.
        2. Gastrointestinal Tract.
        3. Adipose Tissue.
        4. Bone.
    B. Extrapancreatic Effects of Glucagon-Like Peptide-1
        1. Central and Peripheral Nervous System Effects on Food Intake and Glucose Homeostasis.
        2. Gastrointestinal Tract and Gastric Emptying.
        3. Muscle, Adipose Tissue, and Liver.
        4. Bone.
        5. Cardiovascular System.
        6. Hypothalamic-Pituitary Axis.
VIII. The Development of Therapies for Diabetes Based on the Incretin Actions
    A. Exenatide
        1. Relevant Clinical Studies.
    B. Sitagliptin
        1. Relevant clinical studies.
    C. Therapies under Development
        1. Vildagliptin.
        2. Liraglutide.
            a. Selected Clinical Trials.
            b. Side Effects.
IX. Potential Disease-Modifying Effects of Incretin-Based Therapies
X. Concluding Remarks
Incretins are gut hormones that are secreted from enteroendocrine cells into the blood within minutes after eating. One of their many physiological roles is to regulate the amount of insulin that is secreted after eating. In this manner, as well as others to be described in this review, their final common raison d'être is to aid in disposal of the products of digestion. There are two incretins, known as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1), that share many common actions in the pancreas but have distinct actions outside of the pancreas. Both incretins are rapidly deactivated by an enzyme called dipeptidyl peptidase 4 (DPP4). A lack of secretion of incretins or an increase in their clearance are not pathogenic factors in diabetes. However, in type 2 diabetes (T2DM), GIP no longer modulates glucose-dependent insulin secretion, even at supraphysiological (pharmacological) plasma levels, and therefore GIP incompetence is detrimental to β-cell function, especially after eating. GLP-1, on the other hand, is still insulinotropic in T2DM, and this has led to the development of compounds that activate the GLP-1 receptor with a view to improving insulin secretion. Since 2005, two new classes of drugs based on incretin action have been approved for lowering blood glucose levels in T2DM: an incretin mimetic (exenatide, which is a potent long-acting agonist of the GLP-1 receptor) and an incretin enhancer (sitagliptin, which is a DPP4 inhibitor). Exenatide is injected subcutaneously twice daily and its use leads to lower blood glucose and higher insulin levels, especially in the fed state. There is glucose-dependency to its insulin secretory capacity, making it unlikely to cause low blood sugars (hypoglycemia). DPP4 inhibitors are orally active and they increase endogenous blood levels of active incretins, thus leading to prolonged incretin action. The elevated levels of GLP-1 are thought to be the mechanism underlying their blood glucose-lowering effects.

Address correspondence to: Dr. Josephine M. Egan, National Institute on Aging, Intramural Research Program, 5600 Nathan Shock Drive, Baltimore, MD 21224. E-mail: eganj{at}grc.nia.nih.gov




This article has been cited by other articles:


Home page
 Pharmacol. Rev.Home page
E. P. Brass and R. D. Feldman
Sixty Years of Pharmacological Reviews: Has The Role of Review Articles in Biomedical Sciences Changed and, If So, How Does This Affect Pharmacological Reviews?
Pharmacol. Rev., June 1, 2009; 61(2): 115 - 118.
[Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. B. Widenmaier, A. V. Sampaio, T. M. Underhill, and C. H. S. McIntosh
Noncanonical Activation of Akt/Protein Kinase B in {beta}-Cells by the Incretin Hormone Glucose-dependent Insulinotropic Polypeptide
J. Biol. Chem., April 17, 2009; 284(16): 10764 - 10773.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition
Copyright © 2008 by the American Society for Pharmacology and Experimental Therapeutics