The History of Incretin Research, Briefly

The shortest honest version of this story is that a hypothesis proposed in 1906 produced its first approved drug in 2005. Almost a century separates the two, and most of that gap is people waiting for instruments that did not exist yet. The dates below are checked.

Before anyone could measure anything

In 1902 Bayliss and Starling discovered secretin, the first hormone, in extracts of duodenal mucosa. Four years later, in 1906, Moore and colleagues tested the obvious extension of Starling’s idea: they administered duodenal mucosa extracts to three recently diagnosed diabetes patients, reasoning that the gut might carry a signal to the pancreas. The Belgian physiologist Jean La Barre later gave the putative signal a name, coining “incrétine” in 1932.

Carrots, vegetables, harvest — illustrating The History of Incretin Research, Briefly

Sources differ on that date: Rehfeld’s 2018 account in Frontiers in Endocrinology puts the coinage at 1932, while Yabe and colleagues, writing in the Journal of Diabetes Investigation in 2019, date La Barre’s purification and naming to 1929. Both agree the concept then went quiet. Yabe’s review describes the hormone as “forgotten for three decades until radioimmunoassay to measure insulin became available in the 1960s.”

The idea could not advance because nobody could measure insulin. The incretin concept sat dormant from the 1930s until radioimmunoassay arrived in the 1960s and made the central experiment possible.

1964: the experiment that made it real

Once insulin could be measured in blood, the decisive comparison became straightforward. In 1964, laboratories in London (McIntyre and colleagues) and Denver (Elrick and colleagues) independently showed that oral glucose provokes a considerably larger insulin response than intravenous glucose. The gut signal was no longer an inference from extracts; it was a number.

Identifying the hormones took another two decades. In the early 1970s, working first in Viktor Mutt’s laboratory in Stockholm, John Brown isolated GIP, the first incretin. GLP-1 arrived in 1983, not from a purification but from a gene: building on the Habener laboratory’s work sequencing proglucagon cDNAs, the deduced structure revealed two previously unknown glucagon-like peptides, named GLP-1 and GLP-2 by Bell and colleagues.

Lime, 4k wallpaper, mac wallpaper — illustrating The History of Incretin Research, Briefly

From peptide to plausible drug

1986. Nauck and colleagues published in Diabetologia that the incretin effect is markedly reduced in type 2 diabetes: 72.8 ± 6.9% of the insulin response in healthy controls versus 36.0 ± 8.8% in patients. This is what turned a physiological curiosity into a therapeutic target. We cover that study in the incretin effect, explained.
1987. Drucker’s experiments established that GLP-1(7-37), the truncated form, directly augments glucose-dependent insulin biosynthesis and secretion from β cells. Mojsov and Weir showed the same form was active at concentrations as low as 50 pM, while full-length GLP-1(1-37) was not.
December 1987. Kreymann and Bloom reported the first-in-human studies, confirming the insulinotropic action of GLP-1(7-36)amide in people.
Then the problem. Holst and Deacon showed the molecule is cleaved by the enzyme DPP-4, giving native GLP-1 a circulating half-life of only 1.5–2 minutes. An infused hormone that disappears in under two minutes is not a medicine.
1992. John Eng isolated exendin-4, a peptide from the venom of the Gila monster (Heloderma suspectum), which activates the GLP-1 receptor and resists DPP-4. Synthetic exendin-4 became exenatide.

The approvals

The regulatory timeline is the part most people meet first, and it compresses the entire preceding century into eighteen years.

Year	Milestone
2005	Exenatide approved for type 2 diabetes, the first GLP-1 receptor agonist
2010	Liraglutide approved for type 2 diabetes
2014	Dulaglutide approved for type 2 diabetes; liraglutide approved for obesity
2017	Semaglutide approved for type 2 diabetes
2021	Semaglutide approved for obesity
2022	Tirzepatide, a dual GIP/GLP-1 receptor agonist, approved for type 2 diabetes
2023	Tirzepatide approved for obesity

Approval years as reported by Bloomgarden in the Journal of Diabetes (2025); exenatide’s 2005 first-in-class approval is also documented in the Drucker, Habener and Holst review.

Vegetables, fruits, food — illustrating The History of Incretin Research, Briefly

Note what the table also shows: tirzepatide’s 2022 approval brought GIP back into play, more than fifty years after Brown isolated it. See exenatide and tirzepatide for the compound-level detail.

The takeaway

The documentation here does not flatter the “overnight breakthrough” framing. A hypothesis from 1906 waited until 1964 for a measurement technique, until 1983 for the gene, until 1987 for proof the peptide worked in humans, and until 2005 for a drug, because the obvious molecule had a two-minute half-life and the fix came from lizard venom. Nothing in that sequence was foreseeable in advance, which is the lesson worth carrying away from it.