PMID-29202475 – Discovery and Clinical Development of Glucagon-Like Peptides
Drucker DJ, Habener JF, Holst JJ. Discovery, Characterization, and Clinical Development of the Glucagon-Like Peptides. J Clin Invest. 2017;127(12):4217-4227.
Quick Reference
| Property | Value |
|---|---|
| PMID | 29202475 |
| DOI | 10.1172/JCI97233 |
| Year | 2017 |
| Journal | Journal of Clinical Investigation |
| Study Type | Narrative Review |
| Evidence Level | V |
| Sample | N/A (landmark historical review by the three discoverers) |
| Peptide(s) Studied | GLP-1 (Native), GLP-2 |
Key Findings
- Traces the full discovery arc from cloning of the proglucagon gene (Habener lab, early 1980s) through identification of GLP-1 as an incretin (Holst lab) and GLP-2 as an intestinotrophic factor (Drucker lab)
- Proglucagon undergoes tissue-specific post-translational processing: pancreatic alpha-cells produce glucagon, while intestinal L-cells produce GLP-1, GLP-2, oxyntomodulin, and glicentin
- GLP-1 clinical development yielded two major drug classes: GLP-1 receptor agonists (exenatide, liraglutide, semaglutide) and DPP-4 inhibitors (sitagliptin, etc.), now used by tens of millions of patients
- GLP-2 clinical development led to teduglutide (Gattex/Revestive), the first approved therapy for short bowel syndrome with intestinal failure
- The review highlights how basic proglucagon biology research, spanning over 30 years, produced multiple blockbuster therapeutic classes
- Both GLP-1 and GLP-2 are rapidly degraded by DPP-4, and therapeutic analogs required engineering for protease resistance (acylation for GLP-1RAs, Gly2 substitution for teduglutide)
Study Design
Historical narrative review authored jointly by the three principal investigators whose laboratories discovered and characterized the glucagon-like peptides. Provides a first-person account of the scientific discoveries, translational milestones, and clinical development programs that led to approved therapies.
Limitations
- Written as a historical perspective rather than a systematic review of efficacy data
- Published before the obesity-focused GLP-1RA trials (STEP, SURMOUNT) that dramatically expanded the therapeutic scope of GLP-1 pharmacology
- Naturally reflects the perspectives and contributions of the three co-authors, with less emphasis on competing research groups
Clinical Relevance
This is an essential reference for understanding the scientific lineage of both GLP-1 and GLP-2 therapeutics. For the Ageless Pep Academy, it provides the origin story for two major peptide families covered across multiple modules. The proglucagon processing framework helps clinicians understand why GLP-1 and GLP-2 are co-secreted and how their distinct receptor systems produce complementary metabolic and intestinal effects. Bridges Module 5 (Weight Loss) and Module 8 (GI & Gut Health).
Related
#research #narrative-review #glp-1 #glp-2 #evidence-level-V