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From the Incretin Effect to GLP-1: How a Gut Hormone Was Found
If you give someone glucose by mouth and, on another day, give the same amount of glucose directly into a vein so that blood sugar rises to exactly the same level, the insulin response is much larger after the oral dose. That simple observation, made in the 1960s, implies that the gut sends a signal to the pancreas. The signal is the incretin effect, and finding its molecules took decades.
Key takeaways
- The incretin effect accounts for a large share of the insulin response after a meal.
- GIP was identified in the 1970s and GLP-1 in the 1980s.
- GLP-1 is produced from the proglucagon gene and has a half-life of only a minute or two.
- The DPP-4 enzyme destroys it, which shaped later drug design.
The observation
In 1964, McIntyre and colleagues, and independently Elrick and colleagues, compared oral and intravenous glucose and found that the oral route produced a much larger insulin response despite similar blood sugar. Gut-derived factors were proposed, and the term incretin was applied. In humans the effect is large, accounting for a substantial share of the insulin response to oral glucose, and it is reduced in type 2 diabetes.
First candidate: GIP
In the early 1970s, John Brown purified a peptide from the intestine that inhibited gastric acid secretion and named it gastric inhibitory polypeptide. It was later shown to stimulate insulin release in the presence of glucose and renamed glucose-dependent insulinotropic polypeptide (GIP). But GIP alone did not account for the whole effect.
The second candidate: GLP-1
In the early 1980s, the sequencing of the gene for proglucagon, the precursor of glucagon, revealed that it also coded for two other glucagon-like peptides. Work by Graeme Bell, Joel Habener, Svetlana Mojsov, Jens Holst and others showed that the processed form, GLP-1(7-36) amide, stimulated insulin secretion from the pancreas in a glucose-dependent manner. It is released by L cells in the lower intestine in response to food, and it also slows stomach emptying and acts on the brain to reduce appetite.
The problem: a minute-long half-life
Studies in the mid-1990s showed that GLP-1 is chopped by dipeptidyl peptidase-4 (DPP-4) within one to two minutes of release. That explained why it could not be used directly, and suggested two routes: inhibit DPP-4, or make analogs that resist it. The lizard peptide exendin-4, described in the Gila monster story, was a natural example of the second route, and engineered analogs followed (see half-life engineering).
Why glucose dependence matters
A key feature of GLP-1 signaling is that it enhances insulin release mainly when blood sugar is high. This property is why the pathway attracted so much interest as a research target.
The wider family
The same cells and neighboring ones release PYY, oxyntomodulin and others. Their coordinated action is summarized in the appetite hormone map.
What the story shows
- Careful physiology (a comparison of two glucose routes) preceded the molecules by two decades.
- Gene sequencing revealed hidden peptides inside a known precursor.
- Understanding degradation (DPP-4) guided the design.
The bottom line
GLP-1 research is a chain of discoveries, each handing the next one a question. The full timeline from the first insulin extract is in our history of peptide drugs.
Related reading
- The Story of the Gila Monster Peptide: How Lizard Venom Led to a New Drug Class
- A Short History of Peptide Drugs: From Insulin to GLP-1
- The Appetite Hormone Map: Ghrelin, Leptin, PYY, GLP-1, CCK, Amylin and the Brain
- Browse the full Research Library
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For laboratory research use only. Not for human or veterinary use, and not intended to diagnose, treat, cure or prevent any condition. This article is educational and is not medical advice.