The History of Incretin Research: From GIP Discovery to Modern Multi-Receptor Agonists

A chronological overview of incretin hormone research from the initial discovery of GIP in 1971 through the development of modern multi-receptor agonist compounds, tracing the scientific milestones that shaped contemporary metabolic research.

The Incretin Effect: Historical Context

The incretin effect — the observation that oral glucose stimulates greater insulin secretion than intravenous glucose — was first described by McIntyre et al. in 1964. This foundational observation initiated decades of research into the gut-pancreas hormonal axis.

50–70%

of postprandial insulin secretion accounted for by the incretin effect in healthy research subjects

Discovery of GIP (1971)

Gastric inhibitory polypeptide (GIP), later renamed glucose-dependent insulinotropic polypeptide, was first isolated and characterised by Brown et al. in 1971. Initially identified for its inhibitory effects on gastric acid secretion, GIP was subsequently recognised as a major incretin hormone.

—1971: GIP isolated from porcine intestinal extracts
—1973: Insulinotropic properties of GIP characterised
—1985: Human GIP gene sequenced
—1996: GIP receptor cloned and expressed

Discovery of GLP-1 (1983–1987)

Glucagon-like peptide-1 was identified through analysis of the proglucagon gene by Bell et al. in 1983. The mature, biologically active form GLP-1(7-36)amide was characterised by Mojsov et al. in 1987.

50–60%

of the total incretin response contributed by GLP-1 in human research subjects

Development of GLP-1 Receptor Agonists (1990s–2000s)

The recognition that GLP-1 degraded rapidly in vivo (half-life <2 minutes due to DPP-4 cleavage) stimulated research into GLP-1 analogs with extended stability. The isolation of exendin-4 from Heloderma suspectum by Eng et al. in 1992 provided a naturally occurring GLP-1 receptor agonist with DPP-4 resistance. Further structural optimisation produced liraglutide (once-daily) and ultimately semaglutide with a half-life of approximately 165–184 hours enabling once-weekly administration.

The Dual Agonism Era (2010s)

—2011: First dual GLP-1/GIP agonist peptides described in research literature
—2017: Tirzepatide preclinical research published
—2021: Phase 3 SURPASS trials initiated
—2022: SURMOUNT-1 results published

Triple Agonism Research (2020s)

—2018: First triple GLP-1/GIP/GCG agonists described in research literature
—2021: Retatrutide Phase 1 research initiated
—2023: Phase 2 retatrutide results published demonstrating 24.2% weight reduction

Current Research Frontiers

—Amylin co-agonism: Combining GLP-1 agonism with amylin receptor activation
—FGF21 agonism: Fibroblast growth factor 21 as complementary metabolic target
—Oral peptide delivery: Overcoming bioavailability challenges for non-injectable administration

Conclusion

The trajectory from the initial characterisation of the incretin effect in 1964 to modern triple receptor agonists represents six decades of progressive scientific understanding. Each research milestone has built upon prior discoveries to produce compounds with increasingly characterised metabolic effects.