GLP-1 and GIP: a short incretin history

Incretins are gut hormones released after a meal that tell the pancreas to release insulin. Two of them, GLP-1 and GIP, are the basis of a drug class that now includes semaglutide and tirzepatide. The story starts in 1906, with an experiment that did not work^[2].

1902 to 1932: proposed long before it was found

Secretin, described in 1902, was the first hormone anyone identified, and gastrin followed in 1905. Working from that idea, Moore and colleagues proposed in 1906 that the duodenal lining might release a substance acting as, in their phrasing, a chemical excitant for the internal secretion of the pancreas. They tried to treat diabetes by injecting gut extracts. It did not work well^[2].

The idea outlived the failure. Zunz and LaBarre used cross-circulation experiments in dogs in 1929 to show a pancreas-dependent effect, and in 1932 LaBarre published on the possibility of treating diabetes with an incretin. The name stuck, attached to a hormone nobody had isolated^[2].

1964 to 1973: proof, then the first hormone

Radioimmunoassay, developed by Yalow and Berson in the late 1950s, made the question testable. Researchers could finally show that oral glucose produces a larger insulin response than intravenous glucose at matching blood glucose levels. McIntyre and colleagues published that reinterpretation of the oral glucose tolerance test in the Lancet in 1964^[2]. In healthy people the incretin effect accounts for up to 70% of the insulin response to a meal^[2].

The first incretin hormone to be named was GIP, isolated by John Brown. Brown and John Dupre then showed that it strongly enhances glucose-stimulated insulin secretion in humans^[2]. GIP was originally called gastric inhibitory polypeptide because it suppressed acid secretion in canine gastric pouches, an effect that could not be reproduced under physiological conditions in humans. The acronym was gradually redefined to glucose-dependent insulinotropic polypeptide^[2].

1987 to 1993: GLP-1 becomes a drug candidate

Cloning the preproglucagon gene in the early 1980s revealed that the glucagon precursor carried other glucagon-like sequences alongside glucagon itself^[3]. By 1987 several groups had converged on the active form: truncated GLP-1, the 7-36 amide and 7-37 fragments, which release insulin at picomolar concentrations^[3]. This is the hormone that semaglutide was later engineered to imitate.

Clinical proof followed quickly. In 1992 Gutniak and colleagues in Stockholm infused synthetic GLP-1 into people with type 1 and type 2 diabetes and found that with GLP-1 running, almost no insulin administration was needed to normalise blood glucose^[2]. In 1993 Nauck's group showed that GLP-1 keeps its insulin-releasing effect in type 2 diabetes while synthetic human GIP does not, and that GLP-1 infusion could normalise fasting glucose in patients with long-standing, poorly controlled disease^[2].

That same result shelved GIP for roughly three decades. GIP stays inactive in type 2 diabetes regardless of dose, and the molecular reason for the difference is still not known^[2].

1992 to 2022: a lizard peptide, then GIP returns

Native GLP-1 was never going to be a medicine. Its half-life is about 1.5 minutes, and blocking the DPP-4 cleavage site stretched that only to four or five minutes, because the kidneys clear it so fast^[2].

The workaround came from Heloderma suspectum, the Gila monster. Eng and colleagues isolated exendin-4 in 1992^[3]. It runs to 39 amino acids, shares 53% homology with mammalian GLP-1 across its 30 N-terminal residues, is a full agonist at the mammalian GLP-1 receptor and is not a DPP-4 substrate^[2]. A synthetic copy, exenatide, reached the market as the first GLP-1 receptor agonist in 2005^[2], and the European Commission authorised it as Byetta on 20 November 2006^[4]. Liraglutide arrived in 2009 to 2010, and semaglutide followed with a once-weekly profile^[2].

Then GIP came back. Tirzepatide is a single molecule that activates both the GIP and the GLP-1 receptor. The European Commission authorised it as Mounjaro on 15 September 2022 for type 2 diabetes and for weight management in adults with obesity, or overweight plus a weight-related complication^[5]. A hormone written off for diabetes in 1993 is now half of a licensed dual agonist, and the mechanism behind the pairing is still being worked out.

What is licensed, and what is still a hypothesis

The 2026 review that prompted this piece describes incretins as swiss army knife medications^[1]. That framing is worth splitting into three piles, because they carry very different evidence.

Licensed: type 2 diabetes and weight management. That is what the tirzepatide authorisation actually covers in the EU and EEA^[5], and the country-by-country picture is on the tirzepatide regulation table.

In late-stage testing: retatrutide, a triple agonist at the GLP-1, GIP and glucagon receptors^[1]. Eli Lilly's TRIUMPH-Outcomes trial, in adults with obesity plus atherosclerotic cardiovascular disease or chronic kidney disease, is registered as phase 3 and listed as active, not recruiting^[6]. Retatrutide holds no marketing authorisation in any jurisdiction we cover, as the retatrutide regulation table sets out.

Unsettled: the wider claims. Novo Nordisk's EVOKE trial tested semaglutide in 1,840 people with early Alzheimer's disease, against change in the Clinical Dementia Rating Sum of Boxes. It is registered as phase 3 and completed on 30 January 2026, with no results posted to the registry^[7]. MASLD, cardiovascular disease and neurodegeneration appear in the review as areas of promise^[1], which is not the same as an approved indication. Treat that distinction as load-bearing when you read coverage of this class.

The through-line across 120 years is that the physiology ran well ahead of the pharmacology, and then the pharmacology ran ahead of the long-term outcome data. Current regulatory status for each molecule is on the semaglutide regulation table.

This article is for educational and journalistic purposes and does not constitute medical advice. Semaglutide and tirzepatide are prescription-only medicines across every jurisdiction PeptideMethods covers, and retatrutide is investigational and not authorised anywhere. Consult a qualified healthcare professional before making any clinical decision. PeptideMethods.com does not sell, distribute, or facilitate the sale of any peptide product.