The Discovery of GLP-1

Overview

Glucagon-like peptide-1 (GLP-1) is an intestinal peptide hormone that enhances insulin secretion, suppresses glucagon release, slows gastric emptying, and promotes satiety. It was identified in the early 1980s from the cloned proglucagon gene, which was shown to encode not only glucagon but also two additional "glucagon-like" peptides, GLP-1 and GLP-2.

The physiological role of GLP-1 came into focus with the work of Daniel Drucker, Joel Habener, Svetlana Mojsov, and Jens Juul Holst in the mid-to-late 1980s. Mojsov's 1987 demonstration that a truncated form, GLP-1(7-37), was the biologically active incretin resolved what had been a confusing set of results using full-length precursor forms. This active fragment, released from intestinal L-cells in response to nutrient ingestion, was shown to robustly stimulate glucose-dependent insulin secretion.

The "incretin effect" — the observation that oral glucose elicits a larger insulin response than an equivalent intravenous glucose load — had been known since the 1960s. GLP-1, together with gastric inhibitory polypeptide (GIP), turned out to be the principal incretin hormones.

Key People

• Joel Habener: Endocrinologist at Massachusetts General Hospital whose laboratory cloned the proglucagon gene.
• Svetlana Mojsov: Chemist who synthesized active GLP-1 fragments and demonstrated the importance of the 7–37 form.
• Daniel Drucker: Canadian endocrinologist who established the incretin biology and therapeutic potential of GLP-1.
• Jens Juul Holst: Danish physiologist whose clinical studies confirmed GLP-1's effects in humans.
• John Eng: Discovered exendin-4 in the Gila monster, leading to exenatide.

Timeline

• 1964: Elrick and colleagues describe the incretin effect.
• 1983: Habener's lab clones anglerfish proglucagon cDNA, revealing additional glucagon-like sequences.
• 1986: Mammalian proglucagon is sequenced, confirming GLP-1 and GLP-2.
• 1987: Mojsov identifies GLP-1(7-37) as the biologically active form.
• 1990s: Holst and colleagues quantify GLP-1 in human blood and confirm its incretin role.
• 1992: Exendin-4 is isolated from Gila monster venom.
• 2005: Exenatide (Byetta) becomes the first GLP-1 receptor agonist approved for type 2 diabetes.
• 2010–2024: Liraglutide, semaglutide, and tirzepatide extend the class into obesity therapy.

Background

The GLP-1 story is a classic example of how molecular biology reshaped endocrinology. Before gene cloning, glucagon was the only known product of the pancreatic alpha cell and its intestinal cousin, the L-cell. Sequencing of proglucagon revealed that different tissues process the same precursor into different sets of mature peptides — a biological principle now recognized throughout peptide hormone biology.

The incretin concept also helped explain a long-standing puzzle in diabetes physiology. Patients with type 2 diabetes show a blunted incretin effect, meaning the normal amplification of insulin secretion in response to oral glucose is impaired. Pharmacological replacement of GLP-1 signaling, using degradation-resistant analogs, provides a rational basis for therapy that emerged directly from this discovery.

Modern Relevance

GLP-1 receptor agonists are now among the most influential drugs in modern medicine. Agents such as semaglutide and dual agonists such as tirzepatide (which also activates the GIP receptor) produce substantial weight loss, glycemic improvement, and — increasingly — cardiovascular and renal benefits in clinical trials. Oral formulations (e.g., oral semaglutide) and longer-acting weekly injections have expanded the class further.

Research continues into novel combinations (GLP-1/glucagon co-agonists, triple agonists), non-peptide small-molecule GLP-1 receptor activators, and applications beyond diabetes and obesity, including neurodegenerative disease and addiction. For broader background, see peptides-in-metabolic-disease.

Related Compounds

• GLP-1
• Exenatide
• Liraglutide
• Semaglutide
• Tirzepatide