GIP: the first identified incretin hormone

HOLSTOV METABOLIC DYNAMICS

GIP: the first identified incretin hormone

Milestone 5 | From enterogastrone to the first molecular entity of the incretin effect

Executive summary

This document reviews the milestone through which gastric inhibitory polypeptide (GIP) moved from an intestinal fraction with enterogastrone activity to the first experimentally identified incretin hormone. The historical sequence includes the initial purification associated with John C. Brown, Viktor Mutt and Raymond A. Pederson, peptide sequencing, the demonstration of insulinotropic action in humans and the development of analytical tools to measure circulating GIP [1-6].

HMD interprets this milestone as the first conversion of the incretin concept into a concrete molecular entity. Up to this point, incretin history had been a conceptual architecture: gut-pancreas hypotheses, the term incretin and the incretin effect. With GIP, the field obtained for the first time an identifiable, measurable intestinal molecule physiologically linked to glucose-dependent insulin secretion [3-9].

HMD Figure 1. From enterogastrone to the first molecular incretin.

1. Historical context of the milestone

After the modern demonstration of the incretin effect during the 1960s, the scientific question shifted from whether the intestine released insulinotropic signals to which hormone or hormones explained that effect. In this context, research on intestinal fractions with enterogastrone activity identified a peptide entity capable of inhibiting gastric acid secretion: gastric inhibitory polypeptide, or GIP [1,9].

The historical paradox is that GIP was named for its initial gastrointestinal activity, not for its pancreatic role. The name gastric inhibitory polypeptide reflected the reading of the time: an intestinal signal capable of inhibiting acid secretion. Later work showed that its more robust importance for incretin history was potentiation of glucose-dependent insulin secretion [3,5,6,8].

Table 1. Documentary chronology of the milestone

2. Scientific development of GIP

The purification of a fraction with enterogastrone activity in 1970 made it possible to study GIP as a more defined peptide entity [1]. In 1971, Brown and Dryburgh reported the amino-acid sequence of the polypeptide, an essential step in moving the field from impure intestinal extracts toward a molecularly characterized hormone [2].

The decisive shift came in 1973, when Dupré, Ross, Watson and Brown showed that purified GIP stimulated insulin secretion in humans during glucose infusion [3]. This evidence connected the peptide to the core incretin phenomenon: the ability of an intestinal signal to amplify pancreatic beta-cell response in the presence of glucose.

Subsequently, radioimmunoassays enabled measurement of circulating GIP and related its physiological release to nutrient ingestion [4,5]. Studies in animal models and perfused pancreas preparations strengthened the interpretation that GIP was insulinotropic, although its action depended on the glycemic context [5,6].

HMD Figure 3. Early physiological architecture of GIP.

3. From gastric name to incretin identity

The history of GIP shows a semantic shift: from gastric inhibitory polypeptide to glucose-dependent insulinotropic polypeptide. The acronym GIP allowed documentary continuity, but the functional meaning changed. Rather than a hormone defined primarily by gastric inhibition, GIP came to be read as a glucose-dependent insulinotropic intestinal hormone [7-9].

This transition was not merely linguistic. It changed the position of GIP within physiology: from a peripheral gastrointestinal signal to a central component of the entero-insular axis. Creutzfeldt integrated this reading within the modern incretin concept, and later reviews consolidated GIP and GLP-1 as the two principal known incretin hormones [7,8].

HMD Figure 2. Functional identity shift of GIP.

4. Importance for GLP-1 and tirzepatide history

GIP is essential for understanding GLP-1 because it shows that the incretin concept could become a real molecule before GLP-1 became the therapeutically dominant hormone. The later identification of GLP-1 did not replace GIP; it expanded the field and showed that the incretin effect could be mediated by more than one intestinal signal [8,10].

From a contemporary perspective, GIP also has renewed relevance because of the era of dual agonism. For years, GLP-1 dominated pharmacological development because of its clinical efficacy in diabetes and obesity; however, modern interest in GIP has been reactivated by GIP receptor pharmacology and strategies such as GIP/GLP-1 coagonism [11].

5. Independent HMD analysis

HMD classifies the GIP milestone as the first molecular materialization of the incretin concept. Its historical value is not only that it was identified before GLP-1, but that it proved that the entero-pancreatic hypothesis could be linked to a specific, sequenced, measurable and functionally insulinotropic intestinal hormone.

The milestone also cautions against a linear reading of science. GIP was discovered through an activity that later became secondary to its metabolic relevance. This demonstrates that the meaning of a molecule can change when new analytical tools, new physiological models and new therapeutic questions emerge. For HMD, GIP is the first clear example of functional reclassification within incretin history.

HMD Figure 4. HMD matrix of GIP documentary maturation.

Technical conclusion

Milestone 5 establishes GIP as the first molecular entity capable of experimentally sustaining the incretin concept. Its history begins as enterogastrone and evolves toward a glucose-dependent insulinotropic hormone. For HMD, GIP represents the first bridge between intestinal hypotheses, hormone measurement, beta-cell physiology and modern incretin pharmacology. Its re-emergence in the era of GIP/GLP-1 coagonism confirms that historical milestones are not closed artifacts: they may acquire new meaning when the field develops new tools and new therapeutic strategies.

References

1. Brown JC, Mutt V, Pederson RA. Further purification of a polypeptide demonstrating enterogastrone activity. J Physiol. 1970;209(1):57-64.

2. Brown JC, Dryburgh JR. A gastric inhibitory polypeptide. II. The complete amino acid sequence. Can J Biochem. 1971;49(8):867-872. doi:10.1139/o71-122.

3. Dupré J, Ross SA, Watson D, Brown JC. Stimulation of insulin secretion by gastric inhibitory polypeptide in man. J Clin Endocrinol Metab. 1973;37(5):826-828. doi:10.1210/jcem-37-5-826.

4. Kuzio M, Dryburgh JR, Malloy KM, Brown JC. Radioimmunoassay for gastric inhibitory polypeptide. Gastroenterology. 1974;66(3):357-364.

5. Pederson RA, Schubert HE, Brown JC. Gastric inhibitory polypeptide: its physiologic release and insulinotropic action in the dog. Diabetes. 1975;24(12):1050-1056. doi:10.2337/diab.24.12.1050.

6. Pederson RA, Brown JC. The insulinotropic action of gastric inhibitory polypeptide in the perfused isolated rat pancreas. Endocrinology. 1976;99(3):780-785. doi:10.1210/endo-99-3-780.

7. Creutzfeldt W. The incretin concept today. Diabetologia. 1979;16(2):75-85. doi:10.1007/BF01225454.

8. Seino Y, Fukushima M, Yabe D. GIP and GLP-1, the two incretin hormones: similarities and differences. J Diabetes Investig. 2010;1(1-2):8-23. doi:10.1111/j.2040-1124.2010.00022.x.

9. Pederson RA, McIntosh CHS. Discovery of gastric inhibitory polypeptide and its subsequent fate: personal reflections. J Diabetes Investig. 2016;7(Suppl 1):4-7. doi:10.1111/jdi.12480.

10. Holst JJ. From the incretin concept and the discovery of GLP-1 to today’s diabetes therapy. Front Endocrinol (Lausanne). 2019;10:260. doi:10.3389/fendo.2019.00260.

11. Müller TD, Adriaenssens A, Ahrén B, Blüher M, Birkenfeld AL, Campbell JE, et al. Glucose-dependent insulinotropic polypeptide (GIP). Mol Metab. 2025;95:102118. doi:10.1016/j.molmet.2025.102118.