Abstract
Glucagon-like peptide-1-(7-36)-amide (GLP-1) is a potent blood glucose-lowering hormone now under investigation for use as a therapeutic agent in the treatment of type 2 (adult onset) diabetes mellitus. GLP-1 binds with high affinity to G protein-coupled receptors (GPCRs) located on pancreatic β-cells, and it exerts insulinotropic actions that include the stimulation of insulin gene transcription, insulin biosynthesis, and insulin secretion. The beneficial therapeutic action of GLP-1 also includes its ability to act as a growth factor, stimulating formation of new pancreatic islets (neogenesis) while slowing β-cell death (apoptosis). GLP- 1 belongs to a large family of structurally-related hormones and neuropeptides that include glucagon, secretin, GIP, PACAP, and VIP. Biosynthesis of GLP-1 occurs in the enteroendocrine L-cells of the distal intestine, and the release of GLP-1 into the systemic circulation accompanies ingestion of a meal. Although GLP-1 is inactivated rapidly by dipeptidyl peptidase IV (DDP-IV), synthetic analogs of GLP-1 exist, and efforts have been directed at engineering these peptides so that they are resistant to enzymatic hydrolysis. Additional modifications of GLP-1 incorporate fatty acylation and drug affinity complex (DAC) technology to improve serum albumin binding, thereby slowing renal clearance of the peptides. NN2211, LY315902, LY307161, and CJC-1131 are GLP-1 synthetic analogs that reproduce many of the biological actions of GLP-1, but with a prolonged duration of action. AC2993 (Exendin-4) is a naturally occurring peptide isolated from the lizard Heloderma, and it acts as a high affinity agonist at the GLP-1 receptor. This review summarizes structural features and signal transduction properties of GLP-1 and its cognate β-cell GPCR. The usefulness of synthetic GLP-1 analogs as blood glucose-lowering agents is discussed, and the applicability of GLP-1 as a therapeutic agent for treatment of type 2 diabetes is highlighted.
Keywords: glp-1, diabetes mellitus, insulin secretion
Current Medicinal Chemistry
Title: Glucagon-Like Peptide-1 Synthetic Analogs: New Therapeutic Agents for Use in the Treatment of Diabetes Mellitus
Volume: 10 Issue: 22
Author(s): George G. Holz and Oleg G. Chepurny
Affiliation:
Keywords: glp-1, diabetes mellitus, insulin secretion
Abstract: Glucagon-like peptide-1-(7-36)-amide (GLP-1) is a potent blood glucose-lowering hormone now under investigation for use as a therapeutic agent in the treatment of type 2 (adult onset) diabetes mellitus. GLP-1 binds with high affinity to G protein-coupled receptors (GPCRs) located on pancreatic β-cells, and it exerts insulinotropic actions that include the stimulation of insulin gene transcription, insulin biosynthesis, and insulin secretion. The beneficial therapeutic action of GLP-1 also includes its ability to act as a growth factor, stimulating formation of new pancreatic islets (neogenesis) while slowing β-cell death (apoptosis). GLP- 1 belongs to a large family of structurally-related hormones and neuropeptides that include glucagon, secretin, GIP, PACAP, and VIP. Biosynthesis of GLP-1 occurs in the enteroendocrine L-cells of the distal intestine, and the release of GLP-1 into the systemic circulation accompanies ingestion of a meal. Although GLP-1 is inactivated rapidly by dipeptidyl peptidase IV (DDP-IV), synthetic analogs of GLP-1 exist, and efforts have been directed at engineering these peptides so that they are resistant to enzymatic hydrolysis. Additional modifications of GLP-1 incorporate fatty acylation and drug affinity complex (DAC) technology to improve serum albumin binding, thereby slowing renal clearance of the peptides. NN2211, LY315902, LY307161, and CJC-1131 are GLP-1 synthetic analogs that reproduce many of the biological actions of GLP-1, but with a prolonged duration of action. AC2993 (Exendin-4) is a naturally occurring peptide isolated from the lizard Heloderma, and it acts as a high affinity agonist at the GLP-1 receptor. This review summarizes structural features and signal transduction properties of GLP-1 and its cognate β-cell GPCR. The usefulness of synthetic GLP-1 analogs as blood glucose-lowering agents is discussed, and the applicability of GLP-1 as a therapeutic agent for treatment of type 2 diabetes is highlighted.
Export Options
About this article
Cite this article as:
Holz G. George and Chepurny G. Oleg, Glucagon-Like Peptide-1 Synthetic Analogs: New Therapeutic Agents for Use in the Treatment of Diabetes Mellitus, Current Medicinal Chemistry 2003; 10 (22) . https://dx.doi.org/10.2174/0929867033456648
DOI https://dx.doi.org/10.2174/0929867033456648 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Influence of Polyphenol-plasma Protein Interaction on the Antioxidant Properties of Polyphenols
Current Drug Metabolism Cholesterol Oxidation Products and Disease: An Emerging Topic of Interest in Medicinal Chemistry
Current Medicinal Chemistry Flavonoids in the Treatment of Diabetes: Clinical Outcomes and Mechanism to Ameliorate Blood Glucose Levels
Current Diabetes Reviews Diabetes Mellitus and Acute Coronary Syndrome: A Lethal Combination Requiring Better Therapeutic Strategies
Current Vascular Pharmacology Clinical Determination of the Severity of Metabolic Syndrome: Preheparin Lipoprotein Lipase Mass as a New Marker of Metabolic Syndrome
Current Medicinal Chemistry - Cardiovascular & Hematological Agents Targeting JAK3 Tyrosine Kinase-Linked Signal Transduction Pathways with Rationally-Designed Inhibitors
Anti-Cancer Agents in Medicinal Chemistry Targeting Microparticle Biogenesis: A Novel Approach to the Circumvention of Cancer Multidrug Resistance
Current Cancer Drug Targets Sodium-Glucose Cotransporter Inhibitors in Non- Diabetic Heart Failure: A Narrative Review
Cardiovascular & Hematological Disorders-Drug Targets Management of Measurable Variable Cardiovascular Disease' Risk Factors
Current Cardiology Reviews Novel Biomarkers Assessing the Calcium Deposition in Coronary Artery Disease
Current Medicinal Chemistry Inflammatory Bowel Disease in Migrant Populations: Should we Look Even Further Back?
Current Drug Targets Structural Characterization, Biological Effects, and Synthetic Studies on Xanthones from Mangosteen (Garcinia mangostana), a Popular Botanical Dietary Supplement
Mini-Reviews in Organic Chemistry Are Cerebrovascular White Matter Lesions an Early Sign of Vascular Cognitive Impairment and Vascular Dementia?
Vascular Disease Prevention (Discontinued) Patent Selections
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Strong Association of Serum GSK-3β/BDNF Ratio with Mild Cognitive Impairment in Elderly Type 2 Diabetic Patients
Current Alzheimer Research Antioxidative Activity, Polyphenolic Content and Anti-Glycation Effect of Some Thai Medicinal Plants Traditionally Used in Diabetic Patients
Medicinal Chemistry Hypothyroidism and Cardiovascular Disease: Factors, Mechanism and Future Perspectives
Current Medicinal Chemistry Therapeutic Potential of Caffeic Acid Phenethyl Ester (CAPE) in Diabetes
Current Medicinal Chemistry Pulmonary Nocardiosis in Pemphigus Vulgaris Patients from Tehran, Iran
Infectious Disorders - Drug Targets Editorial [Hot topic: Transportalopathy and Vascular Cell Dysfunction (Guest Editor: Luis Sobrevia)]
Current Vascular Pharmacology